Sample records for metformin induces cardioprotection

  1. Combined Vildagliptin and Metformin Exert Better Cardioprotection than Monotherapy against Ischemia-Reperfusion Injury in Obese-Insulin Resistant Rats

    PubMed Central

    Apaijai, Nattayaporn; Chinda, Kroekkiat; Palee, Siripong; Chattipakorn, Siriporn; Chattipakorn, Nipon

    2014-01-01

    Background Obese-insulin resistance caused by long-term high-fat diet (HFD) consumption is associated with left ventricular (LV) dysfunction and increased risk of myocardial infarction. Metformin and vildagliptin have been shown to exert cardioprotective effects. However, the effect of these drugs on the hearts under obese-insulin resistance with ischemia-reperfusion (I/R) injury is unclear. We hypothesized that combined vildagliptin and metformin provide better protective effects against I/R injury than monotherapy in obese-insulin resistant rats. Methodology Male Wistar rats were fed either HFD or normal diet. Rats in each diet group were divided into 4 subgroups to receive vildagliptin, metformin, combined vildagliptin and metformin, or saline for 21 days. Ischemia due to left anterior descending artery ligation was allowed for 30-min, followed by 120-min reperfusion. Metabolic parameters, heart rate variability (HRV), LV function, infarct size, mitochondrial function, calcium transient, Bax and Bcl-2, and Connexin 43 (Cx43) were determined. Rats developed insulin resistance after 12 weeks of HFD consumption. Vildagliptin, metformin, and combined drugs improved metabolic parameters, HRV, and LV function. During I/R, all treatments improved LV function, reduced infarct size and Bax, increased Bcl-2, and improved mitochondrial function in HFD rats. However, only combined drugs delayed the time to the first VT/VF onset, reduced arrhythmia score and mortality rate, and increased p-Cx43 in HFD rats. Conclusion Although both vildagliptin and metformin improved insulin resistance and attenuate myocardial injury caused by I/R, combined drugs provided better outcomes than single therapy by reducing arrhythmia score and mortality rate. PMID:25036861

  2. Effects of metformin treatment on glioma-induced brain edema

    PubMed Central

    Zhao, Bin; Wang, Xiaoke; Zheng, Jun; Wang, Hailiang; Liu, Jun

    2016-01-01

    Considerable evidence has demonstrated that metformin can activate 5’-AMP-activated protein kinase (AMPK) signaling pathway, which plays a critical role in protection of endothelial cell permeability. Hence, the present study evaluated the effects of metformin on blood brain barrier permeability and AQP4 expression in vitro, and assessed the effects of metformin treatment on tumor-induced brain edema in vivo. Hypoxia or VEGF exposure enhanced bEnd3 endothelial cell monolayer permeability and attenuated the expression of tight junction proteins including Occludin, Claudin-5, ZO-1, and ZO-2. However, 0.5 mM metformin treatment protected bEnd3 endothelial cell monolayer from hypoxia or VEGF-induced permeability, which was correlated with increased expression of tight junction proteins. Furthermore, metformin treatment attenuated AQP4 protein expression in cultured astrocytes. Such an effect involved the activation of AMPK and inhibition of NF-κB. Finally, metformin treatment dose-dependently reduced glioma induced vascular permeability and cerebral edema in vivo in rats. Thus, our results suggested that metformin may protect endothelial cell tight junction, prevent damage to the blood brain barrier induced by brain tumor growth, and alleviate the formation of cerebral edema. Furthermore, since the formation of cytotoxic edema and AQP4 expression was positively correlated, our results indicated that metformin may reduce the formation of cytotoxic edema. However, given that AQP4 plays a key role in the elimination of cerebral edema, attenuation of AQP4 expression by metformin may reduce the elimination of cerebral edema. Hence, future studies will be necessary to dissect the specific mechanisms of metformin underlying the dynamics of tumor-induced brain edema in vivo. PMID:27648126

  3. Effects of metformin treatment on glioma-induced brain edema.

    PubMed

    Zhao, Bin; Wang, Xiaoke; Zheng, Jun; Wang, Hailiang; Liu, Jun

    2016-01-01

    Considerable evidence has demonstrated that metformin can activate 5'-AMP-activated protein kinase (AMPK) signaling pathway, which plays a critical role in protection of endothelial cell permeability. Hence, the present study evaluated the effects of metformin on blood brain barrier permeability and AQP4 expression in vitro, and assessed the effects of metformin treatment on tumor-induced brain edema in vivo. Hypoxia or VEGF exposure enhanced bEnd3 endothelial cell monolayer permeability and attenuated the expression of tight junction proteins including Occludin, Claudin-5, ZO-1, and ZO-2. However, 0.5 mM metformin treatment protected bEnd3 endothelial cell monolayer from hypoxia or VEGF-induced permeability, which was correlated with increased expression of tight junction proteins. Furthermore, metformin treatment attenuated AQP4 protein expression in cultured astrocytes. Such an effect involved the activation of AMPK and inhibition of NF-κB. Finally, metformin treatment dose-dependently reduced glioma induced vascular permeability and cerebral edema in vivo in rats. Thus, our results suggested that metformin may protect endothelial cell tight junction, prevent damage to the blood brain barrier induced by brain tumor growth, and alleviate the formation of cerebral edema. Furthermore, since the formation of cytotoxic edema and AQP4 expression was positively correlated, our results indicated that metformin may reduce the formation of cytotoxic edema. However, given that AQP4 plays a key role in the elimination of cerebral edema, attenuation of AQP4 expression by metformin may reduce the elimination of cerebral edema. Hence, future studies will be necessary to dissect the specific mechanisms of metformin underlying the dynamics of tumor-induced brain edema in vivo.

  4. Hypoxia inducible factor 1 (HIF-1) and cardioprotection

    PubMed Central

    Tekin, Demet; Dursun, Ali D; Xi, Lei

    2010-01-01

    Since its discovery in early 1990s, hypoxia inducible factor 1 (HIF-1) has been increasingly recognized for its key role in transcriptional control of more than a hundred genes that regulate a wide-spectrum of cellular functional events, including angiogenesis, vasomotor control, glucose and energy metabolism, erythropoiesis, iron homeostasis, pH regulation, cell proliferation and viability. Evidence accumulated during the past 7 years suggests a critical role for HIF-1α in mediating cardioprotection. The purpose of our present article is to provide an updated overview on this important regulator of gene expression in the cellular stress-responsive and adaptive process. We have particularly emphasized the involvement of HIF-1 in the induction of cardioprotective molecules, such as inducible nitric oxide synthase (iNOS), hemeoxygenase 1 (HO-1), and erythropoietin (EPO), which in turn alleviate myocardial damages caused by harmful events such as ischemia-reperfusion injury. Despite these advances, further in-depth studies are needed to elucidate the possible coordination or interaction between HIF-1α and other key transcription factors in regulating protein expression that leads to cardioprotection. PMID:20711226

  5. Metformin inhibits early stage diethylnitrosamine-induced hepatocarcinogenesis in rats

    PubMed Central

    JO, WOORI; YU, EUN-SIL; CHANG, MINSUN; PARK, HYUN-KYU; CHOI, HYUN-JI; RYU, JAE-EUN; JANG, SUNGWOONG; LEE, HYO-JU; JANG, JA-JUNE; SON, WOO-CHAN

    2016-01-01

    Antitumor effects of metformin have recently emerged despite its original use for type II diabetes. In the present study, the effects of metformin on the development and recurrence of hepatocellular carcinoma (HCC) were investigated using the diethylnitrosamine (DEN)-induced rat model of HCC. Tumor foci were characterized by gross examination and by histopathological characteristics, including proliferation, hepatic progenitor cell content and the expression of hepatocarcinoma-specific molecular markers. Potential target molecules of metformin were investigated to determine the molecular mechanism underlying the inhibitory effects of metformin on chemically induced liver tumorigenesis. The antitumor effects of metformin were increased by the reduction of surface nodules and decreased the incidence of altered hepatocellular foci, hepatocellular adenoma and carcinoma. Also, decreased expression levels of glutathione S-transferase placental form, proliferating cell nuclear antigen and cytokeratin 8 described the inhibitory effects of metformin on HCC. In the present study, Wistar rats receiving treatment with DEN were administered metformin for 16 weeks. In addition, metformin suppressed liver tumorigenesis via an AMPK-dependent pathway. These results suggested that metformin has promising effects on the early stage of HCC in rats. Therefore, metformin may be used for the prevention of HCC recurrence following primary chemotherapy for HCC and/or for high-risk patients, including chronic hepatitis and cirrhosis. PMID:26548419

  6. Metformin-Induced Lactic Acidosis (MILA): Review of current diagnostic paradigm.

    PubMed

    Krowl, Lauren; Al-Khalisy, Hassan; Kaul, Pratibha

    2018-05-01

    A new diagnostic paradigm has been proposed to better categorize causes of Metformin-Associated Lactic Acidosis (MALA). The diagnostic criteria defines a link between Metformin and lactic acidosis if lactate is >5mmol/L, Ph<7.35 and Metformin assay >5mg/L. Metformin assays are not readily available in emergency departments including nationwide Veteran's Affairs Hospitals; thereby making this proposed classification tool difficult to use in today's clinical practice. We describe a case report of a 45-year-old male, who took twice the amount of Metformin prescribed and presented with Metformin-induced lactic acidosis. According to the new criterion, our case would be classified as "Lactic Acidosis in Metformin-Treated Patients (LAMT)." However, the term LAMT does not distinguish between a septic patient taking Metformin with lactic acidosis, and a patient who ingested toxic amounts of Metformin and has lactic acidosis (in absence of Metformin assay). Our case highlights the importance of medication reconciliation done on arrival to emergency department. Timing and dosing of Metformin in patients who present to the emergency department with lactic acidosis may cinch the diagnosis of Metformin-Induced Lactic Acidosis (MILA) in the absence of a Metformin assay but in the right clinical context. Copyright © 2018 Elsevier Inc. All rights reserved.

  7. Metformin induces differentiation in acute promyelocytic leukemia by activating the MEK/ERK signaling pathway

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Huai, Lei; Wang, Cuicui; Zhang, Cuiping

    2012-06-08

    Highlights: Black-Right-Pointing-Pointer Metformin induces differentiation in NB4 and primary APL cells. Black-Right-Pointing-Pointer Metformin induces activation of the MEK/ERK signaling pathway in APL cells. Black-Right-Pointing-Pointer Metformin synergizes with ATRA to trigger maturation of NB4 and primary APL cells. Black-Right-Pointing-Pointer Metformin induces the relocalization and degradation of the PML-RAR{alpha} fusion protein. Black-Right-Pointing-Pointer The study may be applicable for new differentiation therapy in cancer treatment. -- Abstract: Recent studies have shown that metformin, a widely used antidiabetic agent, may reduce the risk of cancer development. In this study, we investigated the antitumoral effect of metformin on both acute myeloid leukemia (AML) and acutemore » promyelocytic leukemia (APL) cells. Metformin induced apoptosis with partial differentiation in an APL cell line, NB4, but only displayed a proapoptotic effect on several non-M3 AML cell lines. Further analysis revealed that a strong synergistic effect existed between metformin and all-trans retinoic acid (ATRA) during APL cell maturation and that metformin induced the hyperphosphorylation of extracellular signal-regulated kinase (ERK) in APL cells. U0126, a specific MEK/ERK activation inhibitor, abrogated metformin-induced differentiation. Finally, we found that metformin induced the degradation of the oncoproteins PML-RAR{alpha} and c-Myc and activated caspase-3. In conclusion, these results suggest that metformin treatment may contribute to the enhancement of ATRA-induced differentiation in APL, which may deepen the understanding of APL maturation and thus provide insight for new therapy strategies.« less

  8. Cardioprotection induced in a mouse model of neuropathic pain via anterior nucleus of paraventricular thalamus.

    PubMed

    Cheng, Yi-Fen; Chang, Ya-Ting; Chen, Wei-Hsin; Shih, Hsi-Chien; Chen, Yen-Hui; Shyu, Bai-Chuang; Chen, Chien-Chang

    2017-10-10

    Myocardial infarction is the leading cause of death worldwide. Restoration of blood flow rescues myocardium but also causes ischemia-reperfusion injury. Here, we show that in a mouse model of chronic neuropathic pain, ischemia-reperfusion injury following myocardial infarction is reduced, and this cardioprotection is induced via an anterior nucleus of paraventricular thalamus (PVA)-dependent parasympathetic pathway. Pharmacological inhibition of extracellular signal-regulated kinase activation in the PVA abolishes neuropathic pain-induced cardioprotection, whereas activation of PVA neurons pharmacologically, or optogenetic stimulation, is sufficient to induce cardioprotection. Furthermore, neuropathic injury and optogenetic stimulation of PVA neurons reduce the heart rate. These results suggest that the parasympathetic nerve is responsible for this unexpected cardioprotective effect of chronic neuropathic pain in mice.Various forms of preconditioning can prevent ischemic-reperfusion injury after myocardial infarction. Here, the authors show that in mice, the presence of chronic neuropathic pain can have a cardioprotective effect, and that this is dependent on neural activation in the paraventricular thalamus.

  9. Metformin prevents methylglyoxal-induced apoptosis of mouse Schwann cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ota, Kimiko; Nakamura, Jiro; Li, Weiguo

    2007-05-25

    Methylglyoxal (MG) is involved in the pathogenesis of diabetic complications via the formation of advanced glycation end products (AGEs) and reactive oxygen species (ROS). To clarify whether the antidiabetic drug metformin prevents Schwann cell damage induced by MG, we cultured mouse Schwann cells in the presence of MG and metformin. Cell apoptosis was evaluated using Hoechst 33342 nuclear staining, caspase-3 activity, and c-Jun-N-terminal kinase (JNK) phosphorylation. Intracellular ROS formation was determined by flow cytometry, and AMP-activated kinase (AMPK) phosphorylation was also examined. MG treatment resulted in blunted cell proliferation, an increase in the number of apoptotic cells, and the activationmore » of caspase-3 and JNK along with enhanced intracellular ROS formation. All of these changes were significantly inhibited by metformin. No significant activation of AMPK by MG or metformin was observed. Taken together, metformin likely prevents MG-induced apoptotic signals in mouse Schwann cells by inhibiting the formation of AGEs and ROS.« less

  10. Metformin inhibits the radiation-induced invasive phenotype of esophageal squamous cell carcinoma.

    PubMed

    Nakayama, Akira; Ninomiya, Itasu; Harada, Shinichi; Tsukada, Tomoya; Okamoto, Koichi; Nakanuma, Shinichi; Sakai, Seisho; Makino, Isamu; Kinoshita, Jun; Hayashi, Hironori; Oyama, Katsunobu; Miyashita, Tomoharu; Tajima, Hidehiro; Takamura, Hiroyuki; Fushida, Sachio; Ohta, Tetsuo

    2016-11-01

    Esophageal cancer is one of the most aggressive tumor types because of its invasiveness and metastatic potential. Several reports have described an association between increased invasiveness after ionizing radiation (IR) treatment and epithelial-to-mesenchymal transition (EMT). The biguanide metformin is reported to prevent transforming growth factor-β (TGF-β)-induced EMT and proliferation of cancer. This study examined whether IR induces EMT and promotes the invasive potential of TE-9 esophageal squamous cell carcinoma cells and the effect of metformin on IR-induced EMT. After IR exposure, TE-9 cells showed a spindle-shaped morphology and lost cell-cell adhesion. Immunoblotting showed that IR induced expression of mesenchymal markers (vimentin and N-cadherin), transcription factors (Slug, Snail, and Twist), and matrix metalloproteinases. A scratch wound assay and Matrigel invasion assay showed that IR enhanced the invasive potential and migratory capacity of TE-9 cells. Expression of hypoxia-related factor-1α and TGF-β was increased after IR. IR also induced phosphorylation of Smad2 and Smad3. Metformin inhibited radiation-induced EMT-like morphological changes, and enhanced invasion and migration of TE-9 cells. Metformin inhibited IR-induced phosphorylation of Smad2 and Smad3. Although phosphorylation of AMP-activated protein kinase was enhanced by IR and metformin, phosphorylation of mammalian target of rapamycin was enhanced by IR and suppressed by metformin. These results indicated that metformin suppressed IR-induced EMT via suppression of the TGF-β-Smad phosphorylation pathway, and a part of the non-Smad pathway. Metformin might be useful to prevent IR-induced invasion and metastasis of esophageal squamous cell carcinoma.

  11. gp-91 mediates histone deacetylase inhibition-induced cardioprotection

    PubMed Central

    Zhao, Ting C; Zhang, Ling X; Cheng, Guangmao; Liu, Jun T

    2010-01-01

    We have recently shown that the inhibition of histone deacetylases (HDAC) protects the heart against ischemia and reperfusion (I/R) injury. The mechanism by which HDAC inhibition induces cardioprotection remains unknown. We sought to investigate whether the genetic disruption of gp-91, a subunit of NADPH-oxidase, would mitigate cardioprotection of HDAC inhibition. Wild-type and gp-91−/− mice were treated with a potent inhibitor of HDACs, trichostatin A (TSA, 0.1mg/kg, i.p.). Twenty-four hours later, the perfused hearts were subjected to 30 min of ischemia and 30 min of reperfusion. HDAC inhibition in wild-type mice produced marked improvements in ventricular functional recovery and the reduction of infarct size. TSA-induced cardioprotection was eliminated with genetic deletion of gp91. Notably, Western blot and immunostaining displayed a significant increase in gp-91 in myocardium following HDAC inhibition, which resulted in a mildly subsequent increase in the production of reactive oxygen species (ROS). The pretreatment of H9c2 cardiomyoblasts with TSA (50 nmol/L) decreased cell necrosis and increased viability in response to simulated ischemia (SI), which was abrogated by the transfection of cells with gp-91 siRNA, but not by scrambled siRNA. Furthermore, treatment of PLB-985 gp91+/+cells with TSA increased the resistance to SI, which also diminished with genetic disruption of gp91 in gp91phox-deficient PLB-985 cells. TSA treatment inhibited the increased active caspase-3 in H9c2 cardiomyoblasts and PLB-985 gp91+/+cells exposed to SI, which were prevented by knockdown of gp-91 by siRNA. These results suggest that a cascade consisting of gp-91 and HDAC inhibition plays an essential role in orchestrating the cardioprotective effect. PMID:20433879

  12. Redox signaling in remote ischemic preconditioning-induced cardioprotection: Evidences and mechanisms.

    PubMed

    Singh, Lovedeep; Randhawa, Puneet Kaur; Singh, Nirmal; Jaggi, Amteshwar Singh

    2017-08-15

    Reactive oxygen species are the reactive molecules that are derived from molecular oxygen and play an important role as redox signaling molecules to confer cardioprotection. Various scientists have demonstrated the key role of redox signaling in cardioprotection by showing a transient increase in their levels during remote ischemic preconditioning (RIPC) phase. The transient increase in reactive oxygen species levels during remote preconditioning phase may take place either through activation of K ATP channels or through increased nitric oxide (NO) production. A transient increase in reactive oxygen species during preconditioning may also increase the expression of heat shock proteins (HSP), the level of antioxidant enzymes and decrease the expression of inflammatory genes (Egr-1) during ischemia-reperfusion phase to confer cardioprotection. The present review describes the role of redox signaling in RIPC-induced cardioprotective effect with possible mechanisms. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Possible role of thromboxane A2 in remote hind limb preconditioning-induced cardioprotection.

    PubMed

    Sharma, Roohani; Randhawa, Puneet Kaur; Singh, Nirmal; Jaggi, Amteshwar Singh

    2016-01-01

    Remote hind limb preconditioning (RIPC) is a protective strategy in which short episodes of ischemia and reperfusion in a remote organ (hind limb) protects the target organ (heart) against sustained ischemic reperfusion injury. The present study was designed to investigate the possible role of thromboxane A2 in RIPC-induced cardioprotection in rats. Remote hind limb preconditioning was performed by four episodes of 5 min of inflation and 5 min of deflation of pressure cuff. Occlusion of the hind limb with blood pressure cuff is most feasible, non-invasive, clinically relevant, and safe method for inducing RIPC. Isolated rat hearts were perfused on Langendorff apparatus and were subjected to global ischemia for 30 min followed by 120-min reperfusion. The levels of lactate dehydrogenase (LDH) and creatine kinase (CK) were measured in coronary effluent to assess the degree of myocardial injury. The extent of myocardial infarct size along with the functional parameters including left ventricular developed pressure (LVDP), dp/dtmax, and dp/dtmin were also measured. Ozagrel (thromboxane synthase inhibitor) and seratrodast (thromboxane A2 receptor antagonist) were employed as pharmacological modulators of thromboxane A2. Remote hind limb preconditioning significantly attenuated ischemia/reperfusion-induced myocardial injury and produced cardioprotective effects. However, administration of ozagrel and seratrodast completely abolished the cardioprotective effects of RIPC suggesting the key role of thromboxane A2 in RIPC-induced cardioprotection. It may be concluded that brief episodes of preconditioning ischemia and reperfusion activates the thromboxane synthase enzyme that produces thromboxane A2, which may elicit cardioprotection either involving humoral or neurogenic pathway.

  14. Metformin enhances TRAIL-induced apoptosis by Mcl-1 degradation via Mule in colorectal cancer cells.

    PubMed

    Park, Seong Hye; Lee, Dae-Hee; Kim, Jung Lim; Kim, Bo Ram; Na, Yoo Jin; Jo, Min Jee; Jeong, Yoon A; Lee, Suk-Young; Lee, Sun Il; Lee, Yong Yook; Oh, Sang Cheul

    2016-09-13

    Metformin is an anti-diabetic drug with a promising anti-cancer potential. In this study, we show that subtoxic doses of metformin effectively sensitize human colorectal cancer (CRC) cells to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), which induces apoptosis. Metformin alone did not induce apoptosis, but significantly potentiated TRAIL-induced apoptosis in CRC cells. CRC cells treated with metformin and TRAIL showed activation of the intrinsic and extrinsic pathways of caspase activation. We attempted to elucidate the underlying mechanism, and found that metformin significantly reduced the protein levels of myeloid cell leukemia 1 (Mcl-1) in CRC cells and, the overexpression of Mcl-1 inhibited cell death induced by metformin and/or TRAIL. Further experiments revealed that metformin did not affect mRNA levels, but increased proteasomal degradation and protein stability of Mcl-1. Knockdown of Mule triggered a significant decrease of Mcl-1 polyubiquitination. Metformin caused the dissociation of Noxa from Mcl-1, which allowed the binding of the BH3-containing ubiquitin ligase Mule followed by Mcl-1ubiquitination and degradation. The metformin-induced degradation of Mcl-1 required E3 ligase Mule, which is responsible for the polyubiquitination of Mcl-1. Our study is the first report indicating that metformin enhances TRAIL-induced apoptosis through Noxa and favors the interaction between Mcl-1 and Mule, which consequently affects Mcl-1 ubiquitination.

  15. Cardioprotective mechanisms of phytochemicals against doxorubicin-induced cardiotoxicity.

    PubMed

    Abushouk, Abdelrahman Ibrahim; Ismail, Ammar; Salem, Amr Muhammad Abdo; Afifi, Ahmed M; Abdel-Daim, Mohamed M

    2017-06-01

    Doxorubicin (DOX) is an anthracycline antibiotic, which is effectively used in the treatment of different malignancies, such as leukemias and lymphomas. Its most serious side effect is dose-dependent cardiotoxicity, which occurs through inducing oxidative stress apoptosis. Due to the myelosuppressive effect of dexrazoxane, a commonly-used drug to alleviate DOX-induced cardiotoxicity, researchers investigated the potential of phytochemicals for prophylaxis and treatment of this condition. Phytochemicals are plant chemicals that have protective or disease preventive properties. Preclinical trials have shown antioxidant properties for several plant extracts, such as those of Aerva lanata, Aronia melanocarpa, Astragalus polysaccharide, and Bombyx mori plants. Other plant extracts showed an ability to inhibit apoptosis, such as those of Astragalus polysaccharide, Azadirachta indica, Bombyx mori, and Allium stavium plants. Unlike synthetic agents, phytochemicals do not impair the clinical activity of DOX and they are particularly safe for long-term use. In this review, we summarized the results of preclinical trials that investigated the cardioprotective effects of phytochemicals against DOX-induced cardiotoxicity. Future human trials are required to translate these cardioprotective mechanisms into practical clinical implications. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  16. Exercise-induced cardioprotection--biochemical, morphological and functional evidence in whole tissue and isolated mitochondria.

    PubMed

    Ascensão, António; Ferreira, Rita; Magalhães, José

    2007-04-12

    Myocardial injury is a major contributor to the morbidity and mortality associated with coronary artery disease. Regular exercise has been confirmed as a pragmatic countermeasure to protect against cardiac injury. Specifically, endurance exercise has been proven to provide cardioprotection against cardiac insults in both young and old animals. Proposed mechanisms to explain the cardioprotective effects of exercise are mediated, at least partially, by redox changes and include the induction of myocardial heat shock proteins, improved cardiac antioxidant capacity, and/or elevation of other cardioprotective molecules. Understanding the molecular basis for exercise-induced cardioprotection is important in developing exercise strategies to protect the heart during and after insults. Data suggest that these positive modulator effects occur at different levels of cellular organization, being mitochondria fundamental organelles that are sensitive to disturbances imposed by exercise on basal homeostasis. At present, which of these protective mechanisms is essential for exercise-induced cardioprotection remains unclear. This review analyzes the biochemical, morphological and functional outcomes of acute and chronic exercise on the overall cardiac muscle tissue and in isolated mitochondria. Some redox-based mechanisms behind the cross-tolerance effects particularly induced by endurance training, against certain stressors responsible for the impairments in cardiac homeostasis caused by aging, diabetes, drug administration or ischemia-reperfusion are also outlined. Further work should be addressed in order to clarify the precise regulatory mechanisms by which physical exercise augments heart tolerance against many cardiotoxic agents.

  17. Metformin alleviated endotoxemia-induced acute lung injury via restoring AMPK-dependent suppression of mTOR.

    PubMed

    Wu, Kejia; Tian, Rui; Huang, Jing; Yang, Yongqiang; Dai, Jie; Jiang, Rong; Zhang, Li

    2018-05-31

    Inflammation requires intensive metabolic support and modulation of the metabolic pathways might become a novel strategy to limit inflammatory injury. Recent studies have revealed the anti-inflammatory effects of the anti-diabetic reagent metformin, but the underlying mechanisms remain unclear. In the present study, the potential effects of metformin on endotoxemia-induced acute lung injury (ALI) and their relationship with the representative metabolic regulator, including AMPK, sirtuin 1 and mTOR, were investigated. The results indicated that treatment with metformin suppressed LPS-induced upregulation of IL-6 and TNF-α, alleviated pulmonary histological abnormalities, improved the survival rate of LPS-challenged mice. Treatment with metformin reversed LPS-induced decline of AMPK phosphorylation. Co-administration of the AMPK inhibitor compound C abolished the stimulatory effects of metformin on AMPK phosphorylation, the suppressive effects of metformin on IL-6 induction and pulmonary lesions. In addition, co-administration of the mTOR activator 3BDO but not the sirtuin 1 inhibitor EX-527 abolished the effects of metformin on IL-6 induction and pulmonary lesions. Finally, treatment with metformin suppressed LPS-induced p70S6K1 phosphorylation, which was abolished by the AMPK inhibitor. These data suggest that metformin might provide anti-inflammatory benefits in endotoxemia-induced inflammatory lung injury via restoring AMPK-dependent suppression of mTOR. Copyright © 2018. Published by Elsevier B.V.

  18. TLR2 ligands induce cardioprotection against ischaemia/reperfusion injury through a PI3K/Akt-dependent mechanism

    PubMed Central

    Ha, Tuanzhu; Hu, Yulong; Liu, Li; Lu, Chen; McMullen, Julie R.; Kelley, Jim; Kao, Race L.; Williams, David L.; Gao, Xiang; Li, Chuanfu

    2010-01-01

    Aims Toll-like receptor (TLR)-mediated signalling pathways have been implicated in myocardial ischaemia/reperfusion (I/R) injury. Activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway protects the myocardium from ischaemic injury. We hypothesized that the modulation of TLR2 would induce cardioprotection against I/R injury via activation of the PI3K/Akt signalling. Methods and results Mice were treated with TLR2 ligands, peptidoglycan (PGN) or Pam3CSK4, respectively, 1 h before the hearts were subjected to ischaemia (1 h), followed by reperfusion (4 h). Infarct size was determined by triphenyltetrazolium chloride staining. Cardiac function and haemodynamic performance were evaluated. Infarct size was significantly reduced in PGN- or Pam3CSK4-treated mice compared with untreated I/R mice. Administration of TLR2 ligands improved cardiac function following I/R. PGN treatment increased the levels of phospho-Akt and phospho-GSK-3β (glycogen synthase kinase-3β), compared with untreated I/R hearts. PGN stimulation increased TLR2 tyrosine phosphorylation and association of the p85 subunit of PI3K with TLR2. To investigate the role of PI3K/Akt signalling in PGN-induced cardioprotection, we administered the PI3K inhibitor, Wortmannin, to the mice 15 min before PGN treatment. We also administered PGN to kinase-deficient Akt (kdAkt) transgenic mice 1 h before myocardial I/R. Both PI3K inhibition and kdAkt mice abolished the cardioprotection induced by PGN. To examine the role of TLR2 in PGN-induced cardioprotection, we administrated PGN to TLR2 knockout mice 1 h before the hearts were subjected to I/R. PGN-induced cardioprotection was lost in TLR2-deficient mice. Conclusion These results demonstrate that TLR2 ligands induced cardioprotection, which is mediated through a TLR2/PI3K/Akt-dependent mechanism. PMID:20421349

  19. Metformin for treatment of antipsychotic-induced weight gain: a randomized, placebo-controlled study.

    PubMed

    Wang, Man; Tong, Jian-hua; Zhu, Gang; Liang, Guang-ming; Yan, Hong-fei; Wang, Xiu-zhen

    2012-06-01

    To evaluate the efficacy of metformin for treatment of antipsychotic-induced weight gain. Seventy-two patients with first-episode schizophrenia who gained more than 7% of their predrug weight were randomly assigned to receive 1000 mg/d of metformin or placebo in addition to their ongoing treatment for 12 weeks using a double-blind study design. The primary outcome was change in body weight. The secondary outcomes included changes in body mass index, fasting glucose and insulin, and insulin resistance index. Of the 72 patients who were randomly assigned, 66 (91.6%) completed treatments. The body weight, body mass index, fasting insulin and insulin resistance index decreased significantly in the metformin group, but increased in the placebo group during the 12-week follow-up period. Significantly more patients in the metformin group lost their baseline weight by more than 7%, which was the cutoff for clinically meaningful weight loss. Metformin was tolerated well by majority patients. Metformin was effective and safe in attenuating antipsychotic-induced weight gain and insulin resistance in first-episode schizophrenia patients. Patients displayed good adherence to metformin. Copyright © 2012 Elsevier B.V. All rights reserved.

  20. Cardioprotective effect of royal jelly on paclitaxel-induced cardio-toxicity in rats.

    PubMed

    Malekinejad, Hassan; Ahsan, Sima; Delkhosh-Kasmaie, Fatemeh; Cheraghi, Hadi; Rezaei-Golmisheh, Ali; Janbaz-Acyabar, Hamed

    2016-02-01

    Paclitaxel is a potent chemotherapy agent with severe side effects, including allergic reactions, cardiovascular problems, complete hair loss, joint and muscle pain, which may limit its use and lower its efficiency. The cardioprotective effect of royal jelly was investigated on paclitaxel-induced damages. Adult male Wistar rats were divided into control and test groups (n=8). The test group was assigned into five subgroups; 4 groups, along with paclitaxel administration (7.5 mg/kg BW, weekly), received various doses of royal jelly (50, 100, and 150 mg/kg BW) for 28 consecutive days. The last group received only royal jelly at 100 mg/kg. In addition to oxidative and nitrosative stress biomarkers, the creatine kinase (CK-BM) level was also determined. To show the cardioprotective effect of royal jelly on paclitaxel-induced damages, histopathological examinations were conducted. Royal jelly lowered the paclitaxel-elevated malondialdehyde and nitric oxide levels in the heart. Royal jelly could also remarkably reduce the paclitaxel-induced cardiac biomarker of creatine kinase (CK-BM) level and pathological injuries such as diffused edema, hemorrhage, congestion, hyaline exudates, and necrosis. Moreover, royal jelly administration in a dose-dependent manner resulted in a significant (P<0.05) increase in the paclitaxel-reduced total antioxidant capacity. Our data suggest that the paclitaxel-induced histopathological and biochemical alterations could be protected by the royal jelly administration. The cardioprotective effect of royal jelly may be related to the suppression of oxidative and nitrosative stress.

  1. Metformin for olanzapine-induced weight gain: a systematic review and meta-analysis.

    PubMed

    Praharaj, Samir Kumar; Jana, Amlan Kusum; Goyal, Nishant; Sinha, Vinod Kumar

    2011-03-01

    Olanzapine is an atypical antipsychotic that is useful in schizophrenia and bipolar affective disorder, but its use is associated with troublesome weight gain and metabolic syndrome. A variety of pharmacological agents has been studied in the efforts to reverse weight gain induced by olanzapine, but current evidence is insufficient to support any particular pharmacological approach. We conducted a systematic review and meta-analysis of randomized controlled trials of metformin for the treatment of olanzapine-induced weight gain. Systematic review of the literature revealed 12 studies that had assessed metformin for antipsychotic-induced weight gain. Of these, four studies (n= 105) met the review inclusion criteria and were included in the final analysis. Meta-analysis was performed to see the effect size of the treatment on body weight, waist circumference and body-mass index (BMI). Weighted mean difference (WMD) for body weight was 5.02 (95% CI 3.93, 6.10) kg lower with metformin as compared with placebo at 12 weeks. For waist circumference, the test for heterogeneity was significant (P= 0.00002, I(2) = 85.1%). Therefore, a random effects model was used to calculate WMD, which was 1.42 (95% CI 0.29, 3.13) cm lower with metformin as compared with placebo at 12 weeks. For BMI, WMD was 1.82 (95% CI 1.44, 2.19) kg m(-2) lower with metformin as compared with placebo at 12 weeks. Existing data suggest that short term modest weight loss is possible with metformin in patients with olanzapine-induced weight gain. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

  2. Exploring the Role of TRPV and CGRP in Adenosine Preconditioning and Remote Hind Limb Preconditioning-Induced Cardioprotection in Rats.

    PubMed

    Singh, Amritpal; Randhawa, Puneet Kaur; Bali, Anjana; Singh, Nirmal; Jaggi, Amteshwar Singh

    2017-04-01

    The cardioprotective effects of remote hind limb preconditioning (RIPC) are well known, but mechanisms by which protection occurs still remain to be explored. Therefore, the present study was designed to investigate the role of TRPV and CGRP in adenosine and remote preconditioning-induced cardioprotection, using sumatriptan, a CGRP release inhibitor and ruthenium red, a TRPV inhibitor, in rats. For remote preconditioning, a pressure cuff was tied around the hind limb of the rat and was inflated with air up to 150 mmHg to produce ischemia in the hind limb and during reperfusion pressure was released. Four cycles of ischemia and reperfusion, each consisting of 5 min of inflation and 5 min of deflation of pressure cuff were used to produce remote limb preconditioning. An ex vivo Langendorff's isolated rat heart model was used to induce ischemia reperfusion injury by 30 min of global ischemia followed by 120 min of reperfusion. RIPC demonstrated a significant decrease in ischemia reperfusion-induced significant myocardial injury in terms of increase in LDH, CK, infarct size and decrease in LVDP, +dp/dt max and -dp/dt min . Moreover, pharmacological preconditioning with adenosine produced cardioprotective effects in a similar manner to RIPC. Pretreatment with sumatriptan, a CGRP release blocker, abolished RIPC and adenosine preconditioning-induced cardioprotective effects. Administration of ruthenium red, a TRPV inhibitor, also abolished adenosine preconditioning-induced cardioprotection. It may be proposed that the cardioprotective effects of adenosine and remote preconditioning are possibly mediated through activation of a TRPV channels and consequent, release of CGRP.

  3. Impact of Mitochondrial Ca2+-Sensitive Potassium (mBKCa) Channels in Sildenafil-Induced Cardioprotection in Rats

    PubMed Central

    Behmenburg, Friederike; Dorsch, Marianne; Huhn, Ragnar; Mally, David; Heinen, André; Hollmann, Markus W.; Berger, Marc M.

    2015-01-01

    Background Mitochondrial large-conductance Ca2+-sensitive potassium (mBKCa) channels are involved in myocardial ischemic preconditioning. Their role in sildenafil-induced cardioprotection is unknown. We investigated whether sildenafil-induced acute cardioprotection is mediated by activation of mBKCa channels in the rat heart in vitro. Methods Male Wistar rats (n = 8 per group) were randomized and anesthetized with pentobarbital (90 mg/kg). Hearts were isolated, mounted on a Langendorff system and perfused with Krebs-Henseleit buffer at a constant pressure of 80 mmHg. Hearts underwent 30 min of global ischemia followed by 60 min of reperfusion. At the end of the experiments infarct size was determined by TTC staining. In the control group rats were not further treated. Sildenafil (3 μM) was administered over 10 min before the beginning of ischemia. The mBKCa channel inhibitor paxilline (1 μM) was administered with and without sildenafil before the onset of ischemia. The pathway underlying sildenafil-induced cardioprotection was further investigated with the protein kinase G blocker KT5823 (1 μM). Myocardial cGMP concentration was measured by ELISA. Data (mean±SD) were analysed with a one and two-way analysis of variance as appropriate. Results In control animals infarct size was 52±8%. Sildenafil increased cGMP concentration and reduced infarct size to 35±6% (P<0.05 vs. control). Paxilline and KT5823 completely blocked sildenafil-induced cardioprotection (paxilline+sildenafil: 50±8%, KT5823+sildenafil: 45±8%; both P<0.05 vs. sildenafil). Functional heart parameters and coronary flow were not different between the study groups. Conclusion This study shows that in male rats protein kinase G-dependent opening of mBKCa channels plays a pivotal role in sildenafil-induced cardioprotection. PMID:26671662

  4. Cardioprotective effect of royal jelly on paclitaxel-induced cardio-toxicity in rats

    PubMed Central

    Malekinejad, Hassan; Ahsan, Sima; Delkhosh-Kasmaie, Fatemeh; Cheraghi, Hadi; Rezaei-Golmisheh, Ali; Janbaz-Acyabar, Hamed

    2016-01-01

    Objective(s): Paclitaxel is a potent chemotherapy agent with severe side effects, including allergic reactions, cardiovascular problems, complete hair loss, joint and muscle pain, which may limit its use and lower its efficiency. The cardioprotective effect of royal jelly was investigated on paclitaxel-induced damages. Materials and Methods: Adult male Wistar rats were divided into control and test groups (n=8). The test group was assigned into five subgroups; 4 groups, along with paclitaxel administration (7.5 mg/kg BW, weekly), received various doses of royal jelly (50, 100, and 150 mg/kg BW) for 28 consecutive days. The last group received only royal jelly at 100 mg/kg. In addition to oxidative and nitrosative stress biomarkers, the creatine kinase (CK-BM) level was also determined. To show the cardioprotective effect of royal jelly on paclitaxel-induced damages, histopathological examinations were conducted. Results: Royal jelly lowered the paclitaxel-elevated malondialdehyde and nitric oxide levels in the heart. Royal jelly could also remarkably reduce the paclitaxel-induced cardiac biomarker of creatine kinase (CK-BM) level and pathological injuries such as diffused edema, hemorrhage, congestion, hyaline exudates, and necrosis. Moreover, royal jelly administration in a dose-dependent manner resulted in a significant (P<0.05) increase in the paclitaxel-reduced total antioxidant capacity. Conclusion: Our data suggest that the paclitaxel-induced histopathological and biochemical alterations could be protected by the royal jelly administration. The cardioprotective effect of royal jelly may be related to the suppression of oxidative and nitrosative stress. PMID:27081469

  5. Gadolinium and ruthenium red attenuate remote hind limb preconditioning-induced cardioprotection: possible role of TRP and especially TRPV channels.

    PubMed

    Randhawa, Puneet Kaur; Jaggi, Amteshwar Singh

    2016-08-01

    Remote ischemic preconditioning is a well reported therapeutic strategy that induces cardioprotective effects but the underlying intracellular mechanisms have not been widely explored. The current study was designed to investigate the involvement of TRP and especially TRPV channels in remote hind limb preconditioning-induced cardioprotection. Remote hind limb preconditioning stimulus (4 alternate cycles of inflation and deflation of 5 min each) was delivered using a blood pressure cuff tied on the hind limb of the anesthetized rat. Using Langendorff's system, the heart was perfused and subjected to 30-min ischemia and 120-min reperfusion. The myocardial injury was assessed by measuring infarct size, lactate dehydrogenase (LDH), creatine kinase (CK), LVDP, +dp/dtmax, -dp/dtmin, heart rate, and coronary flow rate. Gadolinium, TRP blocker, and ruthenium red, TRPV channel blocker, were employed as pharmacological tools. Remote hind limb preconditioning significantly reduced the infarct size, LDH release, CK release and improved coronary flow rate, hemodynamic parameters including LVDP, +dp/dtmax, -dp/dtmin, and heart rate. However, gadolinium (7.5 and 15 mg kg(-1)) and ruthenium red (4 and 8 mg kg(-1)) significantly attenuated the cardioprotective effects suggesting the involvement of TRP especially TRPV channels in mediating remote hind limb preconditioning-induced cardioprotection. Remote hind limb preconditioning stimulus possibly activates TRPV channels on the heart or sensory nerve fibers innervating the heart to induce cardioprotective effects. Alternatively, remote hind limb preconditioning stimulus may also activate the mechanosensitive TRP and especially TRPV channels on the sensory nerve fibers innervating the skeletal muscles to trigger cardioprotective neurogenic signaling cascade. The cardioprotective effects of remote hind limb preconditioning may be mediated via activation of mechanosensitive TRP and especially TRPV channels.

  6. Diazoxide triggers cardioprotection against apoptosis induced by oxidative stress.

    PubMed

    Ichinose, Masashi; Yonemochi, Hidetoshi; Sato, Toshiaki; Saikawa, Tetsunori

    2003-06-01

    Although mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels have been reported to reduce the extent of apoptosis, the critical timing of mitoK(ATP) channel opening required to protect myocytes against apoptosis remains unclear. In the present study, we examined whether the mitoK(ATP) channel serves as a trigger of cardioprotection against apoptosis induced by oxidative stress. Apoptosis of cultured neonatal rat cardiomyocytes was determined by flow cytometry (light scatter and propidium iodide/annexin V-FITC fluorescence) and by nuclear staining with Hoechst 33342. Mitochondrial membrane potential (DeltaPsi) was measured by flow cytometry of cells stained with rhodamine-123 (Rh-123). Exposure to H(2)O(2) (500 microM) induced apoptosis, and the percentage of apoptotic cells increased progressively and peaked at 2 h. This H(2)O(2)-induced apoptosis was associated with the loss of DeltaPsi, and the time course of decrease in Rh-123 fluorescence paralleled that of apoptosis. Pretreatment of cardiomyocytes with diazoxide (100 microM), a putative mitoK(ATP) channel opener, for 30 min before exposure to H(2)O(2) elicited transient and mild depolarization of DeltaPsi and consequently suppressed both apoptosis and DeltaPsi loss after 2-h exposure to H(2)O(2). These protective effects of diazoxide were abrogated by the mitoK(ATP) channel blocker 5-hydroxydecanoate (500 microM) but not by the sarcolemmal K(ATP) channel blocker HMR-1098 (30 microM). Our results suggest for the first time that diazoxide-induced opening of mitoK(ATP) channels triggers cardioprotection against apoptosis induced by oxidative stress in rat cardiomyocytes.

  7. Evaluation of cardioprotective effect of silk cocoon (Abresham) on isoprenaline-induced myocardial infarction in rats.

    PubMed

    Srivastav, Ritesh Kumar; Siddiqui, Hefazat Hussain; Mahmood, Tarique; Ahsan, Farogh

    2013-01-01

    The study was conducted to evaluate cardioprotective effect of silk cocoon (Abresham) Bombyx mori (B. mori) on isoprenaline-induced myocardial infarction. This study deals with the cocoons, which is called Abresham in the Unani system of medicine. It is one of the 64 drugs which Avicenna has mentioned in Avicenna's tract on cardiac drugs and used in the treatment of cardiovascular diseases. Abresham is a chief ingredient of the two very famous Unani formulation viz. Khamira Abresham Sada, and Khamira Abresham Hakim Arshad Wala. The ethanolic extract of B. mori (Abresham) silk cocoons in the dose of 250 mg/kg and 500 mg/kg body weight was administered orally for 28 days before isoprenaline administration to test their cardioprotective effect. Isoprenaline (85 mg/kg) was administered subcutaneously on days 29(th) and 30(th), respectively in order to induce myocardial infarction. The parameters for evaluation of cardioprotective activity were the physical parameters and the biochemical estimations. The physical parameters were gross examination of heart, heart weight/body weight ratio and histopathology examination. In biochemical estimations, the activity of various cardiac enzymes such as aspartate transaminase, alanine transaminase, creatinine kinase, lactate dehydrogenase, and the gold marker troponin-I were determined. The levels altered by isoproterenol were restored significantly by the administration of the both doses of test extract especially at higher dose. The result of this study shows that alcoholic extract B. mori has significant cardioprotective activity against isoprenaline-induced myocardial infarction.

  8. Sugar-Coated Nanobullet: Growth Inhibition of Cancer Cells Induced by Metformin-Loaded Glyconanoparticles.

    PubMed

    Qian, Ruo-Can; Lv, Jian; Li, Hao-Wen; Long, Yi-Tao

    2017-11-22

    Metformin, a widely used drug for treating type-2 diabetes, has now been discovered to reduce cancer cell proliferation. However, further efforts are needed to design effective metformin delivery vehicles, instead of bare metformin. Herein we report a highly efficient transport nanostructure based on core-shell glyconanoparticles (GNPs), with gold as the core and dextran as the shell interspersed with metformin molecules. The dextran shell facilitates the entry of GNPs into living cells, which allows the subsequent release of metformin. Using MCF-7 breast cancer cells as an example, significant cell growth inhibition was observed after treatment of metformin-containing GNPs (MGNPs). Compared with bare metformin or bare GNPs, MGNPs show a stronger capacity for cell growth inhibition with good biocompatibility. Furthermore, inactivation of mitochondria and activation of p53 protein are observed during MGNP treatment, which provides evidence for metformin-induced cell apoptosis pathways. This work provides a new therapeutic tool for the treatment of cancer. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Metformin prevents endoplasmic reticulum stress-induced apoptosis through AMPK-PI3K-c-Jun NH2 pathway

    USGS Publications Warehouse

    Jung, T.W.; Lee, M.W.; Lee, Y.-J.; Kim, S.M.

    2012-01-01

    Type 2 diabetes mellitus is thought to be partially associated with endoplasmic reticulum (ER) stress toxicity on pancreatic beta cells and the result of decreased insulin synthesis and secretion. In this study, we showed that a well-known insulin sensitizer, metformin, directly protects against dysfunction and death of ER stress-induced NIT-1 cells (a mouse pancreatic beta cell line) via AMP-activated protein kinase (AMPK) and phosphatidylinositol-3 (PI3) kinase activation. We also showed that exposure of NIT-1 cells to metformin (5mM) increases cellular resistance against ER stress-induced NIT-1 cell dysfunction and death. AMPK and PI3 kinase inhibitors abolished the effect of metformin on cell function and death. Metformin-mediated protective effects on ER stress-induced apoptosis were not a result of an unfolded protein response or the induced inhibitors of apoptotic proteins. In addition, we showed that exposure of ER stressed-induced NIT-1 cells to metformin decreases the phosphorylation of c-Jun NH(2) terminal kinase (JNK). These data suggest that metformin is an important determinant of ER stress-induced apoptosis in NIT-1 cells and may have implications for ER stress-mediated pancreatic beta cell destruction via regulation of the AMPK-PI3 kinase-JNK pathway.

  10. Metformin ameliorates high uric acid-induced insulin resistance in skeletal muscle cells.

    PubMed

    Yuan, Huier; Hu, Yaqiu; Zhu, Yuzhang; Zhang, Yongneng; Luo, Chaohuan; Li, Zhi; Wen, Tengfei; Zhuang, Wanling; Zou, Jinfang; Hong, Liangli; Zhang, Xin; Hisatome, Ichiro; Yamamoto, Tetsuya; Cheng, Jidong

    2017-03-05

    Hyperuricemia occurs together with abnormal glucose metabolism and insulin resistance. Skeletal muscle is an important organ of glucose uptake, disposal, and storage. Metformin activates adenosine monophosphate-activated protein kinase (AMPK) to regulate insulin signaling and promote the translocation of glucose transporter type 4 (GLUT4), thereby stimulating glucose uptake to maintain energy balance. Our previous study showed that high uric acid (HUA) induced insulin resistance in skeletal muscle tissue. However, the mechanism of metformin ameliorating UA-induced insulin resistance in muscle cells is unknown and we aimed to determine it. In this study, differentiated C2C12 cells were exposed to UA (15 mg/dl), then reactive oxygen species (ROS) was detected with DCFH-DA and glucose uptake with 2-NBDG. The levels of phospho-insulin receptor substrate 1 (IRS1; Ser307), phospho-AKT (Ser473) and membrane GLUT4 were examined by western blot analysis. The impact of metformin on UA-induced insulin resistance was monitored by adding Compound C, an AMPK inhibitor, and LY294002, a PI3K/AKT inhibitor. Our data indicate that UA can increase ROS production, inhibit IRS1-AKT signaling and insulin-stimulated glucose uptake, and induce insulin resistance in C2C12 cells. Metformin can reverse this process by increasing intracellular glucose uptake and ameliorating UA-induced insulin resistance. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  11. Equivalent cardioprotection induced by ischemic and hypoxic preconditioning.

    PubMed

    Xiang, Xujin; Lin, Haixia; Liu, Jin; Duan, Zeyan

    2013-04-01

    We aimed to compare cardioprotection induced by various hypoxic preconditioning (HPC) and ischemic preconditioning (IPC) protocols. Isolated rat hearts were randomly divided into 7 groups (n = 7 per group) and received 3 or 5 cycles of 3-minute ischemia or hypoxia followed by 3-minute reperfusion (IPC33 or HPC33 or IPC53 or HPC53 group), 3 cycles of 5-minute ischemia or hypoxia followed by 5-minute reperfusion (IPC35 group or HPC35 group), or 30-minute perfusion (ischemic/reperfusion group), respectively. Then all the hearts were subjected to 50-minute ischemia and 120-minute reperfusion. Cardiac function, infarct size, and coronary flow rate (CFR) were evaluated. Recovery of cardiac function and CFR in IPC35, HPC35, and HPC53 groups was significantly improved as compared with I/R group (p < 0.01). There were no significant differences in cardiac function parameters between IPC35 and HPC35 groups. Consistently, infarct size was significantly reduced in IPC35, HPC35, and HPC53 groups compared with ischemic/reperfusion group. Multiple-cycle short duration HPC exerted cardioprotection, which was as powerful as that of IPC. Georg Thieme Verlag KG Stuttgart · New York.

  12. Bio-enhancing Effect of Piperine with Metformin on Lowering Blood Glucose Level in Alloxan Induced Diabetic Mice.

    PubMed

    Atal, Shubham; Atal, Sarjana; Vyas, Savita; Phadnis, Pradeep

    2016-01-01

    Diabetes mellitus is the most rampant metabolic pandemic of the 21(st) century. Piperine, the chief alkaloid of Piper nigrum (black pepper) is widely used in alternative and complementary therapies has been extensively studied for its bio-enhancing property. To evaluate the bio-enhancing effect of piperine with metformin in lowering blood glucose levels in alloxan-induced diabetic mice. Piperine was isolated from an extract of fruits of P. nigrum. Alloxan-induced (150 mg/kg intraperitoneal) diabetic mice were divided into four groups. Group I (control 2% gum acacia 2 g/100 mL), Group II (metformin 250 mg/kg), Group III (metformin and piperine 250 mg/kg + 10 mg/kg), and Group IV (metformin and piperine 125 mg/kg + 10 mg/kg). All the drugs were administered orally once daily for 28 days. Blood glucose levels were estimated at day 0, day 14, and end of the study (day 28). The combination of piperine with therapeutic dose of metformin (10 mg/kg + 250 mg/kg) showed significantly more lowering of blood glucose level as compared to metformin alone on both 14(th) and 28(th) day (P < 0.05). Piperine in combination with sub-therapeutic dose of metformin (10 mg/kg + 125 mg/kg) showed significantly more lowering of blood glucose as compared to control group and also showed greater lowering of blood glucose as compared to metformin (250 mg/kg) alone. Piperine has the potential to be used as a bio-enhancing agent in combination with metformin which can help reduce the dose of metformin and its adverse effects. Piperine is known for its bioenhancing property. This study evaluates the effect of piperine in combination with oral antidiabetic drug metformin. Drugs were administered for 28 days in alloxan induced diabetic mice and blood glucose lowering effect was seen. Results showed significantly better effect of combination of piperine with therapeutic dose of metformin in comparison to metformin alone. Piperine in combination with subtherapeutic dose of metformin also showed

  13. Bio-enhancing Effect of Piperine with Metformin on Lowering Blood Glucose Level in Alloxan Induced Diabetic Mice

    PubMed Central

    Atal, Shubham; Atal, Sarjana; Vyas, Savita; Phadnis, Pradeep

    2016-01-01

    Background: Diabetes mellitus is the most rampant metabolic pandemic of the 21st century. Piperine, the chief alkaloid of Piper nigrum (black pepper) is widely used in alternative and complementary therapies has been extensively studied for its bio-enhancing property. Objective: To evaluate the bio-enhancing effect of piperine with metformin in lowering blood glucose levels in alloxan-induced diabetic mice. Materials and Methods: Piperine was isolated from an extract of fruits of P. nigrum. Alloxan-induced (150 mg/kg intraperitoneal) diabetic mice were divided into four groups. Group I (control 2% gum acacia 2 g/100 mL), Group II (metformin 250 mg/kg), Group III (metformin and piperine 250 mg/kg + 10 mg/kg), and Group IV (metformin and piperine 125 mg/kg + 10 mg/kg). All the drugs were administered orally once daily for 28 days. Blood glucose levels were estimated at day 0, day 14, and end of the study (day 28). Results: The combination of piperine with therapeutic dose of metformin (10 mg/kg + 250 mg/kg) showed significantly more lowering of blood glucose level as compared to metformin alone on both 14th and 28th day (P < 0.05). Piperine in combination with sub-therapeutic dose of metformin (10 mg/kg + 125 mg/kg) showed significantly more lowering of blood glucose as compared to control group and also showed greater lowering of blood glucose as compared to metformin (250 mg/kg) alone. Conclusion: Piperine has the potential to be used as a bio-enhancing agent in combination with metformin which can help reduce the dose of metformin and its adverse effects. SUMMARY Piperine is known for its bioenhancing property. This study evaluates the effect of piperine in combination with oral antidiabetic drug metformin. Drugs were administered for 28 days in alloxan induced diabetic mice and blood glucose lowering effect was seen. Results showed significantly better effect of combination of piperine with therapeutic dose of metformin in comparison to metformin alone. Piperine

  14. Metformin exaggerates phenylephrine-induced AMPK phosphorylation independent of CaMKKβ and attenuates contractile response in endothelium-denuded rat aorta

    PubMed Central

    Pyla, Rajkumar; Osman, Islam; Pichavaram, Prahalathan; Hansen, Paul; Segar, Lakshman

    2014-01-01

    Metformin, a widely prescribed antidiabetic drug, has been shown to reduce the risk of cardiovascular disease, including hypertension. Its beneficial effect toward improved vasodilation results from its ability to activate AMPK and enhance nitric oxide formation in the endothelium. To date, metformin regulation of AMPK has not been fully studied in intact arterial smooth muscle, especially during contraction evoked by G protein-coupled receptor (GPCR) agonists. In the present study, ex vivo incubation of endothelium-denuded rat aortic rings with 3 mM metformin for 2 hours resulted in significant accumulation of metformin (~600 pmoles/mg tissue), as revealed by LC-MS/MS MRM analysis. However, metformin did not show significant increase in AMPK phosphorylation under these conditions. Exposure of aortic rings to a GPCR agonist (e.g., phenylephrine) resulted in enhanced AMPK phosphorylation by ~2.5-fold. Importantly, in metformin-treated aortic rings, phenylephrine challenge showed an exaggerated increase in AMPK phosphorylation by ~9.7-fold, which was associated with an increase in AMP/ATP ratio. Pretreatment with compound C (AMPK inhibitor) prevented AMPK phosphorylation induced by phenylephrine alone and also that induced by phenylephrine after metformin treatment. However, pretreatment with STO-609 (CaMKKβ inhibitor) diminished AMPK phosphorylation induced by phenylephrine alone but not that induced by phenylephrine after metformin treatment. Furthermore, attenuation of phenylephrine-induced contraction (observed after metformin treatment) was prevented by AMPK inhibition but not by CaMKKβ inhibition. Together, these findings suggest that, upon endothelial damage in the vessel wall, metformin uptake by the underlying vascular smooth muscle would accentuate AMPK phosphorylation by GPCR agonists independent of CaMKKβ to promote vasorelaxation. PMID:25179145

  15. Effects of fructose-induced metabolic syndrome on rat skeletal cells and tissue, and their responses to metformin treatment.

    PubMed

    Felice, Juan Ignacio; Schurman, León; McCarthy, Antonio Desmond; Sedlinsky, Claudia; Aguirre, José Ignacio; Cortizo, Ana María

    2017-04-01

    Deleterious effects of metabolic syndrome (MS) on bone are still controversial. In this study we evaluated the effects of a fructose-induced MS, and/or an oral treatment with metformin on the osteogenic potential of bone marrow mesenchymal stromal cells (MSC), as well as on bone formation and architecture. 32 male 8week-old Wistar rats were assigned to four groups: control (C), control plus oral metformin (CM), rats receiving 10% fructose in drinking water (FRD), and FRD plus metformin (FRDM). Samples were collected to measure blood parameters, and to perform pQCT analysis and static and dynamic histomorphometry. MSC were isolated to determine their osteogenic potential. Metformin improved blood parameters in FRDM rats. pQCT and static and dynamic histomorphometry showed no significant differences in trabecular and cortical bone parameters among groups. FRD reduced TRAP expression and osteocyte density in trabecular bone and metformin only normalized osteocyte density. FRD decreased the osteogenic potential of MSC and metformin administration could revert some of these parameters. FRD-induced MS shows reduction in MSC osteogenic potential, in osteocyte density and in TRAP activity. Oral metformin treatment was able to prevent trabecular osteocyte loss and the reduction in extracellular mineralization induced by FRD-induced MS. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Investigations on the role of leukotrienes in remote hind limb preconditioning-induced cardioprotection in rats.

    PubMed

    Singh, Baljeet; Randhawa, Puneet Kaur; Singh, Nirmal; Jaggi, Amteshwar Singh

    2016-05-01

    The cardioprotective effects of remote hind limb preconditioning (RIPC) are well established, but its mechanisms still remain to be explored. Therefore, the present study was aimed to explore the possible involvement of 5-lipoxygenase-derived leukotrienes in RIPC. The hind limb was tied by a pressure cuff and was subjected to four episodes of inflation and deflation (5min each) to induce remote hind-limb preconditioning. Thereafter, the hearts were isolated and were subjected to global ischemia (30min) followed by reperfusion (120min) on the Langendorff apparatus. The extent of myocardial injury was assessed by measuring lactate dehydrogenase (LDH) and creatine kinase (CK) levels in the coronary effluent; the infarct size using TTC staining, and the hemodynamic parameters including LVDP, dp/dtmax and dp/dtmin. RIPC significantly decreased ischemia and reperfusion-induced increase in LDH, CK release, infarct size and improved LVDP, dp/dtmax and dp/dtmin. Administration of montelukast, leukotriene receptor antagonist (10 and 20mg/kg) and zileuton, 5-lipoxygenase inhibitor, (2.5 and 5mg/kg) abolished RIPC-induced cardioprotection. It may be concluded that hind limb ischemia stimulates 5-lipoxygenase to release leukotrienes which may elicit cardioprotection by humoral or neurogenic pathway. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Safety and otoprotection of metformin in radiation-induced sensorineural hearing loss in the guinea pig.

    PubMed

    Mujica-Mota, Mario A; Salehi, Pezhman; Devic, Slobodan; Daniel, Sam J

    2014-05-01

    There is currently no treatment available to prevent radiation-induced sensorineural hearing loss. Metformin has antineoplastic effects and is able to regulate the mitochondrial production of reactive oxygen species after cellular stress, which is one of the mechanisms involved in apoptosis after radiation damage. The objective of this study was to determine the safety and radioprotective properties of metformin against radiation-induced cochlear damage both in vitro and in vivo. In vitro and prospective animal study. Animal Care Facilities of the Montreal Children's Hospital Research Institute. Cultured auditory hair cells (HEI-OC1) were exposed to different concentrations of metformin to determine its safety. Cells were incubated with different metformin concentrations and subjected to radiation. Cell viability after experiments was determined with the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Sixteen guinea pigs were divided in 2 groups: drinking tap water (n = 8) and drinking water containing metformin (n = 8). The animals were unilaterally irradiated for 20 days (total dose 70 Gy), and the ears were divided in 4 groups: control (n = 8), irradiated (n = 8), metformin (n = 8), and experimental (n = 8). Auditory brainstem responses were assessed before and 1, 6, and 16 weeks after completion of radiotherapy. Metformin was not cytotoxic or radioprotective in cultured auditory hair cells. Experimental ears had less hearing loss than radiated ones; however, differences were not statistically significant (P > .05). Metformin is not ototoxic or radioprotective in vitro or in vivo. Ears solely subjected to metformin had better hearing thresholds than the rest of the groups.

  18. SIRT3 aggravates metformin-induced energy stress and apoptosis in ovarian cancer cells.

    PubMed

    Wu, Yao; Gao, Wei-Nan; Xue, Ya-Nan; Zhang, Li-Chao; Zhang, Juan-Juan; Lu, Sheng-Yao; Yan, Xiao-Yu; Yu, Hui-Mei; Su, Jing; Sun, Lian-Kun

    2018-06-15

    Increasing evidence suggests that mitochondrial respiratory chain complex I participates in carcinogenesis and cancer progression by providing energy and maintaining mitochondrial function. However, the role of complex I in ovarian cancer is largely unknown. In this study we showed that metformin, considered to be an inhibitor of complex I, simultaneously inhibited cell growth and induced mitochondrial-related apoptosis in human ovarian cancer cells. Metformin interrupted cellular energy metabolism mainly by causing damage to complex I that impacted mitochondrial function. Additionally, treatment with metformin increased the activation of sirtuin 3 (SIRT3), a mitochondrial deacetylase. We demonstrated that SIRT3 overexpression aggravated metformin-induced apoptosis, energy stress and mitochondrial dysfunction. Moreover, treatment with metformin or SIRT3 overexpression increased activation of AMP-activated protein kinase (AMPK), a major sensor of cellular energy status. AMPK compensated for energy loss by increasing glycolysis. The impact of this was assessed by reducing glucose levels in the media or by using inhibitors (2-deoxyglucose, Compound C) of glycolysis and AMPK. The combination of these factors with metformin intensified cytotoxicity through further downregulation of ATP. Our study outlines an important role for SIRT3 in the antitumor effect of mitochondrial complex I inhibitors in human ovarian cancer cells. This effect appears to be mediated by induction of energy stress and apoptosis. Strategies that target the mitochondria could be enhanced by modulating glycolysis to further aggravate energy stress that may increase the antitumor effect. Copyright © 2018 Elsevier Inc. All rights reserved.

  19. Metformin reduces the endotoxin-induced down-regulation of apolipoprotein E gene expression in macrophages

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Stavri, Simona; Trusca, Violeta G.; Simionescu, Maya

    The atheroprotective role of macrophage-derived apolipoprotein E (apoE) is well known. Our previous reports demonstrated that inflammatory stress down-regulates apoE expression in macrophages, aggravating atherogenesis. Metformin, extensively used as an anti-diabetic drug, has also anti-inflammatory properties, and thus confers vascular protection. In this study, we questioned whether metformin could have an effect on apoE expression in macrophages in normal conditions or under lipopolysaccharide (LPS)-induced stress. The results showed that metformin slightly increases the apoE expression only at high doses (5–10 mM). Low doses of metformin (1–3 mM) significantly reduce the LPS down-regulatory effect on apoE expression in macrophages. Our experiments demonstrated thatmore » LPS-induced NF-κB binds to the macrophage-specific distal regulatory element of apoE gene, namely to the multienhancer 2 (ME.2) and its 5′-deletion fragments. The NF-κB binding on ME.2 and apoE promoter has a down-regulatory effect. In addition, data revealed that metformin impairs NF-κB nuclear translocation, and thus, improves the apoE levels in macrophages under inflammatory stress. The positive effect of metformin in the inflammatory states, its clinical safety and low cost, make this drug a potential adjuvant in the therapeutic strategies for atherosclerosis. - Highlights: • High doses of metformin slightly increase apoE expression in macrophages. • Low doses of metformin up-regulate apoE gene in endotoxin-stressed macrophages. • Metformin reduces the negative effect of LPS on apoE expression by NF-κB inhibition.« less

  20. Metformin and phenformin block the peripheral antinociception induced by diclofenac and indomethacin on the formalin test.

    PubMed

    Ortiz, Mario I

    2012-01-02

    Recent evidence has shown that systemic administration of sulfonylureas and biguanides block the diclofenac-induced antinociception, but not the effect produced by indomethacin. However, there are no reports about the peripheral interaction between analgesics and the biguanides metformin and phenformin. Therefore, this work was undertaken to determine whether glibenclamide and glipizide and the biguanides metformin and phenformin have any effect on the peripheral antinociception induced by diclofenac and indomethacin. Diclofenac and indomethacin were administered locally in the formalin-injured rat paw, and the antinociceptive effect was evaluated using the 1% formalin test. To determine whether peripheral antinociception induced by diclofenac or indomethacin was mediated by either the ATP-sensitive K(+) channels or biguanides-induced mechanisms, the effect of pretreatment with the appropriates vehicles or glibenclamide, glipizide, metformin and phenformin on the antinociceptive effect induced by local peripheral diclofenac and indomethacin was assessed. Local peripheral injections of diclofenac (50-200 μg/paw) and indomethacin (200-800 μg/paw) produced a dose-dependent antinociception during the second phase of the test. Local pretreatment with glibenclamide, glipizide, metformin and phenformin blocked the diclofenac-induced antinociception. On the other hand, the pretreatment with glibenclamide and glipizide did not prevent the local antinociception produced by indomethacin. Nonetheless, metformin and phenformin reversed the local antinociception induced by indomethacin. Data suggest that diclofenac could activate the K(+) channels and biguanides-dependent mechanisms to produce its peripheral antinociceptive effects in the formalin test. Likewise, a biguanides-dependent mechanism could be activated by indomethacin consecutively to generate its peripheral antinociceptive effect. Copyright © 2011 Elsevier Inc. All rights reserved.

  1. Morphine preconditioning confers cardioprotection in doxorubicin-induced failing rat hearts via ERK/GSK-3β pathway independent of PI3K/Akt

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    He, Shu-Fang; Jin, Shi-Yun; Wu, Hao

    Preconditioning against myocardial ischemia–reperfusion (I/R) injury can be suppressed in some pathological conditions. This study was designed to investigate whether morphine preconditioning (MPC) exerts cardioprotection in doxorubicin (DOX)-induced heart failure in rats and the mechanisms involved. Phosphatidylinositol-3 kinase/protein kinase B (PI3K/Akt), extracellular signal-regulated kinase (ERK) and glycogen synthase kinase (GSK)-3β pathways were examined. Normal and DOX-induced failing rat hearts were subjected to I/R injury using a Langendorff perfusion system with or without MPC or ischemic preconditioning (IPC). The PI3K inhibitor (wortmannin) or ERK inhibitor (PD98059) was infused before MPC. In normal hearts, both MPC and IPC significantly reduced infarct sizemore » and the rise in lactate dehydrogenase (LDH) level caused by I/R injury. Pretreatment with wortmannin or PD98059 abrogated the protective effects of MPC and suppressed the phosphorylation of Akt, ERK and GSK-3β. In failing rat hearts, however, MPC retained its cardioprotection while IPC did not. This protective effect was abolished by PD98059 but not wortmannin. MPC increased the level of p-ERK rather than p-Akt. The phosphorylation of GSK-3β induced by MPC was reversed by PD98059 only. IPC did not elevate the expression of p-ERK, p-Akt and p-GSK-3β in failing rat hearts. We conclude that MPC is cardioprotective in rats with DOX-induced heart failure while IPC is not. The effect of MPC appears to be mediated via the ERK/GSK-3β pathway independent of PI3K/Akt. - Highlights: • Morphine and ischemic preconditioning are cardioprotective in normal rat hearts. • Ischemic preconditioning fails to confer cardioprotection in rats with heart failure. • Morphine retains cardioprotection in doxorubicin-induced heart failure. • Morphine exerts cardioprotection via the ERK/GSK-β pathway independent of PI3K/Akt.« less

  2. Honey and metformin ameliorated diabetes-induced damages in testes of rat; correlation with hormonal changes

    PubMed Central

    Nasrolahi, Ozra; Khaneshi, Fereshteh; Rahmani, Fatemeh; Razi, Mazdak

    2013-01-01

    Background: The global prevalence of diabetes mellitus is on rise. Diabetes-induced oxidative stress has been known to affect liver, pancreas, kidney and reproductive organs pathologically. Honey is a natural product of bee with antioxidant properties. Objective: Current study aimed to analyze the protective effects of Metformin (MF) alone and MF+ natural honey co-administration on diabetes-induced histological derangements in testis of rats. Materials and Methods: Thirty six, mature male Wistar rats were randomly divided into six groups including; control, honey-dosed non-diabetic, diabetes-induced (65 mg/kg, single dose), honey-administrated diabetic (1.0 g/kg/day), Metformin-received diabetic (100 mg/kg/day), Metformin and honey-co-treated diabetic which were followed 40 days. The animals were anesthetized by diethyl ether and the blood samples were collected. The serum levels of testosterone, Insulin, LH and FSH analyzed using antibody enzyme immunoassay method. The testicular tissues were dissected out and underwent to histological analyses. Results: The biochemical analyses revealed that the diabetes resulted in significantly reduced testosterone (p<0.01), LH and FSH (P<0.01, 0.001) levels in serum. Light microscopic analyses showed remarkable (p<0.01) reduction in seminiferous tubules diameter (STD), spermiogenesis index (SPI) and thickness of the epithelium in the diabetic group versus control and co-treated groups. Simultaneous administration of the honey with MF could fairly up-regulate testosterone, LH and FSH levels. The animals in metformin and honey-treated group exhibited with improved tubules atrophy, elevated spermiogenesis index and germinal epithelium thickness. Conclusion: Our data indicated that co-administration of Metformin and honey could inhibit the diabetes-induced damages in testicular tissue. Moreover, the simultaneous administration of metformin and honey up-regulated the diabetes-reduced insulin, LH, FSH and testosterone levels. This

  3. Honey and metformin ameliorated diabetes-induced damages in testes of rat; correlation with hormonal changes.

    PubMed

    Nasrolahi, Ozra; Khaneshi, Fereshteh; Rahmani, Fatemeh; Razi, Mazdak

    2013-12-01

    The global prevalence of diabetes mellitus is on rise. Diabetes-induced oxidative stress has been known to affect liver, pancreas, kidney and reproductive organs pathologically. Honey is a natural product of bee with antioxidant properties. Current study aimed to analyze the protective effects of Metformin (MF) alone and MF+ natural honey co-administration on diabetes-induced histological derangements in testis of rats. Thirty six, mature male Wistar rats were randomly divided into six groups including; control, honey-dosed non-diabetic, diabetes-induced (65 mg/kg, single dose), honey-administrated diabetic (1.0 g/kg/day), Metformin-received diabetic (100 mg/kg/day), Metformin and honey-co-treated diabetic which were followed 40 days. The animals were anesthetized by diethyl ether and the blood samples were collected. The serum levels of testosterone, Insulin, LH and FSH analyzed using antibody enzyme immunoassay method. The testicular tissues were dissected out and underwent to histological analyses. The biochemical analyses revealed that the diabetes resulted in significantly reduced testosterone (p<0.01), LH and FSH (P<0.01, 0.001) levels in serum. Light microscopic analyses showed remarkable (p<0.01) reduction in seminiferous tubules diameter (STD), spermiogenesis index (SPI) and thickness of the epithelium in the diabetic group versus control and co-treated groups. Simultaneous administration of the honey with MF could fairly up-regulate testosterone, LH and FSH levels. The animals in metformin and honey-treated group exhibited with improved tubules atrophy, elevated spermiogenesis index and germinal epithelium thickness. Our data indicated that co-administration of Metformin and honey could inhibit the diabetes-induced damages in testicular tissue. Moreover, the simultaneous administration of metformin and honey up-regulated the diabetes-reduced insulin, LH, FSH and testosterone levels. This article extracted from M.Sc. thesis. (Ozra Nasrolahi).

  4. Metformin activation of AMPK suppresses AGE-induced inflammatory response in hNSCs.

    PubMed

    Chung, Ming-Min; Nicol, Christopher J; Cheng, Yi-Chuan; Lin, Kuan-Hung; Chen, Yen-Lin; Pei, Dee; Lin, Chien-Hung; Shih, Yi-Nuo; Yen, Chia-Hui; Chen, Shiang-Jiuun; Huang, Rong-Nan; Chiang, Ming-Chang

    2017-03-01

    A growing body of evidence suggests type 2 diabetes mellitus (T2DM) is linked to neurodegenerative diseases such as Alzheimer's disease (AD). Although the precise mechanisms remain unclear, T2DM may exacerbate neurodegenerative processes. AMP-activated protein kinase (AMPK) signaling is an evolutionary preserved pathway that is important during homeostatic energy biogenesis responses at both the cellular and whole-body levels. Metformin, a ubiquitously prescribed anti-diabetic drug, exerts its effects by AMPK activation. However, while the roles of AMPK as a metabolic mediator are generally well understood, its performance in neuroprotection and neurodegeneration are not yet well defined. Given hyperglycemia is accompanied by an accelerated rate of advanced glycosylation end product (AGE) formation, which is associated with the pathogenesis of diabetic neuronal impairment and, inflammatory response, clarification of the role of AMPK signaling in these processes is needed. Therefore, we tested the hypothesis that metformin, an AMPK activator, protects against diabetic AGE induced neuronal impairment in human neural stem cells (hNSCs). In the present study, hNSCs exposed to AGE had significantly reduced cell viability, which correlated with elevated inflammatory cytokine expression, such as IL-1α, IL-1β, IL-2, IL-6, IL-12 and TNF-α. Co-treatment with metformin significantly abrogated the AGE-mediated effects in hNSCs. In addition, metformin rescued the transcript and protein expression levels of acetyl-CoA carboxylase (ACC) and inhibitory kappa B kinase (IKK) in AGE-treated hNSCs. NF-κB is a transcription factor with a key role in the expression of a variety of genes involved in inflammatory responses, and metformin did prevent the AGE-mediated increase in NF-κB mRNA and protein levels in the hNSCs exposed to AGE. Indeed, co-treatment with metformin significantly restored inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) levels in AGE-treated h

  5. Metformin extended release: metformin gastric retention, metformin GR, metformin XR.

    PubMed

    2005-01-01

    Metformin extended release [Glumetza, metformin hydrochloride, metformin gastric retention, metformin GR] is a proprietary once-a-day formulation of metformin hydrochloride under development with Depomed for the treatment of diabetes mellitus. In May 2002, Depomed licensed manufacturing and marketing rights for its proprietary formulation of metformin extended release (500mg dose) to Biovail Corporation for the US (including Puerto Rico) and Canada. Under the terms of the agreement, Biovail will pay DepoMed a 25 million dollars milestone fee upon approval of the 500mg dosage and also customary royalties on the net sales in the US and Canada. Biovail also agreed to acquire approximately 2.4 million of additionally issued Depomed shares for 12.3 million dollars. Biovail has subsequently developed a 1000mg dose of metformin extended release [metformin XR] using its proprietary Smartcoat delivery technology allowing a graduated release of the active drug from the tablet. In April 2004, Depomed and Biovail amended their original license agreement of May 2002. Under the terms of the amended agreement, Depomed will receive royalties on sales of Biovail's 1000mg tablet in the US and Canada. In turn, Biovail acquired access to Depomed's clinical data for the metformin 500mg tablet that will be used to accelerate regulatory filings for Biovail's 1000mg tablet and establish equivalence between the two dosages. Biovail is seeking marketing partners for metformin extended release (Glumetza) in the US. The company anticipates signing an agreement for the US during the second half of 2005. In Canada, Biovail Corporation will market Glumetzatrade mark through its Canadian division, Bioval Pharmaceuticals Canada. Depomed has an agreement with LG Life Sciences for the commercialisation and distribution of metformin extended release in Korea. Metformin GR is available for partnership in Europe and Asia. Biovail Corporation and Depomed announced in June 2005 that the US FDA has

  6. Metformin-induced lactic acidosis: a case series.

    PubMed

    Silvestre, Joana; Carvalho, Susana; Mendes, Vitor; Coelho, Luis; Tapadinhas, Camila; Ferreira, Pedro; Povoa, Pedro; Ceia, Fatima

    2007-10-31

    Unlike other agents used in the treatment of type 2 diabetes mellitus, metformin has been shown to reduce mortality in obese patients. It is therefore being increasingly used in higher doses. The major concern of many physicians is a possible risk of lactic acidosis. The reported frequency of metformin related lactic acidosis is 0.05 per 1000 patient-years; some authors advocate that this rate is equal in those patients not taking metformin. We present two case reports of metformin-associated lactic acidosis. The first case is a 77 year old female with a past medical history of hypertension and type 2 diabetes mellitus who had recently been prescribed metformin (3 g/day), perindopril and acetylsalicylic acid. She was admitted to the emergency department two weeks later with abdominal pain and psychomotor agitation. Physical examination revealed only signs of poor perfusion. Laboratory evaluation revealed hyperkalemia, elevated creatinine and blood urea nitrogen and mild leukocytosis. Arterial blood gases showed severe lactic acidemia. She was admitted to the intensive care unit. Vasopressor and ventilatory support was initiated and continuous venovenous hemodiafiltration was instituted. Twenty-four hours later, full clinical recovery was observed, with return to a normal serum lactate level. The patient was discharged from the intensive care unit on the sixth day. The second patient is a 69 year old male with a past medical history of hypertension, type 2 diabetes mellitus and ischemic heart disease who was on metformin (4 g/day), glycazide, acetylsalicylic acid and isosorbide dinitrate. He was admitted to the emergency department in shock with extreme bradycardia. Initial evaluation revealed severe lactic acidosis and elevated creatinine and urea. The patient was admitted to the Intensive Care Unit and commenced on continuous venovenous hemodiafiltration in addition to other supportive measures. A progressive recovery was observed and he was discharged from the

  7. Metformin-associated lactic acidosis (MALA): Moving towards a new paradigm.

    PubMed

    Lalau, Jean-Daniel; Kajbaf, Farshad; Protti, Alessandro; Christensen, Mette M; De Broe, Marc E; Wiernsperger, Nicolas

    2017-11-01

    Although metformin has been used for over 60 years, the balance between the drug's beneficial and adverse effects is still subject to debate. Following an analysis of how cases of so-called "metformin-associated lactic acidosis" (MALA) are reported in the literature, the present article reviews the pitfalls to be avoided when assessing the purported association between metformin and lactic acidosis. By starting from pathophysiological considerations, we propose a new paradigm for lactic acidosis in metformin-treated patients. Metformin therapy does not necessarily induce metformin accumulation, just as metformin accumulation does not necessarily induce hyperlactatemia, and hyperlactatemia does not necessarily induce lactic acidosis. In contrast to the conventional view, MALA probably accounts for a smaller proportion of cases than either metformin-unrelated lactic acidosis or metformin-induced lactic acidosis. Lastly, this review highlights the need for substantial improvements in the reporting of cases of lactic acidosis in metformin-treated patients. Accordingly, we propose a check-list as a guide to clinical practice. © 2017 John Wiley & Sons Ltd.

  8. Impact of metformin treatment and swimming exercise on visfatin levels in high-fat-induced obesity rats.

    PubMed

    Gao, Ya; Wang, Changjiang; Pan, Tianrong; Luo, Li

    2014-02-01

    Visfatin is a recently discovered adipocytokine that contributes to glucose and obesity-related conditions. Until now, its responses to the insulin-sensitizing agent metformin and to exercise are largely unknown. We aim to investigate the impact of metformin treatment and/or swimming exercise on serum visfatin and visfatin levels in subcutaneous adipose tissue (SAT), peri-renal adipose tissue (PAT) and skeletal muscle (SM) of high-fat-induced obesity rats. Sprague-Dawley rats were fed a normal diet or a high-fat diet for 16 weeks to develop obesity model. The high-fat-induced obesity model rats were then randomized to metformin (MET), swimming exercise (SWI), or adjunctive therapy of metformin and swimming exercise (MAS), besides high-fat obesity control group and a normal control group, all with 10 rats per group. Zoometric and glycemic parameters, lipid profile, and serum visfatin levels were assessed at baseline and after 6 weeks of therapy. Visfatin levels in SAT, PAT and SM were determined by Western Blot. Metformin and swimming exercise improved lipid profile, and increased insulin sensitivity and body weight reduction were observed. Both metformin and swimming exercise down-regulated visfatin levels in SAT and PAT, while the adjunctive therapy conferred greater benefits, but no changes of visfatin levels were observed in SM. Our results indicate that visfatin down-regulation in SAT and PAT may be one of the mechanisms by which metformin and swimming exercise inhibit obesity.

  9. Cardioprotective effect of lemon grass as evidenced by biochemical and histopathological changes in experimentally induced cardiotoxicity.

    PubMed

    Gayathri, K; Jayachandran, K S; Vasanthi, Hannah R; Rajamanickam, G Victor

    2011-08-01

    Isoproterenol is a synthetic catecholamine found to cause toxicity leading to severe stress in the myocardium of experimental animals. The aim of the present study is to evaluate the cardioprotective effect of Cymbopogon citratus, which is used as a culinary item and commonly known as lemon grass (LG), in isoproterenol-induced cardiotoxicity. Male Wistar albino rats were segregated into five different groups as follows. Groups I and II rats were treated with vehicle. Groups III and IV rats were treated with 100 and 200 mg/kg b.wt. of LG. Group V with 100 mg/kg b.wt. of vitamin E. Myocardial necrosis was induced in Groups II, III, IV and V on 58(th) and 59(th) day using isoproterenol at a dose of 85 mg/kg twice at 24-hour interval. Animals were sacrificed on the 60( th) day. LG pretreatment exhibited cardioprotective activity as evidenced by decreased activity of cardiac markers in serum and increased the same in heart homogenate (p < 0.05). LG administration decreased the toxic events of lipid peroxidation (TBARS) in both serum and heart tissue, by increasing the level of enzymatic antioxidants and non-enzymatic antioxidants significantly in both heart homogenate and serum sample (p < 0.05). The histopathological observations also revealed that the cardioprotective effect of LG extract was observed at a dose of 200 mg/kg b.wt. The results of the present study reveal that LG is cardioprotective and antilipid peroxidative by increasing various antioxidants at a dose of 200 mg/kg b.wt., which is comparable with that of vitamin E.

  10. Role of metformin in oxaliplatin-induced peripheral neuropathy in patients with stage III colorectal cancer: randomized, controlled study.

    PubMed

    El-Fatatry, Basma Mahrous; Ibrahim, Osama Mohamed; Hussien, Fatma Zakaria; Mostafa, Tarek Mohamed

    2018-06-21

    Peripheral sensory neuropathy is the most prominently reported adverse effect of oxaliplatin. The purpose of this study was to evaluate metformin role in oxaliplatin-induced neuropathy. From November 2014 to May 2016, 40 patients with stage III colorectal cancer completed 12 cycles of FOLFOX-4 regimen. Twenty patients in the control arm received FOLFOX-4 regimen only, and 20 patients in the metformin arm, received the same regimen along with metformin 500 mg three times daily. The metformin efficacy was evaluated using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE version 4.0), a12-item neurotoxicity questionnaire (Ntx-12) from the validated Functional Assessment of Cancer Therapy/Gynecologic Oncology Group and, the brief pain inventory short form "worst pain" item. In addition to neurotensin, malondialdehyde and interleukin-6 serum levels assessment. At the end of the 12th cycle, there were less patients with grade 2 and 3 neuropathy in metformin arm as compared to control arm. (60 versus 95%, P = 0.009) In addition, metformin arm showed significantly higher total scores of Ntx-12 questionnaire than control arm (24.0 versus 19.2, P < 0.001). Furthermore, the mean pain score in metformin arm was significantly lower than those of control arm, (6.7 versus 7.3, P = 0.005). Mean serum levels of malondialdehyde and neurotensin were significantly lower in metformin arm after the 6th and the 12th cycles. Metformin may be a promising drug in protecting colorectal cancer patients against oxaliplatin-induced chronic peripheral sensory neuropathy.

  11. Effect of natural honey from Ilam and metformin for improving glycemic control in streptozotocin-induced diabetic rats

    PubMed Central

    Nasrolahi, Ozra; Heidari, Reza; Rahmani, Fatima; Farokhi, Farah

    2012-01-01

    Objective(s): Diabetes mellitus is a public health problem and one of the five leading causes of death globally. In the present study, the effect of Metformin with natural honey was investigated on glycemia in the Streptozotocin-induced diabetic rats. Materials and Methods: Thirty Wistar male rats were randomly divided into six groups including C: non diabetic rats received distilled water, CH: non diabetic rats received honey, CD: diabetic rats administered with distilled water, DM: Metformin treated diabetic rats, DH: honey treated diabetic rats, and DMH: diabetic rats treated with a combination of Metformin and natural honey. Diabetes was induced by a single dose of Streptozotocin (65 mg/kg; i.p.). The animals were treated by oral gavage once daily for four weeks. At the end of the treatment period, the animals were sacrificed and their blood samples collected. Amount of glucose, triglyceride (TG), total cholesterol (TC), HDL cholesterol, LDL cholesterol, VLDL cholesterol, total bilirubin, and albumin were determined in serum. Results: Group CD: showed hyperglycemia (252.2±4.1 mg/dl), while level of blood glucose was significantly (p<0.01) reduced in groups DH (124.2±2.7 mg/dl), DM (108.0±3.4 mg/dl), and DMH (115.4±2.1 mg/dl). Honey in combination with Metformin significantly (p<0.01) reduced level of bilirubin but Metformin alone did not reduce bilirubin. Honey alone and in combination with Metformin also significantly reduced triglycerides, total cholesterol, LDL, VLDL and increased HDL, but Metformin did not reduced triglycerides and increased HDL. Conclusion: The results of the present study demonstrated that consuming natural honey with Metformin improves glycemic control and is more useful than consuming Metformin alone. The higher therapeutic effect of Ilam honey on lipid abnormalities than Tualang honey was also evident. PMID:25050251

  12. Mechanisms underlying metformin-induced secretion of glucagon-like peptide-1 from the intestinal L cell.

    PubMed

    Mulherin, Andrew J; Oh, Amy H; Kim, Helena; Grieco, Anthony; Lauffer, Lina M; Brubaker, Patricia L

    2011-12-01

    Glucagon-like peptide-1(7-36NH2) (GLP-1) is secreted by the intestinal L cell in response to both nutrient and neural stimulation, resulting in enhanced glucose-dependent insulin secretion. GLP-1 is therefore an attractive therapeutic for the treatment of type 2 diabetes. The antidiabetic drug, metformin, is known to increase circulating GLP-1 levels, although its mechanism of action is unknown. Direct effects of metformin (5-2000 μm) or another AMP kinase activator, aminoimidazole carboxamide ribonucleotide (100-1000 μm) on GLP-1 secretion were assessed in murine human NCI-H716, and rat FRIC L cells. Neither agent stimulated GLP-1 secretion in any model, despite increasing AMP kinase phosphorylation (P < 0.05-0.01). Treatment of rats with metformin (300 mg/kg, per os) or aminoimidazole carboxamide ribonucleotide (250 mg/kg, sc) increased plasma total GLP-1 over 2 h, reaching 37 ± 9 and 29 ± 9 pg/ml (P < 0.001), respectively, compared with basal (7 ± 1 pg/ml). Plasma activity of the GLP-1-degrading enzyme, dipeptidylpeptidase-IV, was not affected by metformin treatment. Pretreatment with the nonspecific muscarinic antagonist, atropine (1 mg/kg, iv), decreased metformin-induced GLP-1 secretion by 55 ± 11% (P < 0.05). Pretreatment with the muscarinic (M) 3 receptor antagonist, 1-1-dimethyl-4-diphenylacetoxypiperidinium iodide (500 μg/kg, iv), also decreased the GLP-1 area under curve, by 48 ± 8% (P < 0.05), whereas the antagonists pirenzepine (M1) and gallamine (M2) had no effect. Furthermore, chronic bilateral subdiaphragmatic vagotomy decreased basal secretion compared with sham-operated animals (7 ± 1 vs. 13 ± 1 pg/ml, P < 0.001) but did not alter the GLP-1 response to metformin. In contrast, pretreatment with the gastrin-releasing peptide antagonist, RC-3095 (100 μg/kg, sc), reduced the GLP-1 response to metformin, by 55 ± 6% (P < 0.01) at 30 min. These studies elucidate the mechanism underlying metformin-induced GLP-1 secretion and highlight the

  13. Metformin selectively affects human glioblastoma tumor-initiating cell viability: A role for metformin-induced inhibition of Akt.

    PubMed

    Würth, Roberto; Pattarozzi, Alessandra; Gatti, Monica; Bajetto, Adirano; Corsaro, Alessandro; Parodi, Alessia; Sirito, Rodolfo; Massollo, Michela; Marini, Cecilia; Zona, Gianluigi; Fenoglio, Daniela; Sambuceti, Gianmario; Filaci, Gilberto; Daga, Antonio; Barbieri, Federica; Florio, Tullio

    2013-01-01

    Cancer stem cell theory postulates that a small population of tumor-initiating cells is responsible for the development, progression and recurrence of several malignancies, including glioblastoma. In this perspective, tumor-initiating cells represent the most relevant target to obtain effective cancer treatment. Metformin, a first-line drug for type II diabetes, was reported to possess anticancer properties affecting the survival of cancer stem cells in breast cancer models. We report that metformin treatment reduced the proliferation rate of tumor-initiating cell-enriched cultures isolated from four human glioblastomas. Metformin also impairs tumor-initiating cell spherogenesis, indicating a direct effect on self-renewal mechanisms. Interestingly, analyzing by FACS the antiproliferative effects of metformin on CD133-expressing subpopulation, a component of glioblastoma cancer stem cells, a higher reduction of proliferation was observed as compared with CD133-negative cells, suggesting a certain degree of cancer stem cell selectivity in its effects. In fact, glioblastoma cell differentiation strongly reduced sensitivity to metformin treatment. Metformin effects in tumor-initiating cell-enriched cultures were associated with a powerful inhibition of Akt-dependent cell survival pathway, while this pathway was not affected in differentiated cells. The specificity of metformin antiproliferative effects toward glioblastoma tumor-initiating cells was confirmed by the lack of significant inhibition of normal human stem cells (umbilical cord-derived mesenchymal stem cells) in vitro proliferation after metformin exposure. Altogether, these data clearly suggest that metformin exerts antiproliferative activity on glioblastoma cells, showing a higher specificity toward tumor-initiating cells, and that the inhibition of Akt pathway may represent a possible intracellular target of this effect.

  14. Involvement of adenosine and standardization of aqueous extract of garlic (Allium sativum Linn.) on cardioprotective and cardiodepressant properties in ischemic preconditioning and myocardial ischemia-reperfusion induced cardiac injury

    PubMed Central

    Sharma, Ashish Kumar; Munajjam, Arshee; Vaishnav, Bhawna; Sharma, Richa; Sharma, Ashok; Kishore, Kunal; Sharma, Akash; Sharma, Divya; Kumari, Rita; Tiwari, Ashish; Singh, Santosh Kumar; Gaur, Samir; Jatav, Vijay Singh; Srinivasan, Barthu Parthi; Agarwal, Shyam Sunder

    2012-01-01

    The present study investigated the effect of garlic (Allium sativum Linn.) aqueous extracts on ischemic preconditioning and ischemia-reperfusion induced cardiac injury, as well as adenosine involvement in ischemic preconditioning and garlic extract induced cardioprotection. A model of ischemia-reperfusion injury was established using Langendorff apparatus. Aqueous extract of garlic dose was standardized (0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.07%, 0.05%, 0.03%, 0.01%), and the 0.05% dose was found to be the most effective. Higher doses (more than 0.05%) were highly toxic, causing arrhythmia and cardiodepression, whereas the lower doses were ineffective. Garlic exaggerated the cardioprotective effect of ischemic preconditioning. The cardioprotective effect of ischemic preconditioning and garlic cardioprotection was significantly attenuated by theophylline (1,000 µmol/L) and 8-SPT (10 mg/kg, i.p.) and expressed by increased myocardial infarct size, increased LDH level, and reduced nitrite and adenosine levels. These findings suggest that adenosine is involved in the pharmacological and molecular mechanism of garlic induced cardioprotection and mediated by the modulation of nitric oxide. PMID:23554727

  15. Comparison of antioxidant effects of honey, glibenclamide, metformin, and their combinations in the kidneys of streptozotocin-induced diabetic rats.

    PubMed

    Erejuwa, Omotayo Owomofoyon; Sulaiman, Siti Amrah; Wahab, Mohd Suhaimi Ab; Salam, Sirajudeen Kuttulebbai Nainamohammed; Salleh, Md Salzihan Md; Gurtu, Sunil

    2011-01-21

    Hyperglycemia-induced increase in oxidative stress is implicated in diabetic complications. This study investigated the effect of metformin and/or glibenclamide in combination with honey on antioxidant enzymes and oxidative stress markers in the kidneys of streptozotocin (60 mg/kg; intraperitoneal)-induced diabetic rats. Diabetic rats were randomized into eight groups of five to seven rats and received distilled water (0.5 mL); honey (1.0 g/kg); metformin (100 mg/kg); metformin (100 mg/kg) and honey (1.0 g/kg); glibenclamide (0.6 mg/kg); glibenclamide (0.6 mg/kg) and honey (1.0 g/kg); metformin (100 mg/kg) and glibenclamide (0.6 mg/kg); or metformin (100 mg/kg), glibenclamide (0.6 mg/kg) and honey (1.0 g/kg) orally once daily for four weeks. Malondialdehyde (MDA) levels, glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities were significantly elevated while catalase (CAT) activity, total antioxidant status (TAS), reduced glutathione (GSH), and GSH:oxidized glutathione (GSSG) ratio was significantly reduced in the diabetic kidneys. CAT, glutathione reductase (GR), TAS, and GSH remained significantly reduced in the diabetic rats treated with metformin and/or glibenclamide. In contrast, metformin or glibenclamide combined with honey significantly increased CAT, GR, TAS, and GSH. These results suggest that combination of honey with metformin or glibenclamide might offer additional antioxidant effect to these drugs. This might reduce oxidative stress-mediated damage in diabetic kidneys.

  16. Comparison of Antioxidant Effects of Honey, Glibenclamide, Metformin, and Their Combinations in the Kidneys of Streptozotocin-Induced Diabetic Rats

    PubMed Central

    Erejuwa, Omotayo Owomofoyon; Sulaiman, Siti Amrah; Wahab, Mohd Suhaimi Ab; Salam, Sirajudeen Kuttulebbai Nainamohammed; Salleh, Md Salzihan Md; Gurtu, Sunil

    2011-01-01

    Hyperglycemia-induced increase in oxidative stress is implicated in diabetic complications. This study investigated the effect of metformin and/or glibenclamide in combination with honey on antioxidant enzymes and oxidative stress markers in the kidneys of streptozotocin (60 mg/kg; intraperitoneal)-induced diabetic rats. Diabetic rats were randomized into eight groups of five to seven rats and received distilled water (0.5 mL); honey (1.0 g/kg); metformin (100 mg/kg); metformin (100 mg/kg) and honey (1.0 g/kg); glibenclamide (0.6 mg/kg); glibenclamide (0.6 mg/kg) and honey (1.0 g/kg); metformin (100 mg/kg) and glibenclamide (0.6 mg/kg); or metformin (100 mg/kg), glibenclamide (0.6 mg/kg) and honey (1.0 g/kg) orally once daily for four weeks. Malondialdehyde (MDA) levels, glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities were significantly elevated while catalase (CAT) activity, total antioxidant status (TAS), reduced glutathione (GSH), and GSH:oxidized glutathione (GSSG) ratio was significantly reduced in the diabetic kidneys. CAT, glutathione reductase (GR), TAS, and GSH remained significantly reduced in the diabetic rats treated with metformin and/or glibenclamide. In contrast, metformin or glibenclamide combined with honey significantly increased CAT, GR, TAS, and GSH. These results suggest that combination of honey with metformin or glibenclamide might offer additional antioxidant effect to these drugs. This might reduce oxidative stress-mediated damage in diabetic kidneys. PMID:21340016

  17. Metformin inhibits 17β-estradiol-induced epithelial-to-mesenchymal transition via βKlotho-related ERK1/2 signaling and AMPKα signaling in endometrial adenocarcinoma cells.

    PubMed

    Liu, Zhao; Qi, Shasha; Zhao, Xingbo; Li, Mingjiang; Ding, Sentai; Lu, Jiaju; Zhang, Hui

    2016-04-19

    The potential role of metformin in treating endometrial cancer remains to be explored. The current study investigated the role of metformin in 17β-estradiol-induced epithelial-mesenchymal transition (EMT) in endometrial adenocarcinoma cells. We found that 17β-estradiol promoted proliferation and migration, attenuated apoptosis in both estrogen receptor (ER) positive and ER negative endometrial adenocarcinoma cells (Ishikawa and KLE cells, respectively). Metformin abolished 17β-estradiol-induced cell proliferation and reversed 17β-estradiol-induced EMT in Ishikawa cells. In addition, metformin increased the expression of βKlotho, a fibroblast growth factors (FGFs) coreceptor, and decreased ERK1/2 phosphorylation in both Ishikawa and KLE cells. Decreased expression of βKlotho was noted in human endometrial adenocarcinomas, and plasmid-driven expression of βKlotho in Ishikawa cells abolished 17β-estradiol-induced EMT via inhibiting ERK1/2 signaling. βKlotho expression and metformin show synergetic effects on the proliferation and the EMT in Ishikawa cells. Furthermore, we demonstrated that the anti-EMT effects of metformin could be partly abolished by introducing Compound C, a specific AMPKα signaling inhibitor. In conclusion, metformin abolishes 17β-estradiol-induced cell proliferation and EMT in endometrial adenocarcinoma cells by upregulating βKlotho expression, inhibiting ERK1/2 signaling, and activating AMPKα signaling. Our study provides novel mechanistic insight into the anti-tumor effects of metformin.

  18. Metformin inhibits 17β-estradiol-induced epithelial-to-mesenchymal transition via βKlotho-related ERK1/2 signaling and AMPKα signaling in endometrial adenocarcinoma cells

    PubMed Central

    Liu, Zhao; Qi, Shasha; Zhao, Xingbo; Li, Mingjiang; Ding, Sentai; Lu, Jiaju; Zhang, Hui

    2016-01-01

    The potential role of metformin in treating endometrial cancer remains to be explored. The current study investigated the role of metformin in 17β-estradiol-induced epithelial-mesenchymal transition (EMT) in endometrial adenocarcinoma cells. We found that 17β-estradiol promoted proliferation and migration, attenuated apoptosis in both estrogen receptor (ER) positive and ER negative endometrial adenocarcinoma cells (Ishikawa and KLE cells, respectively). Metformin abolished 17β-estradiol-induced cell proliferation and reversed 17β-estradiol-induced EMT in Ishikawa cells. In addition, metformin increased the expression of βKlotho, a fibroblast growth factors (FGFs) coreceptor, and decreased ERK1/2 phosphorylation in both Ishikawa and KLE cells. Decreased expression of βKlotho was noted in human endometrial adenocarcinomas, and plasmid-driven expression of βKlotho in Ishikawa cells abolished 17β-estradiol-induced EMT via inhibiting ERK1/2 signaling. βKlotho expression and metformin show synergetic effects on the proliferation and the EMT in Ishikawa cells. Furthermore, we demonstrated that the anti-EMT effects of metformin could be partly abolished by introducing Compound C, a specific AMPKα signaling inhibitor. In conclusion, metformin abolishes 17β-estradiol-induced cell proliferation and EMT in endometrial adenocarcinoma cells by upregulating βKlotho expression, inhibiting ERK1/2 signaling, and activating AMPKα signaling. Our study provides novel mechanistic insight into the anti-tumor effects of metformin. PMID:26824324

  19. Long-term insulin treatment restores cardioprotection induced by sufentanil postconditioning in diabetic rat heart.

    PubMed

    Zhang, Yuwen; Zhang, Lei; Gu, Erwei; Zhu, Bingqing; Zhao, Xianya; Chen, Jingjing

    2016-03-01

    Sufentanil, a commonly used opioid analgesic, could mimic ischemia postconditioning to attenuate ischemia reperfusion injury, but this effect might be hindered in diabetic animals by inhibition of glycogen synthase kinase-3β phosphorylation. Also, diabetes can abrogate the cardioprotection of sevoflurane (an inhaled anesthetic) against ischemia reperfusion injury, and short-term insulin treatment does not restore protection by sevoflurane postconditioning. We hypothesized that long-term insulin treatment might restore the cardioprotective effect of sufentanil postconditioning in diabetic rats via phosphorylation of glycogen synthase kinase-3β. Streptozotocin (55 mg/kg)-induced diabetic rats received insulin (Novolin N, 6-8 u/d) for two days or two weeks, then were exposed to 30-min ischemia and 120-min reperfusion. Sufentanil postconditioning was performed 5 min before the onset of reperfusion. Controls included non-diabetic rats, sham surgery for ischemia/reperfusion, and sufentanil vehicle. Infarct size, cardiac troponin I, and phosphorylated glycogen synthase kinase-3β were examined. Sufentanil postconditioning reduced infarct size by 46% in non-diabetic rats (P < 0.001), but diabetes prevented this protective effect. Two-day insulin treatment was not effective, but two-week treatment reduced infarct size by 45% (P < 0.001), reduced cardiac troponin I by 33% (P < 0.001), and increased phosphorylated glycogen synthase kinase-3β levels (P < 0.001) in the diabetic sufentanil postconditioning group. In conclusion, sufentanil-induced cardioprotection was restored by long-term insulin treatment. The underlying mechanism may be increased phosphorylation of glycogen synthase kinase-3β. © 2016 by the Society for Experimental Biology and Medicine.

  20. Metformin improves circulating endothelial cells and endothelial progenitor cells in type 1 diabetes: MERIT study.

    PubMed

    Ahmed, Fahad W; Rider, Rachel; Glanville, Michael; Narayanan, Kilimangalam; Razvi, Salman; Weaver, Jolanta U

    2016-08-26

    Type 1 diabetes is associated with increased cardiovascular disease (CVD). Decreased endothelial progenitor cells (EPCs) number plays a pivotal role in reduced endothelial repair and development of CVD. We aimed to determine if cardioprotective effect of metformin is mediated by increasing circulating endothelial progenitor cells (cEPCs), pro-angiogenic cells (PACs) and decreasing circulating endothelial cells (cECs) count whilst maintaining unchanged glycemic control. This study was an open label and parallel standard treatment study. Twenty-three type 1 diabetes patients without overt CVD were treated with metformin for 8 weeks (treatment group-TG). They were matched with nine type 1 diabetes patients on standard treatment (SG) and 23 age- and sex-matched healthy volunteers (HC). Insulin dose was adjusted to keep unchanged glycaemic control. cEPCs and cECs counts were determined by flow cytometry using surface markers CD45(dim)CD34(+)VEGFR-2(+) and CD45(dim)CD133(-)CD34(+)CD144(+) respectively. Peripheral blood mononuclear cells were cultured to assess changes in PACs number, function and colony forming units (CFU-Hill's colonies). At baseline TG had lower cEPCs, PACs, CFU-Hills' colonies and PACs adhesion versus HC (p < 0.001-all variables) and higher cECs versus HC (p = 0.03). Metformin improved cEPCs, PACs, CFU-Hill's colonies number, cECs and PACs adhesion (p < 0.05-all variables) to levels seen in HC whilst HbA1c (one-way ANOVA p = 0.78) and glucose variability (average glucose, blood glucose standard deviation, mean amplitude of glycaemic excursion, continuous overall net glycaemic action and area under curve) remained unchanged. No changes were seen in any variables in SG. There was an inverse correlation between CFU-Hill's colonies with cECs. Metformin has potential cardio-protective effect through improving cEPCs, CFU-Hill's colonies, cECs, PACs count and function independently of hypoglycaemic effect. This finding needs to be confirmed by long

  1. Involvement of cannabinoids in the cardioprotection induced by lipopolysaccharide

    PubMed Central

    Lagneux, Caroline; Lamontagne, Daniel

    2001-01-01

    We have examined the involvement of the endocannabinoid system in the cardioprotection triggered by lipopolysaccharide (LPS). Rats were treated with saline or LPS (10 μg Kg−1). 24 h later, hearts were excised, retrogradely perfused, submitted to a low-flow ischaemia (0.6 ml min−1) for 90 min and reperfused for 60 min. Some hearts were perfused with either SR 141716A (a cannabinoid CB1, receptor antagonist 1 μM), SR 144528 (a CB2 receptor anagonist μM), NNLA (3 μM) or sodium nitroprusside (1 μM) 5 min before ischaemia and during the ischaemic period. The cardioprotective effects of LPS treatment, in terms of infarction and functional recovery, were not altered by the perfusion of SR 141716A but abolished by both SR 144528 and NNLA. Finally, SR 144528 abolished the beneficial effects of SNP perfusion. Our results suggest an involvement of endocannabinoids, acting through the CB2 receptors, in the cardioprotection triggered by LPS against myocardial ischaemia. This could be attributed to a relationship between cannabinoids and NO. PMID:11181418

  2. Antioxidant protective effect of glibenclamide and metformin in combination with honey in pancreas of streptozotocin-induced diabetic rats.

    PubMed

    Erejuwa, Omotayo Owomofoyon; Sulaiman, Siti Amrah; Wahab, Mohd Suhaimi Abdul; Salam, Sirajudeen Kuttulebbai Nainamohammed; Salleh, Md Salzihan Md; Gurtu, Sunil

    2010-05-05

    Hyperglycemia exerts toxic effects on the pancreatic beta-cells. This study investigated the hypothesis that the common antidiabetic drugs glibenclamide and metformin, in combination with tualang honey, offer additional protection for the pancreas of streptozotocin (STZ)-induced diabetic rats against oxidative stress and damage. Diabetes was induced in male Sprague Dawley rats by a single dose of STZ (60 mg/kg; ip). Diabetic rats had significantly elevated levels of lipid peroxidation (TBARS), up-regulated activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) while catalase (CAT) activity was significantly reduced. Glibenclamide and metformin produced no significant effects on TBARS and antioxidant enzymes except GPx in diabetic rats. In contrast, the combination of glibenclamide, metformin and honey significantly up-regulated CAT activity and down-regulated GPx activity while TBARS levels were significantly reduced. These findings suggest that tualang honey potentiates the effect of glibenclamide and metformin to protect diabetic rat pancreas against oxidative stress and damage.

  3. The adjunctive use of metformin to treat or prevent atypical antipsychotic-induced weight gain: a review.

    PubMed

    Khan, Ahsan Y; Macaluso, Matthew; McHale, Robert J; Dahmen, Megan M; Girrens, Kathrine; Ali, Faryal

    2010-09-01

    Patients with schizophrenia have a greater incidence of being overweight or obese compared with the general population. Such individuals are often treated with second-generation (atypical) antipsychotics (SGAs), which are associated with weight gain, dyslipidemia, and other metabolic derangements. As a result, frequent monitoring of weight and other metabolic parameters is recommended. In addition, several pharmacologic strategies to help prevent or reduce SGA-induced weight gain have been proposed. Despite this, clinicians often struggle to manage obesity and metabolic issues in such patients. Metformin has attracted attention as a potential treatment option because it is thought to result in weight reduction and improved glycemic control in obese patients with and without type 2 diabetes mellitus. This article focuses on relevant pharmacologic aspects of metformin and reviews currently available evidence on the use of metformin as an augmentation agent for the treatment or prevention of SGA-induced weight gain.

  4. Effects of metformin on inflammation and short-term memory in streptozotocin-induced diabetic mice.

    PubMed

    Oliveira, Wilma Helena; Nunes, Ana Karolina; França, Maria Eduarda Rocha; Santos, Laise Aline; Lós, Deniele Bezerra; Rocha, Sura Wanessa; Barbosa, Karla Patrícia; Rodrigues, Gabriel Barros; Peixoto, Christina Alves

    2016-08-01

    The aim of the present study was to analyze the action of metformin on short-term memory, glial cell activation and neuroinflammation caused by experimental diabetic encephalopathy in C57BL/6 mice. Diabetes was induced by the intraperitoneal injection of a dose of 90mg/kg of streptozotocin on two successive days. Mice with blood glucose levels ≥200dl/ml were considered diabetic and were given metformin hydrochloride at doses of 100mg/kg and 200mg/kg (by gavage, twice daily) for 21 days. On the final day of treatment, the mice underwent a T-maze test. On the 22nd day of treatment all the animals were anesthetized and euthanized. Diabetic animals treated with metformin had a higher spatial memory score. The hippocampus of the diabetic animals presented reactive gliosis, neuronal loss, NF-kB signaling activation, and high levels of IL-1 and VEGF. In addition, the T-maze test scores of these animals were low. Treatment with metformin reduced the expression of GFAP, Iba-1 (astrocyte and microglial markers) and the inflammation markers (p-IKB, IL-1 and VEGF), while enhancing p-AMPK and eNOS levels and increasing neuronal survival (Fox-1 and NeuN). Treatment with metformin also improved the spatial memory scores of diabetic animals. In conclusion, the present study showed that metformin can significantly reduce neuroinflammation and can decrease the loss of neurons in the hippocampus of diabetic animals, which can subsequently promote improvements in spatial memory. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Sirtuin 1 (SIRT1) activation mediates sildenafil induced delayed cardioprotection against ischemia-reperfusion injury in mice.

    PubMed

    Shalwala, Mona; Zhu, Shu-Guang; Das, Anindita; Salloum, Fadi N; Xi, Lei; Kukreja, Rakesh C

    2014-01-01

    It has been well documented that phosphodiesterase-5 inhibitor, sildenafil (SIL) protects against myocardial ischemia/reperfusion (I-R) injury. SIRT1 is part of the class III Sirtuin family of histone deacetylases that deacetylates proteins involved in cellular stress response including those related to I-R injury. We tested the hypothesis that SIL-induced cardioprotection may be mediated through activation of SIRT1. Adult male ICR mice were treated with SIL (0.7 mg/kg, i.p.), Resveratrol (RSV, 5 mg/kg, a putative activator of SIRT1 used as the positive control), or saline (0.2 mL). The hearts were harvested 24 hours later and homogenized for SIRT1 activity analysis. Both SIL- and RSV-treated mice had increased cardiac SIRT1 activity (P<0.001) as compared to the saline-treated controls 24 hours after drug treatment. In isolated ventricular cardiomyocytes, pretreatment with SIL (1 µM) or RSV (1 µM) for one hour in vitro also upregulated SIRT1 activity (P<0.05). We further examined the causative relationship between SIRT1 activation and SIL-induced late cardioprotection. Pretreatment with SIL (or RSV) 24 hours prior to 30 min ischemia and 24 hours of reperfusion significantly reduced infarct size, which was associated with a significant increase in SIRT1 activity (P<0.05). Moreover, sirtinol (a SIRT1 inhibitor, 5 mg/kg, i.p.) given 30 min before I-R blunted the infarct-limiting effect of SIL and RSV (P<0.001). Our study shows that activation of SIRT1 following SIL treatment plays an essential role in mediating the SIL-induced cardioprotection against I-R injury. This newly identified SIRT1-activating property of SIL may have enormous therapeutic implications.

  6. Substance P induces cardioprotection in ischemia-reperfusion via activation of AKT.

    PubMed

    Jubair, Shaiban; Li, Jianping; Dehlin, Heather M; Manteufel, Edward J; Goldspink, Paul H; Levick, Scott P; Janicki, Joseph S

    2015-08-15

    Accumulating evidence indicates that substance P is cardioprotective following ischemia-reperfusion primarily due to its potent coronary vasodilator actions. However, an anti-apoptotic effect of substance P has been observed in tenocytes following ischemia, which involved activation of the AKT pathway. This suggests the possibility that substance P also provides cardioprotection via direct actions to activate AKT in myocardial cells. The purpose of this study was to test the hypothesis that substance P attenuates ischemia-related cell death via direct effects on myocardial cells by activating cell survival pathways. Seven-week-old male Sprague-Dawley rats, anesthetized with intraperitoneal pentobarbital sodium (100 mg/kg), were used. The ability of substance P to prevent cellular damage was assessed following ischemia-reperfusion in an isolated heart preparation and in short-term hypoxia without reperfusion using a left ventricular tissue slice culture preparation. In addition, the NK-1 receptor and AKT involvement was assessed using the NK-1 receptor antagonist L732138 and the AKT inhibitor LY294002. The results indicate that substance P reduced the ischemia-related release of lactate dehydrogenase in both preparations and the degree of apoptosis and necrosis in the hypoxic left ventricular slices, indicating its ability to attenuate cell damage; and induced AKT phosphorylation, with both the AKT inhibitor and NK-1 receptor antagonist preventing the increased phosphorylation of AKT and the ability of substance P to attenuate hypoxic cellular damage. It is concluded that substance P reduces ischemia/hypoxia-induced myocardial cell death by acting directly on cardiac cells to initiate cell survival pathways via the NK-1 receptor and AKT. Copyright © 2015 the American Physiological Society.

  7. Cardioprotective role of tadalafil against cisplatin-induced cardiovascular damage in rats.

    PubMed

    Saleh, Rasha M; Awadin, Walaa F; El-Shafei, Reham A; Elseady, Yousef Y; Wehaish, Faheim E; Elshal, Mohamed F

    2015-10-15

    The present study investigated the possible cardioprotective effect of tadalafil (Tad) on cisplatin (CDDP)-induced cardiac and vascular damages in rats. A total number of seventy two healthy male albino rats initially weighting between 200 and 220 g were used and randomly divided into four groups,18 rats in each. The control group received no treatment; CDDP group received a single dose of CDDP (4 mg/kg) intraperitoneal (i.p.) per week for 4 weeks the duration of the experiment; Tad group received 0.4 mg/kg BW Tad i.p. daily and Tad +CDDP group received 0.4 mg/kg BW Tad i.p. +4 mg/kg BW CDDP i.p. The results showed that Tad was able to decrease blood pressure, heart rate, levels of serum cardiac troponin (cTn-I), malondialdehyde (MDA) and increased levels of reduced glutathione (GSH) and nitric oxide (NO) in the heart homogenate sample from CDDP treated rats. Semi-quantitative analysis showed that Tad was able to decrease the histopathological scores of cardiac muscular hyalinzation and fibrosis in three sacrifices in CDDP treated rats. CDDP treated rats showed significantly increased thickening in wall of aorta with an irregular luminal layer of endothelial cell linings in three sacrifices when it was compared to other groups. Moreover, immunohistochemical labeling of α- smooth muscle actin (α-SMA) in aorta revealed significant lower scores in Tad +CDDP group when they were compared to CDDP group. In conclusion, Tad alone did not induce any harmful effects on blood pressure, selective antioxidant, peroxidation markers or cardiac histology, in addition, Tad has a cardio-protective role against CDDP. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. Substance P induces cardioprotection in ischemia-reperfusion via activation of AKT

    PubMed Central

    Jubair, Shaiban; Li, Jianping; Dehlin, Heather M.; Manteufel, Edward J.; Goldspink, Paul H.; Levick, Scott P.

    2015-01-01

    Accumulating evidence indicates that substance P is cardioprotective following ischemia-reperfusion primarily due to its potent coronary vasodilator actions. However, an anti-apoptotic effect of substance P has been observed in tenocytes following ischemia, which involved activation of the AKT pathway. This suggests the possibility that substance P also provides cardioprotection via direct actions to activate AKT in myocardial cells. The purpose of this study was to test the hypothesis that substance P attenuates ischemia-related cell death via direct effects on myocardial cells by activating cell survival pathways. Seven-week-old male Sprague-Dawley rats, anesthetized with intraperitoneal pentobarbital sodium (100 mg/kg), were used. The ability of substance P to prevent cellular damage was assessed following ischemia-reperfusion in an isolated heart preparation and in short-term hypoxia without reperfusion using a left ventricular tissue slice culture preparation. In addition, the NK-1 receptor and AKT involvement was assessed using the NK-1 receptor antagonist L732138 and the AKT inhibitor LY294002. The results indicate that substance P reduced the ischemia-related release of lactate dehydrogenase in both preparations and the degree of apoptosis and necrosis in the hypoxic left ventricular slices, indicating its ability to attenuate cell damage; and induced AKT phosphorylation, with both the AKT inhibitor and NK-1 receptor antagonist preventing the increased phosphorylation of AKT and the ability of substance P to attenuate hypoxic cellular damage. It is concluded that substance P reduces ischemia/hypoxia-induced myocardial cell death by acting directly on cardiac cells to initiate cell survival pathways via the NK-1 receptor and AKT. PMID:26071541

  9. Cardioprotective effect of Sida rhomboidea. Roxb extract against isoproterenol induced myocardial necrosis in rats.

    PubMed

    Thounaojam, Menaka C; Jadeja, Ravirajsinh N; Ansarullah; Karn, Sanjay S; Shah, Jigar D; Patel, Dipak K; Salunke, Sunita P; Padate, Geeta S; Devkar, Ranjitsinh V; Ramachandran, A V

    2011-05-01

    The present study investigates cardioprotective effect of Sida rhomboidea. Roxb (SR) extract on heart weight, plasma lipid profile, plasma marker enzymes, lipid peroxidation, endogenous enzymatic and non-enzymatic antioxidants and membrane bound ATPases against isoproterenol (IP) induced myocardial necrosis (MN) in rats. Rats treated with IP (85 mg/kg, s.c.) recorded significant (p<0.05) increment in heart weight, plasma lipid profile, plasma marker enzymes of cardiac damage, cardiac lipid peroxidation (LPO) and activity levels of Ca(+2) ATPase whereas there was significant (p<0.05) decrease in plasma HDL, cardiac endogenous enzymatic and non-enzymatic antioxidants, Na(+)-K(+) ATPase and Mg(+2) ATPase. Pre-treatment with SR extract (400 mg/kg per day, p.o.) for 30 consecutive days followed by IP injections on days 29th and 30th, showed significant (p<0.05) decrease in heart weight, plasma lipid profile, plasma marker enzymes of cardiac damage, cardiac lipid peroxidation, Ca(+2) ATPase and significant increase in plasma HDL, cardiac endogenous enzymatic and non-enzymatic antioxidants, Na(+)-K(+) ATPase and Mg(+2) ATPase compared to IP treated group. Hence, this study is the first scientific report on cardioprotective effect of SR against IP induced MN in rats. Copyright © 2010 Elsevier GmbH. All rights reserved.

  10. Anthocyanins in cardioprotection: A path through mitochondria.

    PubMed

    Liobikas, Julius; Skemiene, Kristina; Trumbeckaite, Sonata; Borutaite, Vilmante

    2016-11-01

    Constantly growing experimental data from in vitro, in vivo and epidemiological studies show the great potential of anthocyanin-containing fruit and berry extracts or pure individual anthocyanins as cardioprotective food components or pharmacological compounds. In general it is regarded that the cardioprotective activity of anthocyanins is related to their antioxidant properties. However there are recent reports that certain anthocyanins may protect the heart against ischemia/reperfusion-induced injury by activating signal transduction pathways and sustaining mitochondrial functions instead of acting solely as antioxidants. In this review, we summarize the proposed mechanisms of direct or indirect actions of anthocyanins within cardiac cells with the special emphasis on recently discovered their pharmacological effects on mitochondria in cardioprotection: reduction of cytosolic cytochrome c preventing apoptosis and sustainment of electron transfer between NADH dehydrogenase and cytochrome c supporting oxidative phosphorylation in ischemia-damaged mitochondria. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. Cardiotoxic and Cardioprotective Features of Chronic β-adrenergic Signaling

    PubMed Central

    Zhang, Xiaoying; Szeto, Christopher; Gao, Erhe; Tang, Mingxin; Jin, Jianguo; Fu, Qin; Makarewich, Catherine; Ai, Xiaojie; Li, Ying; Tang, Allen; Wang, Jenny; Gao, Hui; Wang, Fang; Ge, Xinyi Joy; Kunapuli, Satya P.; Zhou, Lin; Zeng, Chunyu; Xiang, Kevin Yang; Chen, Xiongwen

    2012-01-01

    Rationale In the failing heart, persistent β-adrenergic receptor (βAR) activation is thought to induce myocyte death by protein kinase A (PKA)-dependent and PKA-independent activation of calcium/calmodulin-dependent kinase II (CaMKII). β-Adrenergic signaling pathways are also capable of activating cardioprotective mechanisms. Objective This study used a novel PKA inhibitor peptide (PKI) to inhibit PKA activity to test the hypothesis that βAR signaling causes cell death through PKA-dependent pathways and cardioprotection through PKA-independent pathways. Methods and Results In PKI transgenic mice, chronic isoproterenol (ISO) failed to induce cardiac hypertrophy, fibrosis, myocyte apoptosis and depressed cardiac function. In cultured adult feline ventricular myocytes (AFVMs), PKA inhibition protected myocytes from death induced by β1-AR agonists by preventing cytosolic and SR Ca2+ overload and CaMKII activation. PKA inhibition revealed a cardioprotective role of β-adrenergic signaling via cAMP/EPAC /Rap1/Rac/ERK pathway. Selective PKA inhibition causes protection in the heart after myocardial infarction (MI) that was superior to β-blocker therapy. Conclusion These results suggest that selective block of PKA could be a novel heart failure therapy. PMID:23104882

  12. Identification of the signals for glucose-induced insulin secretion in INS1 (832/13) β-cells using metformin-induced metabolic deceleration as a model.

    PubMed

    Lamontagne, Julien; Al-Mass, Anfal; Nolan, Christopher J; Corkey, Barbara E; Madiraju, S R Murthy; Joly, Erik; Prentki, Marc

    2017-11-24

    Metabolic deceleration in pancreatic β-cells is associated with inhibition of glucose-induced insulin secretion (GIIS), but only in the presence of intermediate/submaximal glucose concentrations. Here, we used acute metformin treatment as a tool to induce metabolic deceleration in INS1 (832/13) β-cells, with the goal of identifying key pathways and metabolites involved in GIIS. Metabolites and pathways previously implicated as signals for GIIS were measured in the cells at 2-25 mm glucose, with or without 5 mm metformin. We defined three criteria to identify candidate signals: 1) glucose-responsiveness, 2) sensitivity to metformin-induced inhibition of the glucose effect at intermediate glucose concentrations, and 3) alleviation of metformin inhibition by elevated glucose concentrations. Despite the lack of recovery from metformin-induced impairment of mitochondrial energy metabolism (glucose oxidation, O 2 consumption, and ATP production), insulin secretion was almost completely restored at elevated glucose concentrations. Meeting the criteria for candidates involved in promoting GIIS were the following metabolic indicators and metabolites: cytosolic NAD + /NADH ratio (inferred from the dihydroxyacetone phosphate:glycerol-3-phosphate ratio), mitochondrial membrane potential, ADP, Ca 2+ , 1-monoacylglycerol, diacylglycerol, malonyl-CoA, and HMG-CoA. On the contrary, most of the purine and nicotinamide nucleotides, acetoacetyl-CoA, H 2 O 2 , reduced glutathione, and 2-monoacylglycerol were not glucose-responsive. Overall these results underscore the significance of mitochondrial energy metabolism-independent signals in GIIS regulation; in particular, the candidate lipid signaling molecules 1-monoacylglycerol, diacylglycerol, and malonyl-CoA; the predominance of K ATP /Ca 2+ signaling control by low ADP·Mg 2+ rather than by high ATP levels; and a role for a more oxidized state (NAD + /NADH) in the cytosol during GIIS that favors high glycolysis rates. © 2017 by

  13. Synergistic interaction between metformin and sulfonylureas on diclofenac-induced antinociception measured using the formalin test in rats

    PubMed Central

    Ortiz, Mario I

    2013-01-01

    BACKGROUND There is evidence that biguanides and sulfonylureas block diclofenac-induced antinociception (DIA) in rat models. However, little is known about the interaction between these hypoglycemics with respect to DIA. OBJECTIVE: To determine whether metformin-sulfonylurea combinations affect DIA during the formalin test. METHODS: Rats received the appropriate vehicle or diclofenac before 1% formaldehyde was injected into the paw. Rats were also pretreated with vehicle, glibenclamide, glipizide, metformin or glibenclamide/metformin and glipizide/metformin combinations before the diclofenac and formaldehyde injections, and the effect on antinociception was assessed. Isobolograms of the combinations were constructed to test for a synergistic interaction. RESULTS: Systemic injection of diclofenac resulted in antinociception during the second phase of the test. Systemic pretreatment with the combinations of glibenclamide (0.56 mg/kg to 10 mg/kg)/metformin (10 mg/kg to 180 mg/kg) and glipizide (0.56 mg/kg to10 mg/kg)/metformin (10 mg/kg to 180 mg/kg) blocked DIA. The derived theoretical effective doses for 50% of subjects (ED50) for the glibenclamide/metformin and glipizide/metformin combinations were 32.52 mg/kg and 32.42 mg/kg, respectively, and were significantly higher than the actual observed experimental ED50 values (7.57 mg/kg and 8.43 mg/kg, respectively). CONCLUSION: Pretreatment with glibenclamide, glipizide or metformin blocked DIA in a dose-dependent manner, and combining either sulfonylurea with metformin produced even greater effects. The observed ED50s for the combinations were approximately fourfold lower than the calculated additive effects. These data indicate that sulfonylureas interact to produce antagonism of DIA. Combination therapy is a common second-line treatment for patients with diabetes and metabolic syndrome, a group that experiences pain from multiple sources. The results suggest that at least some anti-inflammatory agents may not be

  14. Metformin: Multi-faceted protection against cancer

    PubMed Central

    Cufí, Sílvia; Oliveras-Ferraros, Cristina; Bosch-Barrera, Joaquim; Joven, Jorge; Martin-Castillo, Begoña; Menendez, Javier A.

    2011-01-01

    The biguanide metformin, a widely used drug for the treatment of type 2 diabetes, may exert cancer chemopreventive effects by suppressing the transformative and hyperproliferative processes that initiate carcinogenesis. Metformin's molecular targets in cancer cells (e.g., mTOR, HER2) are similar to those currently being used for directed cancer therapy. However, metformin is nontoxic and might be extremely useful for enhancing treatment efficacy of mechanism-based and biologically targeted drugs. Here, we first revisit the epidemiological, preclinical, and clinical evidence from the last 5 years showing that metformin is a promising candidate for oncology therapeutics. Second, the anticancer effects of metformin by both direct (insulin-independent) and indirect (insulin-dependent) mechanisms are discussed in terms of metformin-targeted processes and the ontogenesis of cancer stem cells (CSC), including Epithelial-to-Mesenchymal Transition (EMT) and microRNAs-regulated dedifferentiation of CSCs. Finally, we present preliminary evidence that metformin may regulate cellular senescence, an innate safeguard against cellular immortalization. There are two main lines of evidence that suggest that metformin's primary target is the immortalizing step during tumorigenesis. First, metformin activates intracellular DNA damage response checkpoints. Second, metformin attenuates the anti-senescence effects of the ATP-generating glycolytic metabotype-the Warburg effect-, which is required for self-renewal and proliferation of CSCs. If metformin therapy presents an intrinsic barrier against tumorigenesis by lowering the threshold for stress-induced senescence, metformin therapeutic strategies may be pivotal for therapeutic intervention for cancer. Current and future clinical trials will elucidate whether metformin has the potential to be used in preventive and treatment settings as an adjuvant to current cancer therapeutics. PMID:22203527

  15. Cardioprotective potential of N-acetyl cysteine against hyperglycaemia-induced oxidative damage: a protocol for a systematic review.

    PubMed

    Dludla, Phiwayinkosi V; Nkambule, Bongani B; Dias, Stephanie C; Johnson, Rabia

    2017-05-12

    Hyperglycaemia-induced oxidative damage is a well-established factor implicated in the development of diabetic cardiomyopathy (DCM) in diabetic individuals. Some of the well-known characteristics of DCM include increased myocardial left ventricular wall thickness and remodelling that result in reduced cardiac efficiency. To prevent this, an increasing number of pharmacological compounds such as N-acetyl cysteine (NAC) are explored for their antioxidant properties. A few studies have shown that NAC can ameliorate hyperglycaemia-induced oxidative damage within the heart. Hence, the objective of this review is to synthesise the available evidence pertaining to the cardioprotective role of NAC against hyperglycaemia-induced oxidative damage and thus prevent DCM. This systematic review protocol will be reported in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) 2015 statement. We will perform a comprehensive search on major databases such as EMBASE, Cochrane Library, PubMed and Google scholar for original research articles published from January 1960 to March 2017. We will only report on literature that is available in English. Two authors will independently screen for eligible studies using pre-defined criteria, and data extraction will be done in duplicate. All discrepancies will be resolved by consensus or consultation of a third reviewer. The quality of studies will be checked using Cochrane Risk of Bias Assessment Tool and The Joanna Briggs Institute (JBI) Critical Appraisal tools for non-randomised experimental studies. Heterogeneity across studies will be assessed using the Cochrane Q statistic and the inconsistency index (I 2 ). We will use the random effects model to calculate a pooled estimate. Although several studies have shown that NAC can ameliorate hyperglycaemia-induced oxidative damage within the heart, this systematic review will be the first pre-registered synthesis of data to identify the

  16. Extended-Release Metformin Does Not Reduce the Clomiphene Citrate Dose Required to Induce Ovulation in Polycystic Ovary Syndrome

    PubMed Central

    Cataldo, Nicholas A.; Barnhart, Huiman X.; Legro, Richard S.; Myers, Evan R.; Schlaff, William D.; Carr, Bruce R.; Diamond, Michael P.; Carson, Sandra A.; Steinkampf, Michael P.; Coutifaris, Christos; McGovern, Peter G.; Gosman, Gabriella; Nestler, John E.; Giudice, Linda C.

    2008-01-01

    Context: When used for ovulation induction, higher doses of clomiphene may lead to antiestrogenic side effects that reduce fecundity. It has been suggested that metformin in combination with clomiphene can restore ovulation to some clomiphene-resistant anovulators with polycystic ovary syndrome (PCOS). Objective: Our objective was to determine if cotreatment with extended-release metformin (metformin XR) can lower the threshold dose of clomiphene needed to induce ovulation in women with PCOS. Design: A secondary analysis of data from the National Institute of Child Health and Human Development Cooperative Multicenter Reproductive Medicine Network prospective, double-blind, placebo-controlled multicenter clinical trial, Pregnancy in Polycystic Ovary Syndrome, was performed. Setting: Study volunteers at multiple academic medical centers were included. Participants: Women with PCOS and elevated serum testosterone who were randomized to clomiphene alone or with metformin (n = 209 in each group) were included in the study. Interventions: Clomiphene citrate, 50 mg daily for 5 d, was increased to 100 and 150 mg in subsequent cycles if ovulation was not achieved; half also received metformin XR, 1000 mg twice daily. Treatment was for up to 30 wk or six cycles, or until first pregnancy. Main Outcome Measures: Ovulation was confirmed by a serum progesterone more than or equal to 5 ng/ml, drawn prospectively every 1–2 wk. Results: The overall prevalence of at least one ovulation after clomiphene was 75 and 83% (P = 0.04) for the clomiphene-only and clomiphene plus metformin groups, respectively. Using available data from 314 ovulators, the frequency distribution of the lowest clomiphene dose (50, 100, or 150 mg daily) resulting in ovulation was indistinguishable between the two treatment groups. Conclusion: Metformin XR does not reduce the lowest dose of clomiphene that induces ovulation in women with PCOS. PMID:18505764

  17. Extended-release metformin does not reduce the clomiphene citrate dose required to induce ovulation in polycystic ovary syndrome.

    PubMed

    Cataldo, Nicholas A; Barnhart, Huiman X; Legro, Richard S; Myers, Evan R; Schlaff, William D; Carr, Bruce R; Diamond, Michael P; Carson, Sandra A; Steinkampf, Michael P; Coutifaris, Christos; McGovern, Peter G; Gosman, Gabriella; Nestler, John E; Giudice, Linda C

    2008-08-01

    When used for ovulation induction, higher doses of clomiphene may lead to antiestrogenic side effects that reduce fecundity. It has been suggested that metformin in combination with clomiphene can restore ovulation to some clomiphene-resistant anovulators with polycystic ovary syndrome (PCOS). Our objective was to determine if cotreatment with extended-release metformin (metformin XR) can lower the threshold dose of clomiphene needed to induce ovulation in women with PCOS. A secondary analysis of data from the National Institute of Child Health and Human Development Cooperative Multicenter Reproductive Medicine Network prospective, double-blind, placebo-controlled multicenter clinical trial, Pregnancy in Polycystic Ovary Syndrome, was performed. Study volunteers at multiple academic medical centers were included. Women with PCOS and elevated serum testosterone who were randomized to clomiphene alone or with metformin (n = 209 in each group) were included in the study. Clomiphene citrate, 50 mg daily for 5 d, was increased to 100 and 150 mg in subsequent cycles if ovulation was not achieved; half also received metformin XR, 1000 mg twice daily. Treatment was for up to 30 wk or six cycles, or until first pregnancy. Ovulation was confirmed by a serum progesterone more than or equal to 5 ng/ml, drawn prospectively every 1-2 wk. The overall prevalence of at least one ovulation after clomiphene was 75 and 83% (P = 0.04) for the clomiphene-only and clomiphene plus metformin groups, respectively. Using available data from 314 ovulators, the frequency distribution of the lowest clomiphene dose (50, 100, or 150 mg daily) resulting in ovulation was indistinguishable between the two treatment groups. Metformin XR does not reduce the lowest dose of clomiphene that induces ovulation in women with PCOS.

  18. Metformin-associated respiratory alkalosis.

    PubMed

    Bryant, Sean M; Cumpston, Kirk; Lipsky, Martin S; Patel, Nirali; Leikin, Jerrold B

    2004-01-01

    We present an 84-year-old man with a history of chronic obstructive pulmonary disease, type 2 diabetes, hypertension, glaucoma, and bladder cancer who presented to the emergency department after the police found him disoriented and confused. Metformin therapy began 3 days before, and he denied any overdose or suicidal ideation. Other daily medications included glipizide, fluticasone, prednisone, aspirin, furosemide, insulin, and potassium supplements. In the emergency department, his vital signs were significant for hypertension (168/90), tachycardia (120 bpm), and Kussmaul respirations at 24 breaths per minute. Oxygen saturation was 99% on room air, and a fingerstick glucose was 307 mg/dL. He was disoriented to time and answered questions slowly. Metformin was discontinued, and by day 3, the patient's vital signs and laboratory test results normalized. He has been asymptomatic at subsequent follow-up visits. Metformin-associated lactic acidosis is a well-known phenomenon. Respiratory alkalosis may be an early adverse event induced by metformin prior to the development of lactic acidosis.

  19. Does metformin augment the ovulation inducing effects of clomiphene in non-obese women with polycystic ovary syndrome?

    PubMed

    Chaudhury, Kalyansree; Chaudhury, Sudeshna; Chowdhury, Subhankar

    2008-10-01

    To decide if metformin augments clomiphene response for ovulation induction in non-obese women with polycystic ovary syndrome, a prospective randomised placebo-controlled trial was undertaken among 27 patients, who were found eligible for this study following clinical assessment and basic investigations. Women with polycystic ovary syndrome, even when non-obese, has increased insulin-resistance and do not respond favourably when treated with clomiphene for ovulation induction. The hypothesis is that by improving insulin- resistance and thus reversing from hyperinsulinaemia towards normal insulin secretion will enhance the responsiveness of these women to ovulation inducing effects of clomiphene. In the metformin group there were 15 patients who were given metformin 500mg orally 8 hourly daily for initial 3 months whereas in the placebo group there were 12 patients who were given folic acid (as placebo) 5mg orally once daily for initial 3 months. Thereafter, all the 27 patients in both groups were treated with clomiphene 50mg orally once daily from day 2 for 5 days in each month for subsequent 3 months. However, metformin and folic acid was continued in the metformin group and placebo group respectively for these subsequent 3 months when these patients were being treated with clomiphene for ovulation induction. Ovulation, as the outcome measure, was assessed by serial transvaginal ultrasound scanning from day 8/ day 9 and serum progesterone estimation on the 7th or 8th day following the ultrasound evidence of ovulation. Ovulation is taken to have occurred when serum progesterone was > or =8 ng/ml. Ovulation was noted to have occurred in 71.11% of the 45 cycles studied in 15 patients in the metformin group whereas ovulation occurred in 11.11% of the 36 cycles studied in 12 patients in the placebo group. This difference was highly statistically significant (p < 0.001) by Fisher's exact test. It can be conducted that metformin augments the ovulation inducing effects of

  20. Metformin Protects Neurons against Oxygen-Glucose Deprivation/Reoxygenation -Induced Injury by Down-Regulating MAD2B.

    PubMed

    Meng, Xianfang; Chu, Guangpin; Yang, Zhihua; Qiu, Ping; Hu, Yue; Chen, Xiaohe; Peng, Wenpeng; Ye, Chen; He, Fang-Fang; Zhang, Chun

    2016-01-01

    Metformin, the common medication for type II diabetes, has protective effects on cerebral ischemia. However, the molecular mechanisms are far from clear. Mitotic arrest deficient 2-like protein 2 (MAD2B), an inhibitor of the anaphase-promoting complex (APC), is widely expressed in hippocampal and cortical neurons and plays an important role in mediating high glucose-induced neurotoxicity. The present study investigated whether metformin modifies the expression of MAD2B and to exert its neuroprotective effects in primary cultured cortical neurons during oxygen-glucose deprivation/reoxygenation (OGD/R), a widely used in vitro model of ischemia/reperfusion. Primary cortical neurons were cultured, deprived of oxygen-glucose for 1 h, and then recovered with oxygen-glucose for 12 h and 24 h. Cell viability was measured by detecting the levels of lactate dehydrogenase (LDH) in culture medium. The levels of MAD2B, cyclin B and p-histone 3 were measured by Western blot. Cell viability of neurons was reduced under oxygen-glucose deprivation/reoxygenation (OGD/R). The expression of MAD2B was increased under OGD/R. The levels of cyclin B1, which is a substrate of APC, were also increased. Moreover, OGD/R up-regulated the phosphorylation levels of histone 3, which is the induction of aberrant re-entry of post-mitotic neurons. However, pretreatment of neurons with metformin alleviated OGD/R-induced injury. Metformin further decreased the expression of MAD2B, cyclin B1 and phosphorylation levels of histone 3. Metformin exerts its neuroprotective effect through regulating the expression of MAD2B in neurons under OGD/R. © 2016 The Author(s) Published by S. Karger AG, Basel.

  1. [Constitutional syndrome associated to metformin induced hepatotoxicity].

    PubMed

    de la Poza Gómez, Gema; Rivero Fernández, Miguel; Vázquez Romero, Manuel; Angueira Lapeña, Teresa; Arranz de la Mata, Gemma; Boixeda de Miquel, Daniel

    2008-12-01

    Metformin is an oral antidiabetic agent frequently used to manage type II diabetes. This drug produces nonspecific gastrointestinal symptoms in 5-20% of patients and, more rarely, has also been associated with severe adverse effects such as lactic acidosis. Only a few isolated cases of hepatotoxicity due to this drug have been documented. We report the case of an 83-year-old man with constitutional syndrome and hepatic biochemical alterations, which were attributed to metformin after ruling out an oncologic etiology and observing complete clinical and biochemical resolution after withdrawal of the drug.

  2. Exercise training prevents the attenuation of anesthetic pre-conditioning-mediated cardioprotection in diet-induced obese rats.

    PubMed

    Li, L; Meng, F; Li, N; Zhang, L; Wang, J; Wang, H; Li, D; Zhang, X; Dong, P; Chen, Y

    2015-01-01

    Obesity abolishes anesthetic pre-conditioning-induced cardioprotection due to impaired reactive oxygen species (ROS)-mediated adenosine monophosphate-activated protein kinase (AMPK) pathway, a consequence of increased basal myocardial oxidative stress. Exercise training has been shown to attenuate obesity-related oxidative stress. This study tests whether exercise training could normalize ROS-mediated AMPK pathway and prevent the attenuation of anesthetic pre-conditioning-induced cardioprotection in obesity. Male Sprague-Dawley rats were divided into lean rats fed with control diet and obese rats fed with high-fat diet. After 4 weeks of feeding, lean and obese rats were assigned to sedentary conditions or treadmill exercise for 8 weeks. There was no difference in infarct size between lean sedentary and obese sedentary rats after 25 min of myocardial ischemia followed by 120 min reperfusion. In lean rats, sevoflurane equally reduced infarct size in lean sedentary and lean exercise-trained rats. Molecular studies revealed that AMPK activity, endothelial nitric oxide synthase, and superoxide production measured at the end of ischemia in lean rats were increased in response to sevoflurane. In obese rats, sevoflurane increased the above molecular parameters and reduced infarct size in obese exercise-trained rats but not in obese sedentary rats. Additional study showed that obese exercise-trained rats had decreased basal oxidative stress than obese sedentary rats. The results indicate that exercise training can prevent the attenuation of anesthetic cardioprotection in obesity. Preventing the attenuation of this strategy may be associated with reduced basal oxidative stress and normalized ROS-mediated AMPK pathway, but the causal relationship remains to be determined. © 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

  3. Metformin and liraglutide ameliorate high glucose-induced oxidative stress via inhibition of PKC-NAD(P)H oxidase pathway in human aortic endothelial cells.

    PubMed

    Batchuluun, Battsetseg; Inoguchi, Toyoshi; Sonoda, Noriyuki; Sasaki, Shuji; Inoue, Tomoaki; Fujimura, Yoshinori; Miura, Daisuke; Takayanagi, Ryoichi

    2014-01-01

    Metformin and glucagon like peptide-1 (GLP-1) prevent diabetic cardiovascular complications and atherosclerosis. However, the direct effects on hyperglycemia-induced oxidative stress in endothelial cells are not fully understood. Thus, we aimed to evaluate the effects of metformin and a GLP-1 analog, liraglutide on high glucose-induced oxidative stress. Production of reactive oxygen species (ROS), activation of protein kinase C (PKC) and NAD(P)H oxidase, and changes in signaling molecules in response to high glucose exposure were evaluated in human aortic endothelial cells with and without treatment of metformin and liraglutide, alone or in combination. PKC-NAD(P)H oxidase pathway was assessed by translocation of GFP-fused PKCβ2 isoform and GFP-fused p47phox, a regulatory subunit of NAD(P)H oxidase, in addition to endogenous PKC phosphorylation and NAD(P)H oxidase activity. High glucose-induced ROS overproduction was blunted by metformin or liraglutide treatment, with a further decrease by a combination of these drugs. Exposure to high glucose caused PKCβ2 translocation and a time-dependent phosphorylation of endogenous PKC but failed to induce its translocation and phosphorylation in the cells treated with metformin and liraglutide. Furthermore, both drugs inhibited p47phox translocation and NAD(P)H oxidase activation, and prevented the high glucose-induced changes in intracellulalr diacylglycerol (DAG) level and phosphorylation of AMP-activated protein kinase (AMPK). A combination of these drugs further enhanced all of these effects. Metformin and liraglutide ameliorate high glucose-induced oxidative stress by inhibiting PKC-NAD(P)H oxidase pathway. A combination of these two drugs provides augmented protective effects, suggesting the clinical usefulness in prevention of diabetic vascular complications. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  4. Cardioprotective Effects of Malvidin Against Isoproterenol-Induced Myocardial Infarction in Rats: A Mechanistic Study

    PubMed Central

    Wei, Hui; Li, Hui; Wan, Shu-Ping; Zeng, Qiu-Tang; Cheng, Long-Xian; Jiang, Li-Li; Peng, Yu-Dong

    2017-01-01

    Background Malvidin (alvidin-3-glucoside) is a polyphenol that belongs to the class of natural anthocyanin, which is abundantly found in red wines, colored fruits, and the skin of red grapes. Therefore, the current investigation was intended to evaluate the effect of malvidin against myocardial infarction induced by isoproterenol in the rats. Material/Methods The cardioprotective effects was assessed by determining the effect of malvidin on the activities of endogenous antioxidants – catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH) – and on the levels of lipid peroxidation and serum marker enzymes. The serum levels of IL-6 and TNF-α were also determined using an enzyme-linked immunosorbent assay (ELISA) kit. Result The present study demonstrated a significant cardioprotective effect of malvidin by restoring the defensive activities of endogenous antioxidants – catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH) – and by reducing the levels of lipid peroxidation and serum marker enzymes lactate dehydrogenase (LD) and creatine kinase (CK). Malvidin significantly ameliorated the histopathological changes and impaired mitochondria in the cardiac necrosis stimulated with isoproterenol. Additionally, the results also demonstrated that nuclear translocation of Nrf-2 and subsequent HO-1 expression might be associated with nuclear factor kappa B (NF-κB) pathway activation. Conclusions Our findings suggest that malvidin exerts cardioprotective effects that might be due to possible strong antioxidant and anti-inflammatory activities. Therefore, this study provides the basis for the development of malvidin as a safe and effective treatment of myocardial infarction. PMID:28445445

  5. Metformin Inhibits Advanced Glycation End Products-Induced Inflammatory Response in Murine Macrophages Partly through AMPK Activation and RAGE/NFκB Pathway Suppression

    PubMed Central

    Zhou, Zhong'e; Tang, Yong; Chen, Chengjun; Lu, Yi; Liu, Liang

    2016-01-01

    Advanced glycation end products (AGEs) are major inflammatory mediators in diabetes, affecting atherosclerosis progression via macrophages. Metformin slows diabetic atherosclerosis progression through mechanisms that remain to be fully elucidated. The present study of murine bone marrow derived macrophages showed that (1) AGEs enhanced proinflammatory cytokines (interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α)) mRNA expression, RAGE expression, and NFκB activation; (2) metformin pretreatment inhibited AGEs effects and AGEs-induced cluster designation 86 (CD86) (M1 marker) expression, while promoting CD206 (M2 marker) surface expression and anti-inflammatory cytokine (IL-10) mRNA expression; and (3) the AMPK inhibitor, Compound C, attenuated metformin effects. In conclusion, metformin inhibits AGEs-induced inflammatory response in murine macrophages partly through AMPK activation and RAGE/NFκB pathway suppression. PMID:27761470

  6. Caffeine induces metformin anticancer effect on fibrosarcoma in hamsters.

    PubMed

    Popović, D J; Lalošević, D; Miljković, D; Popović, K J; Čapo, I; Popović, J K

    2018-04-01

    We investigated the effect of metformin and caffeine on fibrosarcoma in hamsters. 32 Syrian golden hamsters of both sexes, weighing approximately 100 g, were randomly allocated to 3 experimental and 2 control groups, with a minimum of 6 animals per group. 2 x 106 BHK-21/C13 cells in 1 ml were injected subcutaneously into the animals' back in 4 groups. The first experimental group started peroral treatment with metformin 500 mg/kg daily, the second with caffeine 100 mg/kg daily and the third with a combination of metformin 500 mg/kg and caffeine 100 mg/kg daily, via a gastric probe 3 days before tumor inoculation. After 2 weeks, when the tumors were approximately 2 cm in the control group, all animals were sacrificed. The blood was collected for glucose and other analyses. The tumors were excised and weighed and their diameters were measured. The tumor samples were pathohistologically (HE) and immunohistochemically (Ki-67, CD 31, COX IV, GLUT-1, iNOS) assessed and the main organs toxicologically analyzed, including the control animals that had received metformin and caffeine. Tumor volume was determined using the formula LxS2/2, where L was the longest and S the shortest diameter. Ki-67-positive cells in the tumor samples were quantified. Images were taken and processed by software UTHSCSA Image Tools for Windows Version 3.00. Statistical significances were determined by the Student's t-test. The combination of metformin and caffeine inhibited fibrosarcoma growth in hamsters without toxicity. Administration of metformin with caffeine might be an effective and safe approach in novel nontoxic adjuvant anticancer treatment.

  7. Metformin treatment modulates the tumour-induced wasting effects in muscle protein metabolism minimising the cachexia in tumour-bearing rats.

    PubMed

    Oliveira, André G; Gomes-Marcondes, Maria Cristina C

    2016-07-07

    Cancer-cachexia state frequently induces both fat and protein wasting, leading to death. In this way, the knowledge of the mechanism of drugs and their side effects can be a new feature to treat and to have success, contributing to a better life quality for these patients. Metformin is an oral drug used in type 2 diabetes mellitus, showing inhibitory effect on proliferation in some neoplastic cells. For this reason, we evaluated its modulatory effect on Walker-256 tumour evolution and also on protein metabolism in gastrocnemius muscle and body composition. Wistar rats received or not tumour implant and metformin treatment and were distributed into four groups, as followed: control (C), Walker 256 tumour-bearing (W), metformin-treated (M) and tumour-bearing treated with metformin (WM). Animals were weighed three times a week, and after cachexia state has been detected, the rats were euthanised and muscle and tumour excised and analysed by biochemical and molecular assays. Tumour growth promoted some deleterious effects on chemical body composition, increasing water and decreasing fat percentage, and reducing lean body mass. In muscle tissue, tumour led to a decreased protein synthesis and an increased proteolysis, showing the higher activity of the ubiquitin-proteasome pathway. On the other hand, the metformin treatment likely minimised the tumour-induced wasting state; in this way, this treatment ameliorated chemical body composition, reduced the higher activities of proteolytic enzymes and decreased the protein waste. Metformin treatment not only decreases the tumour growth but also improves the protein metabolism in gastrocnemius muscle in tumour-bearing rats.

  8. Oral metformin-ascorbic acid co-administration ameliorates alcohol-induced hepatotoxicity in rats.

    PubMed

    Adeneye, A A; Benebo, A S

    2007-01-01

    Alcoholic liver disease remains a major cause of liver failure worldwide with no available curative or prophylactic therapy as at present. High dose metformin is reported to ameliorate liver injuries in both human and animal models of acute and chronic alcoholic liver injuries. The aim of the present in vivo animal study was to determine whether metformin-ascorbic acid co-administration also prevents alcoholic hepatotoxicity in chronic alcohol exposure. In the present study, ameliorating effect of 200 mg/ kg/day of ascorbic acid (Asc), 500 mg/kg/day of metformin (Met) and their co-administration (Met-Asc) were investigated in 5 groups of 50% ethanol-treated male Wistar rats for 2 weeks of the experiment. The body weight of each rat was taken on days 1, 7, and 14 of the experiment, respectively. On day 15, fasted blood samples for plasma lipids and liver enzyme markers were collected via cardiac puncture from the rats under diethyl ether anaesthesia. Results showed that administration of graded oral doses of 50% ethanol for 14 days significantly (p<0.001) elevated the plasma liver enzymes--aspartate aminotransferase (AST), alanine aminotansferase (ALT) and alkaline phosphatase (ALP). Two weeks of ethanol treatment also induced alterations in the plasma triglycerides (PTG), total cholesterol (PTC), high density lipoprotein (HDL-c), and low density lipoprotein (LDL-c). However, these elevations were significantly (p<0.05) attenuated by Asc, Met, and Met-Asc after 14 days of oral treatment, with Met-Asc having higher significant (p<0.001) ameliorating effect than Asc alone but with comparative effect to that of Met alone. High dose metformin-ascorbic acid co-administration protected the liver against the deleterious effects of chronic high dose alcohol and the hepatoprotective effect of Met-Asc appeared to be due mainly to the metformin molecule of the drug combination. However, further studies would be required to evaluate the mechanisms underlying the observed

  9. Drug-induced bullous pemphigoid in diabetes mellitus patients receiving dipeptidyl peptidase-IV inhibitors plus metformin.

    PubMed

    Skandalis, K; Spirova, M; Gaitanis, G; Tsartsarakis, A; Bassukas, I D

    2012-02-01

    Preclinical data and reports of adverse skin reactions in patients treated with dipeptidyl peptidase-IV inhibitors (gliptins) have increased awareness towards skin-targeting side-effects of these anti-hyperglycaemic drugs. Bullous pemphigoid (BP), sometimes drug-induced, is the most commonly acquired autoimmune blistering dermatosis in western countries, typically a disease of the elderly people with significant morbidity and excess mortality. To report the development of BP in five diabetics under gliptin (4 vildagliptin, 1 sitagliptin) plus metformin in fixed-dose drug combinations. From March to August 2010 six out of nine newly diagnosed BP patients in our Department were type 2 diabetics. Five of them were on gliptin plus metformin (three different trade preparations) for 2-13 months prior to BP onset. In all cases BP was controlled after withdrawal of the suspected medication and relatively mild therapeutic interventions. In two cases the eliciting role of the preceding treatment is supported by evidence at the level 'probable/likely' according to the WHO-UMC algorithm. This is the first report of drug-induced BP as a group adverse event of the gliptins plus metformin combination therapy for glycaemia control in type 2 diabetes mellitus patients. © 2011 The Authors. Journal of the European Academy of Dermatology and Venereology © 2011 European Academy of Dermatology and Venereology.

  10. Cardioprotective activity of flax lignan concentrate extracted from seeds of Linum usitatissimum in isoprenalin induced myocardial necrosis in rats

    PubMed Central

    Zanwar, Anand A.; Hegde, Mahabaleshwar V.; Bodhankar, Subhash L.

    2011-01-01

    The objective of the study was to evaluate the cardioprotective activity of flax lignan concentrate (FLC) in isoprenalin (ISO) induced cardiotoxicity in rats. Male Wistar rats (200–230 g) were divided into three groups. Group I: control, Group II: isoprenalin, Group III: FLC (500 mg/kg, p.o.) orally for 8 days and in group II and III isoprenalin 5.25 mg/kg, s.c. on day 9 and 8.5 mg/kg on day 10. On day 10 estimation of marker enzymes in serum and haemodynamic parameters were recorded. Animals were sacrificed, histology of heart was performed. Isoprenalin showed cardiotoxicity, manifested by increased levels of marker enzymes and increased heart rate. FLC treatment reversed these biochemical changes significantly compared with ISO group. The cardiotoxic effect of isoprenalin was less in FLC pretreated animals, which was confirmed in histopathological alterations. Haemodynamic, biochemical alteration and histopathological results suggest a cardioprotective protective effect of FLC in isoprenalin induced cardiotoxicity. PMID:21753905

  11. Brief Report: Metformin for Antipsychotic-Induced Weight Gain in Youth with Autism Spectrum Disorder

    ERIC Educational Resources Information Center

    Wink, Logan K.; Adams, Ryan; Pedapati, Ernest V.; Dominick, Kelli C.; Fox, Emma; Buck, Catherine; Erickson, Craig A.

    2017-01-01

    Antipsychotic treatment in youth with autism spectrum disorder (ASD) is becoming increasingly common, placing individuals at risk for antipsychotic-induced weight gain and associated complications. Metformin hydrochloride, a biguanide medication FDA-approved for treatment of type-2 diabetes in youth, may hold promise for treatment of…

  12. Mitophagy is required for acute cardioprotection by simvastatin.

    PubMed

    Andres, Allen M; Hernandez, Genaro; Lee, Pamela; Huang, Chengqun; Ratliff, Eric P; Sin, Jon; Thornton, Christine A; Damasco, Marichris V; Gottlieb, Roberta A

    2014-11-10

    We have shown that autophagy and mitophagy are required for preconditioning. While statin's cardioprotective effects are well known, the role of autophagy/mitophagy in statin-mediated cardioprotection is not. In this study, we used HL-1 cardiomyocytes and mice subjected to ischemia/reperfusion to elucidate the mechanism of statin-mediated cardioprotection. HL-1 cardiomyocytes exposed to simvastatin for 24 h exhibited diminished protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling, increased activation of unc-51-like kinase 1, and upregulation of autophagy and mitophagy. Similar findings were obtained in hearts of mice given simvastatin. Mevalonate abolished simvastatin's effects on Akt/mTOR signaling and autophagy induction in HL-1 cells, indicating that the effects are mediated through inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Simvastatin-treated HL-1 cells exhibited mitochondrial translocation of Parkin and p62/SQSTM1, fission, and mitophagy. Because Parkin is required for mitophagy and is expressed in heart, we investigated the effect of simvastatin on infarct size in Parkin knockout mice. Simvastatin reduced infarct size in wild-type mice but showed no benefit in Parkin knockout mice. Inhibition of HMG-CoA reductase limits mevalonate availability for both cholesterol and coenzyme Q10 (CoQ) biosynthesis. CoQ supplementation had no effect on statin-induced Akt/mTOR dephosphorylation or macroautophagy in HL-1 cells, but it potently blocked mitophagy. Importantly, CoQ supplementation abolished statin-mediated cardioprotection in vivo. Acute simvastatin treatment suppresses mTOR signaling and triggers Parkin-dependent mitophagy, the latter which is required for cardioprotection. Coadministration of CoQ with simvastatin impairs mitophagy and cardioprotection. These results raise the concern that CoQ may interfere with anti-ischemic benefits of statins mediated through stimulation of mitophagy.

  13. Mitophagy Is Required for Acute Cardioprotection by Simvastatin

    PubMed Central

    Andres, Allen M.; Hernandez, Genaro; Lee, Pamela; Huang, Chengqun; Ratliff, Eric P.; Sin, Jon; Thornton, Christine A.; Damasco, Marichris V.

    2014-01-01

    Abstract Aims: We have shown that autophagy and mitophagy are required for preconditioning. While statin's cardioprotective effects are well known, the role of autophagy/mitophagy in statin-mediated cardioprotection is not. In this study, we used HL-1 cardiomyocytes and mice subjected to ischemia/reperfusion to elucidate the mechanism of statin-mediated cardioprotection. Results: HL-1 cardiomyocytes exposed to simvastatin for 24 h exhibited diminished protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling, increased activation of unc-51-like kinase 1, and upregulation of autophagy and mitophagy. Similar findings were obtained in hearts of mice given simvastatin. Mevalonate abolished simvastatin's effects on Akt/mTOR signaling and autophagy induction in HL-1 cells, indicating that the effects are mediated through inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Simvastatin-treated HL-1 cells exhibited mitochondrial translocation of Parkin and p62/SQSTM1, fission, and mitophagy. Because Parkin is required for mitophagy and is expressed in heart, we investigated the effect of simvastatin on infarct size in Parkin knockout mice. Simvastatin reduced infarct size in wild-type mice but showed no benefit in Parkin knockout mice. Inhibition of HMG-CoA reductase limits mevalonate availability for both cholesterol and coenzyme Q10 (CoQ) biosynthesis. CoQ supplementation had no effect on statin-induced Akt/mTOR dephosphorylation or macroautophagy in HL-1 cells, but it potently blocked mitophagy. Importantly, CoQ supplementation abolished statin-mediated cardioprotection in vivo. Innovation and Conclusion: Acute simvastatin treatment suppresses mTOR signaling and triggers Parkin-dependent mitophagy, the latter which is required for cardioprotection. Coadministration of CoQ with simvastatin impairs mitophagy and cardioprotection. These results raise the concern that CoQ may interfere with anti-ischemic benefits of statins mediated through

  14. Cardioprotective effect of saffron extract and safranal in isoproterenol-induced myocardial infarction in wistar rats.

    PubMed

    Mehdizadeh, Roya; Parizadeh, Mohammad-Reza; Khooei, Ali-Reza; Mehri, Soghra; Hosseinzadeh, Hossein

    2013-01-01

    This study was designed to evaluate the cardioprotective effect of Crocus sativus L. (saffron) aqueous extract and safranal, the major constituent of the essential oil of saffron, on lipid peroxidation, biochemical parameters and histopathological findings in isoproterenol (ISO)-induced myocardial infarction in Wistar rats. The saffron extract (20, 40, 80 and 160 mg/kg/day IP) or control were administered for 9 days along with ISO (85 mg/kg, SC, at 24 hr interval) on 8th and 9th day in rats. Activities of creatine kinase-muscle, brain (CK-MB) and lactate dehydrogenase (LDH) were measured using standard commercial kits. The level of malondialdehyde in heart tissue was estimated with thiobarbituric acid reactive species test. For histopathological examination, hematoxylin and eosin (H&E) staining was used. ISO administration induced a statistically significant increase (P< 0.001) in serum LDH and CK-MB and a significant increase (P< 0.001) in the levels of thiobarbituric acid reactive substances (TBARs) in the heart as compared to vehicle control rats. Saffron pretreatment (20, 40, 80 and 160 mg/kg IP) or safranal pretreatment (0.025, 0.050, 0.075 ml/kg IP) for 8 days, significantly decreased (P< 0.001) the serum LDH and CK-MB and myocardial lipid peroxidation as compared to ISO- induced rats. Histological findings of the heart sections confirmed myocardial injury with ISO administration and preserved nearly normal tissue architecture with saffron or safranal pretreatment. Saffron and safranal may have cardioprotective effect in ISO-induced myocardial infarction through modulation of oxidative stress in such a way that they maintain the redox status of the cell.

  15. Hyperglycaemia-induced resistance to Docetaxel is negated by metformin: a role for IGFBP-2.

    PubMed

    Biernacka, K M; Persad, R A; Bahl, A; Gillatt, D; Holly, J M P; Perks, C M

    2017-01-01

    The incidence of many common cancers varies between different populations and appears to be affected by a Western lifestyle. Highly proliferative malignant cells require sufficient levels of nutrients for their anabolic activity. Therefore, targeting genes and pathways involved in metabolic pathways could yield future therapeutics. A common pathway implicated in energetic and nutritional requirements of a cell is the LKB1/AMPK pathway. Metformin is a widely studied anti-diabetic drug, which improves glycaemia in patients with type 2 diabetes by targeting this pathway. We investigated the effect of metformin on prostate cancer cell lines and evaluated its mechanism of action using DU145, LNCaP, PC3 and VCaP prostate cancer cell lines. Trypan blue dye-exclusion assay was used to assess levels of cell death. Western immunoblotting was used to determine the abundance of proteins. Insulin-like growth factor-binding protein-2 (IGFBP-2) and AMPK genes were silenced using siRNA. Effects on cell morphology were visualised using microscopy. IGFBP-2 gene expression was assessed using real-time RT-PCR. With DU145 and LNCaP cells metformin alone induced cell death, but this was reduced in hyperglycaemic conditions. Hyperglycaemia also reduced the sensitivity to Docetaxel, but this was countered by co-treatment with metformin. LKB1 was required for the activation of AMPK but was not essential to mediate the induction of cell death. An alternative pathway by which metformin exerted its action was through downregulation of IGFBP-2 in DU145 and LNCaP cells, independently of AMPK. This finding could have important implications in relation to therapeutic strategies in prostate cancer patients presenting with diabetes. © 2017 The authors.

  16. Metformin inhibits TGF-β1-induced epithelial-to-mesenchymal transition-like process and stem-like properties in GBM via AKT/mTOR/ZEB1 pathway.

    PubMed

    Song, Yang; Chen, Yong; Li, Yunqian; Lyu, Xiaoyan; Cui, Jiayue; Cheng, Ye; Zhao, Liyan; Zhao, Gang

    2018-01-23

    Glioblastoma (GBM) is the most frequent and aggressive brain tumor in adults. In spite of advances in diagnosis and therapy, the prognosis is still relatively poor. The invasive property of GBM is the major cause of death in patients. Epithelial-to-mesenchymal transition-like process (EMT-like process) is considered to play an important role in the invasive property. Metformin has been reported as a regulator of EMT-like process. In this study, we confirmed that metformin inhibited TGF-β1-induced EMT-like process and EMT-associated migration and invasion in LN18 and U87 GBM cells. Our results also showed that metformin significantly suppressed self-renewal capacity of glioblastoma stem cells (GSCs), and expression of stem cell markers Bmi1, Sox2 and Musashi1, indicating that metformin can inhibit cancer stem-like properties of GBM cells. We further clarified that metformin specifically inhibited TGF-β1 activated AKT, the downstream molecular mTOR and the leading transcription factor ZEB1. Taken together, our data demonstrate that metformin inhibits TGF-β1-induced EMT-like process and cancer stem-like properties in GBM cells via AKT/mTOR/ZEB1 pathway and provide evidence of metformin for further clinical investigation targeted GBM.

  17. Role of angiopoietin-2 in the cardioprotective effect of fibroblast growth factor 21 on ischemia/reperfusion-induced injury in H9c2 cardiomyocytes

    PubMed Central

    Hu, Shuoqiang; Cao, Shujun; Liu, Jinghua

    2017-01-01

    Fibroblast growth factor 21 (FGF21) exerts a protective effect in ischemia/reperfusion (I/R)-induced cardiac injury. However, the exact molecular mechanism underlying the FGF21 action remains unclear. The present study aimed to evaluate the role of angiopoietin-2 (Angpt2) in the cardioprotective effect of FGF21. For this purpose, the H9C2 cell line was subjected to simulated I/R or aerobic conditions with or without FGF21 administration. Certain groups were also transfected with Angpt2 small interfering RNA (siRNA). Cell viability, apoptosis rate and cell migration were examined, and the expression levels of Angpt2, glucose transporter 1 (GLUT1) and caspase-3 were measured by quantitative polymerase chain reaction (qPCR) and western blot analyses. The results demonstrated that FGF21 administration suppressed apoptosis and increased the cell migration ability following I/R-induced injury. qPCR and western blot data showed a decreased level of GLUT1 after I/R-induced injury, which was reversed by FGF21 administration. Furthermore, inhibition of Angpt2 expression using siRNA enhanced the cardioprotective effect of FGF21 by upregulation of GLUT1. In conclusion, FGF21 administration protected against I/R-induced injury in cardiomyocytes, and further inhibition of Angpt2 with FGF21 administration induced the expression of GLUT1, which may promote the energy metabolism in cardiomyocytes, consequently resulting in a more efficient cardioprotective effect. These results suggested that FGF21 administration and inhibition of Angpt2 could be a novel therapeutic approach for I/R-induced cardiac injury. PMID:28672998

  18. Effect of N-benzoyl-D-phenylalanine and metformin on insulin receptors in neonatal streptozotocin-induced diabetic rats: studies on insulin binding to erythrocytes.

    PubMed

    Ashokkumar, N; Pari, L; Rao, Ch Appa

    2006-07-01

    In the present study, we focused on the insulin-receptor binding in circulating erythrocytes of N-benzoyl-D-phenylalanine (NBDP) and metformin in neonatal streptozotocin (nSTZ)-induced male Wistar rats. We measured blood levels of glucose and plasma insulin and the binding of insulin to cell-membrane ER receptors in NBDP and metformin-treated diabetic rats. The mean specific binding of insulin to ER was significantly lower in diabetic control rats (DC) (53.0 +/- 3.1%) than in NBDP (62.0 +/- 3.1%), metformin (66.0 +/- 3.3%) and NBDP and metformin combination-treated (72.0 +/- 4.2%) diabetic rats, resulting in a significant decrease in plasma insulin. Scatchard plot analysis demonstrated that the decrease in insulin binding was accounted for by a lower number of insulin receptor sites per cell in DC rats when compared with NBDP and metformin-treated rats. High-affinity (Kd1), low-affinity (Kd2), and kinetic analysis revealed an increase in the average receptor affinity in ER from NBDP and metformin-treated diabetic rats having NBDP 2.0 +/- 0.10 x 10(-10) M(-1) (Kd1); 12.0 +/- 0.85 x 10(-8) M(-1) (Kd2), Metformin 2.1 +/- 0.15 x 10(-10) M(-1) (Kd1); 15.0 +/- 0.80 x 10(-8) M(-1) (Kd2), NBDP and metformin 2.7 +/- 0.10 x 10(-10) M(-1) (Kd1); 20.0 +/- 1.2 x 10(-8) M(-1) (Kd2) compared with 0.9 +/- 0.06 x 10(-10) M(-1) (Kd1); 6.0 +/- 0.30 x 10(-8) M(-1) (Kd2) in DC rats. The results suggest an acute alteration in the number of insulin receptors on ER membranes in nSTZ induced diabetic control rats. Treatment with NBDP along with metformin significantly improved specific insulin binding, with receptor number and affinity binding reaching almost normal non-diabetic levels. The data presented here show that NBDP along with metformin increase total ER membrane insulin binding sites with a concomitant significant increase in plasma insulin.

  19. Metformin effects on clomifene-induced ovulation in the polycystic ovary syndrome.

    PubMed

    Ben Ayed, B; Dammak dit Mlik, S; Ben Arab, H; Trabelssi, H; Chahtour, H; Mathlouthi, N; Dhuib, M; Kassis, M; Saiidane, D; Trabelssi, K; Guermazi, M

    2009-01-01

    Polycystic ovary syndrome (PCOS) is a common, complex endocrine disorder for women on reproductive age. A high incidence of ovulation failure is observed in PCO women and perhaps linked to insulin resistance related to metabolic features In the last few years some studies assessed hyperinsulinimea and insulin resistance attenuation effects, by insulin sensitizing agents such as metformin, in PCOS women suggesting potential scope for these drugs in CC ovulation induction quality improvement. Our prospective study aim is to compare the effectiveness of clomifene citrate plus metformin and clomifene citrate plus placebo in women with newly diagnosed polycystic ovary syndrome. From February 24 to September 29 (2007), PCOS was explored on women attending the Department of Obstetrics & Gynaecology sterility consultation unit (CHU Hedi Chaker-Sfax) according to the Rotterdam 2003 diagnostic criteria. PCOS patients were randomized to receive, in addition to clomifene citrate treatment, placebo or metformin 850 mg two times a day all ovulatory cycle for three trials maximum. Ovulation detection was done by the E2 serum measurements and ovarian transvaginal ultrasonography' evolution controlling on 7th, 11th and 13th day of the cycle. Within 7 months, 32 PCOS women were recruited in the study and equally allocated to the two groups. Baseline characteristics were similar in metformin group and placebo one. Ovulation was characterized by the presence of at least one mature follicle (> 16 mm), a circulating estradiol concentration in the edge of 150-250 pg and accessory an endometrial depth > 8 mm. The ovulation rate in the metformin group was 62.5% compared with 37.5% in the placebo group, a non-statistically significant (small study population) but important difference (1.66 times). Analyses show a higher mature follicle number and estradiol concentration in metformin group than in the placebo one. Metformin effect was, in our study, his only insulinosensitizer property

  20. Early treatment with metformin induces resistance against tumor growth in adult rats

    PubMed Central

    Trombini, Amanda B; Franco, Claudinéia CS; Miranda, Rosiane A; de Oliveira, Júlio C; Barella, Luiz F; Prates, Kelly V; de Souza, Aline A; Pavanello, Audrei; Malta, Ananda; Almeida, Douglas L; Tófolo, Laize P; Rigo, Kesia P; Ribeiro, Tatiane AS; Fabricio, Gabriel S; de Sant’Anna, Juliane R; Castro-Prado, Marialba AA; de Souza, Helenir Medri; de Morais, Hely; Mathias, Paulo CF

    2015-01-01

    It is known that antidiabetic drug metformin, which is used worldwide, has anti-cancer effects and can be used to prevent cancer growth. We tested the hypothesis that tumor cell growth can be inhibited by early treatment with metformin. For this purpose, adult rats chronically treated with metformin in adolescence or in adulthood were inoculated with Walker 256 carcinoma cells. Adult rats that were treated with metformin during adolescence presented inhibition of tumor growth, and animals that were treated during adult life did not demonstrate any changes in tumor growth. Although we do not have data to disclose a molecular mechanism to the preventive metformin effect, we present, for the first time, results showing that cancer growth in adult life is dependent on early life intervention, thus supporting a new therapeutic prevention for cancer. PMID:26024008

  1. Experimental evidence for the cardioprotective effects of red wine

    PubMed Central

    Das, Samarjit; Santani, Dev D; Dhalla, Naranjan S

    2007-01-01

    Both epidemiological and experimental studies have revealed that intake of wine, particularly red wine, in moderation protects cardiovascular health; however, the experimental basis for such an action is not fully understood. Because all types of red wine contain varying amounts of alcohol and antioxidants, it is likely that the cardioprotective effect of red wine is due to both these constituents. In view of its direct action on the vascular smooth muscle cells, alcohol may produce coronary vasodilation in addition to attenuating oxidative stress by its action on the central nervous system. The antioxidant components of red wine may provide cardioprotection by their ability to reduce oxidative stress in the heart under different pathological conditions. Mild-to-moderate red wine consumption improves cardiac function in the ischemic myocardium through the protection of endothelial function, the expression of several cardioprotective oxidative stress-inducible proteins, as well as the activation of adenosine receptors and nitrous oxide synthase mechanisms. PMID:18650973

  2. Experimental evidence for the cardioprotective effects of red wine.

    PubMed

    Das, Samarjit; Santani, Dev D; Dhalla, Naranjan S

    2007-01-01

    Both epidemiological and experimental studies have revealed that intake of wine, particularly red wine, in moderation protects cardiovascular health; however, the experimental basis for such an action is not fully understood. Because all types of red wine contain varying amounts of alcohol and antioxidants, it is likely that the cardioprotective effect of red wine is due to both these constituents. In view of its direct action on the vascular smooth muscle cells, alcohol may produce coronary vasodilation in addition to attenuating oxidative stress by its action on the central nervous system. The antioxidant components of red wine may provide cardioprotection by their ability to reduce oxidative stress in the heart under different pathological conditions. Mild-to-moderate red wine consumption improves cardiac function in the ischemic myocardium through the protection of endothelial function, the expression of several cardioprotective oxidative stress-inducible proteins, as well as the activation of adenosine receptors and nitrous oxide synthase mechanisms.

  3. Metformin promotes focal angiogenesis and neurogenesis in mice following middle cerebral artery occlusion.

    PubMed

    Liu, Yanqun; Tang, Guanghui; Zhang, Zhijun; Wang, Yongting; Yang, Guo-Yuan

    2014-09-05

    Current studies demonstrated that metformin is not only a hypoglycemic drug, but also a neuro-protective agent. However, the effect of metformin during ischemic brain injury is unclear. The aim of the present study is to explore the effect of metformin during ischemic brain injury. Adult male CD1 mice underwent 90min transient middle cerebral artery occlusion. Metformin (200mg/kg) was given at the time of reperfusion daily until sacrifice. Results showed that metformin treatment significantly reduced ischemia-induced brain atrophy volume compared to the control (p<0.05). Immunostaining results showed that the microvessel density in the peri-focal region of metformin treated mice was greatly increased compared to the control (p<0.05). Similarly, the numbers of BrdU+/DCX+ and nestin+ cells in the subventricular zone were increased in metformin treated mice compared to the control (p<0.05). Furthermore, we demonstrated that metformin treatment activated AMPK signaling pathway and promoted eNOS phosphorylation. Thus, we concluded that metformin promoted focal angiogenesis and neurogenesis and attenuated ischemia-induced brain injury in mice after middle cerebral artery occlusion, suggesting that metformin is a potential new drug for ischemic stroke therapy. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  4. Consecutive pharmacological activation of PKA and PKC mimics the potent cardioprotection of temperature preconditioning

    PubMed Central

    Khaliulin, Igor; Parker, Joanna E.; Halestrap, Andrew P.

    2010-01-01

    Aims Temperature preconditioning (TP) provides very powerful protection against ischaemia/reperfusion. Understanding the signalling pathways involved may enable the development of effective pharmacological cardioprotection. We investigated the interrelationship between activation of protein kinase A (PKA) and protein kinase C (PKC) in the signalling mechanisms of TP and developed a potent pharmacological intervention based on this mechanism. Methods and results Isolated rat hearts were subjected to TP, 30 min global ischaemia, and 60 min reperfusion. Other control and TP hearts were perfused with either sotalol (β-adrenergic blocker) or H-89 (PKA inhibitor). Some hearts were pre-treated with either isoproterenol (β-adrenergic agonist) or adenosine (PKC activator) that were given alone, simultaneously, or sequentially. Pre-treatment with isoproterenol, adenosine, and the consecutive isoproterenol/adenosine treatment was also combined with the PKC inhibitor chelerythrine. Cardioprotection was evaluated by haemodynamic function recovery, lactate dehydrogenase release, measurement of mitochondrial permeability transition pore opening, and protein carbonylation during reperfusion. Cyclic AMP and PKA activity were increased in TP hearts. H-89 and sotalol blocked the cardioprotective effect of TP and TP-induced PKC activation. Isoproterenol, adenosine, and the consecutive treatment increased PKC activity during pre-ischaemia. Isoproterenol significantly reduced myocardial glycogen content. Isoproterenol and adenosine, alone or simultaneously, protected hearts but the consecutive treatment gave the highest protection. Cardioprotective effects of adenosine were completely blocked by chelerythrine but those of the consecutive treatment only attenuated. Conclusion The signal transduction pathway of TP involves PKA activation that precedes PKC activation. Pharmacologically induced consecutive PKA/PKC activation mimics TP and induces extremely potent cardioprotection. PMID

  5. mTORC1 inhibitors rapamycin and metformin affect cardiovascular markers differentially in ZDF rats.

    PubMed

    Nistala, Ravi; Raja, Ahmad; Pulakat, Lakshmi

    2017-03-01

    Mammalian target for rapamycin complex 1 (mTORC1) is a common target for the action of immunosuppressant macrolide rapamycin and glucose-lowering metformin. Inhibition of mTORC1 can exert both beneficial and detrimental effects in different pathologies. Here, we investigated the differential effects of rapamycin (1.2 mg/kg per day delivered subcutaneously for 6 weeks) and metformin (300 mg/kg per day delivered orally for 11 weeks) treatments on male Zucker diabetic fatty (ZDF) rats that mimic the cardiorenal pathology of type 2 diabetic patients and progress to insulin insufficiency. Rapamycin and metformin improved proteinuria, and rapamycin also reduced urinary gamma glutamyl transferase (GGT) indicating improvement of tubular health. Metformin reduced food and water intake, and urinary sodium and potassium, whereas rapamycin increased urinary sodium. Metformin reduced plasma alkaline phosphatase, but induced transaminitis as evidenced by significant increases in plasma AST and ALT. Metformin also induced hyperinsulinemia, but did not suppress fasting plasma glucose after ZDF rats reached 17 weeks of age, and worsened lipid profile. Rapamycin also induced mild transaminitis. Additionally, both rapamycin and metformin increased plasma uric acid and creatinine, biomarkers for cardiovascular and renal disease. These observations define how rapamycin and metformin differentially modulate metabolic profiles that regulate cardiorenal pathology in conditions of severe type 2 diabetes.

  6. Piracetam Facilitates the Anti-Amnesic but not Anti-Diabetic Activity of Metformin in Experimentally Induced Type-2 Diabetic Encephalopathic Rats.

    PubMed

    Pandey, Shruti; Garabadu, Debapriya

    2017-07-01

    Piracetam exhibits anti-amnesic activity in several animal models of dementia. However, its anti-amnesic potential has yet to be evaluated in type-2 diabetes mellitus (T2DM)-induced encephalopathy. Therefore, in the present study, piracetam (25, 50 and 100 mg/kg) was screened for anti-amnesic and anti-diabetic activity in T2DM-induced encephalopathic male rats. Subsequently, anti-amnesic and anti-diabetic activities were evaluated for piracetam, metformin and their combination in T2DM-induced encephalopathic animals. Rats received streptozotocin (45 mg/kg) and nicotinamide (110 mg/kg) injections on day-1 (D-1) of the experimental schedule and were kept undisturbed for 35 days to exhibit T2DM-induced encephalopathy. All drug treatments were continued from D-7 to D-35 in both experiments. Piracetam (100 mg/kg) attenuated loss in learning and memory in terms of increase in escape latency on D-4 (D-34) and decrease in time spent in the target quadrant on D-5 (D-35) of Morris water maze test protocol, and spatial memory in terms of reduced spontaneous alternation behavior in Y-maze test of encephalopathic rats. Additionally, piracetam attenuated altered levels of fasting plasma glucose and insulin, HOMA-IR and HOMA-B in encephalopathic animals, comparatively lesser than metformin. In the next experiment, combination of piracetam and metformin exhibited better anti-amnesic but not anti-diabetic activity than respective monotherapies in encephalopathic rats. Further, the combination attenuated reduced acetylcholine level and increased acetylcholinesterase activity, increased glycogen synthase kinase-3β level and decreased brain-derived neurotropic factor level in hippocampus and pre-frontal cortex of encephalopathic animals. Thus, piracetam could be used as an adjuvant to metformin in the management of dementia in T2DM-induced encephalopathy.

  7. Metformin sensitizes triple-negative breast cancer to proapoptotic TRAIL receptor agonists by suppressing XIAP expression.

    PubMed

    Strekalova, Elena; Malin, Dmitry; Rajanala, Harisha; Cryns, Vincent L

    2017-06-01

    Despite robust antitumor activity in diverse preclinical models, TNF-related apoptosis-inducing ligand (TRAIL) receptor agonists have not demonstrated efficacy in clinical trials, underscoring the need to identify agents that enhance their activity. We postulated that the metabolic stress induced by the diabetes drug metformin would sensitize breast cancer cells to TRAIL receptor agonists. Human triple (estrogen receptor, progesterone receptor, and HER2)-negative breast cancer (TNBC) cell lines were treated with TRAIL receptor agonists (monoclonal antibodies or TRAIL peptide), metformin, or the combination. The effects on cell survival, caspase activation, and expression of TRAIL receptors and the antiapoptotic protein XIAP were determined. In addition, XIAP was silenced by RNAi in TNBC cells and the effects on sensitivity to TRAIL were determined. The antitumor effects of metformin, TRAIL, or the combination were evaluated in an orthotopic model of metastatic TNBC. Metformin sensitized diverse TNBC cells to TRAIL receptor agonists. Metformin selectively enhanced the sensitivity of transformed breast epithelial cells to TRAIL receptor agonist-induced caspase activation and apoptosis with little effect on untransformed breast epithelial cells. These effects of metformin were accompanied by robust reductions in the protein levels of XIAP, a negative regulator of TRAIL-induced apoptosis. Silencing XIAP in TNBC cells mimicked the TRAIL-sensitizing effects of metformin. Metformin also enhanced the antitumor effects of TRAIL in a metastatic murine TNBC model. Our findings indicate that metformin enhances the activity of TRAIL receptor agonists, thereby supporting the rationale for additional translational studies combining these agents.

  8. Morphine preconditioning confers cardioprotection in doxorubicin-induced failing rat hearts via ERK/GSK-3β pathway independent of PI3K/Akt.

    PubMed

    He, Shu-Fang; Jin, Shi-Yun; Wu, Hao; Wang, Bin; Wu, Yun-Xiang; Zhang, Shu-Jie; Irwin, Michael G; Wong, Tak-Ming; Zhang, Ye

    2015-11-01

    Preconditioning against myocardial ischemia-reperfusion (I/R) injury can be suppressed in some pathological conditions. This study was designed to investigate whether morphine preconditioning (MPC) exerts cardioprotection in doxorubicin (DOX)-induced heart failure in rats and the mechanisms involved. Phosphatidylinositol-3 kinase/protein kinase B (PI3K/Akt), extracellular signal-regulated kinase (ERK) and glycogen synthase kinase (GSK)-3β pathways were examined. Normal and DOX-induced failing rat hearts were subjected to I/R injury using a Langendorff perfusion system with or without MPC or ischemic preconditioning (IPC). The PI3K inhibitor (wortmannin) or ERK inhibitor (PD98059) was infused before MPC. In normal hearts, both MPC and IPC significantly reduced infarct size and the rise in lactate dehydrogenase (LDH) level caused by I/R injury. Pretreatment with wortmannin or PD98059 abrogated the protective effects of MPC and suppressed the phosphorylation of Akt, ERK and GSK-3β. In failing rat hearts, however, MPC retained its cardioprotection while IPC did not. This protective effect was abolished by PD98059 but not wortmannin. MPC increased the level of p-ERK rather than p-Akt. The phosphorylation of GSK-3β induced by MPC was reversed by PD98059 only. IPC did not elevate the expression of p-ERK, p-Akt and p-GSK-3β in failing rat hearts. We conclude that MPC is cardioprotective in rats with DOX-induced heart failure while IPC is not. The effect of MPC appears to be mediated via the ERK/GSK-3β pathway independent of PI3K/Akt. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. AT1 and aldosterone receptors blockade prevents the chronic effect of nandrolone on the exercise-induced cardioprotection in perfused rat heart subjected to ischemia and reperfusion.

    PubMed

    Marques-Neto, Silvio Rodrigues; Ferraz, Emanuelle Baptista; Rodrigues, Deivid Carvalho; Njaine, Brian; Rondinelli, Edson; Campos de Carvalho, Antônio Carlos; Nascimento, Jose Hamilton Matheus

    2014-04-01

    Myocardial tolerance to ischaemia/reperfusion (I/R) injury is improved by exercise training, but this cardioprotection is impaired by the chronic use of anabolic androgenic steroids (AAS). The present study evaluated whether blockade of angiotensin II receptor (AT1-R) with losartan and aldosterone receptor (mineralocorticoid receptor, MR) with spironolactone could prevent the deleterious effect of AAS on the exercise-induced cardioprotection. Male Wistar rats were exercised and treated with either vehicle, nandrolone decanoate (10 mg/kg/week i.m.) or the same dose of nandrolone plus losartan or spironolactone (20 mg/kg/day orally) for 8 weeks. Langendorff-perfused hearts were subjected to I/R and evaluated for the postischaemic recovery of left ventricle (LV) function and infarct size. mRNA and protein expression of angiotensin II type 1 receptor (AT1-R), mineralocorticoid receptor (MR), and KATP channels were determined by reverse-transcriptase polymerase chain reaction and Western blotting. Postischaemic recovery of LV function was better and infarct size was smaller in the exercised rat hearts than in the sedentary rat hearts. Nandrolone impaired the exercise-induced cardioprotection, but this effect was prevented by losartan (AT1-R antagonist) and spironolactone (MR antagonist) treatments. Myocardial AT1-R and MR expression levels were increased, and the expression of the KATP channel subunits SUR2a and Kir6.1 was decreased and Kir6.2 increased in the nandrolone-treated rat hearts. The nandrolone-induced changes of AT1-R, MR, and KATP subunits expression was normalized by the losartan and spironolactone treatments. The chronic nandrolone treatment impairs the exercise-induced cardioprotection against ischaemia/reperfusion injury by activating the cardiac renin-angiotensin-aldosterone system and downregulating KATP channel expression.

  10. Cardioprotective effect of mumie (shilajit) on experimentally induced myocardial injury.

    PubMed

    Joukar, Siyavash; Najafipour, Hamid; Dabiri, Shahriar; Sheibani, Mohammad; Sharokhi, Nader

    2014-09-01

    This study assessed the effects of mumie (shilajit) pre-treatment, a traditional drug which is well known in the ancient medicine of both east and west, on cardiac performance of rats subjected to myocardial injury. Animals were divided into control, M250, and M500 (received mumie at dosages of 250 and 500 mg/kg/day, orally for 7 days, respectively) main groups each consisting of two subgroups-with and without heart injury. On the 6th and 7th days, isoproterenol (ISO) (85 mg/kg i.p.) was injected (s.c.) to half of the animal subgroups to induce myocardial damage. On the 8th day, after hemodynamic parameter recordings, hearts were removed for further evaluation. Mumie pre-treatment had no significant effects on hemodynamic and cardiac indices of normal animals. When the cardiac injury was induced, mumie maintained the ±dp/dt maximum, attenuated the serum cardiac troponin I, and reduced the severity of cardiac lesions. Despite the mild positive effects of mumie on total antioxidant capacity and lipid proxidation index, no significant difference was observed among animal groups. The findings suggest the prominent cardioprotective effect of mumie against destructive effects of ISO. It seems that other mechanisms than reinforcements of antioxidant system are involved in this beneficial effect.

  11. Metformin for treatment of antipsychotic-induced amenorrhea and weight gain in women with first-episode schizophrenia: a double-blind, randomized, placebo-controlled study.

    PubMed

    Wu, Ren-Rong; Jin, Hua; Gao, Keming; Twamley, Elizabeth W; Ou, Jian-Jun; Shao, Ping; Wang, Juan; Guo, Xiao-Feng; Davis, John M; Chan, Philip K; Zhao, Jing-Ping

    2012-08-01

    Data on the treatment of antipsychotic-induced amenorrhea, particularly when occurring with weight gain, are limited. The authors investigated the efficacy and safety of metformin in the treatment of antipsychotic-induced amenorrhea and weight gain in women with first-episode schizophrenia. Eighty-four women (ages 18-40 years) with first-episode schizophrenia who suffered from amenorrhea during antipsychotic treatment were randomly assigned, in a double-blind study design, to receive 1000 mg/day of metformin or placebo in addition to their antipsychotic treatment for 6 months. The primary outcome measures were restoration of menstruation and change in body weight and body mass index (BMI). Secondary outcome measures were changes in levels of prolactin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, and testosterone; in fasting levels of insulin and glucose; in LH/FSH ratio; and in insulin resistance index. Repeated mixed models with repeated-measures regression analyses and binary logistic regression were used in the analysis. A total of 76 patients completed the 6-month trial. Significantly more patients in the metformin group (N=28, 66.7%) than in placebo group (N=2, 4.8%) resumed their menstruation. Among patients treated with metformin, BMI decreased by a mean of 0.93 and the insulin resistance index by 2.04. In contrast, patients who received placebo had a mean increase in BMI of 0.85. The prolactin, LH, and testosterone levels and LH/FSH ratio decreased significantly in the metformin group at months 2, 4, and 6, but these levels did not change in the placebo group. Metformin was effective in reversing antipsychotic-induced adverse events, including restoration of menstruation, promotion of weight loss, and improvement in insulin resistance in female patients with schizophrenia.

  12. Exosomal miR-21a-5p mediates cardioprotection by mesenchymal stem cells.

    PubMed

    Luther, Kristin M; Haar, Lauren; McGuinness, Myc; Wang, Yang; Lynch Iv, Thomas L; Phan, Anh; Song, Yang; Shen, Zilong; Gardner, George; Kuffel, Gina; Ren, Xiaoping; Zilliox, Michael J; Jones, W Keith

    2018-06-01

    Though experimental, stem cell transplantation has the potential to improve the condition of the heart after myocardial infarction. It does so by reducing infarct size and inducing repair of heart muscle and its blood supply. Mesenchymal stem cells (MSC) have been found to be effective in pre-clinical animal models and clinical trials, but the mechanisms by which they induce cardioprotection and repair are still not fully understood. Small extracellular vesicles known as exosomes are now recognized to be key mediators of beneficial MSC paracrine effects, and the concept that they transfer miRNA to change gene expression in recipient cells is of current therapeutic interest. We present complete deep miRNA sequencing of MSC exosome cargo, and found that of several cardioprotective miRNAs, miR-21a-5p was the most abundant. Because miR-21a-5p is a well-known cardioprotective miRNA, we investigated the hypothesis that MSC exosomes can cardioprotect the heart by increasing the level of miR-21a-5p in recipient cardiac cells, thereby downregulating expression of the pro-apoptotic gene products PDCD4, PTEN, Peli1 and FasL in the myocardium. Using miR-21 mimic transfection and treatment with wild type and miR-21a knockout MSC exosomes, we confirmed that exosomal miR-21a-5p is transferred into myocardium and is a major cardioprotective paracrine factor produced by MSCs acting via synergistic activity on multiple pathways. The data supports that residual cardioprotective effect may be due to other ncRNA or protein cargo. In silico analyses support that MSC exosomes may also contribute to angiogenesis, cell proliferation and other aspects of cardiac repair. Copyright © 2018. Published by Elsevier Ltd.

  13. Involvement of catalase in the protective benefits of metformin in mice with oxidative liver injury.

    PubMed

    Dai, Jie; Liu, Mingwei; Ai, Qing; Lin, Ling; Wu, Kunwei; Deng, Xinyu; Jing, Yuping; Jia, Mengying; Wan, Jingyuan; Zhang, Li

    2014-06-05

    Metformin is a commonly used anti-diabetic drug with AMP-activated protein kinase (AMPK)-dependent hypoglycemic activities. Recent studies have revealed its anti-inflammatory and anti-oxidative properties. In the present study, the anti-oxidative potential of metformin and its potential mechanisms were investigated in a mouse model with carbon tetrachloride (CCl₂)-induced severe oxidative liver injury. Our results showed that treatment with metformin significantly attenuated CCl₂-induced elevation of serum aminotransferases and hepatic histological abnormalities. The alleviated liver injury was associated with decreased hepatic contents of oxidized glutathione (GSSG) and malondialdehyde (MDA). In addition, metformin treatment dose-dependently enhanced the activities of catalase (CAT) and decreased CCl₄-induced elevation of hepatic H₂O₂ levels, but it had no obvious effects on the protein level of CAT. We also found that metformin increased the level of phosphorylated AMP-activated protein kinase (AMPK), but treatment with AMPK activator AICAR had no obvious effects on CAT activity. A molecular docking analysis indicated that metformin might interact with CAT via hydrogen bonds. These data suggested that metformin effectively alleviated CCl₄-induced oxidative liver injury in mice and these hepatoprotective effects might be associated with CAT. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  14. Modulation of gut microbiota by berberine and metformin during the treatment of high-fat diet-induced obesity in rats.

    PubMed

    Zhang, Xu; Zhao, Yufeng; Xu, Jia; Xue, Zhengsheng; Zhang, Menghui; Pang, Xiaoyan; Zhang, Xiaojun; Zhao, Liping

    2015-09-23

    Accumulating evidence suggests that the gut microbiota is an important factor in mediating the development of obesity-related metabolic disorders, including type 2 diabetes. Metformin and berberine, two clinically effective drugs for treating diabetes, have recently been shown to exert their actions through modulating the gut microbiota. In this study, we demonstrated that metformin and berberine similarly shifted the overall structure of the gut microbiota in rats. Both drugs showed reverting effects on the high-fat diet-induced structural changes of gut microbiota. The diversity of gut microbiota was significantly reduced by both berberine- and metformin-treatments. Nearest shrunken centroids analysis identified 134 operational taxonomic units (OTUs) responding to the treatments, which showed close associations with the changes of obese phenotypes. Sixty out of the 134 OTUs were decreased by both drugs, while those belonging to putative short-chain fatty acids (SCFA)-producing bacteria, including Allobaculum, Bacteriodes, Blautia, Butyricoccus, and Phascolarctobacterium, were markedly increased by both berberine and, to a lesser extent, metformin. Taken together, our findings suggest that berberine and metformin showed similarity in modulating the gut microbiota, including the enrichment of SCFA-producing bacteria and reduction of microbial diversity, which may contribute to their beneficial effects to the host.

  15. Metformin induces oxidative stress in white adipocytes and raises uncoupling protein 2 levels.

    PubMed

    Anedda, Andrea; Rial, Eduardo; González-Barroso, M Mar

    2008-10-01

    Metformin is a drug widely used to treat type 2 diabetes. It enhances insulin sensitivity by improving glucose utilization in tissues like liver or muscle. Metformin inhibits respiration, and the decrease in cellular energy activates the AMP-activated protein kinase that in turn switches on catabolic pathways. Moreover, metformin increases lipolysis and beta-oxidation in white adipose tissue, thereby reducing the triglyceride stores. The uncoupling proteins (UCPs) are transporters that lower the efficiency of mitochondrial oxidative phosphorylation. UCP2 is thought to protect against oxidative stress although, alternatively, it could play an energy dissipation role. The aim of this work was to analyse the involvement of UCP2 on the effects of metformin in white adipocytes. We studied the effect of this drug in differentiating 3T3-L1 adipocytes and found that metformin causes oxidative stress since it increases the levels of reactive oxygen species (ROS) and lowers the aconitase activity. Variations in UCP2 protein levels parallel those of ROS. Metformin also increases lipolysis in these cells although only when the levels of ROS and UCP2 have decreased. Hence, UCP2 does not appear to be needed to facilitate fatty acid oxidation. Furthermore, treatment of C57BL/6 mice with metformin also augmented the levels of UCP2 in epididymal white adipose tissue. We conclude that metformin treatment leads to the overexpression of UCP2 in adipocytes to minimize the oxidative stress that is probably due to the inhibition of respiration caused by the drug.

  16. Prospects for Creation of Cardioprotective Drugs Based on Cannabinoid Receptor Agonists.

    PubMed

    Maslov, Leonid N; Khaliulin, Igor; Zhang, Yi; Krylatov, Andrey V; Naryzhnaya, Natalia V; Mechoulam, Raphael; De Petrocellis, Luciano; Downey, James M

    2016-05-01

    Cannabinoids can mimic the infarct-reducing effect of early ischemic preconditioning, delayed ischemic preconditioning, and ischemic postconditioning against myocardial ischemia/reperfusion. They do this primarily through both CB1 and CB2 receptors. Cannabinoids are also involved in remote preconditioning of the heart. The cannabinoid receptor ligands also exhibit an antiapoptotic effect during ischemia/reperfusion of the heart. The acute cardioprotective effect of cannabinoids is mediated by activation of protein kinase C, extracellular signal-regulated kinase, and p38 kinase. The delayed cardioprotective effect of cannabinoid anandamide is mediated via stimulation of phosphatidylinositol-3-kinase-Akt signaling pathway and enhancement of heat shock protein 72 expression. The delayed cardioprotective effect of another cannabinoid, Δ9-tetrahydrocannabinol, is associated with augmentation of nitric oxide (NO) synthase expression, but data on the involvement of NO synthase in the acute cardioprotective effect of cannabinoids are contradictory. The adenosine triphosphate-sensitive K(+)channel is involved in the synthetic cannabinoid HU-210-induced cardiac resistance to ischemia/reperfusion injury. Cannabinoids inhibit Na(+)/Ca(2+)exchange via peripheral cannabinoid receptor (CB2) activation that may also be related to the antiapoptotic and cardioprotective effects of cannabinoids. The cannabinoid receptor agonists should be considered as prospective group of compounds for creation of drugs that are able to protect the heart against ischemia-reperfusion injury in the clinical setting. © The Author(s) 2015.

  17. Metformin Restores Parkin-Mediated Mitophagy, Suppressed by Cytosolic p53

    PubMed Central

    Song, Young Mi; Lee, Woo Kyung; Lee, Yong-ho; Kang, Eun Seok; Cha, Bong-Soo; Lee, Byung-Wan

    2016-01-01

    Metformin is known to alleviate hepatosteatosis by inducing 5’ adenosine monophosphate (AMP)-kinase-independent, sirtuin 1 (SIRT1)-mediated autophagy. Dysfunctional mitophagy in response to glucolipotoxicities might play an important role in hepatosteatosis. Here, we investigated the mechanism by which metformin induces mitophagy through restoration of the suppressed Parkin-mediated mitophagy. To this end, our ob/ob mice were divided into three groups: (1) ad libitum feeding of a standard chow diet; (2) intraperitoneal injections of metformin 300 mg/kg; and (3) 3 g/day caloric restriction (CR). HepG2 cells were treated with palmitate (PA) plus high glucose in the absence or presence of metformin. We detected enhanced mitophagy in ob/ob mice treated with metformin or CR, whereas mitochondrial spheroids were observed in mice fed ad libitum. Metabolically stressed ob/ob mice and PA-treated HepG2 cells showed an increase in expression of endoplasmic reticulum (ER) stress markers and cytosolic p53. Cytosolic p53 inhibited mitophagy by disturbing the mitochondrial translocation of Parkin, as demonstrated by immunoprecipitation. However, metformin decreased ER stress and p53 expression, resulting in induction of Parkin-mediated mitophagy. Furthermore, pifithrin-α, a specific inhibitor of p53, increased mitochondrial incorporation into autophagosomes. Taken together, these results indicate that metformin treatment facilitates Parkin-mediated mitophagy rather than mitochondrial spheroid formation by decreasing the inhibitory interaction with cytosolic p53 and increasing degradation of mitofusins. PMID:26784190

  18. OCT1-Mediated Metformin Uptake Regulates Pancreatic Stellate Cell Activity.

    PubMed

    Wu, Chunhua; Qiu, Shanhu; Zhu, Xiangyun; Lin, Hao; Li, Ling

    2018-06-27

    Metformin treatment is reported to be associated with a lower incidence of and mortality from pancreatic cancer (PC) in type 2 diabetes patients. Activated pancreatic stellate cells (PSCs) are key stroma cells responsible for pancreatic fibrogenesis and PC progression. However, little research is about the influence of metformin on PSCs. Given the potential beneficial effects of metformin on PC, pancreatic tumour stroma is an important target for new therapeutics. We observed the effects of metformin on PSCs. We investigated the effects of metformin on human PSCs proliferation and the production of extracellular matrix (ECM) proteins. Cells were cultured with different concentrations of metformin (0-10 mmol/L). Cell proliferation was determined by immunofluorescence staining for nuclear Ki67 labelling. ECM production was studied by quantitative real-time polymerase chain reaction, immunoblotting and immunofluorescence microscopy. Adenosine monophosphate-activated protein kinase (AMPK), an important regulatory molecule responsible for metformin action, and the organic cation transporter member 1 (OCT1), which is believed to be the most important transporter for the pharmacological action of metformin, were investigated for their possible involvements in metformin-induced proliferation and ECM production. Our results showed that metformin inhibited PSCs proliferation and decreased the production of ECM proteins by activation of AMPK phosphorylation. Silencing of OCT1 expression resulted in a reduction in the effects of metformin on PSCs activity. Collectively, the data indicate that OCT1 may contribute to uptake metformin and regulate PSCs activity. OCT1 is a target of metformin in regulating PSCs activity. © 2018 The Author(s). Published by S. Karger AG, Basel.

  19. Metformin reduces morphine tolerance by inhibiting microglial-mediated neuroinflammation.

    PubMed

    Pan, Yinbing; Sun, Xiaodi; Jiang, Lai; Hu, Liang; Kong, Hong; Han, Yuan; Qian, Cheng; Song, Chao; Qian, Yanning; Liu, Wentao

    2016-11-17

    Tolerance seriously impedes the application of morphine in clinical medicine. Thus, it is necessary to investigate the exact mechanisms and efficient treatment. Microglial activation and neuroinflammation in the spinal cord are thought to play pivotal roles on the genesis and maintaining of morphine tolerance. Activation of adenosine monophosphate-activated kinase (AMPK) has been associated with the inhibition of inflammatory nociception. Metformin, a biguanide class of antidiabetic drugs and activator of AMPK, has a potential anti-inflammatory effect. The present study evaluated the effects and potential mechanisms of metformin in inhibiting microglial activation and alleviating the antinociceptive tolerance of morphine. The microglial cell line BV-2 cells and mouse brain-derived endothelial cell line bEnd3 cells were used. Cytokine expression was measured using quantitative polymerase chain reaction. Cell signaling was assayed by western blot and immunohistochemistry. The antinociception and morphine tolerance were assessed in CD-1 mice using tail-flick tests. We found that morphine-activated BV-2 cells, including the upregulation of p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation, pro-inflammatory cytokines, and Toll-like receptor-4 (TLR-4) mRNA expression, which was inhibited by metformin. Metformin suppressed morphine-induced BV-2 cells activation through increasing AMPK phosphorylation, which was reversed by the AMPK inhibitor compound C. Additionally, in BV-2 cells, morphine did not affect the cell viability and the mRNA expression of anti-inflammatory cytokines. In bEnd3 cells, morphine did not affect the mRNA expression of interleukin-1β (IL-1β), but increased IL-6 and tumor necrosis factor-α (TNF-α) mRNA expression; the effect was inhibited by metformin. Morphine also did not affect the mRNA expression of TLR-4 and chemokine ligand 2 (CCL2). Furthermore, systemic administration of metformin significantly blocked morphine-induced

  20. Cardioprotective role of H₃R agonist imetit on isoproterenol-induced hemodynamic changes and oxidative stress in rats.

    PubMed

    Yadav, Chander Hass; Najmi, Abul Kalam; Akhtar, Mohd; Khanam, Razia

    2015-01-01

    The cardioprotective role of histamine H3 receptor (H3R) agonist imetit (IMT) in isoproterenol (ISO)-induced alterations of hemodynamic and oxidative stress was investigated in Wistar rats. In this study, rats were treated with IMT (5 and 10 mg/kg, per orally [p.o.]), carvedilol (10 mg/kg, p.o.) and ISO control group (normal saline) for 7 d, with concurrent subcutaneous administration of ISO (85 mg/kg) at 24 h interval on last two consecutive days whereas control group was administered with vehicle only. ISO significantly attenuated cardiac antioxidant enzymes superoxide dismutase, catalase and increased plasma cardiac injury biomarkers creatine kinase-MB, alanine transaminase and aspartate transaminase. ISO also altered cardiac activity as evidenced by decrease in blood pressure (34.60%) and increase in heart rate (11.40%). The damage due to oxidative stress was revealed by histopathology alterations such as myocyte necrosis, myofibrillar degeneration and pyknotic nucleus. However, pre-treatment with IMT demonstrated restoration of hemodynamic alterations along with significant preservation of antioxidants and myocyte injury-specific marker enzymes. Furthermore, protective effect of IMT was reconfirmed by the histopathological salvage of myocardium. Results of the present study demonstrated the cardioprotective potential of IMT, as evidenced by favorable improvement in ISO-induced hemodynamic, plasma cardiac biomarkers and tissue antioxidant status along with maintenance of integrity of myocardium.

  1. Activation of the ATF2/CREB-PGC-1α pathway by metformin leads to dopaminergic neuroprotection

    PubMed Central

    Jeong, Ga Ram; Kim, Hyojung; Jo, Minkyung; Lee, Byoung Dae; Lee, Yun Il; Jo, Areum; Park, ChiHu; Kim, Hyein; Seo, Jeongkon; Paek, Sun Ha; Lee, Yun-Song; Choi, Jeong-Yun; Lee, Yunjong; Shin, Joo-Ho

    2017-01-01

    Progressive dopaminergic neurodegeneration is responsible for the canonical motor deficits in Parkinson's disease (PD). The widely prescribed anti-diabetic medicine metformin is effective in preventing neurodegeneration in animal models; however, despite the significant potential of metformin for treating PD, the therapeutic effects and molecular mechanisms underlying dopaminergic neuroprotection by metformin are largely unknown. In this study, we found that metformin induced substantial proteomic changes, especially in metabolic and mitochondrial pathways in the substantia nigra (SN). Consistent with this data, metformin increased mitochondrial marker proteins in SH-SY5Y neuroblastoma cells. Mitochondrial protein expression by metformin was found to be brain region specific, with metformin increasing mitochondrial proteins in the SN and the striatum, but not the cortex. As a potential upstream regulator of mitochondria gene transcription by metformin, PGC-1α promoter activity was stimulated by metformin via CREB and ATF2 pathways. PGC-1α and phosphorylation of ATF2 and CREB by metformin were selectively increased in the SN and the striatum, but not the cortex. Finally, we showed that metformin protected dopaminergic neurons and improved dopamine-sensitive motor performance in an MPTP-induced PD animal model. Together these results suggest that the metformin-ATF2/CREB-PGC-1α pathway might be promising therapeutic target for PD. PMID:28611284

  2. Antihyperalgesic Effects of Indomethacin, Ketorolac, and Metamizole in Rats: Effects of Metformin.

    PubMed

    Guzmán-Priego, Crystell Guadalupe; Méndez-Mena, Roberto; Baños-González, Manuel Alfonso; Araiza-Saldaña, Claudia Ivonne; Castañeda-Corral, Gabriela; Torres-López, Jorge Elías

    2017-03-01

    Preclinical Research Metformin-dependent mechanisms have been implicated in the antinociceptive effect of some non-steroidal anti-inflammatory drugs (NSAIDs). In this study, the effect of local peripheral or systemic administration of metformin on the local peripheral or systemic antinociception induced by indomethacin, ketorolac and metamizole was assessed in the rat carrageenan-induced thermal hyperalgesia model. Rats were injected with carrageenan (1%, 50 µl) into the right hindpaw which reduced paw withdrawal latency, a measure of thermal hyperalgesia. Local peripheral or systemic administration of indomethacin, ketorolac or metamizole dose-dependently reduced carrageenan-induced thermal hyperalgesia. Local peripheral pre-treatment with metformin (800 µg/paw) partially inhibited the anti-hyperalgesic effect of indomethacin (200 µg/paw) and metamizole (200 µg/paw), but not that of ketorolac (200 µg/paw). In contrast, systemic pre-treatment with metformin (200 mg/kg) attenuated the antihyperalgesic effect of metamizole (10 mg/kg), but not that observed with either indomethacin (10 mg/kg) or ketorolac (10 mg/kg). These findings suggest that some but not all NSAIDs have effects mediated by metformin-dependent mechanisms. Drug Dev Res 78 : 98-104, 2017. ©2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  3. Metformin Reduces Hepatic Expression of SIRT3, the Mitochondrial Deacetylase Controlling Energy Metabolism

    PubMed Central

    Buler, Marcin; Aatsinki, Sanna-Mari; Izzi, Valerio; Hakkola, Jukka

    2012-01-01

    Metformin inhibits ATP production in mitochondria and this may be involved in the anti-hyperglycemic effects of the drug. Sirtuin 3 (SIRT3) is a mitochondrial protein deacetylase that regulates the function of the electron transport chain and maintains basal ATP yield. We hypothesized that metformin treatment could diminish mitochondrial ATP production through downregulation of SIRT3 expression. Glucagon and cAMP induced SIRT3 mRNA in mouse primary hepatocytes. Metformin prevented SIRT3 induction by glucagon. Moreover, metformin downregulated constitutive expression of SIRT3 in primary hepatocytes and in the liver in vivo. Estrogen related receptor alpha (ERRα) mediates regulation of Sirt3 gene by peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). ERRα mRNA expression was regulated in a similar manner as SIRT3 mRNA by glucagon, cAMP and metformin. However, a higher metformin concentration was required for downregulation of ERRα than SIRT3. ERRα siRNA attenuated PGC-1α mediated induction of SIRT3, but did not affect constitutive expression. Overexpression of the constitutively active form of AMP-activated protein kinase (AMPK) induced SIRT3 mRNA, indicating that the SIRT3 downregulation by metformin is not mediated by AMPK. Metformin reduced the hepatocyte ATP level. This effect was partially counteracted by SIRT3 overexpression. Furthermore, metformin decreased mitochondrial SIRT3 protein levels and this was associated with enhanced acetylation of several mitochondrial proteins. However, metformin increased mitochondrial mass in hepatocytes. Altogether, our results indicate that metformin attenuates mitochondrial expression of SIRT3 and suggest that this mechanism is involved in regulation of energy metabolism by metformin in the liver and may contribute to the therapeutic action of metformin. PMID:23166782

  4. Metformin suppresses cancer initiation and progression in genetic mouse models of pancreatic cancer.

    PubMed

    Chen, Ke; Qian, Weikun; Jiang, Zhengdong; Cheng, Liang; Li, Jie; Sun, Liankang; Zhou, Cancan; Gao, Luping; Lei, Meng; Yan, Bin; Cao, Junyu; Duan, Wanxing; Ma, Qingyong

    2017-07-24

    Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-associated mortality worldwide with an overall five-year survival rate less than 7%. Accumulating evidence has revealed the cancer preventive and therapeutic effects of metformin, one of the most widely prescribed medications for type 2 diabetes mellitus. However, its role in pancreatic cancer is not fully elucidated. Herein, we aimed to further study the preventive and therapeutic effects of metformin in genetically engineered mouse models of pancreatic cancer. LSL-Kras G12D/+ ; Pdx1-Cre (KC) mouse model was established to investigate the effect of metformin in pancreatic tumorigenesis suppression; LSL-Kras G12D/+ ; Trp53 fl/+ ; Pdx1-Cre (KPC) mouse model was used to evaluate the therapeutic efficiency of metformin in PDAC. Chronic pancreatitis was induced in KC mice by peritoneal injection of cerulein. Following metformin treatment, pancreatic acinar-to-ductal metaplasia (ADM) and mouse pancreatic intraepithelial neoplasia (mPanIN) were decreased in KC mice. Chronic pancreatitis induced a stroma-rich and duct-like structure and increased the formation of ADM and mPanIN lesions, in line with an increased cytokeratin 19 (CK19)-stained area. Metformin treatment diminished chronic pancreatitis-mediated ADM and mPanIN formation. In addition, it alleviated the percent area of Masson's trichrome staining, and decreased the number of Ki67-positive cells. In KPC mice, metformin inhibited tumor growth and the incidence of abdominal invasion. More importantly, it prolonged the overall survival. Metformin inhibited pancreatic cancer initiation, suppressed chronic pancreatitis-induced tumorigenesis, and showed promising therapeutic effect in PDAC.

  5. Metformin-Induced Changes of the Coding Transcriptome and Non-Coding RNAs in the Livers of Non-Alcoholic Fatty Liver Disease Mice.

    PubMed

    Guo, Jun; Zhou, Yuan; Cheng, Yafen; Fang, Weiwei; Hu, Gang; Wei, Jie; Lin, Yajun; Man, Yong; Guo, Lixin; Sun, Mingxiao; Cui, Qinghua; Li, Jian

    2018-01-01

    Recent studies have suggested that changes in non-coding mRNA play a key role in the progression of non-alcoholic fatty liver disease (NAFLD). Metformin is now recommended and effective for the treatment of NAFLD. We hope the current analyses of the non-coding mRNA transcriptome will provide a better presentation of the potential roles of mRNAs and long non-coding RNAs (lncRNAs) that underlie NAFLD and metformin intervention. The present study mainly analysed changes in the coding transcriptome and non-coding RNAs after the application of a five-week metformin intervention. Liver samples from three groups of mice were harvested for transcriptome profiling, which covered mRNA, lncRNA, microRNA (miRNA) and circular RNA (circRNA), using a microarray technique. A systematic alleviation of high-fat diet (HFD)-induced transcriptome alterations by metformin was observed. The metformin treatment largely reversed the correlations with diabetes-related pathways. Our analysis also suggested interaction networks between differentially expressed lncRNAs and known hepatic disease genes and interactions between circRNA and their disease-related miRNA partners. Eight HFD-responsive lncRNAs and three metformin-responsive lncRNAs were noted due to their widespread associations with disease genes. Moreover, seven miRNAs that interacted with multiple differentially expressed circRNAs were highlighted because they were likely to be associated with metabolic or liver diseases. The present study identified novel changes in the coding transcriptome and non-coding RNAs in the livers of NAFLD mice after metformin treatment that might shed light on the underlying mechanism by which metformin impedes the progression of NAFLD. © 2018 The Author(s). Published by S. Karger AG, Basel.

  6. Metformin inhibition of neuroblastoma cell proliferation is differently modulated by cell differentiation induced by retinoic acid or overexpression of NDM29 non-coding RNA.

    PubMed

    Costa, Delfina; Gigoni, Arianna; Würth, Roberto; Cancedda, Ranieri; Florio, Tullio; Pagano, Aldo

    2014-01-01

    Metformin is a widely used oral hypoglycemizing agent recently proposed as potential anti-cancer drug. In this study we report the antiproliferative effect of metformin treatment in a high risk neuroblastoma cell model, focusing on possible effects associated to different levels of differentiation and/or tumor initiating potential. Antiproliferative and cytotoxic effects of metformin were tested in human SKNBE2 and SH-SY5Y neuroblastoma cell lines and in SKNBE2 cells in which differentiation is induced by retinoic acid treatment or stable overexpression of NDM29 non-coding RNA, both conditions characterized by a neuron-like differentiated phenotype. We found that metformin significantly inhibits the proliferation of NB cells, an effect that correlates with the inhibition of Akt, while AMPK activity resulted unchanged. Notably, metformin effects were modulated in a different ways by differentiating stimuli, being abolished after retinoic acid treatment but potentiated by overexpression of NDM29. These data suggest the efficacy of metformin as neuroblastoma anticancer agent, and support the requirement of further studies on the possible role of the differentiation status on the antiproliferative effects of this drug.

  7. Metformin Induces Apoptosis and Cell Cycle Arrest Mediated by Oxidative Stress, AMPK and FOXO3a in MCF-7 Breast Cancer Cells

    PubMed Central

    Queiroz, Eveline A. I. F.; Puukila, Stephanie; Eichler, Rosangela; Sampaio, Sandra C.; Forsyth, Heidi L.; Lees, Simon J.; Barbosa, Aneli M.; Dekker, Robert F. H.; Fortes, Zuleica B.; Khaper, Neelam

    2014-01-01

    Recent studies have demonstrated that the anti-diabetic drug, metformin, can exhibit direct antitumoral effects, or can indirectly decrease tumor proliferation by improving insulin sensitivity. Despite these recent advances, the underlying molecular mechanisms involved in decreasing tumor formation are not well understood. In this study, we examined the antiproliferative role and mechanism of action of metformin in MCF-7 cancer cells treated with 10 mM of metformin for 24, 48, and 72 hours. Using BrdU and the MTT assay, it was found that metformin demonstrated an antiproliferative effect in MCF-7 cells that occurred in a time- and concentration- dependent manner. Flow cytometry was used to analyze markers of cell cycle, apoptosis, necrosis and oxidative stress. Exposure to metformin induced cell cycle arrest in G0-G1 phase and increased cell apoptosis and necrosis, which were associated with increased oxidative stress. Gene and protein expression were determined in MCF-7 cells by real time RT-PCR and western blotting, respectively. In MCF-7 cells metformin decreased the activation of IRβ, Akt and ERK1/2, increased p-AMPK, FOXO3a, p27, Bax and cleaved caspase-3, and decreased phosphorylation of p70S6K and Bcl-2 protein expression. Co-treatment with metformin and H2O2 increased oxidative stress which was associated with reduced cell number. In the presence of metformin, treating with SOD and catalase improved cell viability. Treatment with metformin resulted in an increase in p-p38 MAPK, catalase, MnSOD and Cu/Zn SOD protein expression. These results show that metformin has an antiproliferative effect associated with cell cycle arrest and apoptosis, which is mediated by oxidative stress, as well as AMPK and FOXO3a activation. Our study further reinforces the potential benefit of metformin in cancer treatment and provides novel mechanistic insight into its antiproliferative role. PMID:24858012

  8. New insights on the modulatory roles of metformin or alpha-lipoic acid versus their combination in dextran sulfate sodium-induced chronic colitis in rats.

    PubMed

    Samman, Fatma S; Elaidy, Samah M; Essawy, Soha S; Hassan, Mohammad S

    2017-11-24

    Dextran sulfate sodium (DSS)-induced colitis is the most widely used model that resembles ulcerative colitis (UC) in human with challenging chronic mechanistic oxidative stress-inflammatory/immunological cascades. In models of acute colitis, reduction of oxidative stress and inflammatory burdens beside manipulation of many transcriptional factors were achieved by metformin or alpha-lipoic acid (α-LA). Currently, in vivo DSS-induced chronic colitis was conducted and the possible therapeutic roles of metformin and/or α-LA were explored. Chronic UC was induced by adding 5% DSS orally in drinking water for 7 days followed by 3% DSS in drinking water for 14 days in adult male albino Wistar rats. Intraperitoneal administration of α-LA (25 mg/kg, twice/day) and/or metformin (100 mg/kg/day) were set at day 7 of DSS administration and continued for 14 days. Body weights, survival rates, disease activity index (DAI), colonic oxidative stress markers, tumor necrosis factor (TNF)-α levels, colonic nuclear factor-kappa-B (NF-κB) immunohistochemical expression, and the colonic histopathological changes were observed. Metformin or/and α-LA attenuated the severity of the DSS-induced colitis through improving the reductions in body weights, the DAI, the colonic oxidative stress markers, TNF-α, and NF-κB levels, and the morphological mucosal damage scores. Significant synergetic therapeutic effects were observed with combined therapeutic regimens. Therapeutically, metformin and α-LA could be administered in chronic colitis. The combination of currently used pharmaceutics with natural and synthetic potent antioxidant compounds will become a therapeutic strategy of choice for UC to improve the quality of life if sufficient clinical trials are available. Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.

  9. Cardiovascular risk associated with acarbose versus metformin as the first-line treatment in patients with type 2 diabetes: a nationwide cohort study.

    PubMed

    Chang, Chia-Hsuin; Chang, Yi-Cheng; Lin, Jou-Wei; Chen, Shu-Ting; Chuang, Lee-Ming; Lai, Mei-Shu

    2015-03-01

    Metformin is the first-line oral therapy for type 2 diabetes with proven benefits against cardiovascular risk. Recent evidence suggested that acarbose might be similar to metformin in glucose-lowering efficacy and cardiovascular risk reduction. Therefore, international guidelines have suggested the use of acarbose as alternative first-line antidiabetic therapy. To compare the cardiovascular outcomes in the first-line users of acarbose vs metformin. DESIGN, SETTING, PATIENTS, AND OUTCOME MEASURES: A nationwide cohort study was conducted by analyzing the Taiwan National Health Insurance (NHI) Database. A total of 17,366 acarbose initiators and 230,023 metformin initiators were identified between January 1, 2009 and December 31, 2010. The primary outcome is hospitalization due to any cardiovascular events, including acute myocardial infarction, congestive heart failure, and ischemic stroke. The propensity score method was used to adjust for baseline differences between the two groups. Patients were followed from drug initiation to the earliest of outcome occurrence, death or disenrollment from NHI, or study termination. In intention-to-treat analyses, acarbose was associated with a higher risk of any cardiovascular event (adjusted hazard ratio [HR]: 1.05; 95% confidence interval [CI], 1.01-1.09), heart failure (HR, 1.08; 95% CI, 1.00-1.16), and ischemic stroke (HR, 1.05, 95% CI, 1.00-1.10) than metformin. No significant difference in risk was found in subgroups of patients with or without underlying hypertension, ischemic heart disease, or cerebrovascular disease. Similar results were found in auxiliary as-treated analyses or analyses stratified by propensity score quintiles. Our data do not support that acarbose has a cardio-protective effect similar to metformin as a first-line antidiabetic agent.

  10. Metformin inhibits inflammatory response via AMPK-PTEN pathway in vascular smooth muscle cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kim, Sun Ae; Choi, Hyoung Chul, E-mail: hcchoi@med.yu.ac.kr

    2012-09-07

    Highlights: Black-Right-Pointing-Pointer PTEN was induced by metformin and inhibited by compound C and AMPK siRNA. Black-Right-Pointing-Pointer Metformin suppressed TNF-{alpha}-induced COX-2 and iNOS mRNA expression. Black-Right-Pointing-Pointer Compound C and bpv (pic) increased iNOS and COX-2 protein expression. Black-Right-Pointing-Pointer NF-{kappa}B activation was restored by inhibiting AMPK and PTEN. Black-Right-Pointing-Pointer AMPK and PTEN regulated TNF-{alpha}-induced ROS production in VSMCs. -- Abstract: Atherosclerosis is a chronic inflammation of the coronary arteries. Vascular smooth muscle cells (VSMCs) stimulated by cytokines and chemokines accelerate the inflammatory response and migrate to the injured endothelium during the progression of atherosclerosis. Activation of AMP activated protein kinase (AMPK), amore » key sensor maintaining metabolic homeostasis, suppresses the inflammatory response. However, how AMPK regulates the inflammatory response is poorly understood. To identify the mechanism of this response, we focused on phosphatase and tensin homolog (PTEN), which is a negative regulator of inflammation. We investigated that activation of AMPK-induced PTEN expression and suppression of the inflammatory response through the AMPK-PTEN pathway in VSMCs. We treated with the well-known AMPK activator metformin to induce PTEN expression. PTEN was induced by metformin (2 mM) and inhibited by compound C (10 {mu}M) and AMPK siRNA. Tumor necrosis factor-alpha (TNF-{alpha}) was used to induce inflammation. The inflammatory response was confirmed by cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) expression, and activation of nuclear factor (NF)-{kappa}B. Metformin suppressed COX-2 and iNOS mRNA and protein expression dose dependently. Treatment with compound C and bpv (pic) in the presence of metformin, iNOS and COX-2 protein expression increased. NF-{kappa}B activation decreased in response to metformin and was restored by inhibiting

  11. Pre-Treatment with Metformin in Comparison with Post-Treatment Reduces Cerebral Ischemia Reperfusion Induced Injuries in Rats.

    PubMed

    Karimipour, Mojtaba; Shojaei Zarghani, Sara; Mohajer Milani, Majid; Soraya, Hamid

    2018-04-01

    To explore the effects of pre versus post ischemic treatment with metformin after global cerebral ischemia in rats. Male Wister rats underwent forebrain ischemia by bilateral common carotid artery occlusion for 17 min. Metformin (200 mg/kg) or vehicle was given orally by gavage for 7-14 days. Rats were divided into: control, metformin pre-treatment, metformin post-treatment and metformin pre and post continuous treatment groups. Cerebral infarct size, histopathology, myeloperoxidase and serum malondialdehyde were measured 7 days after ischemia. Histopathological analysis showed that metformin pre-treatment significantly decreased leukocyte infiltration, myeloperoxidase activity and also malondialdehyde level. Metformin pre-treatment and metformin post-treatment reduced infarct size compared with the control group, but it was not significant in the pre and post continuous treatment group. Our findings suggest that pre-treatment with metformin in comparison with post-treatment in experimental stroke can reduce the extent of brain damage and is more neuroprotective at least in part by inhibiting oxidative stress and inflammation.

  12. Role of calcitonin gene-related peptide in cardioprotection of short-term and long-term exercise preconditioning.

    PubMed

    Sun, Xiao-Juan; Pan, Shan-Shan

    2014-07-01

    To examine the role of calcitonin gene-related peptide (CGRP) in cardioprotection of short-term and long-term exercise preconditioning (EP). Male Sprague-Dawley rats were, respectively, subjected to continuous intermittent treadmill training 3 days or 3 weeks as short-term or long-term EP protocols. The myocardial injury induced by isoproterenol (ISO) was performed 24 hours after short-term and long-term EP. The myocardial injury was evaluated in terms of the serum cardiac troponin levels and the hematoxylin-basic fuchsin-picric acid staining. Additionally, serum CGRP levels, CGRP expression in the dorsal root ganglion (DRG), and heart were analyzed as possible mechanisms to explain short-term and long-term EP-induced cardioprotection. Both short-term and long-term EP markedly attenuated the isoproterenol-induced myocardial ischemia with lower serum cardiac troponin levels. Short-term EP does not alter serum CGRP levels and CGRP expression in the DRG and heart. Long-term EP significantly increases serum CGRP levels and CGRP expression in the DRG and heart. The results indicate that short-term EP does not increase the synthesis and release of CGRP. Therefore, the cardioprotective effect of short-term EP does not involve CGRP adaptation. Furthermore, long-term EP increases CGRP synthesis in the DRG and promotes CGRP release in the blood and heart. Hence, CGRP may play an important role in the cardioprotective effect of long-term EP.

  13. Metformin does not enhance ovulation induction in clomiphene resistant polycystic ovary syndrome in clinical practice

    PubMed Central

    Sturrock, N D C; Lannon, B; Fay, T N

    2002-01-01

    Aims To determine whether metformin pretreatment has beneficial effects in clomiphene resistant infertile women with polycystic ovary syndrome (PCOS) in an infertility clinic. Methods This was a randomized placebo controlled double-blind crossover study of 3 months metformin (1500 mg day−1)/placebo, followed by 3 months metformin/placebo together with clomiphene (50–100 mg for 5 days) for three cycles in clomiphene resistant women with PCOS. The primary outcomes were restoration of spontaneous menses, ovulation induction (spontaneous or clomiphene induced) and pregnancy. Secondary endpoints were changes in biochemical parameters related to androgens and insulin. Results Twelve women completed the metformin arm and 14 the placebo arm. Spontaneous menstruation resumed in five metformin treated patients and in six placebo treated women, P = 0.63. No women given metformin spontaneously ovulated, although one patient given placebo did, P = 0.30. There was no difference in the efficacy of clomiphene between the two groups with ovulation being induced in five (out of 12) metformin treated women and four (out of 14) placebo treated women, P = 0.63. Pregnancy occurred in three (out of 12) women given metformin and two (out of 14) women given placebo, P = 0.59. Conclusions Metformin is not always beneficial when given to clomiphene resistant infertile women with PCOS in clinical practice. PMID:11994052

  14. Metformin ameliorates IL-6-induced hepatic insulin resistance via induction of orphan nuclear receptor small heterodimer partner (SHP) in mouse models.

    PubMed

    Kim, Y D; Kim, Y H; Cho, Y M; Kim, D K; Ahn, S W; Lee, J M; Chanda, D; Shong, M; Lee, C H; Choi, H S

    2012-05-01

    IL-6 is a proinflammatory cytokine associated with the pathogenesis of hepatic diseases. Metformin is an anti-diabetic drug used for the treatment of type 2 diabetes, and orphan nuclear receptor small heterodimer partner (SHP, also known as NR0B2), a transcriptional co-repressor, plays an important role in maintaining metabolic homeostasis. Here, we demonstrate that metformin-mediated activation of AMP-activated protein kinase (AMPK) increases SHP protein production and regulates IL-6-induced hepatic insulin resistance. We investigated metformin-mediated SHP production improved insulin resistance through the regulation of an IL-6-dependent pathway (involving signal transducer and activator of transcription 3 [STAT3] and suppressor of cytokine signalling 3 [SOCS3]) in both Shp knockdown and Shp null mice. IL-6-induced STAT3 transactivation and SOCS3 production were significantly repressed by metformin, adenoviral constitutively active AMPK (Ad-CA-AMPK), and adenoviral SHP (Ad-SHP), but not in Shp knockdown, or with the adenoviral dominant negative form of AMPK (Ad-DN-AMPK). Chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP) and protein localisation studies showed that SHP inhibits DNA binding of STAT3 on the Socs3 gene promoter via interaction and colocalisation within the nucleus. Upregulation of inflammatory genes and downregulation of hepatic insulin signalling by acute IL-6 treatment were observed in wild-type mice but not in Shp null mice. Finally, chronic IL-6 exposure caused hepatic insulin resistance, leading to impaired insulin tolerance and elevated gluconeogenesis, and these phenomena were aggravated in Shp null mice. Our results demonstrate that SHP upregulation by metformin may prevent hepatic disorders by regulating the IL-6-dependent pathway, and that this pathway can help to ameliorate the pathogenesis of cytokine-mediated metabolic dysfunction.

  15. Metformin suppresses ovarian cancer growth and metastasis with enhancement of cisplatin cytotoxicity in vivo.

    PubMed

    Rattan, Ramandeep; Graham, Rondell P; Maguire, Jacie L; Giri, Shailendra; Shridhar, Viji

    2011-05-01

    Ovarian cancer is the most lethal gynecologic cancer in women. Its high mortality rate (68%) reflects the fact that 75% of patients have extensive (>stage III) disease at diagnosis and also the limited efficacy of currently available therapies. Consequently, there is clearly a great need to develop improved upfront and salvage therapies for ovarian cancer. Here, we investigated the efficacy of metformin alone and in combination with cisplatin in vivo. A2780 ovarian cancer cells were injected intraperitoneally in nude mice; A2780-induced tumors in nude mice, when treated with metformin in drinking water, resulted in a significant reduction of tumor growth, accompanied by inhibition of tumor cell proliferation (as assessed by immunohistochemical staining of Ki-67, Cyclin D1) as well as decreased live tumor size and mitotic cell count. Metformin-induced activation of AMPK/mTOR pathway was accompanied by decreased microvessel density and vascular endothelial growth factor expression. More importantly, metformin treatment inhibited the growth of metastatic nodules in the lung and significantly potentiated cisplatin-induced cytotoxicity resulting in approximately 90% reduction in tumor growth compared with treatment by either of the drugs alone. Collectively, our data show for the first time that, in addition to inhibiting tumor cell proliferation, metformin treatment inhibits both angiogenesis and metastatic spread of ovarian cancer. Overall, our study provides a strong rationale for use of metformin in ovarian cancer treatment.

  16. Minoxidil opens mitochondrial KATP channels and confers cardioprotection

    PubMed Central

    Sato, Toshiaki; Li, Yulong; Saito, Tomoaki; Nakaya, Haruaki

    2003-01-01

    ATP-sensitive potassium channel in the mitochondrial inner membrane (mitoKATP channel) rather than in the sarcolemma (sarcKATP channel) appears to play an important role in cardioprotection. We examined the effect of minoxidil, a potent antihypertensive agent and hair growth stimulator, on sarcKATP and mitoKATP channels in guinea-pig ventricular myocytes. Minoxidil activated a glybenclamide-sensitive sarcKATP channel current in the whole-cell recording mode with an EC50 of 182.6 μM. Minoxidil reversibly increased the flavoprotein oxidation, an index of mitoKATP channel activity, in a concentration-dependent manner. The EC50 for mitoKATP channel activation was estimated to be 7.3 μM; this value was notably ≈25-fold lower than that for sarcKATP channel activation. Minoxidil (10 μM) significantly attenuated the ouabain-induced increase of mitochondrial Ca2+ concentration, which was measured by loading cells with rhod-2 fluorescence. Furthermore, pretreatment with minoxidil (10 μM) before 20-min no-flow ischaemia significantly improved the recovery of developed tension measured after 60 min of reperfusion in coronary perfused guinea-pig ventricular muscles. These cardioprotective effects of minoxidil were completely abolished by the mitoKATP channel blocker 5-hydroxydecanoate (500 μM). Our results indicate that minoxidil exerts a direct cardioprotective effect on heart muscle cells, an effect mediated by the selective activation of mitoKATP channels. PMID:14691056

  17. Mechanisms Involved in Exercise-Induced Cardioprotection: A Systematic Review

    PubMed Central

    Borges, Juliana Pereira; Lessa, Marcos Adriano

    2015-01-01

    Background Acute myocardial infarction is the leading cause of morbidity and mortality worldwide. Furthermore, research has shown that exercise, in addition to reducing cardiovascular risk factors, can also protect the heart against injury due to ischemia and reperfusion through a direct effect on the myocardium. However, the specific mechanism involved in exerciseinduced cardiac preconditioning is still under debate. Objective To perform a systematic review of the studies that have addressed the mechanisms by which aerobic exercise promotes direct cardioprotection against ischemia and reperfusion injury. Methods A search was conducted using MEDLINE, Literatura Latino-Americana e do Caribe de Informação em Ciências da Saúde, and Scientific Electronic Library Online databases. Data were extracted in a standardized manner by two independent researchers, who were responsible for assessing the methodological quality of the studies. Results The search retrieved 78 studies; after evaluating the abstracts, 30 studies were excluded. The manuscripts of the remaining 48 studies were completely read and, of these, 20 were excluded. Finally, 28 studies were included in this systematic review. Conclusion On the basis of the selected studies, the following are potentially involved in the cardioprotective response to exercise: increased heat shock protein production, nitric oxide pathway involvement, increased cardiac antioxidant capacity, improvement in ATP-dependent potassium channel function, and opioid system activation. Despite all the previous investigations, further research is still necessary to obtain more consistent conclusions. PMID:25830711

  18. Increase in apoptosis by combination of metformin with silibinin in human colorectal cancer cells

    PubMed Central

    Tsai, Cheng-Chia; Chuang, Tang-Wei; Chen, Li-Jen; Niu, Ho-Shan; Chung, Kun-Ming; Cheng, Juei-Tang; Lin, Kao-Chang

    2015-01-01

    AIM: To investigate the effect of metformin on silibinin-induced apoptosis in human colorectal cancer (COLO 205) cells. METHODS: MTT assays were performed to quantify cell viability. Western blot assays were applied to identify the expression of signaling proteins. RESULTS: The combined treatment of COLO 205 cells with metformin and silibinin decreased cell survival at a dose insufficient to influence the non-malignant cells [Human colonic epithelial cells (HCoEpiC)]. Silibinin and metformin increased phosphatase and tensin homolog and 5’-adenosine monophosphate-activated protein kinase expression in COLO 205 cells and inhibited the phosphorylation of mammol/Lalian target of rapamycin. This combined treatment resulted in an increase in the expression of activated caspase 3 and apoptosis inducing factor, indicating apoptosis. CONCLUSION: The combined treatment of human colorectal cancer cells with silibinin and metformin may induce apoptosis at a dose that does not affect HCoEpiC. This finding reveals a potential therapeutic strategy for the treatment of colorectal cancer. PMID:25892866

  19. Metformin improves urine concentration in rodents with nephrogenic diabetes insipidus

    PubMed Central

    Efe, Orhan; Klein, Janet D.; LaRocque, Lauren M.; Ren, Huiwen; Sands, Jeff M.

    2016-01-01

    Urine concentration is regulated by vasopressin. Congenital nephrogenic diabetes insipidus (NDI) is caused by vasopressin type 2 receptor (V2R) mutations. We studied whether metformin could improve urine concentration in rodent models of congenital NDI by stimulating AMPK. To block the V2R in rats, tolvaptan (10 mg/kg/d) was given by oral gavage with or without metformin (800 mg/kg/d). Control rats received vehicle with or without metformin. Tamoxifen-induced V2R KO mice were given metformin (600 mg/kg) or vehicle twice daily. Urine osmolality in tolvaptan-treated rats (1,303 ± 126 mOsM) was restored to control levels by metformin (2,335 ± 273 mOsM) within 3 days and was sustained for up to 10 days. Metformin increased protein abundance of inner medullary urea transporter UT-A1 by 61% and aquaporin 2 (AQP2) by 44% in tolvaptan-treated rats, and immunohistochemistry showed increased membrane accumulation of AQP2 with acute and chronic AMPK stimulation. Outer medullary Na+-K+-2Cl– cotransporter 2 (NKCC2) abundance increased (117%) with AMPK stimulation in control rats but not in V2R-blocked rats. Metformin increased V2R KO mouse urine osmolality within 3 hours, and the increase persisted for up to 12 hours. Metformin increased AQP2 in the V2R KO mice similar to the tolvaptan-treated rats. These results indicate that AMPK activators, such as metformin, might provide a promising treatment for congenital NDI. PMID:27478876

  20. Valproic acid sensitizes metformin-resistant human renal cell carcinoma cells by upregulating H3 acetylation and EMT reversal.

    PubMed

    Wei, Muyun; Mao, Shaowei; Lu, Guoliang; Li, Liang; Lan, Xiaopeng; Huang, Zhongxian; Chen, Yougen; Zhao, Miaoqing; Zhao, Yueran; Xia, Qinghua

    2018-04-17

    Metformin (Met) is a widely available diabetic drug and shows suppressed effects on renal cell carcinoma (RCC) metabolism and proliferation. Laboratory studies in RCC suggested that metformin has remarkable antitumor activities and seems to be a potential antitumor drug. But the facts that metformin may be not effective in reducing the risk of RCC in cancer clinical trials made it difficult to determine the benefits of metformin in RCC prevention and treatment. The mechanisms underlying the different conclusions between laboratory experiments and clinical analysis remains unclear. The goal of the present study was to determine whether long-term metformin use can induce resistance in RCC, whether metformin resistance could be used to explain the disaccord in laboratory and clinical studies, and whether the drug valproic acid (VPA), which inhibits histone deacetylase, exhibits synergistic cytotoxicity with metformin and can counteract the resistance of metformin in RCC. We performed CCK8, transwell, wound healing assay, flow cytometry and western blotting to detect the regulations of proliferation, migration, cell cycle and apoptosis in 786-O, ACHN and metformin resistance 786-O (786-M-R) cells treated with VPA, metformin or a combination of two drugs. We used TGF-β, SC79, LY294002, Rapamycin, protein kinase B (AKT) inhibitor to treat the 786-O or 786-M-R cells and detected the regulations in TGF-β /pSMAD3 and AMPK/AKT pathways. 786-M-R was refractory to metformin-induced antitumor effects on proliferation, migration, cell cycle and cell apoptosis. AMPK/AKT pathways and TGF-β/SMAD3 pathways showed low sensibilities in 786-M-R. The histone H3 acetylation diminished in the 786-M-R cells. However, the addition of VPA dramatically upregulated histone H3 acetylation, increased the sensibility of AKT and inhibited pSMAD3/SMAD4, letting the combination of VPA and metformin remarkably reappear the anti-tumour effects of metformin in 786-M-R cells. VPA not only exhibits

  1. Inflammatory response and cardioprotection during open-heart surgery: the importance of anaesthetics.

    PubMed

    Suleiman, M-S; Zacharowski, K; Angelini, G D

    2008-01-01

    Open-heart surgery triggers an inflammatory response that is largely the result of surgical trauma, cardiopulmonary bypass, and organ reperfusion injury (e.g. heart). The heart sustains injury triggered by ischaemia and reperfusion and also as a result of the effects of systemic inflammatory mediators. In addition, the heart itself is a source of inflammatory mediators and reactive oxygen species that are likely to contribute to the impairment of cardiac pump function. Formulating strategies to protect the heart during open heart surgery by attenuating reperfusion injury and systemic inflammatory response is essential to reduce morbidity. Although many anaesthetic drugs have cardioprotective actions, the diversity of the proposed mechanisms for protection (e.g. attenuating Ca(2+) overload, anti-inflammatory and antioxidant effects, pre- and post-conditioning-like protection) may have contributed to the slow adoption of anaesthetics as cardioprotective agents during open heart surgery. Clinical trials have suggested at least some cardioprotective effects of volatile anaesthetics. Whether these benefits are relevant in terms of morbidity and mortality is unclear and needs further investigation. This review describes the main mediators of myocardial injury during open heart surgery, explores available evidence of anaesthetics induced cardioprotection and addresses the efforts made to translate bench work into clinical practice.

  2. Radiation-Induced Glycogen Accumulation Detected by Single Cell Raman Spectroscopy Is Associated with Radioresistance that Can Be Reversed by Metformin

    PubMed Central

    Matthews, Quinn; Isabelle, Martin; Harder, Samantha J.; Smazynski, Julian; Beckham, Wayne; Brolo, Alexandre G.; Jirasek, Andrew; Lum, Julian J.

    2015-01-01

    Altered cellular metabolism is a hallmark of tumor cells and contributes to a host of properties associated with resistance to radiotherapy. Detection of radiation-induced biochemical changes can reveal unique metabolic pathways affecting radiosensitivity that may serve as attractive therapeutic targets. Using clinically relevant doses of radiation, we performed label-free single cell Raman spectroscopy on a series of human cancer cell lines and detected radiation-induced accumulation of intracellular glycogen. The increase in glycogen post-irradiation was highest in lung (H460) and breast (MCF7) tumor cells compared to prostate (LNCaP) tumor cells. In response to radiation, the appearance of this glycogen signature correlated with radiation resistance. Moreover, the buildup of glycogen was linked to the phosphorylation of GSK-3β, a canonical modulator of cell survival following radiation exposure and a key regulator of glycogen metabolism. When MCF7 cells were irradiated in the presence of the anti-diabetic drug metformin, there was a significant decrease in the amount of radiation-induced glycogen. The suppression of glycogen by metformin following radiation was associated with increased radiosensitivity. In contrast to MCF7 cells, metformin had minimal effects on both the level of glycogen in H460 cells following radiation and radiosensitivity. Our data demonstrate a novel approach of spectral monitoring by Raman spectroscopy to assess changes in the levels of intracellular glycogen as a potential marker and resistance mechanism to radiation therapy. PMID:26280348

  3. Metformin in cancer.

    PubMed

    Mallik, Ritwika; Chowdhury, Tahseen A

    2018-05-26

    Metformin is a lipophilic biguanide which inhibits hepatic gluconeogenesis and improves peripheral utilization of glucose. It is the first line pharmacotherapy for glucose control in patients with Type 2 diabetes due to its safety, efficacy and tolerability. Metformin exhibits pleotropic effects, which may have beneficial effects on a variety of tissues independent of glucose control. A potential anti-tumourigenic effect of metformin may be mediated by its role in activating AMP-kinase, which in turn inhibits mammalian target of rapamycin (mTOR). Non-AMPK dependent protective pathways may include reduction of insulin, insulin-like growth factor-1, leptin, inflammatory pathways and potentiation of adiponectin, all of which may have a role in tumourigenesis. A role in inhibiting cancer stem cells is also postulated. A number of large scale observational and cohort studies suggest metformin is associated with a reduced risk of a number of cancers, although the data is not conclusive. Recent randomised studies reporting use of metformin in treatment of cancer have revealed mixed results, and the results of much larger randomised trials of metformin as an adjuvant therapy in breast and colorectal cancers are awaited. Copyright © 2018 Elsevier B.V. All rights reserved.

  4. Novel Insights into the Cardio-Protective Effects of FGF21 in Lean and Obese Rat Hearts

    PubMed Central

    Chen, Jing; Ramanjaneya, Manjunath; Bari, Muhammad F.; Bhudia, Sunil K.; Hillhouse, Edward W.; Tan, Bee K.; Randeva, Harpal S.

    2014-01-01

    Aims Fibroblast growth factor 21 (FGF21) is a hepatic metabolic regulator with pleotropic actions. Its plasma concentrations are increased in obesity and diabetes; states associated with an increased incidence of cardiovascular disease. We therefore investigated the direct effect of FGF21 on cardio-protection in obese and lean hearts in response to ischemia. Methods and Results FGF21, FGF21-receptor 1 (FGFR1) and beta-Klotho (βKlotho) were expressed in rodent, human hearts and primary rat cardiomyocytes. Cardiac FGF21 was expressed and secreted (real time RT-PCR/western blot and ELISA) in an autocrine-paracrine manner, in response to obesity and hypoxia, involving FGFR1-βKlotho components. Cardiac-FGF21 expression and secretion were increased in response to global ischemia. In contrast βKlotho was reduced in obese hearts. In isolated adult rat cardiomyocytes, FGF21 activated PI3K/Akt (phosphatidylinositol 3-kinase/Akt), ERK1/2(extracellular signal-regulated kinase) and AMPK (AMP-activated protein kinase) pathways. In Langendorff perfused rat [adult male wild-type wistar] hearts, FGF21 administration induced significant cardio-protection and restoration of function following global ischemia. Inhibition of PI3K/Akt, AMPK, ERK1/2 and ROR-α (retinoic-acid receptor alpha) pathway led to significant decrease of FGF21 induced cardio-protection and restoration of cardiac function in response to global ischemia. More importantly, this cardio-protective response induced by FGF21 was reduced in obesity, although the cardiac expression profiles and circulating FGF21 levels were increased. Conclusion In an ex vivo Langendorff system, we show that FGF21 induced cardiac protection and restoration of cardiac function involving autocrine-paracrine pathways, with reduced effect in obesity. Collectively, our findings provide novel insights into FGF21-induced cardiac effects in obesity and ischemia. PMID:24498293

  5. Screening Novel Molecular Targets of Metformin in Breast Cancer by Proteomic Approach

    PubMed Central

    Al-Zaidan, Lobna; El Ruz, Rasha Abu; Malki, Ahmed M.

    2017-01-01

    Metformin is a commonly prescribed antihyperglycemic drug, and has been investigated in vivo and in vitro for its effect to improve the comorbidity of diabetes and various types of cancers. Several studies investigated the therapeutic mechanisms of metformin on cancer cells, but the exact mechanism of metformin’s effect on the proteomic pathways of cancer cells is yet to be further investigated. The main objective of our research line is to discover safe and alternative therapeutic options for breast cancer, we aimed in this study to design a novel “bottom up proteomics workflow” in which proteins were first broken into peptides to reveal their identity, then the proteomes were precisely evaluated using spectrometry analysis. In our study, metformin suppressed cell proliferation and induced apoptosis in human breast carcinoma cell line MCF-7 with minimal toxicity to normal breast epithelial cells MCF-10. Metformin induced apoptosis by arresting cells in G1 phase as evaluated by flow cytometric analysis. Moreover, The G1 phase arrest for the MCF-7 has been confirmed by increased expression levels of p21 and reduction in cyclin D1 level. Additionally, metformin increased the expression levels of p53, Bax, Bad while it reduced expression levels of Akt, Bcl-2, and Mdm2. The study employed a serviceable strategy that investigates metformin-dependent changes in the proteome using a literature-derived network. The protein extracts of the treated and untreated cell lines were analyzed employing proteomic approaches; the findings conveyed a proposed mechanism of the effectual tactics of metformin on breast cancer cells. Metformin proposed an antibreast cancer effect through the examination of the proteomic pathways upon the MCF-7 and MCF-10A exposure to the drug. Our findings proposed prolific proteomic changes that revealed the therapeutic mechanisms of metformin on breast cancer cells upon their exposure. In conclusion, the reported proteomic pathways lead to

  6. The influence of rapamycin on the early cardioprotective effect of hypoxic preconditioning on cardiomyocytes

    PubMed Central

    Wang, Jiang; Maimaitili, YiLiyaer; Yu, Jin; Guo, Hai; Ma, Hai-Ping; Chen, Chun-ling

    2016-01-01

    Introduction The purpose of this study was to examine the effects of rapamycin on the cardioprotective effect of hypoxic preconditioning (HPC) and on the mammalian target of rapamycin (mTOR)-mediated hypoxia-inducible factor 1 (HIF-1) signaling pathway. Material and methods Primary cardiomyocytes were isolated from rat pups and underwent rapamycin and/or HPC, followed by hypoxia/re-oxygenation (H/R) injury. Cell viability and cell injury were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays, and qRT-PCR was used to measure HIF-1α and mTOR mRNA expression. A Langendorff heart perfusion model was conducted to observe the effect of rapamycin. Results Rapamycin treatment nearly abolished the cardioprotective effect of HPC in cardiomyocytes, reduced cell viability (p = 0.007) and increased cell damage (p = 0.032). HIF-1α and mTOR mRNA expression increased in cardiomyocytes undergoing I/R injury within 2 h after HPC. After rapamycin treatment, mTOR mRNA expression and HPC-induced HIF-1α mRNA expression were both reduced (p < 0.001). A Langendorff heart perfusion model in rat hearts showed that rapamycin greatly attenuated the cardioprotective effect of HPC in terms of heart rate, LVDP, and dp/dtmax (all, p < 0.029). Conclusions Rapamycin, through inhibition of mTOR, reduces the elevated HIF-1α expression at an early stage of HPC, and attenuates the early cardioprotective effect of HPC. PMID:28721162

  7. Activation of AMP-activated Protein Kinase by Metformin Induces Protein Acetylation in Prostate and Ovarian Cancer Cells*

    PubMed Central

    Galdieri, Luciano; Gatla, Himavanth; Vancurova, Ivana; Vancura, Ales

    2016-01-01

    AMP-activated protein kinase (AMPK) is an energy sensor and master regulator of metabolism. AMPK functions as a fuel gauge monitoring systemic and cellular energy status. Activation of AMPK occurs when the intracellular AMP/ATP ratio increases and leads to a metabolic switch from anabolism to catabolism. AMPK phosphorylates and inhibits acetyl-CoA carboxylase (ACC), which catalyzes carboxylation of acetyl-CoA to malonyl-CoA, the first and rate-limiting reaction in de novo synthesis of fatty acids. AMPK thus regulates homeostasis of acetyl-CoA, a key metabolite at the crossroads of metabolism, signaling, chromatin structure, and transcription. Nucleocytosolic concentration of acetyl-CoA affects histone acetylation and links metabolism and chromatin structure. Here we show that activation of AMPK with the widely used antidiabetic drug metformin or with the AMP mimetic 5-aminoimidazole-4-carboxamide ribonucleotide increases the inhibitory phosphorylation of ACC and decreases the conversion of acetyl-CoA to malonyl-CoA, leading to increased protein acetylation and altered gene expression in prostate and ovarian cancer cells. Direct inhibition of ACC with allosteric inhibitor 5-(tetradecyloxy)-2-furoic acid also increases acetylation of histones and non-histone proteins. Because AMPK activation requires liver kinase B1, metformin does not induce protein acetylation in liver kinase B1-deficient cells. Together, our data indicate that AMPK regulates the availability of nucleocytosolic acetyl-CoA for protein acetylation and that AMPK activators, such as metformin, have the capacity to increase protein acetylation and alter patterns of gene expression, further expanding the plethora of metformin's physiological effects. PMID:27733682

  8. Involvement of glycogen synthase kinase-3β in liver ischemic conditioning induced cardioprotection against myocardial ischemia and reperfusion injury in rats

    PubMed Central

    Yang, Shuai; Abbott, Geoffrey W.; Gao, Wei Dong; Liu, Jin; Luo, Chaozhi

    2017-01-01

    Remote ischemic conditioning has been convincingly shown to render the myocardium resistant to a subsequent more severe sustained episode of ischemia. Compared with other organs, little is known regarding the effect of transient liver ischemic conditioning. We proposed the existence of cardioprotection induced by remote liver conditioning. Male Sprague-Dawley rats were divided into sham-operated control (no further hepatic intervention) and remote liver ischemic conditioning groups. For liver ischemic conditioning, three cycles of 5 min of liver ischemia-reperfusion stimuli were conducted before-(liver preconditioning), post-myocardial ischemia (liver postconditioning), or in combination of both (liver preconditioning + liver postconditioning). Rats were exposed to 45 min of left anterior descending coronary artery occlusion, followed by 3 h of reperfusion thereafter. ECG and hemodynamics were measured throughout the experiment. The coronary artery was reoccluded at the end of reperfusion for infarct size determination. Blood samples were taken for serum lactate dehydrogenase and creatine kinase-MB test. Heart tissues were taken for apoptosis measurements and Western blotting. Our data demonstrate that liver ischemic preconditioning, postconditioning, or a combination of both, offered strong cardioprotection, as evidenced by reduction in infarct size and cardiac tissue damage, recovery of cardiac function, and inhibition of apoptosis after ischemia-reperfusion. Moreover, liver ischemic conditioning increased cardiac (not hepatic) glycogen synthase kinase-3β (GSK-3β) phosphorylation. Accordingly, inhibition of GSK-3β mimicked the cardioprotective action of liver conditioning. These results demonstrate that remote liver ischemic conditioning protected the heart against ischemia and reperfusion injury via GSK-3β-dependent cell-survival signaling pathway. NEW & NOTEWORTHY Remote ischemic conditioning protects hearts against ischemia and reperfusion (I/R) injury

  9. Metformin selectively targets redox control of complex I energy transduction.

    PubMed

    Cameron, Amy R; Logie, Lisa; Patel, Kashyap; Erhardt, Stefan; Bacon, Sandra; Middleton, Paul; Harthill, Jean; Forteath, Calum; Coats, Josh T; Kerr, Calum; Curry, Heather; Stewart, Derek; Sakamoto, Kei; Repiščák, Peter; Paterson, Martin J; Hassinen, Ilmo; McDougall, Gordon; Rena, Graham

    2018-04-01

    Many guanide-containing drugs are antihyperglycaemic but most exhibit toxicity, to the extent that only the biguanide metformin has enjoyed sustained clinical use. Here, we have isolated unique mitochondrial redox control properties of metformin that are likely to account for this difference. In primary hepatocytes and H4IIE hepatoma cells we found that antihyperglycaemic diguanides DG5-DG10 and the biguanide phenformin were up to 1000-fold more potent than metformin on cell signalling responses, gluconeogenic promoter expression and hepatocyte glucose production. Each drug inhibited cellular oxygen consumption similarly but there were marked differences in other respects. All diguanides and phenformin but not metformin inhibited NADH oxidation in submitochondrial particles, indicative of complex I inhibition, which also corresponded closely with dehydrogenase activity in living cells measured by WST-1. Consistent with these findings, in isolated mitochondria, DG8 but not metformin caused the NADH/NAD + couple to become more reduced over time and mitochondrial deterioration ensued, suggesting direct inhibition of complex I and mitochondrial toxicity of DG8. In contrast, metformin exerted a selective oxidation of the mitochondrial NADH/NAD + couple, without triggering mitochondrial deterioration. Together, our results suggest that metformin suppresses energy transduction by selectively inducing a state in complex I where redox and proton transfer domains are no longer efficiently coupled. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  10. Effects of Metformin, Buformin, and Phenformin on the Post Initiation Stage of Chemically-Induced Mammary Carcinogenesis in the Rat

    PubMed Central

    Zhu, Zongjian; Jiang, Weiqin; Thompson, Matthew D.; Echeverria, Dimas; McGinley, John N.; Thompson, Henry J.

    2015-01-01

    Metformin is a widely prescribed drug for the treatment of type-2 diabetes. Although epidemiological data have provided a strong rationale for investigating the potential of this biguanide for use in cancer prevention and control, uncertainty exists whether metformin should be expected to have an impact in non-diabetic patients. Furthermore, little attention has been given to the possibility that other biguanides may have anticancer activity. In this study, the effects of clinically relevant doses of metformin (9.3mmol/kg diet), buformin (7.6 mmol/kg diet), and phenformin (5.0 mmol/kg diet) were compared to rats fed control diet (AIN93-G) during the post initiation stage of 1-methyl-1-nitrosourea-induced (50 mg/kg body weight) mammary carcinogenesis (n = 30/group). Plasma, liver, skeletal muscle, visceral fat, mammary gland, and mammary carcinoma concentrations of the biguanides were determined. In comparison to the control group, buformin decreased cancer incidence, multiplicity, and burden; whereas, metformin and phenformin had no statistically significant effect on the carcinogenic process relative to the control group. Buformin did not alter fasting plasma glucose or insulin. Within mammary carcinomas, evidence was obtained that buformin treatment perturbed signaling pathways related to energy sensing. However, further investigation is needed to determine the relative contributions of host systemic and cell autonomous mechanisms to the anticancer activity of biguanides such as buformin. PMID:25804611

  11. Effects of metformin, buformin, and phenformin on the post-initiation stage of chemically induced mammary carcinogenesis in the rat.

    PubMed

    Zhu, Zongjian; Jiang, Weiqin; Thompson, Matthew D; Echeverria, Dimas; McGinley, John N; Thompson, Henry J

    2015-06-01

    Metformin is a widely prescribed drug for the treatment of type II diabetes. Although epidemiologic data have provided a strong rationale for investigating the potential of this biguanide for use in cancer prevention and control, uncertainty exists whether metformin should be expected to have an impact in nondiabetic patients. Furthermore, little attention has been given to the possibility that other biguanides may have anticancer activity. In this study, the effects of clinically relevant doses of metformin (9.3 mmol/kg diet), buformin (7.6 mmol/kg diet), and phenformin (5.0 mmol/kg diet) were compared with rats fed control diet (AIN93-G) during the post-initiation stage of 1-methyl-1-nitrosourea-induced (50 mg/kg body weight) mammary carcinogenesis (n = 30/group). Plasma, liver, skeletal muscle, visceral fat, mammary gland, and mammary carcinoma concentrations of the biguanides were determined. In comparison with the control group, buformin decreased cancer incidence, multiplicity, and burden, whereas metformin and phenformin had no statistically significant effect on the carcinogenic process relative to the control group. Buformin did not alter fasting plasma glucose or insulin. Within mammary carcinomas, evidence was obtained that buformin treatment perturbed signaling pathways related to energy sensing. However, further investigation is needed to determine the relative contributions of host systemic and cell autonomous mechanisms to the anticancer activity of biguanides such as buformin. ©2015 American Association for Cancer Research.

  12. Rescue of mutant rhodopsin traffic by metformin-induced AMPK activation accelerates photoreceptor degeneration

    PubMed Central

    Athanasiou, Dimitra; Aguila, Monica; Opefi, Chikwado A.; South, Kieron; Bellingham, James; Bevilacqua, Dalila; Munro, Peter M.; Kanuga, Naheed; Mackenzie, Francesca E.; Dubis, Adam M.; Georgiadis, Anastasios; Graca, Anna B.; Pearson, Rachael A.; Ali, Robin R.; Sakami, Sanae; Palczewski, Krzysztof; Sherman, Michael Y.; Reeves, Philip J.

    2017-01-01

    Abstract Protein misfolding caused by inherited mutations leads to loss of protein function and potentially toxic ‘gain of function’, such as the dominant P23H rhodopsin mutation that causes retinitis pigmentosa (RP). Here, we tested whether the AMPK activator metformin could affect the P23H rhodopsin synthesis and folding. In cell models, metformin treatment improved P23H rhodopsin folding and traffic. In animal models of P23H RP, metformin treatment successfully enhanced P23H traffic to the rod outer segment, but this led to reduced photoreceptor function and increased photoreceptor cell death. The metformin-rescued P23H rhodopsin was still intrinsically unstable and led to increased structural instability of the rod outer segments. These data suggest that improving the traffic of misfolding rhodopsin mutants is unlikely to be a practical therapy, because of their intrinsic instability and long half-life in the outer segment, but also highlights the potential of altering translation through AMPK to improve protein function in other protein misfolding diseases. PMID:28065882

  13. Metformin blocks progression of obesity-activated thyroid cancer in a mouse model.

    PubMed

    Park, Jeongwon; Kim, Won Gu; Zhao, Li; Enomoto, Keisuke; Willingham, Mark; Cheng, Sheue-Yann

    2016-06-07

    Compelling epidemiologic evidence indicates that obesity is associated with a high risk of human malignancies, including thyroid cancer. We previously demonstrated that a high fat diet (HFD) effectively induces the obese phenotype in a mouse model of aggressive follicular thyroid cancer (ThrbPV/PVPten+/-mice). We showed that HFD promotes cancer progression through aberrant activation of the leptin-JAK2-STAT3 signaling pathway. HFD-promoted thyroid cancer progression allowed us to test other molecular targets for therapeutic opportunity for obesity-induced thyroid cancer. Metformin is a widely used drug to treat patients with type II diabetes. It has been shown to reduce incidences of neoplastic diseases and cancer mortality in type II diabetes patients. The present study aimed to test whether metformin could be a therapeutic for obesity-activated thyroid cancer. ThrbPV/PVPten+/-mice were fed HFD together with metformin or vehicle-only, as controls, for 20 weeks. While HFD-ThrbPV/PVPten+/-mice had shorter survival than LFD-treated mice, metformin had no effects on the survival of HFD-ThrbPV/PVPten+/-mice. Remarkably, metformin markedly decreased occurrence of capsular invasion and completely blocked vascular invasion and anaplasia in HFD-ThrbPV/PVPten+/-mice without affecting thyroid tumor growth. The impeded cancer progression was due to the inhibitory effect of metformin on STAT3-ERK-vimentin and fibronectin-integrin signaling to decrease tumor cell invasion and de-differentiation. The present studies provide additional molecular evidence to support the link between obesity and thyroid cancer risk. Importantly, our findings suggest that metformin could be used as an adjuvant in combination with antiproliferative modalities to improve the outcome of patients with obesity-activated thyroid cancer.

  14. Antioxidant Properties and Cardioprotective Mechanism of Malaysian Propolis in Rats.

    PubMed

    Ahmed, Romana; Tanvir, E M; Hossen, Md Sakib; Afroz, Rizwana; Ahmmed, Istiyak; Rumpa, Nur-E-Noushin; Paul, Sudip; Gan, Siew Hua; Sulaiman, Siti Amrah; Khalil, Md Ibrahim

    2017-01-01

    Propolis contains high concentrations of polyphenols, flavonoids, tannins, ascorbic acid, and reducing sugars and proteins. Malaysian Propolis (MP) has been reported to exhibit high 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging activity and ferric reducing antioxidant power (FRAP) values. Herein, we report the antioxidant properties and cardioprotective properties of MP in isoproterenol- (ISO-) induced myocardial infarction in rats. Male Wistar rats ( n = 32) were pretreated orally with an ethanol extract of MP (100 mg/kg/day) for 30 consecutive days. Subcutaneous injection of ISO (85 mg/kg in saline) for two consecutive days caused a significant increase in serum cardiac marker enzymes and cardiac troponin I levels and altered serum lipid profiles. In addition significantly increased lipid peroxides and decreased activities of cellular antioxidant defense enzymes were observed in the myocardium. However, pretreatment of ischemic rats with MP ameliorated the biochemical parameters, indicating the protective effect of MP against ISO-induced ischemia in rats. Histopathological findings obtained for the myocardium further confirmed the biochemical findings. It is concluded that MP exhibits cardioprotective activity against ISO-induced oxidative stress through its direct cytotoxic radical-scavenging activities. It is also plausible that MP contributed to endogenous antioxidant enzyme activity via inhibition of lipid peroxidation.

  15. Antioxidant Properties and Cardioprotective Mechanism of Malaysian Propolis in Rats

    PubMed Central

    Ahmed, Romana; Hossen, Md. Sakib; Ahmmed, Istiyak; Rumpa, Nur-E-Noushin; Sulaiman, Siti Amrah

    2017-01-01

    Propolis contains high concentrations of polyphenols, flavonoids, tannins, ascorbic acid, and reducing sugars and proteins. Malaysian Propolis (MP) has been reported to exhibit high 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging activity and ferric reducing antioxidant power (FRAP) values. Herein, we report the antioxidant properties and cardioprotective properties of MP in isoproterenol- (ISO-) induced myocardial infarction in rats. Male Wistar rats (n = 32) were pretreated orally with an ethanol extract of MP (100 mg/kg/day) for 30 consecutive days. Subcutaneous injection of ISO (85 mg/kg in saline) for two consecutive days caused a significant increase in serum cardiac marker enzymes and cardiac troponin I levels and altered serum lipid profiles. In addition significantly increased lipid peroxides and decreased activities of cellular antioxidant defense enzymes were observed in the myocardium. However, pretreatment of ischemic rats with MP ameliorated the biochemical parameters, indicating the protective effect of MP against ISO-induced ischemia in rats. Histopathological findings obtained for the myocardium further confirmed the biochemical findings. It is concluded that MP exhibits cardioprotective activity against ISO-induced oxidative stress through its direct cytotoxic radical-scavenging activities. It is also plausible that MP contributed to endogenous antioxidant enzyme activity via inhibition of lipid peroxidation. PMID:28261310

  16. Polyunsaturated fatty acid induces cardioprotection against ischemia-reperfusion through the inhibition of NF-kappaB and induction of Nrf2

    PubMed Central

    Farías, Jorge G; Carrasco-Pozo, Catalina; Carrasco Loza, Rodrigo; Sepúlveda, Néstor; Álvarez, Pedro; Quezada, Mauricio; Quiñones, John; Molina, Víctor

    2016-01-01

    The mechanistic evidence to support the cardioprotective effects of polyunsaturated fatty acids (PUFA) are controversial. The aim was to test cardioprotective mechanisms induced by PUFA supplementation against cardiac ischemia-reperfusion (IR) injury. Ten-week-old male Wistar rats (225 ± 14 g, n = 14) were divided in two groups: rats without supplementation (n = 7) and a PUFA group, supplemented by PUFA (0.6 g/kg/day; DHA:EPA = 3:1) for eight weeks (n = 7). Hearts were perfused with Krebs–Henseleit buffer for 20 min (control conditions); others were subjected to control conditions, 30 min of global ischemia and 120 min of reperfusion (IR group). Infarct size (IS) and left ventricular developed pressure (LVDP) were measured at 120 min of reperfusion. Oxidative stress biomarkers (TBARS, total carbonyls), antioxidant status (CAT, catalase; SOD, superoxide dismutase; GSH-Px, glutathione peroxidase activity and GSH/GSSG ratio), myeloperoxidase activity, ATP levels and nuclear transcription factor erythroid 2-related factor 2 (Nrf2) and nuclear factor kappaB (NF-κB) were determined in both experimental conditions. At the end of reperfusion, hearts supplemented with PUFA showed lower IS and a higher LVDP compared with the nonsupplemented rats. Hearts in the group supplemented with PUFA showed lower levels of oxidative stress markers and higher antioxidant activity, decreased MPO activity and NF-κB and Nrf2 activation compared with the nonsupplemented group. Cardioprotective effects of PUFA are exerted through induction of anti-inflammatory and antioxidant mechanism at tissue level. PMID:27190274

  17. Polyunsaturated fatty acid induces cardioprotection against ischemia-reperfusion through the inhibition of NF-kappaB and induction of Nrf2.

    PubMed

    Farías, Jorge G; Carrasco-Pozo, Catalina; Carrasco Loza, Rodrigo; Sepúlveda, Néstor; Álvarez, Pedro; Quezada, Mauricio; Quiñones, John; Molina, Víctor; Castillo, Rodrigo L

    2017-05-01

    The mechanistic evidence to support the cardioprotective effects of polyunsaturated fatty acids (PUFA) are controversial. The aim was to test cardioprotective mechanisms induced by PUFA supplementation against cardiac ischemia-reperfusion (IR) injury. Ten-week-old male Wistar rats (225 ± 14 g, n = 14) were divided in two groups: rats without supplementation ( n = 7) and a PUFA group, supplemented by PUFA (0.6 g/kg/day; DHA:EPA = 3:1) for eight weeks ( n = 7). Hearts were perfused with Krebs-Henseleit buffer for 20 min (control conditions); others were subjected to control conditions, 30 min of global ischemia and 120 min of reperfusion (IR group). Infarct size (IS) and left ventricular developed pressure (LVDP) were measured at 120 min of reperfusion. Oxidative stress biomarkers (TBARS, total carbonyls), antioxidant status (CAT, catalase; SOD, superoxide dismutase; GSH-Px, glutathione peroxidase activity and GSH/GSSG ratio), myeloperoxidase activity, ATP levels and nuclear transcription factor erythroid 2-related factor 2 (Nrf2) and nuclear factor kappaB (NF-κB) were determined in both experimental conditions. At the end of reperfusion, hearts supplemented with PUFA showed lower IS and a higher LVDP compared with the nonsupplemented rats. Hearts in the group supplemented with PUFA showed lower levels of oxidative stress markers and higher antioxidant activity, decreased MPO activity and NF-κB and Nrf2 activation compared with the nonsupplemented group. Cardioprotective effects of PUFA are exerted through induction of anti-inflammatory and antioxidant mechanism at tissue level.

  18. Metformin treatment prevents gallstone formation but mimics porcelain gallbladder in C57Bl/6 mice.

    PubMed

    Dorvash, Mohammad Reza; Khoshnood, Mohammad Javad; Saber, Hossein; Dehghanian, Amirreza; Mosaddeghi, Pouria; Firouzabadi, Negar

    2018-06-05

    Gallstone disease (GD) is highly correlated with metabolic syndrome and its related illnesses including type II diabetes (DMII) and polycystic ovary syndrome (PCOS). While previous studies claimed that metformin decreases the chance of developing GD in PCOS patients, this phenomenon has not been investigated in animal models to date. Here we fed a high fat diet (HFD) containing 2% of cholesterol and 1% of cholic acid to ten-week-old male C57Bl/6 mice for 105 days. The groups were as follows: Low fat diet; HFD; HFD + Ursodeoxycholic acid (UDCA) (day 1-105); HFD + Metformin (day 1-105); HFD + Metformin (Met) (day 64-105). All drugs were administered by oral gavage (Met = 300 mg/kg & UDCA = 750 mg/kg). Serum lipid profile and gross organ examination were performed after euthanasia. A microscopic evaluation of the paraffin-embedded gallbladders was done after hematoxylin & eosin and Von Kossa staining. HFD successfully induces gallstone (4 out of 4 of the HFD members). While both UDCA and metformin (d 1-105) prevented gallstone formation and cholecystitis, Metformin (d 64-105) group had a few small stones. Additionally, metformin induces mucosal calcification in gallbladder (porcelain GB) of more than 80% of the HFD + Met (day 1-105) and HFD + Met (day 64-105) groups, collectively, which can be a potential problem by itself. While metformin shows a noticeable benefit towards GB health by reducing the chance for gallstone formation, if it induces porcelain gallbladder in humans as well, it might inflict patients with preventable medical charges. Copyright © 2018 Elsevier B.V. All rights reserved.

  19. Metformin and aspirin treatment could lead to an improved survival rate for Type 2 diabetic patients with stage II and III colorectal adenocarcinoma relative to non-diabetic patients.

    PubMed

    De Monte, Ariella; Brunetti, Davide; Cattin, Luigi; Lavanda, Francesca; Naibo, Erica; Malagoli, Maria; Stanta, Giorgio; Bonin, Serena

    2018-03-01

    Metformin, the drug of choice in the treatment of type 2 diabetes mellitus (DM2), in addition to aspirin (ASA), the drug prescribed for cardioprotection of diabetic and non-diabetic patients, have an inhibitory effect on cancer cell survival. The present population-based study conducted in the province of Trieste (Italy), aimed to investigate the prevalence of DM2 in patients with colorectal adenocarcinoma (CRC) and survival for CRC in diabetic and nondiabetic patients. All permanent residents diagnosed with a CRC between 2004 and 2007 were ascertained through the regional health information system. CRC-specific and relative survival probabilities were computed for each group of patients defined by CRC stage, presence or absence of DM2 treated with metformin, and presence or absence of daily ASA therapy. A total of 515 CRC patients without DM2 and 156 with DM2 treated with metformin were enrolled in the study. At the time of CRC diagnosis, 71 (14%) nondiabetic and 39 (25%) diabetic patients were taking ASA daily. The five-year relative survival for stage III CRC was 101% [95% confidence interval (CI)=76-126] in the 18 patients with DM2 treated with metformin and ASA, 55% (95% CI=31-78) in the 23 without DM2 treated with ASA, 55% (95% CI=45-65) in the 150 without DM2 not taking ASA, and 29% (95% CI=13-45) in the 43 with DM2 treated with metformin, however not with ASA. The findings support the hypothesis of a possible inhibitory effect of metformin and ASA on CRC cells. Randomized controlled trials are required to verify this hypothesis.

  20. Suppressive effects of metformin on T-helper 1-related chemokines expression in the human monocytic leukemia cell line THP-1.

    PubMed

    Chen, Yen-Chun; Kuo, Chang-Hung; Tsai, Ying-Ming; Lin, Yi-Ching; Hsiao, Hui-Pin; Chen, Bai-Hsiun; Chen, Yi-Ting; Wang, Shih-Ling; Hung, Chih-Hsing

    2018-04-09

    Type 1 and type 2 diabetes mellitus (DM) are chronic T-cell-mediated inflammatory diseases. Metformin is a widely used drug for type 2 DM that reduces the need for insulin in type 1 DM. However, whether metformin has an anti-inflammatory effect for treating DM is unknown. We investigated the anti-inflammatory mechanism of metformin in the human monocytic leukemia cell line THP-1. The human monocytic leukemia cell line THP-1 was pretreated with metformin and stimulated with lipopolysaccharide (LPS). The production of T-helper (Th)-1-related chemokines including interferon-γ-induced protein-10 (IP-10) and monocyte chemoattractant protein-1 (MCP-1), Th2-related chemokine macrophage-derived chemokine, and the proinflammatory chemokine tumor necrosis factor-α was measured using enzyme-linked immunosorbent assay. Intracellular signaling pathways were investigated using Western blot analysis and chromatin immunoprecipitation assay. Metformin suppressed LPS-induced IP-10 and MCP-1 production as well as LPS-induced phosphorylation of c-Jun N-terminal kinase (JNK), p38, extracellular signal-regulated kinase (ERK), and nuclear factor-kappa B (NF-κB). Moreover, metformin suppressed LPS-induced acetylation of histones H3 and H4 at the IP-10 promoter. Metformin suppressed the production of Th1-related chemokines IP-10 and MCP-1 in THP-1 cells. Suppressive effects of metformin on IP-10 production might be attributed at least partially to the JNK, p38, ERK, and NF-κB pathways as well as to epigenetic regulation through the acetylation of histones H3 and H4. These results indicated the therapeutic anti-inflammatory potential of metformin.

  1. Metformin and insulin receptors

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Vigneri, R.; Gullo, D.; Pezzino, V.

    The authors evaluated the effect of metformin (N,N-dimethylbiguanide), a biguanide known to be less toxic than phenformin, on insulin binding to its receptors, both in vitro and in vivo. Specific /sup 125/I-insulin binding to cultured IM-9 human lymphocytes and MCF-7 human breast cancer cells was determined after preincubation with metformin. Specific /sup 125/I-insulin binding to circulating monocytes was also evaluated in six controls, eight obese subjects, and six obese type II diabetic patients before and after a short-term treatment with metformin. Plasma insulin levels and blood glucose were also measured on both occasions. Metformin significantly increased insulin binding in vitromore » to both IM-9 lymphocytes and MCF-7 cells; the maximum increment was 47.1% and 38.0%, respectively. Metformin treatment significantly increased insulin binding in vivo to monocytes of obese subjects and diabetic patients. Scatchard analysis indicated that the increased binding was mainly due to an increase in receptor capacity. Insulin binding to monocytes of normal controls was unchanged after metformin as were insulin levels in all groups; blood glucose was significantly reduced after metformin only in diabetic patients. These data indicate that metformin increases insulin binding to its receptors in vitro and in vivo. The effect in vivo is observed in obese subjects and in obese type II diabetic patients, paralleling the clinical effectiveness of this antidiabetic agent, and is not due to receptor regulation by circulating insulin, since no variation in insulin levels was recorded.« less

  2. N-Acetylcysteine Restores Sevoflurane Postconditioning Cardioprotection against Myocardial Ischemia-Reperfusion Injury in Diabetic Rats.

    PubMed

    Lin, Jiefu; Wang, Tingting; Li, Yalan; Wang, Mengxia; Li, Haobo; Irwin, Michael G; Xia, Zhengyuan

    2016-01-01

    The effect of sevoflurane postconditioning (sevo-postC) cardioprotection is compromised in diabetes which is associated with increased oxidative stress. We hypothesized that antioxidant N-Acetylcysteine may enhance or restore sevo-postC cardioprotection in diabetes. Control or streptozotocin-induced Type 1 diabetic rats were either untreated or treated with N-Acetylcysteine for four weeks starting at five weeks after streptozotocin injection and were subjected to myocardial ischemia-reperfusion injury (IRI), in the absence or presence of sevo-postC. Diabetes showed reduction of cardiac STAT3 activation (p-STAT3) and adiponectin with concomitantly increase of FoxO1 and CD36, which associated with reduced sevo-postC cardioprotection. N-Acetylcysteine and sevo-postC synergistically reduced the infarct size in diabetic groups. N-Acetylcysteine remarkably increased cardiac p-STAT3 which was further enhanced by sevo-postC. N-Acetylcysteine but not sevo-postC decreased myocardial FoxO1 while sevo-postC but not N-Acetylcysteine significantly increased myocardiac adiponectin in diabetic rats. It is concluded that late stage diabetic rats displayed reduction of cardiac p-STAT3, adiponectin deficiency, and increase of FoxO1 and CD36 expression, which may be responsible for the loss of myocardial responsiveness to sevo-postC cardioprotection. N-Acetylcysteine restored Sevo-postC cardioprotection in diabetes possibly through enhancing cardiac p-STAT3 and adiponectin and reducing Fox1 and CD36.

  3. Efficacy and safety of combination therapy: repaglinide plus metformin versus nateglinide plus metformin.

    PubMed

    Raskin, Philip; Klaff, Leslie; McGill, Janet; South, Stephen A; Hollander, Priscilla; Khutoryansky, Naum; Hale, Paula M

    2003-07-01

    An open-label, parallel-group, randomized, multicenter trial was conducted to compare efficacy and safety of repaglinide versus nateglinide, when used in a combination regimen with metformin for treatment of type 2 diabetes. Enrolled patients (n = 192) had HbA(1c) >7% and < or =12% during previous treatment with a sulfonylurea, metformin, or low-dose Glucovance (glyburide < or =2.5 mg, metformin < or =500 mg). After a 4-week metformin run-in therapy period (doses escalated to 1,000 mg b.i.d.), patients were randomized to addition of repaglinide (n = 96) (1 mg/meal, maximum 4 mg/meal) or nateglinide (n = 96) (120 mg/meal, reduced to 60 mg if needed) to the regimen for 16 weeks. Glucose, insulin, and glucagon were assessed after a liquid test meal at baseline and week 16. Final HbA(1c) values were lower for repaglinide/metformin treatment than for nateglinide/metformin (7.1 vs. 7.5%). Repaglinide/metformin therapy showed significantly greater mean reductions of HbA(1c) (-1.28 vs. -0.67%; P < 0.001) and of fasting plasma glucose (FPG) (-39 vs. -21 mg/dl; P = 0.002). Self-monitoring of blood glucose profiles were significantly lower for repaglinide/metformin before breakfast, before lunch, and at 2:00 A.M. Changes in the area under the curve of postprandial glucose, insulin, or glucagon peaks after a test meal were not significantly different for the two treatment groups during this study. Median final doses were 5.0 mg/day for repaglinide and 360 mg/day for nateglinide. Safety assessments were comparable for the two regimens. The addition of repaglinide to metformin therapy resulted in reductions of HbA(1c) and FPG values that were significantly greater than the reductions observed for addition of nateglinide.

  4. Metformin enhances the radiosensitivity of human liver cancer cells to γ–rays and carbon ion beams

    PubMed Central

    Kim, Eun Ho; Kim, Mi-Sook; Furusawa, Yoshiya; Uzawa, Akiko; Han, Soorim; Jung, Won-Gyun; Sai, Sei

    2016-01-01

    The purpose of this study was to investigate the effect of metformin on the responses of hepatocellular carcinoma (HCC) cells to γ–rays (low-linear energy transfer (LET) radiation) and carbon-ion beams (high-LET radiation). HCC cells were pretreated with metformin and exposed to a single dose of γ–rays or carbon ion beams. Metformin treatment increased radiation-induced clonogenic cell death, DNA damage, and apoptosis. Carbon ion beams combined with metformin were more effective than carbon ion beams or γ-rays alone at inducing subG1 and decreasing G2/M arrest, reducing the expression of vimentin, enhancing phospho-AMPK expression, and suppressing phospho-mTOR and phospho-Akt. Thus, metformin effectively enhanced the therapeutic effect of radiation with a wide range of LET, in particular carbon ion beams and it may be useful for increasing the clinical efficacy of carbon ion beams. PMID:27802188

  5. Is red wine a SAFE sip away from cardioprotection? Mechanisms involved in resveratrol- and melatonin-induced cardioprotection.

    PubMed

    Lamont, Kim T; Somers, Sarin; Lacerda, Lydia; Opie, Lionel H; Lecour, Sandrine

    2011-05-01

    Epidemiological studies suggest that regular moderate consumption of red wine confers cardioprotection but the mechanisms involved in this effect remain unclear. Recent studies demonstrate the presence of melatonin in wine. We propose that melatonin, at a concentration found in red wine, confers cardioprotection against ischemia-reperfusion injury. Furthermore, we investigated whether both melatonin and resveratrol protect via the activation of the newly discovered survivor activating factor enhancement (SAFE) prosurvival signaling pathway that involves the activation of tumor necrosis factor alpha (TNFα) and the signal transducer and activator of transcription 3 (STAT3). Isolated perfused male mouse (wild type, TNFα receptor 2 knockout mice, and cardiomyocyte-specific STAT3-deficient mice) or rat hearts (Wistars) were subjected to ischemia-reperfusion. Resveratrol (2.3 mg/L) or melatonin (75 ng/L) was perfused for 15 min with a 10-min washout period prior to an ischemia-reperfusion insult. Infarct size was measured at the end of the protocol, and Western blot analysis was performed to evaluate STAT3 activation prior to the ischemic insult. Both resveratrol and melatonin, at concentrations found in red wine, significantly reduced infarct size compared with control hearts in wild-type mouse hearts (25 ± 3% and 25 ± 3% respectively versus control 69 ± 3%, P < 0.001) but failed to protect in TNF receptor 2 knockout or STAT3-deficient mice. Furthermore, perfusion with either melatonin or resveratrol increased STAT3 phosphorylation prior to ischemia by 79% and 50%, respectively (P < 0.001 versus control). Our data demonstrate that both melatonin and resveratrol, as found in red wine, protect the heart in an experimental model of myocardial infarction via the SAFE pathway. © 2011 John Wiley & Sons A/S.

  6. Metformin blocks progression of obesity-activated thyroid cancer in a mouse model

    PubMed Central

    Park, Jeongwon; Kim, Won Gu; Zhao, Li; Enomoto, Keisuke; Willingham, Mark; Cheng, Sheue-Yann

    2016-01-01

    Compelling epidemiologic evidence indicates that obesity is associated with a high risk of human malignancies, including thyroid cancer. We previously demonstrated that a high fat diet (HFD) effectively induces the obese phenotype in a mouse model of aggressive follicular thyroid cancer (ThrbPV/PVPten+/−mice). We showed that HFD promotes cancer progression through aberrant activation of the leptin-JAK2-STAT3 signaling pathway. HFD-promoted thyroid cancer progression allowed us to test other molecular targets for therapeutic opportunity for obesity-induced thyroid cancer. Metformin is a widely used drug to treat patients with type II diabetes. It has been shown to reduce incidences of neoplastic diseases and cancer mortality in type II diabetes patients. The present study aimed to test whether metformin could be a therapeutic for obesity-activated thyroid cancer. ThrbPV/PVPten+/−mice were fed HFD together with metformin or vehicle-only, as controls, for 20 weeks. While HFD-ThrbPV/PVPten+/−mice had shorter survival than LFD-treated mice, metformin had no effects on the survival of HFD-ThrbPV/PVPten+/−mice. Remarkably, metformin markedly decreased occurrence of capsular invasion and completely blocked vascular invasion and anaplasia in HFD-ThrbPV/PVPten+/−mice without affecting thyroid tumor growth. The impeded cancer progression was due to the inhibitory effect of metformin on STAT3-ERK-vimentin and fibronectin-integrin signaling to decrease tumor cell invasion and de-differentiation. The present studies provide additional molecular evidence to support the link between obesity and thyroid cancer risk. Importantly, our findings suggest that metformin could be used as an adjuvant in combination with antiproliferative modalities to improve the outcome of patients with obesity-activated thyroid cancer. PMID:27145454

  7. Cardiac Sirt1 mediates the cardioprotective effect of caloric restriction by suppressing local complement system activation after ischemia-reperfusion.

    PubMed

    Yamamoto, Tsunehisa; Tamaki, Kayoko; Shirakawa, Kohsuke; Ito, Kentaro; Yan, Xiaoxiang; Katsumata, Yoshinori; Anzai, Atsushi; Matsuhashi, Tomohiro; Endo, Jin; Inaba, Takaaki; Tsubota, Kazuo; Sano, Motoaki; Fukuda, Keiichi; Shinmura, Ken

    2016-04-15

    Caloric restriction (CR) confers cardioprotection against ischemia-reperfusion (I/R) injury. We previously found the essential roles of endothelial nitric oxide synthase in the development of CR-induced cardioprotection and Sirt1 activation during CR (Shinmura K, Tamaki K, Ito K, Yan X, Yamamoto T, Katsumata Y, Matsuhashi T, Sano M, Fukuda K, Suematsu M, Ishii I. Indispensable role of endothelial nitric oxide synthase in caloric restriction-induced cardioprotection against ischemia-reperfusion injury.Am J Physiol Heart Circ Physiol 308: H894-H903, 2015). However, the exact mechanism by which Sirt1 in cardiomyocytes mediates the cardioprotective effect of CR remains undetermined. We subjected cardiomyocyte-specific Sirt1 knockout (CM-Sirt1(-/-)) mice and the corresponding control mice to either 3-mo ad libitum feeding or CR (-40%). Isolated perfused hearts were subjected to 25-min global ischemia, followed by 60-min reperfusion. The recovery of left ventricle function after I/R was improved, and total lactate dehydrogenase release into the perfusate during reperfusion was attenuated in the control mice treated with CR, but a similar cardioprotective effect of CR was not observed in the CM-Sirt1(-/-)mice. The expression levels of cardiac complement component 3 (C3) at baseline and the accumulation of C3 and its fragments in the ischemia-reperfused myocardium were attenuated by CR in the control mice, but not in the CM-Sirt1(-/-)mice. Resveratrol treatment also attenuated the expression levels of C3 protein in cultured neonatal rat ventricular cardiomyocytes. Moreover, the degree of myocardial I/R injury in conventional C3 knockout (C3(-/-)) mice treated with CR was similar to that in the ad libitum-fed C3(-/-)mice, although the expression levels of Sirt1 were enhanced by CR. These results demonstrate that cardiac Sirt1 plays an essential role in CR-induced cardioprotection against I/R injury by suppressing cardiac C3 expression. This is the first report suggesting

  8. A phase I window, dose escalating and safety trial of metformin in combination with induction chemotherapy in relapsed refractory acute lymphoblastic leukemia: Metformin with induction chemotherapy of vincristine, dexamethasone, PEG-asparaginase, and doxorubicin.

    PubMed

    Trucco, Matteo; Barredo, Julio C; Goldberg, John; Leclerc, Gilles M; Hale, Gregory A; Gill, Jonathan; Setty, Bhuvana; Smith, Tiffany; Lush, Richard; Lee, Jae K; Reed, Damon R

    2018-06-01

    Acute lymphoblastic leukemia (ALL) remains a major cause of death in children. AMP-activated protein kinase (AMPK) affects the unfolded protein response (UPR), leading to increased vulnerability to endoplasmic reticulum (ER) stress in ALL cells. In vitro, metformin causes ALL cell death via AMPK-mediated inhibition of the UPR. It was evaluated whether ER stress could be induced in relapsed ALL through a phase I study investigating the safety and feasibility of metformin in combination with relapse induction chemotherapy. Metformin was administered twice daily for 28 days in addition to vincristine, dexamethasone, PEG-asparaginase and doxorubicin (VXLD). Dose escalation of metformin was evaluated using a 3+3 design. Pharmacokinetics (PK), pharmacodynamic (PD) evaluation of the AMPK and ER stress/UPR pathways, and treatment response were assessed. Fourteen patients were enrolled; all were evaluable for toxicity. The recommended phase 2 dose (RP2D) was Dose level 2, 1,000 mg/m 2 /day. A single dose-limiting toxicity (DLT), hypoglycemia with acidosis, was observed at the RP2D and two DLTs, diarrhea and acidosis, were observed at Dose Level 3. Nine patients were evaluable for response as defined by the protocol, receiving at least 85% of planned metformin doses. Five complete remissions, one partial response, and one stable disease were observed. PD evaluation showed induction of ER stress, activation of AMPK, and inhibition of the UPR. The VXLD with metformin was tolerable with a RP2D for metformin of 1,000 mg/m 2 /day and yielded responses in a heavily pretreated population. ER stress was induced and toxicities attributable to metformin occurred in all dose levels. © 2018 Wiley Periodicals, Inc.

  9. Metformin reduces lipid accumulation in macrophages by inhibiting FOXO1-mediated transcription of fatty acid-binding protein 4

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Song, Jun; Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX; Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, TX

    2010-02-26

    Objective: The accumulation of lipids in macrophages contributes to the development of atherosclerosis. Strategies to reduce lipid accumulation in macrophages may have therapeutic potential for preventing and treating atherosclerosis and cardiovascular complications. The antidiabetic drug metformin has been reported to reduce lipid accumulation in adipocytes. In this study, we examined the effects of metformin on lipid accumulation in macrophages and investigated the mechanisms involved. Methods and results: We observed that metformin significantly reduced palmitic acid (PA)-induced intracellular lipid accumulation in macrophages. Metformin promoted the expression of carnitine palmitoyltransferase I (CPT-1), while reduced the expression of fatty acid-binding protein 4 (FABP4)more » which was involved in PA-induced lipid accumulation. Quantitative real-time PCR showed that metformin regulates FABP4 expression at the transcriptional level. We identified forkhead transcription factor FOXO1 as a positive regulator of FABP4 expression. Inhibiting FOXO1 expression with FOXO1 siRNA significantly reduced basal and PA-induced FABP4 expression. Overexpression of wild-type FOXO1 and constitutively active FOXO1 significantly increased FABP4 expression, whereas dominant negative FOXO1 dramatically decreased FABP4 expression. Metformin reduced FABP4 expression by promoting FOXO1 nuclear exclusion and subsequently inhibiting its activity. Conclusions: Taken together, these results suggest that metformin reduces lipid accumulation in macrophages by repressing FOXO1-mediated FABP4 transcription. Thus, metformin may have a protective effect against lipid accumulation in macrophages and may serve as a therapeutic agent for preventing and treating atherosclerosis in metabolic syndrome.« less

  10. Metformin Improves Ileal Epithelial Barrier Function in Interleukin-10 Deficient Mice

    PubMed Central

    Xue, Yansong; Zhang, Hanying; Sun, Xiaofei; Zhu, Mei-Jun

    2016-01-01

    Background and aims The impairment of intestinal epithelial barrier is the main etiologic factor of inflammatory bowel disease. The proper intestinal epithelial proliferation and differentiation is crucial for maintaining intestinal integrity. Metformin is a common anti-diabetic drug. The objective is to evaluate the protective effects of metformin on ileal epithelial barrier integrity using interleukin-10 deficient (IL10KO) mice. Methods Wild-type and IL10KO mice were fed with/without metformin for 6 weeks and then ileum was collected for analyses. The mediatory role of AMP-activated protein kinase (AMPK) was further examined by gain and loss of function study in vitro. Results Compared to wild-type mice, IL10KO mice had increased proliferation, reduced goblet cell and Paneth cell lineage differentiation in the ileum tissue, which was accompanied with increased crypt expansion. Metformin supplementation mitigated intestinal cell proliferation, restored villus/crypt ratio, increased goblet cell and Paneth cell differentiation and improved barrier function. In addition, metformin supplementation in IL10KO mice suppressed macrophage pro-inflammatory activity as indicated by reduced M1 macrophage abundance and decreased pro-inflammatory cytokine IL-1β, TNF-α and IFN-γ expressions. As a target of metformin, AMPK phosphorylation was enhanced in mice treated with metformin, regardless of mouse genotypes. In correlation, the mRNA level of differentiation regulator including bmp4, bmpr2 and math1 were also increased in IL10KO mice supplemented with metformin, which likely explains the enhanced epithelial differentiation in IL10KO mice with metformin. Consistently, in Caco-2 cells, metformin promoted claudin-3 and E-cadherin assembly and mitigated TNF-α-induced fragmentation of tight junction proteins. Gain and loss of function assay also demonstrated AMPK was correlated with epithelial differentiation and proliferation. Conclusions Metformin supplementation promotes

  11. Minoxidil opens mitochondrial K(ATP) channels and confers cardioprotection.

    PubMed

    Sato, Toshiaki; Li, Yulong; Saito, Tomoaki; Nakaya, Haruaki

    2004-01-01

    1. ATP-sensitive potassium channel in the mitochondrial inner membrane (mitoK(ATP) channel) rather than in the sarcolemma (sarcK(ATP) channel) appears to play an important role in cardioprotection. We examined the effect of minoxidil, a potent antihypertensive agent and hair growth stimulator, on sarcK(ATP) and mitoK(ATP) channels in guinea-pig ventricular myocytes. 2. Minoxidil activated a glybenclamide-sensitive sarcK(ATP) channel current in the whole-cell recording mode with an EC(50) of 182.6 microm. Minoxidil reversibly increased the flavoprotein oxidation, an index of mitoK(ATP) channel activity, in a concentration-dependent manner. The EC(50) for mitoK(ATP) channel activation was estimated to be 7.3 microm; this value was notably approximately 25-fold lower than that for sarcK(ATP) channel activation. 3. Minoxidil (10 microm) significantly attenuated the ouabain-induced increase of mitochondrial Ca(2+) concentration, which was measured by loading cells with rhod-2 fluorescence. Furthermore, pretreatment with minoxidil (10 microm) before 20-min no-flow ischaemia significantly improved the recovery of developed tension measured after 60 min of reperfusion in coronary perfused guinea-pig ventricular muscles. These cardioprotective effects of minoxidil were completely abolished by the mitoK(ATP) channel blocker 5-hydroxydecanoate (500 microm). 4. Our results indicate that minoxidil exerts a direct cardioprotective effect on heart muscle cells, an effect mediated by the selective activation of mitoK(ATP) channels.

  12. Aqueous extract from leaf of Artocarpus altilis provides cardio-protection from isoproterenol induced myocardial damage in rats: Negative chronotropic and inotropic effects.

    PubMed

    Nwokocha, Chukwuemeka; Palacios, Javier; Simirgiotis, Mario J; Thomas, Jemesha; Nwokocha, Magdalene; Young, Lauriann; Thompson, Rory; Cifuentes, Fredi; Paredes, Adrian; Delgoda, Rupika

    2017-05-05

    The leaves of Artocarpus altilis (Parkinson ex F.A.Zorn, Fosberg) (Moraceae) are used in the management of hypertension; this study assessed the cardio-protective effects of the leaf extract on isoproterenol (ISO) induced myocardial damage in rats. Twenty (20) adult male Sprague-Dawley rats (175-230g) were divided into 5 groups. Group 1 (Control), 2 (AA) received 50mg/Kg Artocarpus altilis (AA) only; 3 (ISO) received 85mg/Kg ISO only; 4 (ISO+AA/50) and 5 (ISO+AA/100) received 50 and 100mg/Kg AA respectively for 6 days, after induced with ISO twice (85mg/Kg) at a 24-h period. Blood pressure readings were taken before and after the administering of ISO using the tail cuff method. ECG was performed on anaesthetized rats. Cardiac contractility was measured in isolated right atrial muscles. Assessment of myocardial infarct (MI) size, heart/body weight ratio, biochemical, hematological and histo-morphological parameters were conducted at the end of seven days. An aqueous extract from leaves of A. altilis was analyzed for organic compounds using UHPLC mass spectrometry. ISO induced myocardial damage through an elevation of the heart rate (HR), infarct size and ECG distortions. Treatment with AA significantly (p˂0.05) reduced heart/body weight ratio (49%), MI (96%), HR (27%), sympathovagal imbalance (36%) and serum cardiac biomarkers (AST, LDH, HDL, triglycerides and CCK) caused by ISO. AA decreased the beat frequency of isolated right atrium (11%) cause by ISO, an action similar to propranolol (beta-adrenergic antagonist; 20%), but showed no significant changes in the QTc intervals of the ECG (suggesting no cardio-toxic drug-herb interactions), Thirty nine compounds were detected using high resolution LC-MS analysis (HPLC-Orbitrap-APCI-MS) in the extract. Pure compounds, as gallic acid and rutin, presented a higher negative chronotropic effect, similar to propranolol. Oral administration of aqueous extract of Artocarpus artilis has cardio-protective functions in

  13. Ozone Induced Impairment of Systemic Metabolic Processes: Influence of Prior Ozone Exposure and Metformin Pre-treatment on Aged Wistar Kyoto (WKY) Rats.

    EPA Science Inventory

    SOT2014 Abstract for presentation: March 23-27, 2014; Phoenix, AZ Ozone Induced Impairment of Systemic Metabolic Processes: Influence of Prior Ozone Exposure and Metformin Pre-treatment on Aged Wistar Kyoto (WKY) Rats. V. Bass, D. Andrews, J. Richards, M. Schladweiler, A. Ledb...

  14. Characterization of Rubia cordifolia L. root extract and its evaluation of cardioprotective effect in Wistar rat model

    PubMed Central

    Chandrashekar, BS; Prabhakara, S; Mohan, T; Shabeer, D; Bhandare, Basavaraj; Nalini, M; Sharmila, PS; Meghana, DL; Reddy, Basanth Kumar; Hanumantha Rao, HM; Sahajananda, H; Anbazhagan, K

    2018-01-01

    OBJECTIVES: Rubia cordifolia L. (RC) is a well-known and highly valuable medicinal plant in the Ayurvedic system. The present study involves evaluating antioxidant and cardioprotective property of RC root extract. MATERIALS AND METHODS: The characterization of RC root extract was carried out using standard phytochemical and biochemical analysis. The functional groups were analyzed by Fourier transform infrared (FTIR) spectroscopy and phytotherapeutic compounds were identified using high-resolution mass spectrometry (HR-MS). Cardioprotective activity of RC root extract was investigated against cyclophosphamide (CP; 100 mg/kg, i.p)-induced cardiotoxicity in male albino Wistar rats. RC (100, 200, and 400 mg/kg, p.o) or silymarin (100 mg/kg, p.o) was administered immediately after CP on the 1st day and the next consecutive 10 days. Biochemical and histopathological analysis was performed to observe the cardioprotective effects of RC root extract. RESULTS: Phytochemical analysis revealed the presence of secondary metabolites that include alkaloids, flavonoids, saponins, and anthraquinones in RC root extract. FTIR analysis revealed the presence of several functional groups. Based on HR-MS analysis, eight major phytotherapeutic compounds were identified in methanol root extract of RC. Biochemical analysis in CP-induced rat model administered with RC extract revealed significantly enhanced levels of antioxidant markers such as superoxide dismutase, catalase, and glutathione S-transferase. Histopathological study showed that the rat model treated with the root extract had reduced the cardiac injury. CONCLUSION: Our results have shown that the RC extract contains various antioxidant compounds with cardioprotective effect. Treatment with RC root extract could significantly protect CP-induced rats from cardiac tissue injury by restoring the antioxidant markers. PMID:29861523

  15. Inhibition of RhoA/Rho kinase by ibuprofen exerts cardioprotective effect on isoproterenol induced myocardial infarction in rats.

    PubMed

    Patel, Prexita; Parikh, Mihir; Shah, Hital; Gandhi, Tejal

    2016-11-15

    Myocardial infarction (MI) and hypertension are the leading cause of death worldwide so protection of heart is focus of intense research. Rho-kinase, a downstream effector of protein involved in MI and hypertension, is inhibited by ibuprofen. This study aims to elucidate cardioprotective effect of ibuprofen in rats. MI was produced in rats with 85mg/kg isoproterenol (ISO) administered s.c. twice at an interval of 24h. The rats were randomized into six groups: (I) Normal; (II) ISO; (III) ISO + ascorbic acid (250mg/kg p.o.); (IV-VI) ISO + ibuprofen (30, 60 and 90mg/kg p.o). After the completion of the study period of 21 days, cardiac function and biomarkers were assessed. Pre-treatment with ibuprofen (30, 60 and 90mg/kg p.o) ameliorated high BP and left ventricular dysfunction, furthermore it prevented the rise in CKMB, LDH and α-HBDH, suggesting the effect of ibuprofen in maintenance of cell membrane integrity. In addition, it also prevented alteration in the levels of electrolytes, ATPase activity and antioxidant status. Ibuprofen suppressed ISO-induced ROCK-1 mRNA expression and histological changes. Ibuprofen provided cardioprotection in a model of myocardial infarction, by restoring most of the altered physical, physiological, biochemical, haemodynamic parameters, antioxidant status, and histological changes and by inhibiting ROCK-1 mRNA expression. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. The cardioprotective efficacy of TVP1022 in a rat model of ischaemia/reperfusion

    PubMed Central

    Ertracht, Offir; Liani, Esti; Bachner-Hinenzon, Noa; Bar-Am, Orit; Frolov, Luba; Ovcharenko, Elena; Awad, Huda; Blum, Shany; Barac, Yaron; Amit, Tamar; Adam, Dan; Youdim, Moussa; Binah, Ofer

    2011-01-01

    BACKGROUND AND PURPOSE Because myocardial infarction is a major cause of morbidity and mortality worldwide, protecting the heart from the ischaemia and reperfusion (I/R) damage is the focus of intense research. Based on our in vitro findings showing that TVP1022 (the S-enantiomer of rasagiline, an anti-Parkinsonian drug) possesses cardioprotective effects, in the present study we investigated the hypothesis that TVP1022 can attenuate myocardial damage in an I/R model in rats. EXPERIMENTAL APPROACH The model consisted of 30-min occlusion of the left anterior descending artery followed by 4 or 24 h reperfusion. In addition, we investigated the possible mechanisms of cardioprotection in H9c2 cells and neonatal rat ventricular myocytes (NRVM) exposed to oxidative stress induced by H2O2. KEY RESULTS TVP1022 (20 and 40 mg·kg−1) administered 5 min before reperfusion followed by an additional dose 4 h after reperfusion reduced the infarct size and attenuated the decline in ventricular function. TVP1022 also attenuated I/R-induced deterioration in cardiac mitochondrial integrity evaluated by mitochondrial swelling capacity. In vitro, using H9c2 cells and NRVM, TVP1022 attenuated both serum free- and H2O2-induced damage, preserved mitochondrial membrane potential and Bcl-2 levels, inhibited mitochondrial cytochrome c release and the increase in cleaved caspase 9 and 3 levels, and enhanced the phosphorylation of protein kinase C and glycogen synthase kinase-3β. CONCLUSIONS AND IMPLICATIONS TVP1022 provided cardioprotection in a model of myocardial infarction, and therefore should be considered as a novel adjunctive therapy for attenuating myocardial damage resulting from I/R injuries. PMID:21323905

  17. The cardioprotective efficacy of TVP1022 in a rat model of ischaemia/reperfusion.

    PubMed

    Ertracht, Offir; Liani, Esti; Bachner-Hinenzon, Noa; Bar-Am, Orit; Frolov, Luba; Ovcharenko, Elena; Awad, Huda; Blum, Shany; Barac, Yaron; Amit, Tamar; Adam, Dan; Youdim, Moussa; Binah, Ofer

    2011-06-01

    Because myocardial infarction is a major cause of morbidity and mortality worldwide, protecting the heart from the ischaemia and reperfusion (I/R) damage is the focus of intense research. Based on our in vitro findings showing that TVP1022 (the S-enantiomer of rasagiline, an anti-Parkinsonian drug) possesses cardioprotective effects, in the present study we investigated the hypothesis that TVP1022 can attenuate myocardial damage in an I/R model in rats. The model consisted of 30-min occlusion of the left anterior descending artery followed by 4 or 24 h reperfusion. In addition, we investigated the possible mechanisms of cardioprotection in H9c2 cells and neonatal rat ventricular myocytes (NRVM) exposed to oxidative stress induced by H(2) O(2) . TVP1022 (20 and 40 mg·kg(-1) ) administered 5 min before reperfusion followed by an additional dose 4 h after reperfusion reduced the infarct size and attenuated the decline in ventricular function. TVP1022 also attenuated I/R-induced deterioration in cardiac mitochondrial integrity evaluated by mitochondrial swelling capacity. In vitro, using H9c2 cells and NRVM, TVP1022 attenuated both serum free- and H(2) O(2) -induced damage, preserved mitochondrial membrane potential and Bcl-2 levels, inhibited mitochondrial cytochrome c release and the increase in cleaved caspase 9 and 3 levels, and enhanced the phosphorylation of protein kinase C and glycogen synthase kinase-3β. TVP1022 provided cardioprotection in a model of myocardial infarction, and therefore should be considered as a novel adjunctive therapy for attenuating myocardial damage resulting from I/R injuries. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

  18. The combined effect of metformin and L-cysteine on inflammation, oxidative stress and insulin resistance in streptozotocin-induced type 2 diabetes in rats.

    PubMed

    Salman, Zenat K; Refaat, Rowaida; Selima, Eman; El Sarha, Ashgan; Ismail, Menna A

    2013-08-15

    Increasing evidence has established causative links between obesity, chronic inflammation and insulin resistance; the core pathophysiological feature in type 2 diabetes mellitus. This study was designed to examine whether the combination of L-cysteine and metformin would provide additional benefits in reducing oxidative stress, inflammation and insulin resistance in streptozotocin-induced type 2 diabetes in rats. Male Wistar rats were fed a high-fat diet (HFD) for 8 weeks to induce insulin resistance after which they were rendered diabetic with low-dose streptozotocin. Diabetic rats were treated with metformin (300 mg/kg/day), L-cysteine (300 mg/kg/day) and their combination along with HFD for another 2 weeks. Control rats were fed normal rat chow throughout the experiment. At the end of treatment, fasting blood glucose, fasting serum insulin, homeostasis model assessment-insulin resistance index (HOMA-IR) and serum free fatty acids (FFAs) were measured. Serum levels of the inflammatory markers; monocyte chemoattractant protein-1 (MCP-1), C-reactive protein (CRP) and nitrite/nitrate were also determined. The liver was isolated and used for determination of malondialdehyde (MDA), reduced glutathione (GSH), caspase-3 and cytochrome c levels. The hypoglycemic effect of the combination therapy exceeded that of metformin and L-cysteine monotherapies with more improvement in insulin resistance. All treated groups exhibited significant reductions in serum FFAs, oxidative stress and inflammatory parameters, caspase-3 and cytochrome c levels compared to untreated diabetic rats with the highest improvement observed in the combination group. In conclusion, the present results clearly suggest that L-cysteine can be strongly considered as an adjunct to metformin in management of type 2 diabetes. © 2013 Elsevier B.V. All rights reserved.

  19. Cardioprotection and lifespan extension by the natural polyamine spermidine

    PubMed Central

    Eisenberg, Tobias; Abdellatif, Mahmoud; Schroeder, Sabrina; Primessnig, Uwe; Stekovic, Slaven; Pendl, Tobias; Harger, Alexandra; Schipke, Julia; Zimmermann, Andreas; Schmidt, Albrecht; Tong, Mingming; Ruckenstuhl, Christoph; Dammbrueck, Christopher; Gross, Angelina S.; Herbst, Viktoria; Magnes, Christoph; Trausinger, Gert; Narath, Sophie; Meinitzer, Andreas; Hu, Zehan; Kirsch, Alexander; Eller, Kathrin; Gutierrez, Didac-Carmona; Büttner, Sabrina; Pietrocola, Federico; Knittelfelder, Oskar; Schrepfer, Emilie; Rockenfeller, Patrick; Simonini, Corinna; Rahn, Alexandros; Horsch, Marion; Moreth, Kristin; Beckers, Johannes; Fuchs, Helmut; Gailus-Durner, Valerie; Neff, Frauke; Janik, Dirk; Rathkolb, Birgit; Rozman, Jan; de Angelis, Martin Hrabe; Moustafa, Tarek; Haemmerle, Guenter; Mayr, Manuel; Willeit, Peter; von Frieling-Salewsky, Marion; Pieske, Burkert; Scorrano, Luca; Pieber, Thomas; Pechlaner, Raimund; Willeit, Johann; Sigrist, Stephan J.; Linke, Wolfgang A.; Mühlfeld, Christian; Sadoshima, Junichi; Dengjel, Joern; Kiechl, Stefan; Kroemer, Guido; Sedej, Simon; Madeo, Frank

    2018-01-01

    Aging is associated with an increased risk of cardiovascular disease and death. Here we show that oral supplementation of the natural polyamine spermidine extends the lifespan of mice and exerts cardioprotective effects, reducing cardiac hypertrophy and preserving diastolic function in old mice. Spermidine feeding enhanced cardiac autophagy, mitophagy and mitochondrial respiration, and it also improved the mechano-elastical properties of cardiomyocytes in vivo, coinciding with increased titin phosphorylation and suppressed subclinical inflammation. Spermidine feeding failed to provide cardioprotection in mice that lack the autophagy-related protein Atg5 in cardiomyocytes. In Dahl salt-sensitive rats that were fed a high-salt diet, a model for hypertension-induced congestive heart failure, spermidine feeding reduced systemic blood pressure, increased titin phosphorylation and prevented cardiac hypertrophy and a decline in diastolic function, thus delaying the progression to heart failure. In humans, high levels of dietary spermidine, as assessed from food questionnaires, correlated with reduced blood pressure and a lower incidence of cardiovascular disease. Our results suggest a new and feasible strategy for the protection from cardiovascular disease. PMID:27841876

  20. Beneficial effect of zinc chloride and zinc ionophore pyrithione on attenuated cardioprotective potential of preconditioning phenomenon in STZ-induced diabetic rat heart.

    PubMed

    Jamwal, Sumit; Kumar, Kushal; Reddy, B V Krishna

    2016-05-01

    Ischemic preconditioning (IPC) is well demonstrated to produce cardioprotection by phosphorylation and subsequent inactivation of glycogen synthase kinase-3β (GSk-3β) in the normal rat heart, but its effect is attenuated in the diabetic rat heart. This study was designed to investigate the effect of zinc chloride and zinc ionophore pyrithione (ZIP) on the attenuated cardioprotective potential of IPC in the diabetic rat heart. Diabetes mellitus (DM) was induced by a single intraperitoneal administration of streptozotocin (STZ) (50 mg/kg; i.p). The isolated perfused rat heart was subjected to 30 minutes of ischemia followed by 120 minutes of reperfusion. Myocardial infarct size was estimated by triphenyltetrazolium chloride (TTC) staining and cardiac injury was measured by estimating lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) in the coronary effluent. Also, GSK-3β was measured and neutrophil accumulation was measured by estimating myeloperoxidase (MPO) levels. IPC significantly decreased the myocardial infarct size, the release of LDH and CK-MB, the GSK-3β levels and the MPO levels in the normal rat heart. Pre- and post-ischemic treatment with zinc chloride and zinc ionophore pyrithione (ZIP) in the normal and diabetic rat hearts significantly decreased the myocardial infarct size, the level of CK-MB and LDH in the coronary effluent and GSK-3β and MPO levels. Our results suggest that pharmacological preconditioning with zinc chloride and ZIP significantly restored the attenuated cardioprotective potential of IPC in the diabetic rat heart. © The Author(s) 2015.

  1. Modulation by metformin of molecular and histopathological alterations in the lung of cigarette smoke-exposed mice

    PubMed Central

    Izzotti, Alberto; Balansky, Roumen; D'Agostini, Francesco; Longobardi, Mariagrazia; Cartiglia, Cristina; Micale, Rosanna T; La Maestra, Sebastiano; Camoirano, Anna; Ganchev, Gancho; Iltcheva, Marietta; Steele, Vernon E; De Flora, Silvio

    2014-01-01

    The anti-diabetic drug metformin is endowed with anti-cancer properties. Epidemiological and experimental studies, however, did not provide univocal results regarding its role in pulmonary carcinogenesis. We used Swiss H mice of both genders in order to detect early molecular alterations and tumors induced by mainstream cigarette smoke. Based on a subchronic toxicity study, oral metformin was used at a dose of 800 mg/kg diet, which is 3.2 times higher than the therapeutic dose in humans. Exposure of mice to smoke for 4 months, starting at birth, induced a systemic clastogenic damage, formation of DNA adducts, oxidative DNA damage, and extensive downregulation of microRNAs in lung after 10 weeks. Preneoplastic lesions were detectable after 7.5 months in both lung and urinary tract along with lung tumors, both benign and malignant. Modulation by metformin of 42 of 1281 pulmonary microRNAs in smoke-free mice highlighted a variety of mechanisms, including modulation of AMPK, stress response, inflammation, NFκB, Tlr9, Tgf, p53, cell cycle, apoptosis, antioxidant pathways, Ras, Myc, Dicer, angiogenesis, stem cell recruitment, and angiogenesis. In smoke-exposed mice, metformin considerably decreased DNA adduct levels and oxidative DNA damage, and normalized the expression of several microRNAs. It did not prevent smoke-induced lung tumors but inhibited preneoplastic lesions in both lung and kidney. In conclusion, metformin was able to protect the mouse lung from smoke-induced DNA and microRNA alterations and to inhibit preneoplastic lesions in lung and kidney but failed to prevent lung adenomas and malignant tumors induced by this complex mixture. PMID:24683044

  2. Advanced onset of puberty after metformin therapy in swine with thrifty genotype.

    PubMed

    Astiz, S; Gonzalez-Bulnes, A; Astiz, I; Barbero, A; Perez-Solana, M L; Garcia-Real, I

    2014-09-01

    The prevention and treatment of obesity in children is based on adequate nutrition and exercise plus antihyperglycaemic drugs. Currently, the incidence of childhood obesity is aggravated in ethnicities with thrifty genotype, but there is no available information on the effects of metformin therapy. The relative effects of lifestyle and metformin on patterns of growth, fattening, metabolic status and attainment of puberty were assessed in females of an obese swine model (Iberian gilts), allocated to three experimental groups (group A, obesogenic diet and scarce exercise; group DE, adequate diet and opportunity for exercise; and group DEM, adequate diet and opportunity for exercise plus metformin). Group A evidenced high weight, corpulence and adiposity, high plasma triglycerides and impairments of glucose regulation predisposing to insulin resistance. These features were favourably modulated by adequate lifestyle (group DE), and these effects were strengthened by metformin treatment (group DEM), which induced an improvement in body development by favouring muscle deposition. However, contrary to expectations, metformin advanced the onset of puberty. Metformin treatments would have positive effects on growth patterns, adiposity and metabolic features of young females from ethnicities with thrifty genotype or developing leptin resistance, but a negative effect by advancing the attainment of puberty. This study provides a warning regarding the use of metformin, without further studies, in girls from these ethnicities. © 2014 The Authors. Experimental Physiology © 2014 The Physiological Society.

  3. Metformin Use and Endometrial Cancer Survival

    PubMed Central

    Nevadunsky, Nicole S.; Van Arsdale, Anne; Strickler, Howard D.; Moadel, Alyson; Kaur, Gurpreet; Frimer, Marina; Conroy, Erin; Goldberg, Gary L.; Einstein, Mark H.

    2013-01-01

    Objective Impaired glucose tolerance and diabetes are risk factors for the development of uterine cancer. Although greater progression free survival among diabetic patients with ovarian and breast cancer using metformin have been reported, no studies have assessed the association of metformin use with survival in women with endometrial cancer (EC). Methods We conducted a single-institution retrospective cohort study of all patients treated for uterine cancer from January 1999 through December 2009. Demographic, medical, social, and survival data were abstracted from medical records and the national death registry. Overall survival (OS) was estimated using Kaplan-Meier methods. Cox models were utilized for multivariate analysis. All statistical tests were two-sided. Results Of 985 patients, 114 (12%) had diabetes and were treated with metformin, 136 (14%) were diabetic but did not use metformin, and 735 (74%) had not been diagnosed with diabetes. Greater OS was observed in diabetics with non-endometrioid EC who used metformin than in diabetic cases not using metformin and non-endometrioid EC cases without diabetes (log rank test (p=0.02)). This association remained significant (hazard ratio = 0.54, 95% CI: 0.30–0.97, p<0.04) after adjusting for age, clinical stage, grade, chemotherapy treatment, radiation treatment and presence of hyperlipidemia in multivariate analysis. No association between metformin use and OS in diabetics with endometrioid histology was observed. Conclusion Diabetic EC patients with non-endometrioid tumors who used metformin had lower risk of death than women with EC who did not use metformin. These data suggest that metformin might be useful as adjuvant therapy for non-endometrioid EC. PMID:24189334

  4. Metformin use and endometrial cancer survival.

    PubMed

    Nevadunsky, Nicole S; Van Arsdale, Anne; Strickler, Howard D; Moadel, Alyson; Kaur, Gurpreet; Frimer, Marina; Conroy, Erin; Goldberg, Gary L; Einstein, Mark H

    2014-01-01

    Impaired glucose tolerance and diabetes are risk factors for the development of uterine cancer. Although greater progression free survival among diabetic patients with ovarian and breast cancers using metformin has been reported, no studies have assessed the association of metformin use with survival in women with endometrial cancer (EC). We conducted a single-institution retrospective cohort study of all patients treated for uterine cancer from January 1999 through December 2009. Demographic, medical, social, and survival data were abstracted from medical records and the national death registry. Overall survival (OS) was estimated using Kaplan-Meier methods. Cox models were utilized for multivariate analysis. All statistical tests were two-sided. Of 985 patients, 114 (12%) had diabetes and were treated with metformin, 136 (14%) were diabetic but did not use metformin, and 735 (74%) had not been diagnosed with diabetes. Greater OS was observed in diabetics with non-endometrioid EC who used metformin than in diabetic cases not using metformin and non-endometrioid EC cases without diabetes (log rank test (p=0.02)). This association remained significant (hazard ratio=0.54, 95% CI: 0.30-0.97, p<0.04) after adjusting for age, clinical stage, grade, chemotherapy treatment, radiation treatment and the presence of hyperlipidemia in multivariate analysis. No association between metformin use and OS in diabetics with endometrioid histology was observed. Diabetic EC patients with non-endometrioid tumors who used metformin had lower risk of death than women with EC who did not use metformin. These data suggest that metformin might be useful as adjuvant therapy for non-endometrioid EC. © 2013. Published by Elsevier Inc. All rights reserved.

  5. Cardioprotective Effects of Tualang Honey: Amelioration of Cholesterol and Cardiac Enzymes Levels.

    PubMed

    Khalil, Md Ibrahim; Tanvir, E M; Afroz, Rizwana; Sulaiman, Siti Amrah; Gan, Siew Hua

    2015-01-01

    The present study was designed to investigate the cardioprotective effects of Malaysian Tualang honey against isoproterenol- (ISO-) induced myocardial infarction (MI) in rats by investigating changes in the levels of cardiac marker enzymes, cardiac troponin I (cTnI), triglycerides (TG), total cholesterol (TC), lipid peroxidation (LPO) products, and antioxidant defense system combined with histopathological examination. Male albino Wistar rats (n = 40) were pretreated orally with Tualang honey (3 g/kg/day) for 45 days. Subcutaneous injection of ISO (85 mg/kg in saline) for two consecutive days caused a significant increase in serum cardiac marker enzymes (creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), and aspartate transaminase (AST)), cTnI, serum TC, and TG levels. In addition, ISO-induced myocardial injury was confirmed by a significant increase in heart lipid peroxidation (LPO) products (TBARS) and a significant decrease in antioxidant enzymes (SOD, GPx, GRx, and GST). Pretreatment of ischemic rats with Tualang honey conferred significant protective effects on all of the investigated biochemical parameters. The biochemical findings were further confirmed by histopathological examination in both Tualang-honey-pretreated and ISO-treated hearts. The present study demonstrates that Tualang honey confers cardioprotective effects on ISO-induced oxidative stress by contributing to endogenous antioxidant enzyme activity via inhibition of lipid peroxidation.

  6. Modified Metformin as a More Potent Anticancer Drug: Mitochondrial Inhibition, Redox Signaling, Antiproliferative Effects and Future EPR Studies.

    PubMed

    Kalyanaraman, Balaraman; Cheng, Gang; Hardy, Micael; Ouari, Olivier; Sikora, Adam; Zielonka, Jacek; Dwinell, Michael B

    2017-12-01

    Metformin, one of the most widely prescribed antidiabetic drugs in the world, is being repurposed as a potential drug in cancer treatment. Epidemiological studies suggest that metformin exerts anticancer effects in diabetic patients with pancreatic cancer. However, at typical antidiabetic doses the bioavailability of metformin is presumably too low to exert antitumor effects. Thus, more potent analogs of metformin are needed in order to increase its anticancer efficacy. To this end, a new class of mitochondria-targeted metformin analogs (or mito-metformins) containing a positively-charged lipophilic triphenylphosphonium group was synthesized and tested for their antitumor efficacy in pancreatic cancer cells. Results indicate that the lead compound, mito-metformin 10 , was nearly 1000-fold more potent than metformin in inhibiting mitochondrial complex I activity, inducing reactive oxygen species (superoxide and hydrogen peroxide) that stimulate redox signaling mechanisms, including the activation of adenosinemonophosphate kinase and inhibition of proliferation of pancreatic cancer cells. The potential use of the low-temperature electron paramagnetic resonance technique in assessing the role of mitochondrial complexes including complex I in tumor regression in response to metformin and mito-metformins in the in vivo setting is discussed.

  7. Cardioprotective mIGF-1/SIRT1 signaling induces hypertension, leukocytosis and fear response in mice

    PubMed Central

    Bolasco, Giulia; Calogero, Raffaele; Carrara, Matteo; Al Banchaabouchi, Mumna; Bilbao, Daniel; Mazzoccoli, Gianluigi; Vinciguerra, Manlio

    2012-01-01

    Locally acting insulin growth factor isoform (mIGF-1) and the NAD+-dependent protein deacetylase SIRT1 are implicated in life and health span. Heart failure is associated with aging and is a major cause of death. mIGF-1 protects the heart from oxidative stresses via SIRT1. SIRT1 subcellular localization and its genomic regulation by mIGF-1 are unknown. We show here that SIRT1 is located in the nuclei of a significant fraction of cardiomyocytes. Using high throughput sequencing approaches in mIGF-1 transgenic mice, we identified new targets of the mIGF-1/SIRT1 signaling. In addition to its potent cardioprotective properties, cardiac-restricted mIGF-1 transgene induced systemic changes such as high blood pressure, leukocytosis and an enhanced fear response, in a SIRT1-dependent manner. Cardiac mIGF-1/SIRT1 signaling may thus modulate disparate systemic functions. PMID:22691943

  8. Twice-daily dosing of a repaglinide/metformin fixed-dose combination tablet provides glycaemic control comparable to rosiglitazone/metformin tablet.

    PubMed

    Raskin, P; Lewin, A; Reinhardt, R; Lyness, W

    2009-09-01

    To assess the use of a new repaglinide/metformin fixed-dose combination (FDC) tablet for the treatment of type 2 diabetes. In this 26-week, multicentre, open-label, parallel-group trial, subjects poorly controlled with mono- or dual-oral antidiabetic therapy were randomized 1 : 1 : 1 to receive a repaglinide/metformin FDC tablet either two times daily (BID) or three times daily (TID) or a rosiglitazone/metformin FDC tablet BID. The primary objective comprised two hypotheses tested in a hierarchical order: (i) that treatment with the repaglinide/metformin FDC BID is non-inferior to that of a rosiglitazone/metformin FDC tablet BID as measured by changes in haemoglobin A1c (HbA1c) (results presented here) and (ii) if true, that treatment with the repaglinide/metformin FDC BID was non-inferior to that of the repaglinide/metformin FDC TID as measured by changes in HbA1c (results presented in a companion paper). Additional efficacy and safety end-points were also assessed. Of the 561 subjects randomized, 383 completed the study. Reductions in HbA1c values became apparent at earlier times for repaglinide/metformin FDC BID treatment than rosiglitazone/metformin FDC BID, and final changes in HbA1c were not significantly different between treatment arms (p = 0.8186); thus, the predefined statistical criterion for non-inferiority was met. Overall adverse event profiles were comparable between treatment groups, and no major hypoglycaemic episodes were reported during the study. The repaglinide/metformin FDC BID regimen showed efficacy that was non-inferior to that of the rosiglitazone/metformin FDC BID regimen currently in clinical use and a more rapid reduction of HbA1c values. Thus, repaglinide/metformin FDC BID is a clinically feasible alternative to rosiglitazone/metformin FDC BID.

  9. Chemosensitizing effects of metformin on cisplatin- and paclitaxel-resistant ovarian cancer cell lines.

    PubMed

    Dos Santos Guimarães, Isabella; Ladislau-Magescky, Taciane; Tessarollo, Nayara Gusmão; Dos Santos, Diandra Zipinotti; Gimba, Etel Rodrigues Pereira; Sternberg, Cinthya; Silva, Ian Victor; Rangel, Leticia Batista Azevedo

    2017-11-21

    Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy. Primary cytoreductive surgery with adjuvant taxane-platinum chemotherapy is the standard treatment to fight ovarian cancer, however, their side effects are severe, and chemoresistance emerges at high rates. Therefore, EOC clinic urges for novel treatment strategies to reverse chemoresistance and to improve the survival rates. Metformin has been shown to act in synergy with certain anti-cancer agents, overcoming chemoresistance in various types of tumors. This paper aims to investigate the use of metformin as a new treatment option for cisplatin- and paclitaxel-resistant ovarian cancer. The effects of metformin alone or in combination with conventional drugs on resistant EOC cell lines were investigated using the MTT assay for cell proliferation; Flow Cytometry analysis for cell cycle and the mRNA expression was analyzed using the real-time PCR technique. We found that metformin exhibited antiproliferative effects in paclitaxel-resistant A2780-PR, and in cisplatin-resistant ACRP cell lines. The combined therapy containing conventional drugs and metformin improved the effect of the treatment in cell proliferation rate, especially in the resistant cells. We found that metformin, in clinical relevant doses, could significantly reduce the mRNA expression of inflammatory cytokines and NF-κB signaling pathway. Taken together, our observations suggest that metformin inhibits the inflammatory pathway induced by paclitaxel and cisplatin treatment. Furthermore, metformin in combination with paclitaxel or cisplatin improved the sensitivity in drug-resistant ovarian cancer cells. Therefore, metformin may be beneficial treatment strategy, particularly in patients with tumors refractory to platinum and taxanes. Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.

  10. PolyMetformin combines carrier and anticancer activities for in vivo siRNA delivery.

    PubMed

    Zhao, Yi; Wang, Wei; Guo, Shutao; Wang, Yuhua; Miao, Lei; Xiong, Yang; Huang, Leaf

    2016-06-06

    Metformin, a widely implemented anti-diabetic drug, exhibits potent anticancer efficacies. Herein a polymeric construction of Metformin, PolyMetformin (PolyMet) is successfully synthesized through conjugation of linear polyethylenimine (PEI) with dicyandiamide. The delocalization of cationic charges in the biguanide groups of PolyMet reduces the toxicity of PEI both in vitro and in vivo. Furthermore, the polycationic properties of PolyMet permits capture of siRNA into a core-membrane structured lipid-polycation-hyaluronic acid (LPH) nanoparticle for systemic gene delivery. Advances herein permit LPH-PolyMet nanoparticles to facilitate VEGF siRNA delivery for VEGF knockdown in a human lung cancer xenograft, leading to enhanced tumour suppressive efficacy. Even in the absence of RNAi, LPH-PolyMet nanoparticles act similarly to Metformin and induce antitumour efficacy through activation of the AMPK and inhibition of the mTOR. In essence, PolyMet successfully combines the intrinsic anticancer efficacy of Metformin with the capacity to carry siRNA to enhance the therapeutic activity of an anticancer gene therapy.

  11. Metformin suppresses CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating aryl hydrocarbon receptor expression

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Do, Minh Truong; Kim, Hyung Gyun; Tran, Thi Thu Phuong

    2014-10-01

    Induction of cytochrome P450 (CYP) 1A1 and CYP1B1 by environmental xenobiotic chemicals or endogenous ligands through the activation of the aryl hydrocarbon receptor (AhR) has been implicated in a variety of cellular processes related to cancer, such as transformation and tumorigenesis. Here, we investigated the effects of the anti-diabetes drug metformin on expression of CYP1A1 and CYP1B1 in breast cancer cells under constitutive and inducible conditions. Our results indicated that metformin down-regulated the expression of CYP1A1 and CYP1B1 in breast cancer cells under constitutive and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced conditions. Down-regulation of AhR expression was required for metformin-mediated decreases in CYP1A1 andmore » CYP1B1 expression, and the metformin-mediated CYP1A1 and CYP1B1 reduction is irrelevant to estrogen receptor α (ERα) signaling. Furthermore, we found that metformin markedly down-regulated Sp1 protein levels in breast cancer cells. The use of genetic and pharmacological tools revealed that metformin-mediated down-regulation of AhR expression was mediated through the reduction of Sp1 protein. Metformin inhibited endogenous AhR ligand-induced CYP1A1 and CYP1B1 expression by suppressing tryptophan-2,3-dioxygenase (TDO) expression in MCF-7 cells. Finally, metformin inhibits TDO expression through a down-regulation of Sp1 and glucocorticoid receptor (GR) protein levels. Our findings demonstrate that metformin reduces CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating AhR signaling. Metformin would be able to act as a potential chemopreventive agent against CYP1A1 and CYP1B1-mediated carcinogenesis and development of cancer. - Graphical abstract: Schematic of the CYP1A1 and CYP1B1 gene regulation by metformin. - Highlights: • Metformin inhibits CYP1A1 and CYP1B1 expression. • Metformin down-regulates the AhR signaling. • Metformin reduces Sp1 protein expression. • Metformin suppresses TDO

  12. Metformin Therapy for Fanconis Anemia

    DTIC Science & Technology

    2017-08-01

    Specifically, the commonly used diabetes drug metformin will be tested by itself and in combination with the current standard of care, anabolic steroids...pertains to the treatment of the inherited bone marrow failure syndrome Fanconi’s Anemia. Specifically, the commonly used diabetes drug metformin will be... drug , small molecule, DNA damage, metformin 3. Accomplishments We started work on this project less than a year ago and already have made good progress

  13. MiRNA-21 mediates the antiangiogenic activity of metformin through targeting PTEN and SMAD7 expression and PI3K/AKT pathway

    PubMed Central

    Luo, Mao; Tan, Xiaoyong; Mu, Lin; Luo, Yulin; Li, Rong; Deng, Xin; Chen, Ni; Ren, Meiping; Li, Yongjie; Wang, Liqun; Wu, Jianbo; Wan, Qin

    2017-01-01

    Metformin, an anti-diabetic drug commonly used for type 2 diabetes therapy, is associated with anti-angiogenic effects in conditions beyond diabetes. miR-21 has been reported to be involved in the process of angiogenesis. However, the precise regulatory mechanisms by which the metformin-induced endothelial suppression and its effects on miR-21-dependent pathways are still unclear. Bioinformatic analysis and identification of miR-21 and its targets and their effects on metformin-induced antiangiogenic activity were assessed using luciferase assays, quantitative real-time PCR, western blots, scratch assays, CCK-8 assays and tubule formation assays. In this study, miR-21 was strikingly downregulated by metformin in a time- and dose-dependent manner. miR-21 directly targeted the 3′-UTR of PTEN and SMAD7, and negatively regulated their expression. Overexpression of miR-21 abrogated the metformin-mediated inhibition of endothelial cells proliferation, migration, tubule formation and the TGF-β-induced AKT, SMAD- and ERK-dependent phosphorylations, and conversely, down-regulation of miR-21 aggravated metformin’s action and revealed significant promotion effects. Our study broadens our understanding of the regulatory mechanism of miR-21 mediating metformin-induced anti-angiogenic effects, providing important implications regarding the design of novel miRNA-based therapeutic strategies against angiogenesis. PMID:28230206

  14. Noble gases as cardioprotectants – translatability and mechanism

    PubMed Central

    Smit, Kirsten F; Weber, Nina C; Hollmann, Markus W; Preckel, Benedikt

    2015-01-01

    Several noble gases, although classified as inert substances, exert a tissue-protective effect in different experimental models when applied before organ ischaemia as an early or late preconditioning stimulus, after ischaemia as a post-conditioning stimulus or when given in combination before, during and/or after ischaemia. A wide range of organs can be protected by these inert substances, in particular cardiac and neuronal tissue. In this review we summarize the data on noble gas-induced cardioprotection, focusing on the underlying protective mechanisms. We will also look at translatability of experimental data to the clinical situation. PMID:25363501

  15. Involvement of atrial natriuretic peptide in abrogated cardioprotective effect of ischemic preconditioning in ovariectomized rat heart.

    PubMed

    Vishwakarma, V K; Goyal, A; Gupta, J K; Upadhyay, P K; Yadav, H N

    2018-07-01

    Nitric oxide (NO) is an effective mediator of ischemic preconditioning (IPC)-induced cardioprotection. Atrial natriuretic peptide (ANP) is downregulated after ovariectomy, which results in reduction in the level of NO. The present study deals with the investigation of the role of ANP in abrogated cardioprotective effect of IPC in the ovariectomized rat heart. Heart was isolated from ovariectomized rat and mounted on Langendorff's apparatus, subjected to 30 min of ischemia and 120 min of reperfusion. IPC was given by four cycles of 5 min of ischemia and 5 min of reperfusion with Krebs-Henseleit solution. The myocardial infract size was estimated employing triphenyltetrazolium chloride stain, and coronary effluent was analyzed for creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) release to consider the degree of myocardial injury. The cardiac release of NO was estimated by measuring the level of nitrite in coronary effluent. IPC-mediated cardioprotection was significantly attenuated in ovariectomized rat as compared to normal rat, which was restored by perfusion with ANP. However, this observed cardioprotection was significantly attenuated by perfusion with L-NAME, an endothelial nitric oxide synthase inhibitor, and Glibenclamide, a K ATP channel blocker, alone or in combination noted in terms of increase in myocardial infract size, release of CK-MB and LDH, and also decrease in release of NO. Thus, it is suggested that ANP restores the attenuated cardioprotective effect of IPC in the ovariectomized rat heart which may be due to increase in the availability of NO and consequent increase activation of mitochondrial K ATP channels.

  16. Evaluating the effect of insulin sensitizers metformin and pioglitazone alone and in combination on women with polycystic ovary syndrome: An RCT

    PubMed Central

    Sohrevardi, Seyed Mojtaba; Nosouhi, Fahime; Hossein Khalilzade, Saeed; Kafaie, Parichehr; Karimi-Zarchi, Mojgan; Halvaei, Iman; Mohsenzadeh, Mehdi

    2016-01-01

    Background: Insulin resistance and hyperinsulinemia may play a role in pathogenesis of PCOS. One of the common therapeutic methods is using insulin-sensitizing drugs such as metformin and thiazolidinediones. Objective: The purpose was to determine the effect of metformin and pioglitazone on clinical, hormonal and metabolic parameters in women with PCOS. Materials and Methods: Eighty four women randomly received one of the following for 3 months: metformin (n=28) (500 mg three times a day), pioglitazone (30 mg daily) (n=28) and combination of both metformin and pioglitazone (n=28) (30 mg/day pioglitazone plus 500 mg metformin three times a day). Hormonal profile, fasting serum insulin, body weight, body mass index, menstrual status and waist to hip ratio were evaluated before and after treatment. Results: Metformin and pioglitazone and combination therapy induced favorable changes in fasting serum insulin, HOMA-IR index, QUICKI, fasting glucose to insulin ratio in women with PCOS. Body weight, BMI, and waist to hip ratio increased significantly after treatment with pioglitazone but the data were similar after administration of metformin or combination therapy. Total testosterone level decreased significantly only after treatment with metformin. After 3 months in patients who received pioglitazone or combination therapy, menstrual cycles became regular in 71.4% and 73.9% respectively. While menstrual improvement happened only in 36.4% of the patients treated with metformin. Conclusion: These findings suggest that insulin-sensitizing drugs induce beneficial effect in insulin resistance and menstrual cyclicity but only metformin ameliorated hyperandrogenemia in women with PCOS. Treatment with combination of metformin and pioglitazone did not show more benefit than monotherapy with each drug alone. PMID:28331909

  17. Destabilization of MYC/MYCN by the mitochondrial inhibitors, metaiodobenzylguanidine, metformin and phenformin

    PubMed Central

    WANG, STEPHANIE S.; HSIAO, RUTH; LIMPAR, MARIKO M.; LOMAHAN, SARAH; TRAN, TUAN-ANH; MALONEY, NOLAN J.; IKEGAKI, NAOHIKO; TANG, XAO X.

    2014-01-01

    In the present study, we investigated the anticancer effects of the mitochondrial inhibitors, metaiodobenzylguanidine (MIBG), metformin and phenformin. 131I-MIBG has been used for scintigraphic detection and the targeted radiotherapy of neuroblastoma (NB), a pediatric malignancy. Non-radiolabeled MIBG has been reported to be cytotoxic to NB cells in vitro and in vivo. However, the mechanisms behind its growth suppressive effects have not yet been fully elucidated. Metformin and phenformin are diabetes medications that are being considered in anticancer therapeutics. We investigated the anticancer mechanisms of action of MIBG and metformin in NB. Our data revealed that both drugs suppressed NB cell growth and that the combination drug treatment was more potent. MIBG reduced MYCN and MYC expression in MYCN-amplified and non-MYCN-amplified NB cells in a dose- and time-dependent manner. Metformin was less effective than MIBG in destabilizing MYC/MYCN. The treatment of NB cells with metformin or MIBG resulted in an increased expression of genes encoding biomarkers for favorable outcome in NB [(ephrin (EFN)B2, EFNB3, EPH receptor B6 (EPHB6), neurotrophic tyrosine kinase, receptor, type 1 (NTRK1), CD44 and Myc-interacting zinc finger protein (MIZ-1)] and tumor suppressor genes [(early growth response 1 (EGR1), EPH receptor A2 (EPHA2), growth arrest and DNA-damage-inducible, beta (GADD45B), neuregulin 1 (NRG1), TP53 apoptosis effector (PERP) and sel-1 suppressor of lin-12-like (C. elegans) (SEL1L)]. Accordingly, metformin and MIBG augmented histone H3 acetylation in these cells. Phenformin also exhibited histone modification and was more effective than metformin in destabilizing MYC/MYCN in NB cells. Our data suggest that the destabilization of MYC/MYCN by MIBG, metformin and phenformin and their effects on histone modification are important mechanisms underlying their anticancer effects. PMID:24190252

  18. Destabilization of MYC/MYCN by the mitochondrial inhibitors, metaiodobenzylguanidine, metformin and phenformin.

    PubMed

    Wang, Stephanie S; Hsiao, Ruth; Limpar, Mariko M; Lomahan, Sarah; Tran, Tuan-Anh; Maloney, Nolan J; Ikegaki, Naohiko; Tang, Xao X

    2014-01-01

    In the present study, we investigated the anticancer effects of the mitochondrial inhibitors, metaiodobenzylguanidine (MIBG), metformin and phenformin. 131I-MIBG has been used for scintigraphic detection and the targeted radiotherapy of neuroblastoma (NB), a pediatric malignancy. Non-radiolabeled MIBG has been reported to be cytotoxic to NB cells in vitro and in vivo. However, the mechanisms behind its growth suppressive effects have not yet been fully elucidated. Metformin and phenformin are diabetes medications that are being considered in anticancer therapeutics. We investigated the anticancer mechanisms of action of MIBG and metformin in NB. Our data revealed that both drugs suppressed NB cell growth and that the combination drug treatment was more potent. MIBG reduced MYCN and MYC expression in MYCN-amplified and non-MYCN-amplified NB cells in a dose- and time-dependent manner. Metformin was less effective than MIBG in destabilizing MYC/MYCN. The treatment of NB cells with metformin or MIBG resulted in an increased expression of genes encoding biomarkers for favorable outcome in NB [(ephrin (EFN)B2, EFNB3, EPH receptor B6 (EPHB6), neurotrophic tyrosine kinase, receptor, type 1 (NTRK1), CD44 and Myc-interacting zinc finger protein (MIZ-1)] and tumor suppressor genes [(early growth response 1 (EGR1), EPH receptor A2 (EPHA2), growth arrest and DNA-damage-inducible, beta (GADD45B), neuregulin 1 (NRG1), TP53 apoptosis effector (PERP) and sel-1 suppressor of lin-12-like (C. elegans) (SEL1L)]. Accordingly, metformin and MIBG augmented histone H3 acetylation in these cells. Phenformin also exhibited histone modification and was more effective than metformin in destabilizing MYC/MYCN in NB cells. Our data suggest that the destabilization of MYC/MYCN by MIBG, metformin and phenformin and their effects on histone modification are important mechanisms underlying their anticancer effects.

  19. Metformin Accumulation Correlates with Organic Cation Transporter 2 Protein Expression and Predicts Mammary Tumor Regression in Vivo

    PubMed Central

    Checkley, L. Allyson; Rudolph, Michael C.; Wellberg, Elizabeth A.; Giles, Erin D.; Wahdan-Alaswad, Reema S.; Houck, Julie A.; Edgerton, Susan M.; Thor, Ann D.; Schedin, Pepper; Anderson, Steven M.; MacLean, Paul S.

    2017-01-01

    Several epidemiological studies have associated metformin treatment with a reduction in breast cancer incidence in pre-diabetic and type II diabetic populations. Uncertainty exists regarding which patient populations and/or tumor subtypes will benefit from metformin treatment, and most preclinical in vivo studies have given little attention to the cellular pharmacology of intratumoral metformin uptake. Epidemiological reports consistently link western-style high fat diets, which drive overweight and obesity, with increased risk of breast cancer. We used a rat model of high fat diet (HFD) induced overweight and mammary carcinogenesis to define intratumoral factors that confer metformin sensitivity. Mammary tumors were initiated with N-methyl-N-nitrosourea (MNU), and rats were randomized into metformin-treated (2 mg/ml drinking water) or control groups (water only) for 8 weeks. Two-thirds of existing mammary tumors responded to metformin treatment with decreased tumor volumes (p<0.05), reduced proliferative index (p<0.01), and activated AMPK (p<0.05). Highly responsive tumors accumulated 3-fold greater metformin amounts (p<0.05) that were positively correlated with organic cation transporter-2 (OCT2) protein expression (r=0.57, P=0.038). Importantly, intratumoral metformin concentration negatively associated with tumor volume (P=0.03), and each 10 pmol increase in intratumoral metformin predicted >0.11 cm3 reduction in tumor volume. Metformin treatment also decreased proinflammatory arachidonic acid >1.5 fold in responsive tumors (P=0.023). Collectively, these preclinical data provide evidence for a direct effect of metformin in vivo and suggest that OCT2 expression may predict metformin uptake and tumor response. PMID:28154203

  20. Antioxidative and Cardioprotective Properties of Anthocyanins from Defatted Dabai Extracts

    PubMed Central

    Khoo, Hock Eng; Azlan, Azrina; Nurulhuda, M. Halid; Ismail, Amin; Abas, Faridah; Hamid, Muhajir; Roowi, Suri

    2013-01-01

    This study aimed to determine anthocyanins and their antioxidative and cardioprotective properties in defatted dabai parts. Anthocyanins in crude extracts and extract fractions of defatted dabai peel and pericarp were quantified using UHPLC, while their antioxidant capacity and oxidative stress inhibition ability were evaluated by using DPPH and CUPRAC assays as well as linoleic acid oxidation system, hemoglobin oxidation, and PARP-1 inhibition ELISA. Cardioprotective effect of the defatted dabai peel extract was evaluated using hypercholesterolemic-induced New Zealand white rabbits. Six anthocyanins were detected in the defatted dabai peel, with the highest antioxidant capacities and oxidative stress inhibition effect compared to the other part. The defatted dabai peel extract has also inhibited lipid peroxidation (plasma MDA) and elevated cellular antioxidant enzymes (SOD and GPx) in the tested animal model. Major anthocyanin (cyanidin-3-glucoside) and other anthocyanins (pelargonidin-3-glucoside, malvidin-3-glucoside, cyanidin-3-galactoside, cyanidin-3-arabinoside, and peonidin-3-glucoside) detected in the defatted dabai peel are potential future nutraceuticals with promising medicinal properties. PMID:24368926

  1. Cardioprotective abilities of white wine.

    PubMed

    Cui, Jianhua; Tosaki, Arpad; Cordis, Gerald A; Bertelli, Alberto A E; Bertelli, Aldo; Maulik, Nilanjana; Das, Dipak K

    2002-05-01

    To study if white wines, like red wine, can also protect the heart from ischemia reperfusion injury, ethanol-free extracts of three different white wines (WW1, WW2 and WW3) (100 mg/100 g body weight) were given orally to Sprague Dawley rats (200 g body weight) for three weeks. Control rats were given water only for the same period of time. After three weeks, rats were anesthetized and sacrificed, and the hearts excised for the preparation of isolated working rat heart. All hearts were subjected to 30 min global ischemia followed by two hours of reperfusion. The results demonstrated that among the three different white wines, only WW2 showed cardioprotection as evidenced by improved post-ischemic ventricular recovery compared to control. The amount of malonaldehyde production in white wine-fed rat hearts were lower compared to that found in control hearts indicating reduced formation of the reactive oxygen species. In vitro studies using chemiluminescence technique revealed that these white wines scavenged both superoxide anions and hydroxyl radicals. The results of our study demonstrated that only WW2 white wine provided cardioprotection as evidenced by the improved the post-ischemic contractile recovery and reduced myocardial infarct size. The cardioprotective effect of this white wine may be attributed, at least in part, from its ability to function as an in vivo antioxidant.

  2. SMILE upregulated by metformin inhibits the function of androgen receptor in prostate cancer cells.

    PubMed

    Lee, Seung-Yon; Song, Chin-Hee; Xie, Yuan-Bin; Jung, Chaeyong; Choi, Hueng-Sik; Lee, Keesook

    2014-11-28

    Metformin, a diabetes drug, has been reported to inhibit the growth of prostate cancer cells. In this study, we investigated the effect and action mechanism of metformin on the function of androgen receptor (AR), a key molecule in the proliferation of prostate cancer cells. Metformin was found to reduce androgen-dependent cell growth and the expression of AR target genes by inhibiting AR function in prostate cancer cells such as LNCaP and C4-2 cells. Interestingly, metformin upregulated the protein level of small heterodimer partner-interacting leucine zipper (SMILE), a coregulator of nuclear receptors, and knockdown of SMILE expression with shRNA abolished the inhibitory effect of metformin on AR function. Further studies revealed that SMILE protein itself suppressed the transactivation of AR, and its ectopic expression resulted in the repressed expression of endogenous AR target genes, PSA and NKX3.1, in LNCaP cells. In addition, SMILE protein physically interacted with AR and competed with the AR coactivator SRC-1 to modulate AR transactivation. As expected, SMILE repressed androgen-dependent growth of LNCaP and C4-2 cells. Taken together, these results suggest that SMILE, which is induced by metformin, functions as a novel AR corepressor and may mediate the inhibitory effect of metformin on androgen-dependent growth of prostate cancer cells. Copyright © 2014. Published by Elsevier Ireland Ltd.

  3. Combined regimen of photodynamic therapy mediated by Gallium phthalocyanine chloride and Metformin enhances anti-melanoma efficacy

    PubMed Central

    Filip, Gabriela Adriana; Olteanu, Diana; Cenariu, Mihai; Tabaran, Flaviu; Ion, Rodica Mariana; Gligor, Lucian; Baldea, Ioana

    2017-01-01

    Background Melanoma therapy is challenging, especially in advanced cases, due to multiple developed tumor defense mechanisms. Photodynamic therapy (PDT) might represent an adjuvant treatment, because of its bimodal action: tumor destruction and immune system awakening. In this study, a combination of PDT mediated by a metal substituted phthalocyanine—Gallium phthalocyanine chloride (GaPc) and Metformin was used against melanoma. The study aimed to: (1) find the anti-melanoma efficacy of GaPc-PDT, (2) assess possible beneficial effects of Metformin addition to PDT, (3) uncover some of the mechanisms underlining cell killing and anti-angiogenic effects. Methods Two human lightly pigmented melanoma cell lines: WM35 and M1/15 subjected to previous Metformin exposure were treated by GaPc-PDT. Cell viability, death mechanism, cytoskeleton alterations, oxidative damage, were assessed by means of colorimetry, flowcytometry, confocal microscopy, spectrophotometry, ELISA, Western Blotting. Results GaPc proved an efficient photosensitizer. Metformin addition enhanced cell killing by mechanisms dependent on the cell line, namely apoptosis in the metastatic M1/15 and necrosis in the radial growth phase, WM35. Cell death mechanism relied on the inhibition of nuclear transcription factor (NF)-κB activation and tumor necrosis factor (TNF)—related apoptosis-inducing ligand (TRAIL) sensitization, leading to TRAIL and TNF-α induced apoptosis. Metformin diminished the anti-angiogenic effect of PDT. Conclusions Metformin addition to GaPc-PDT increased tumor cell killing through enhanced oxidative damage and induction of proapoptotic mechanisms, but altered PDT anti-angiogenic effects. General significance Combination of Metformin and PDT might represent a solution to enhance the efficacy, leading to a potential adjuvant role of PDT in melanoma therapy. PMID:28278159

  4. Combined regimen of photodynamic therapy mediated by Gallium phthalocyanine chloride and Metformin enhances anti-melanoma efficacy.

    PubMed

    Tudor, Diana; Nenu, Iuliana; Filip, Gabriela Adriana; Olteanu, Diana; Cenariu, Mihai; Tabaran, Flaviu; Ion, Rodica Mariana; Gligor, Lucian; Baldea, Ioana

    2017-01-01

    Melanoma therapy is challenging, especially in advanced cases, due to multiple developed tumor defense mechanisms. Photodynamic therapy (PDT) might represent an adjuvant treatment, because of its bimodal action: tumor destruction and immune system awakening. In this study, a combination of PDT mediated by a metal substituted phthalocyanine-Gallium phthalocyanine chloride (GaPc) and Metformin was used against melanoma. The study aimed to: (1) find the anti-melanoma efficacy of GaPc-PDT, (2) assess possible beneficial effects of Metformin addition to PDT, (3) uncover some of the mechanisms underlining cell killing and anti-angiogenic effects. Two human lightly pigmented melanoma cell lines: WM35 and M1/15 subjected to previous Metformin exposure were treated by GaPc-PDT. Cell viability, death mechanism, cytoskeleton alterations, oxidative damage, were assessed by means of colorimetry, flowcytometry, confocal microscopy, spectrophotometry, ELISA, Western Blotting. GaPc proved an efficient photosensitizer. Metformin addition enhanced cell killing by mechanisms dependent on the cell line, namely apoptosis in the metastatic M1/15 and necrosis in the radial growth phase, WM35. Cell death mechanism relied on the inhibition of nuclear transcription factor (NF)-κB activation and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) sensitization, leading to TRAIL and TNF-α induced apoptosis. Metformin diminished the anti-angiogenic effect of PDT. Metformin addition to GaPc-PDT increased tumor cell killing through enhanced oxidative damage and induction of proapoptotic mechanisms, but altered PDT anti-angiogenic effects. Combination of Metformin and PDT might represent a solution to enhance the efficacy, leading to a potential adjuvant role of PDT in melanoma therapy.

  5. Metformin repositioning as antitumoral agent: selective antiproliferative effects in human glioblastoma stem cells, via inhibition of CLIC1-mediated ion current

    PubMed Central

    Barbieri, Federica; Peretti, Marta; Pizzi, Erika; Pattarozzi, Alessandra; Carra, Elisa; Sirito, Rodolfo; Daga, Antonio; Curmi, Paul M.G.; Mazzanti, Michele; Florio, Tullio

    2014-01-01

    Epidemiological and preclinical studies propose that metformin, a first-line drug for type-2 diabetes, exerts direct antitumor activity. Although several clinical trials are ongoing, the molecular mechanisms of this effect are unknown. Here we show that chloride intracellular channel-1 (CLIC1) is a direct target of metformin in human glioblastoma cells. Metformin exposure induces antiproliferative effects in cancer stem cell-enriched cultures, isolated from three individual WHO grade IV human glioblastomas. These effects phenocopy metformin-mediated inhibition of a chloride current specifically dependent on CLIC1 functional activity. CLIC1 ion channel is preferentially active during the G1-S transition via transient membrane insertion. Metformin inhibition of CLIC1 activity induces G1 arrest of glioblastoma stem cells. This effect was time-dependent, and prolonged treatments caused antiproliferative effects also for low, clinically significant, metformin concentrations. Furthermore, substitution of Arg29 in the putative CLIC1 pore region impairs metformin modulation of channel activity. The lack of drugs affecting cancer stem cell viability is the main cause of therapy failure and tumor relapse. We identified CLIC1 not only as a modulator of cell cycle progression in human glioblastoma stem cells but also as the main target of metformin's antiproliferative activity, paving the way for novel and needed pharmacological approaches to glioblastoma treatment. PMID:25361004

  6. Metformin repositioning as antitumoral agent: selective antiproliferative effects in human glioblastoma stem cells, via inhibition of CLIC1-mediated ion current.

    PubMed

    Gritti, Marta; Würth, Roberto; Angelini, Marina; Barbieri, Federica; Peretti, Marta; Pizzi, Erika; Pattarozzi, Alessandra; Carra, Elisa; Sirito, Rodolfo; Daga, Antonio; Curmi, Paul M G; Mazzanti, Michele; Florio, Tullio

    2014-11-30

    Epidemiological and preclinical studies propose that metformin, a first-line drug for type-2 diabetes, exerts direct antitumor activity. Although several clinical trials are ongoing, the molecular mechanisms of this effect are unknown. Here we show that chloride intracellular channel-1 (CLIC1) is a direct target of metformin in human glioblastoma cells. Metformin exposure induces antiproliferative effects in cancer stem cell-enriched cultures, isolated from three individual WHO grade IV human glioblastomas. These effects phenocopy metformin-mediated inhibition of a chloride current specifically dependent on CLIC1 functional activity. CLIC1 ion channel is preferentially active during the G1-S transition via transient membrane insertion. Metformin inhibition of CLIC1 activity induces G1 arrest of glioblastoma stem cells. This effect was time-dependent, and prolonged treatments caused antiproliferative effects also for low, clinically significant, metformin concentrations. Furthermore, substitution of Arg29 in the putative CLIC1 pore region impairs metformin modulation of channel activity. The lack of drugs affecting cancer stem cell viability is the main cause of therapy failure and tumor relapse. We identified CLIC1 not only as a modulator of cell cycle progression in human glioblastoma stem cells but also as the main target of metformin's antiproliferative activity, paving the way for novel and needed pharmacological approaches to glioblastoma treatment.

  7. Metformin combined with quercetin synergistically repressed prostate cancer cells via inhibition of VEGF/PI3K/Akt signaling pathway.

    PubMed

    Sun, Shuben; Gong, Fanger; Liu, Ping; Miao, Qilong

    2018-04-17

    The aim of present study was to examine whether metformin in association with quercetin has any synergistically anti-tumor effects on prostate cancer. Our findings showed that metformin in combination with quercetin synergistically inhibited the growth, migration and invasion of both PC-3 and LNCaP cells. Co-treatment of these two agents induced more apoptosis than single agent treatment. The co-treatment-induced apoptosis was caspase-dependent and accompanied by the down-regulation of Bcl-2 family members. Our data also indicated that co-treatment of metformin and quercetin strongly inhibited the VEGF/Akt/PI3K pathway. Moreover, these two agents acted synergistically to repress the growth of human prostate cancer cell xenograft in vivo in nude mice. In conclusion, our findings indicate that the combination therapy of metformin and quercetin exerted synergistic antitumor effects in prostate cancers via inhibition of VEGF/Akt/PI3K pathway. Thus, combination treatment of metformin and quercetin would be a promising therapeutic strategy for prostate cancer patients. Copyright © 2017. Published by Elsevier B.V.

  8. Mito-Tempol and Dexrazoxane Exhibit Cardioprotective and Chemotherapeutic Effects through Specific Protein Oxidation and Autophagy in a Syngeneic Breast Tumor Preclinical Model

    PubMed Central

    Aryal, Baikuntha; Mog, Steven; Nakamura, Asako J.; Redon, Christophe E.; Baxa, Ulrich; Rosen, Elliot; Cheng, Gang; Zielonka, Jacek; Parekh, Palak; Mason, Karen P.; Joseph, Joy; Kalyanaraman, Balaraman; Bonner, William; Herman, Eugene; Shacter, Emily; Rao, V. Ashutosh

    2013-01-01

    Several front-line chemotherapeutics cause mitochondria-derived, oxidative stress-mediated cardiotoxicity. Iron chelators and other antioxidants have not completely succeeded in mitigating this effect. One hindrance to the development of cardioprotectants is the lack of physiologically-relevant animal models to simultaneously study antitumor activity and cardioprotection. Therefore, we optimized a syngeneic rat model and examined the mechanisms by which oxidative stress affects outcome. Immune-competent spontaneously hypertensive rats (SHRs) were implanted with passaged, SHR-derived, breast tumor cell line, SST-2. Tumor growth and cytokine responses (IL-1A, MCP-1, TNF-α) were observed for two weeks post-implantation. To demonstrate the utility of the SHR/SST-2 model for monitoring both anticancer efficacy and cardiotoxicity, we tested cardiotoxic doxorubicin alone and in combination with an established cardioprotectant, dexrazoxane, or a nitroxide conjugated to a triphenylphosphonium cation, Mito-Tempol (4) [Mito-T (4)]. As predicted, tumor reduction and cardiomyopathy were demonstrated by doxorubicin. We confirmed mitochondrial accumulation of Mito-T (4) in tumor and cardiac tissue. Dexrazoxane and Mito-T (4) ameliorated doxorubicin-induced cardiomyopathy without altering the antitumor activity. Both agents increased the pro-survival autophagy marker LC3-II and decreased the apoptosis marker caspase-3 in the heart, independently and in combination with doxorubicin. Histopathology and transmission electron microscopy demonstrated apoptosis, autophagy, and necrosis corresponding to cytotoxicity in the tumor and cardioprotection in the heart. Changes in serum levels of 8-oxo-dG-modified DNA and total protein carbonylation corresponded to cardioprotective activity. Finally, 2D-electrophoresis/mass spectrometry identified specific serum proteins oxidized under cardiotoxic conditions. Our results demonstrate the utility of the SHR/SST-2 model and the potential of

  9. Preclinical evaluation of olaparib and metformin combination in BRCA1 wildtype ovarian cancer.

    PubMed

    Hijaz, M; Chhina, J; Mert, I; Taylor, M; Dar, S; Al-Wahab, Z; Ali-Fehmi, R; Buekers, T; Munkarah, A R; Rattan, R

    2016-08-01

    BRCA mutated ovarian cancers show increased responsiveness to PARP inhibitors. PARP inhibitors target DNA repair and provide a second hit to BRCA mutated tumors, resulting in "synthetic lethality". We investigated a combination of metformin and olaparib to provide "synthetic lethality" in BRCA intact ovarian cancer cells. Ovarian cancer cell lines (UWB1.289, UWB1.289.BRCA, SKOV3, OVCAR5, A2780 and C200) were treated with a combination of metformin and olaparib. Cell viability was assessed by MTT and colony formation assays. Flow cytometry was used to detect cell cycle events. In vivo studies were performed in SKOV3 or A2780 xenografts in nude mice. Animals were treated with single agent, metformin or olaparib or combination. Molecular downstream effects were examined by immunohistochemistry. Compared to single drug treatment, combination of olaparib and metformin resulted in significant reduction of cell proliferation and colony formation (p<0.001) in ovarian cancer cells. This treatment was associated with a significant S-phase cell cycle arrest (p<0.05). Combination of olaparib and metformin significantly inhibited SKOV3 and A2780 ovarian tumor xenografts which were accompanied with decreased Ki-index (p<0.001). Metformin did not affect DNA damage signaling, while olaparib induced adenosine monophosphate activated kinase activation; that was further potentiated with metformin combination in vivo. Combining PARP inhibitors with metformin enhances its anti-proliferative activity in BRCA mutant ovarian cancer cells. Furthermore, the combination showed significant activity in BRCA intact cancer cells in vitro and in vivo. This is a promising treatment regimen for women with epithelial ovarian cancer irrespective of BRCA status. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Cardioprotective and Metabolomic Profiling of Selected Medicinal Plants against Oxidative Stress

    PubMed Central

    Afsheen, Nadia; Jahan, Nazish; Ijaz, Misbah; Manzoor, Asad; Khan, Khalid Mahmood; Hina, Saman

    2018-01-01

    In this research work, the antioxidant and metabolomic profiling of seven selected medicinally important herbs including Rauvolfia serpentina, Terminalia arjuna, Coriandrum sativum, Elettaria cardamom, Piper nigrum, Allium sativum, and Crataegus oxyacantha was performed. The in vivo cardioprotective potential of these medicinal plants was evaluated against surgically induced oxidative stress through left anterior descending coronary artery ligation (LADCA) in dogs. The antioxidant profiling of these plants was done through DPPH and DNA protection assay. The C. oxyacantha and T. arjuna showed maximum antioxidant potential, while the E. cardamom showed poor antioxidative strength even at its high concentration. Different concentrations of extracts of the said plants exhibited the protection of plasmid DNA against H2O2 damage as compared to the plasmid DNA merely treated with H2O2. The metabolomic profiling through LC-MS analysis of these antioxidants revealed the presence of active secondary metabolites responsible for their antioxidant potential. During in vivo analysis, blood samples of all treatment groups were drawn at different time intervals to analyze the cardiac and hemodynamic parameters. The results depicted that the group pretreated with HC4 significantly sustained the level of CK-MB, SGOT, and LDH as well as hemodynamic parameters near to normal. The histopathological examination also confirmed the cardioprotective potential of HC4. Thus, the HC4 being safe and inexpensive cardioprotective herbal combination could be considered as an alternate of synthetic drugs. PMID:29576858

  11. Metformin inhibits cell cycle progression of B-cell chronic lymphocytic leukemia cells.

    PubMed

    Bruno, Silvia; Ledda, Bernardetta; Tenca, Claudya; Ravera, Silvia; Orengo, Anna Maria; Mazzarello, Andrea Nicola; Pesenti, Elisa; Casciaro, Salvatore; Racchi, Omar; Ghiotto, Fabio; Marini, Cecilia; Sambuceti, Gianmario; DeCensi, Andrea; Fais, Franco

    2015-09-08

    B-cell chronic lymphocytic leukemia (CLL) was believed to result from clonal accumulation of resting apoptosis-resistant malignant B lymphocytes. However, it became increasingly clear that CLL cells undergo, during their life, iterative cycles of re-activation and subsequent clonal expansion. Drugs interfering with CLL cell cycle entry would be greatly beneficial in the treatment of this disease. 1, 1-Dimethylbiguanide hydrochloride (metformin), the most widely prescribed oral hypoglycemic agent, inexpensive and well tolerated, has recently received increased attention for its potential antitumor activity. We wondered whether metformin has apoptotic and anti-proliferative activity on leukemic cells derived from CLL patients. Metformin was administered in vitro either to quiescent cells or during CLL cell activation stimuli, provided by classical co-culturing with CD40L-expressing fibroblasts. At doses that were totally ineffective on normal lymphocytes, metformin induced apoptosis of quiescent CLL cells and inhibition of cell cycle entry when CLL were stimulated by CD40-CD40L ligation. This cytostatic effect was accompanied by decreased expression of survival- and proliferation-associated proteins, inhibition of signaling pathways involved in CLL disease progression and decreased intracellular glucose available for glycolysis. In drug combination experiments, metformin lowered the apoptotic threshold and potentiated the cytotoxic effects of classical and novel antitumor molecules. Our results indicate that, while CLL cells after stimulation are in the process of building their full survival and cycling armamentarium, the presence of metformin affects this process.

  12. [Metformin and kidney].

    PubMed

    Sessa, Concetto; Blanco, Julien; Granata, Antonio; Fatuzzo, Pasquale; Castellino, Pietro; Zanoli, Luca

    2016-01-01

    Metformin is the first choice among drugs used for the treatment of type II diabetes mellitus mainly because of several advantages: proven hypoglycemic effect, good safety profile, virtually no risk of hypoglycemia, body weight reduction, lipid-lowering effect, efficacy in preventing micro- and macrovascular complications as well as adverse cardiac and cerebrovascular events and reduced cost. Previous reports had shown an increased risk of lactic acidosis in patients receiving metformin. However, the current Guidelines have greatly limited this risk to certain categories of patients, such as those with severe chronic renal failure, particularly when predisposing risk factors such as administration of iodinated contrast are present. In this review, we reported the main data of the literature on the use of metformin in patients with chronic renal failure and both highly expected benefits and high potential risks.

  13. Dietary energy availability affects primary and metastatic breast cancer and metformin efficacy

    PubMed Central

    Phoenix, Kathryn N.; Vumbaca, Frank; Fox, Melissa M.; Evans, Rebecca

    2010-01-01

    Dietary energy restriction has been shown to repress both mammary tumorigenesis and aggressive mammary tumor growth in animal studies. Metformin, a caloric restriction mimetic, has a long history of safe use as an insulin sensitizer in diabetics and has been shown to reduce cancer incidence and cancer-related mortality in humans. To determine the potential impact of dietary energy availability and metformin therapy on aggressive breast tumor growth and metastasis, an orthotopic syngeneic model using triple negative 66cl4 tumor cells in Balb/c mice was employed. The effect of dietary restriction, a standard maintenance diet or a diet with high levels of free sugar, were tested for their effects on tumor growth and secondary metastases to the lung. Metformin therapy with the various diets indicated that metformin can be highly effective at suppressing systemic metabolic biomarkers such as IGF-1, insulin and glucose, especially in the high energy diet treated animals. Long-term metformin treatment demonstrated moderate yet significant effects on primary tumor growth, most significantly in conjunction with the high energy diet. When compared to the control diet, the high energy diet promoted tumor growth, expression of the inflammatory adipokines leptin and resistin, induced lung priming by bone marrow-derived myeloid cells and promoted metastatic potential. Metformin had no effect on adipokine expression or the development of lung metastases with the standard or the high energy diet. These data indicate that metformin may have tumor suppressing activity where a metabolic phenotype of high fuel intake, metabolic syndrome, and diabetes exist, but may have little or no effect on events controlling the metastatic niche driven by proinflammatory events. PMID:20204498

  14. The Phantom of Metformin-Induced Lactic Acidosis in End-Stage Renal Disease Patients: Time to Reconsider with Peritoneal Dialysis Treatment.

    PubMed

    Al-Hwiesh, Abdullah K; Abdul-Rahman, Ibrahiem Saeed; Noor, Abdul-Salam; Nasr-El-Deen, Mohammed A; Abdelrahman, Abdalla; El-Salamoni, Tamer S; Al-Muhanna, Fahd A; Al-Otaibi, Khalid; Al-Audah, Nehad

    ♦ OBJECTIVE: Metformin continues to be the safest and most widely used antidiabetic drug. In spite of its well-known benefits; metformin use in end-stage renal disease (ESRD) patients is still restricted. Little has been reported about the effect of peritoneal dialysis (PD) on metformin clearance and the phantom of lactic acidosis deprives ESRD patients from metformin therapeutic advantages. Peritoneal dialysis is probably a safeguard against lactic acidosis, and it is likely that using this drug would be feasible in this group of patients. ♦ MATERIAL AND METHODS: The study was conducted on 83 PD patients with type 2 diabetes mellitus. All patients were on automated PD (APD). Metformin was administered in a dose of 500 - 1,000 mg daily. Patients were monitored for glycemic control. Plasma lactic acid and plasma metformin levels were monitored on a scheduled basis. Peritoneal fluid metformin levels were measured. In addition, the relation between plasma metformin and plasma lactate was studied. ♦ RESULTS: Mean fasting blood sugar (FBS) was 10.9 ± 0.5 and 7.8 ± 0.7, and mean hemoglobin A1-C (HgA1C) was 8.2 ± 0.8 and 6.4 ± 1.1 at the beginning and end of the study, respectively (p < 0.001). The mean body mass index (BMI) was 29.1 ± 4.1 and 27.3 ± 4.5 at the beginning and at the end of the study, respectively (p < 0.001). The overall mean plasma lactate level across all blood samples was 1.44 ± 0.6. Plasma levels between 2 and 3 mmol/L were found in 11.8% and levels of 3 - 3.6 mmol/L in 2.4% plasma samples. Hyperlactemia (level > 2 and ≤ 5 mmol/L) was not associated with overt acidemia. None of our patients had lactic acidosis (levels > 5 mmol/L). Age ≥ 60 was a predictor for hyperlactemia. No relationship was found between plasma metformin and lactate levels. ♦ CONCLUSION: Metformin may be used with caution in a particular group of ESRD patients who are on APD. Metformin allows better diabetic control with significant reduction of BMI. Information

  15. Metformin-induced ablation of microRNA 21-5p releases Sestrin-1 and CAB39L antitumoral activities

    PubMed Central

    Pulito, Claudio; Mori, Federica; Sacconi, Andrea; Goeman, Frauke; Ferraiuolo, Maria; Pasanisi, Patrizia; Campagnoli, Carlo; Berrino, Franco; Fanciulli, Maurizio; Ford, Rebecca J; Levrero, Massimo; Pediconi, Natalia; Ciuffreda, Ludovica; Milella, Michele; Steinberg, Gregory R; Cioce, Mario; Muti, Paola; Strano, Sabrina; Blandino, Giovanni

    2017-01-01

    Metformin is a commonly prescribed type II diabetes medication that exhibits promising anticancer effects. Recently, these effects were found to be associated, at least in part, with a modulation of microRNA expression. However, the mechanisms by which single modulated microRNAs mediate the anticancer effects of metformin are not entirely clear and knowledge of such a process could be vital to maximize the potential therapeutic benefits of this safe and well-tolerated therapy. Our analysis here revealed that the expression of miR-21-5p was downregulated in multiple breast cancer cell lines treated with pharmacologically relevant doses of metformin. Interestingly, the inhibition of miR-21-5p following metformin treatment was also observed in mouse breast cancer xenografts and in sera from 96 breast cancer patients. This modulation occurred at the levels of both pri-miR-21 and pre-miR-21, suggesting transcriptional modulation. Antagomir-mediated ablation of miR-21-5p phenocopied the effects of metformin on both the clonogenicity and migration of the treated cells, while ectopic expression of miR-21-5p had the opposite effect. Mechanistically, this reduction in miR-21-5p enhanced the expression of critical upstream activators of the AMP-activated protein kinase, calcium-binding protein 39-like and Sestrin-1, leading to AMP-activated protein kinase activation and inhibition of mammalian target of rapamycin signaling. Importantly, these effects of metformin were synergistic with those of everolimus, a clinically relevant mammalian target of rapamycin inhibitor, and were independent of the phosphatase and tensin homolog status. This highlights the potential relevance of metformin in combinatorial settings for the treatment of breast cancer. PMID:28698800

  16. Metformin-induced ablation of microRNA 21-5p releases Sestrin-1 and CAB39L antitumoral activities.

    PubMed

    Pulito, Claudio; Mori, Federica; Sacconi, Andrea; Goeman, Frauke; Ferraiuolo, Maria; Pasanisi, Patrizia; Campagnoli, Carlo; Berrino, Franco; Fanciulli, Maurizio; Ford, Rebecca J; Levrero, Massimo; Pediconi, Natalia; Ciuffreda, Ludovica; Milella, Michele; Steinberg, Gregory R; Cioce, Mario; Muti, Paola; Strano, Sabrina; Blandino, Giovanni

    2017-01-01

    Metformin is a commonly prescribed type II diabetes medication that exhibits promising anticancer effects. Recently, these effects were found to be associated, at least in part, with a modulation of microRNA expression. However, the mechanisms by which single modulated microRNAs mediate the anticancer effects of metformin are not entirely clear and knowledge of such a process could be vital to maximize the potential therapeutic benefits of this safe and well-tolerated therapy. Our analysis here revealed that the expression of miR-21-5p was downregulated in multiple breast cancer cell lines treated with pharmacologically relevant doses of metformin. Interestingly, the inhibition of miR-21-5p following metformin treatment was also observed in mouse breast cancer xenografts and in sera from 96 breast cancer patients. This modulation occurred at the levels of both pri-miR-21 and pre-miR-21, suggesting transcriptional modulation. Antagomir-mediated ablation of miR-21-5p phenocopied the effects of metformin on both the clonogenicity and migration of the treated cells, while ectopic expression of miR-21-5p had the opposite effect. Mechanistically, this reduction in miR-21-5p enhanced the expression of critical upstream activators of the AMP-activated protein kinase, calcium-binding protein 39-like and Sestrin-1, leading to AMP-activated protein kinase activation and inhibition of mammalian target of rapamycin signaling. Importantly, these effects of metformin were synergistic with those of everolimus, a clinically relevant mammalian target of rapamycin inhibitor, and were independent of the phosphatase and tensin homolog status. This highlights the potential relevance of metformin in combinatorial settings for the treatment of breast cancer.

  17. Cyclosporine A administered during reperfusion fails to restore cardioprotection in prediabetic Zucker obese rats in vivo.

    PubMed

    Huhn, R; Heinen, A; Hollmann, M W; Schlack, W; Preckel, B; Weber, N C

    2010-12-01

    Hyperglycaemia blocks sevoflurane-induced postconditioning, and cardioprotection in hyperglycaemic myocardium can be restored by inhibition of the mitochondrial permeability transition pore (mPTP). We investigated whether sevoflurane-induced postconditioning is also blocked in the prediabetic heart and if so, whether cardioprotection could be restored by inhibiting mPTP. Zucker lean (ZL) and Zucker obese (ZO) rats were assigned to one of seven groups. Animals underwent 25 min of ischaemia and 120 min of reperfusion. Control (ZL-/ZO Con) animals were not further treated. postconditioning groups (ZL-/ZO Sevo-post) received sevoflurane for 5 min starting 1min prior to the onset of reperfusion. The mPTP inhibitor cyclosporine A (CsA) was administered intravenously in a concentration of 5 (ZO CsA and ZO CsA+Sevo-post) or 10 mg/kg (ZO CsA10+Sevo-post) 5 min before the onset of reperfusion. At the end of reperfusion, infarct sizes were measured by TTC staining. Blood samples were collected to measure plasma levels of insulin, cholesterol and triglycerides. Sevoflurane postconditioning reduced infarct size in ZL rats to 35±12% (p<0.05 vs. ZL Con: 60±6%). In ZO rats sevoflurane postconditioning was abolished (ZO Sevo-post: 59±12%, n.s. vs. ZO Con: 58±6%). 5 mg and 10 mg CsA could not restore cardioprotection (ZO CsA+Sevo-post: 59±7%, ZO CsA10+Sevo-post: 57±14%; n.s. vs. ZO Con). In ZO rats insulin, cholesterol and triglyceride levels were significant higher than in ZL rats (all p<0.05). Inhibition of mPTP with CsA failed to restore cardioprotection in the prediabetic but normoglycaemic heart of Zucker obese rats in vivo. Copyright © 2009 Elsevier B.V. All rights reserved.

  18. Impact of bromocriptine-QR therapy on cardiovascular outcomes in type 2 diabetes mellitus subjects on metformin.

    PubMed

    Chamarthi, Bindu; Ezrokhi, Michael; Rutty, Dean; Cincotta, Anthony H

    2016-11-01

    Type 2 diabetes mellitus (T2DM) is associated with a substantially increased risk of cardiovascular disease (CVD). Bromocriptine-QR (B-QR), a quick release sympatholytic dopamine D 2 receptor agonist, is a FDA-approved therapy for T2DM which may provide CVD risk reduction. Metformin is considered to be an agent with a potential cardioprotective benefit. This large placebo controlled clinical study assessed the impact of B-QR addition to existing metformin therapy on CVD outcomes in T2DM subjects. 1791 subjects (1208 B-QR; 583 placebo) on metformin ± another anti-diabetes therapy at baseline derived from the Cycloset Safety Trial, a 12-month, randomized, multicenter, placebo-controlled, double-blind study in T2DM, were included in this study. The primary CVD endpoint evaluated was treatment impact on CVD event rate, prespecified as a composite of time to first myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina/congestive heart failure. Impact on glycemic control was evaluated as a secondary analysis. The composite CVD end point occurred in 16/1208 B-QR treated (1.3%) and 18/583 placebo treated (3.1%) subjects resulting in a 55% CVD hazard risk reduction (intention-to-treat, Cox regression analysis; HR: 0.45 [0.23-0.88], p = 0.028). Kaplan-Meier curves demonstrated a significantly lower cumulative incidence rate of the CVD endpoint in the B-QR treatment group (Log-Rank p = 0.017). In subjects with poor glycemic control (HbA1c ≥ 7.5) at baseline, B-QR therapy relative to placebo resulted in a significant mean %HbA1c reduction of -0.59 at week 12 and -0.51 at week 52 respectively (p < 0.001 for both) and a 10 fold higher percent of subjects achieving HbA1c goal of ≤7% by week 52 (B-QR 30%, placebo 3%; p = 0.003). These findings suggest that in T2DM subjects on metformin, BQR therapy may represent an effective strategy for reducing CVD risk. Cycloset Safety Trial registration: ClinicalTrials.gov Identifier

  19. [Dexrazoxane (ICRF-187)--a cardioprotectant and modulator of action of some anticancer drugs].

    PubMed

    Kik, Krzysztof; Szmigiero, Leszek

    2006-01-01

    The nthracycline antibiotics are among the most widely used and effective anticancer drugs. The therapeutic efficacy of this class of drugs is limited by cumulative cardiac toxicity. Dexrazoxane is the only clinically approved cardioprotective agent used in anthracycline-containing anticancer therapy. Its cardioprotective action allows the use of a much higher cumulative dose of anthracyclines and improvement in the effectiveness of treatment. Anthracyclines form complexes with iron ions, which are very active in the production of reactive oxygen species responsible for the lipid peroxidation of mitochondrial and endoplasmatic reticulum membranes. This process seems to be the major cause of anthracycline-induced cardiotoxicity. Dexrazoxane exerts its protective effects by rapid and complete binding of ferric and ferrous ions, even by displacing the metal ions from complexes with anthracyclines. Besides its cardioprotective effect, dexrazoxane also exhibits anticancer properties. Like other derivatives of bisdioxopiperazine, dexrazoxane is a catalytic inhibitor of eukaryotic DNA topoisomerase II, the key enzyme controlling DNA topology and contributing to the replication and transcription processes. Dexrazoxane is able to lock topoisomerase II at the stage of the enzyme reaction cycle where the enzyme forms a closed clamp around the DNA. This phenomenon seems to be the main reason for the generation of DNA double-strand breaks by dexrazoxane as well as its cytotoxicity against quickly proliferating cancer cells. Other effects of its topoisomerase II catalytic inhibition is the induction of cell differentiation and apoptosis. Dexrazoxane may be used not only as a cardioprotective agent, but also as a modulator of action of some anticancer drugs by enhancing their selectivity or by delaying the development of multidrug resistance.

  20. Metformin improves healthspan and lifespan in mice

    PubMed Central

    Martin-Montalvo, Alejandro; Mercken, Evi M.; Mitchell, Sarah J.; Palacios, Hector H.; Mote, Patricia L.; Scheibye-Knudsen, Morten; Gomes, Ana P.; Ward, Theresa M.; Minor, Robin K.; Blouin, Marie-José; Schwab, Matthias; Pollak, Michael; Zhang, Yongqing; Yu, Yinbing; Becker, Kevin G.; Bohr, Vilhelm A.; Ingram, Donald K.; Sinclair, David A.; Wolf, Norman S.; Spindler, Stephen R.; Bernier, Michel; de Cabo, Rafael

    2013-01-01

    Metformin is a drug commonly prescribed to treat patients with type 2 diabetes. Here we show that long-term treatment with metformin (0.1% w/w in diet) starting at middle age extends healthspan and lifespan in male mice, while a higher dose (1% w/w) was toxic. Treatment with metformin mimics some of the benefits of calorie restriction, such as improved physical performance, increased insulin sensitivity, and reduced LDL and cholesterol levels without a decrease in caloric intake. At a molecular level, metformin increases AMP-activated protein kinase activity and increases antioxidant protection, resulting in reductions in both oxidative damage accumulation and chronic inflammation. Our results indicate that these actions may contribute to the beneficial effects of metformin on healthspan and lifespan. These findings are in agreement with current epidemiological data and raise the possibility of metformin-based interventions to promote healthy aging. PMID:23900241

  1. Metformin improves healthspan and lifespan in mice.

    PubMed

    Martin-Montalvo, Alejandro; Mercken, Evi M; Mitchell, Sarah J; Palacios, Hector H; Mote, Patricia L; Scheibye-Knudsen, Morten; Gomes, Ana P; Ward, Theresa M; Minor, Robin K; Blouin, Marie-José; Schwab, Matthias; Pollak, Michael; Zhang, Yongqing; Yu, Yinbing; Becker, Kevin G; Bohr, Vilhelm A; Ingram, Donald K; Sinclair, David A; Wolf, Norman S; Spindler, Stephen R; Bernier, Michel; de Cabo, Rafael

    2013-01-01

    Metformin is a drug commonly prescribed to treat patients with type 2 diabetes. Here we show that long-term treatment with metformin (0.1% w/w in diet) starting at middle age extends healthspan and lifespan in male mice, while a higher dose (1% w/w) was toxic. Treatment with metformin mimics some of the benefits of calorie restriction, such as improved physical performance, increased insulin sensitivity, and reduced low-density lipoprotein and cholesterol levels without a decrease in caloric intake. At a molecular level, metformin increases AMP-activated protein kinase activity and increases antioxidant protection, resulting in reductions in both oxidative damage accumulation and chronic inflammation. Our results indicate that these actions may contribute to the beneficial effects of metformin on healthspan and lifespan. These findings are in agreement with current epidemiological data and raise the possibility of metformin-based interventions to promote healthy aging.

  2. Cardioprotection Via Modulation of Calcium Homeostasis by Thiopental in Hypoxia-Reoxygenated Neonatal Rat Cardiomyocytes

    PubMed Central

    Kim, Hyun-Soo; Hwang, Ki-Chul

    2010-01-01

    Purpose Ca2+ homeostasis plays an important role in myocardial cell injury induced by hypoxia-reoxygenation, and prevention of intracellular Ca2+ overload is key to cardioprotection. Even though thiopental is a frequently used anesthetic agent, little is known about its cardioprotective effects, particulary in association with Ca2+ homeostasis. We investigated whether thiopental protects cardiomyocytes against hypoxia-reoxygenation injury by regulating Ca2+ homeostasis. Materials and Methods Neonatal rat cardiomyocytes were isolated. Cardiomyocytes were exposed to different concentrations of thiopental and immediately replaced in the hypoxic chamber to maintain hypoxia. After 1 hour of exposure, a culture dish was transferred to the CO2 incubator and cells were incubated at 37℃ for 5 hours. At the end of the experiments, the authors assessed cell protection using immunoblot analysis and caspase activity. The mRNA of genes involved in Ca2+ homeostasis, mitochondrial membrane potential, and cellular Ca2+ levels were examined. Results In thiopental-treated cardiomyocytes, there was a decrease in expression of the proapoptotic protein Bax, caspase-3 activation, and intracellular Ca2+ content. In addition, both enhancement of anti-apoptotic protein Bcl-2 and activation of Erk concerned with survival were shown. Furthermore, thiopental attenuated alterations of genes involving Ca2+ regulation and significantly modulated abnormal changes of NCX and SERCA2a genes in hypoxia-reoxygenated neonatal cardiomyocytes. Thiopental suppressed disruption of mitochondrial membrane potential (ΔΨm) induced by hypoxia-reoxygenation. Conclusion Thiopental is likely to modulate expression of genes that regulate Ca2+ homeostasis, which reduces apoptotic cell death and results in cardioprotection. PMID:20191008

  3. High amylose starch consumption induces obesity in Drosophila melanogaster and metformin partially prevents accumulation of storage lipids and shortens lifespan of the insects.

    PubMed

    Abrat, Oleksandra B; Storey, Janet M; Storey, Kenneth B; Lushchak, Volodymyr I

    2018-01-01

    There are very few studies that have directly analyzed the effects of dietary intake of slowly digestible starches on metabolic parameters of animals. The present study examined the effects of slowly digestible starch with high amylose content (referred also as amylose starch) either alone, or in combination with metformin on the development, lifespan, and levels of glucose and storage lipids in the fruit fly Drosophila melanogaster. Consumption of amylose starch in concentrations 0.25-10% did not affect D. melanogaster development, whereas 20% starch delayed pupation and reduced the number of larvae that reached the pupal stage. Starch levels in larval food, but not in adult food, determined levels of triacylglycerides in eight-day-old adult flies. Rearing on diet with 20% starch led to shorter lifespan and a higher content of triacylglycerides in the bodies of adult flies as compared with the same parameters in flies fed on 4% starch diet. Food supplementation with 10mM metformin partly attenuated the negative effects of high starch concentrations on larval pupation and decreased triacylglyceride levels in adult flies fed on 20% starch. Long-term consumption of diets supplemented with metformin and starch decreased lifespan of the insects, compared with the diet supplemented with starch only. The data show that in Drosophila high starch consumption may induce a fat fly phenotype and metformin may partially prevent it. Copyright © 2017. Published by Elsevier Inc.

  4. MicroRNA-320 involves in the cardioprotective effect of insulin against myocardial ischemia by targeting survivin.

    PubMed

    Yang, Ni; Wu, Liuzhong; Zhao, Ying; Zou, Ning; Liu, Chunfeng

    2018-04-01

    It is generally accepted that insulin exerts an antiapoptotic effect against ischemia/reperfusion through the activation of PI3K/Akt/mTOR pathway. MicroRNAs involve in multiple cardiac pathophysiological processes, including ischemia/reperfusion-induced cardiac injury. However, the regulation of microRNAs in the cardioprotective effect of insulin is rarely discussed. In this study, using a cell model of ischemia through culturing H9C2 cardiac myocytes in serum-free medium with hypoxia, we demonstrated that pretreatment with insulin significantly inhibited cell apoptosis and downregulated microRNA-320 (miR-320) expression. Interestingly, miR-320 mimic impaired the cardioprotective effect of insulin against myocardial ischemia injury by targeting survivin, which is a member of the family of inhibitor of apoptosis proteins. Suppression miR-320 expression by miR-320 inhibitor in H9C2 cells with myocardial ischemia mimics the cardioprotective effect of insulin by maintaining survivin expression. Taken together, miR-320-mediated survivin expression involves in cardioprotective effect of insulin against myocardial ischemia injury. Myocardial ischemia/reperfusion (I/R) injury remains an important clinical problem with extremely deficient clinical therapies. Insulin exerts an antiapoptotic effect against I/R through the activation of PI3K/Akt/mTOR pathway. Here, we provided evidences to show that microRNA-320 involves in the cardioprotective effect of insulin by targeting survivin, which is an inhibitor of apoptosis protein and functions as a key regulator in cell apoptosis and involves in the tumour genesis and progression. Our findings may provide a new potential therapeutic strategy for I/R injury and ischemic heart disease. Copyright © 2018 John Wiley & Sons, Ltd.

  5. Metformin Induces Cell Cycle Arrest, Reduced Proliferation, Wound Healing Impairment In Vivo and Is Associated to Clinical Outcomes in Diabetic Foot Ulcer Patients.

    PubMed

    Ochoa-Gonzalez, Fatima; Cervantes-Villagrana, Alberto R; Fernandez-Ruiz, Julio C; Nava-Ramirez, Hilda S; Hernandez-Correa, Adriana C; Enciso-Moreno, Jose A; Castañeda-Delgado, Julio E

    2016-01-01

    Several epidemiological studies in diabetic patients have demonstrated a protective effect of metformin to the development of several types of cancer. The underlying mechanisms of such phenomenon is related to the effect of metformin on cell proliferation among which, mTOR, AMPK and other targets have been identified. However, little is known about the role that metformin treatment have on other cell types such as keratinocytes and whether exposure to metformin of these cells might have serious repercussions in wound healing delay and in the development of complications in diabetic patients with foot ulcers or in their exacerbation. HaCaT Cells were exposed to various concentrations of metformin and cell viability was evaluated by a Resazurin assay; Proliferation was also evaluated with a colony formation assay and with CFSE dilution assay by flow cytometry. Cell cycle was also evaluated by flow cytometry by PI staining. An animal model of wound healing was used to evaluate the effect of metformin in wound closure. Also, an analysis of patients receiving metformin treatment was performed to determine the effect of metformin treatment on the outcome and wound area. Statistical analysis was performed on SPSS v. 18 and GraphPad software v.5. Metformin treatment significantly reduces cell proliferation; colony formation and alterations of the cell cycle are observed also in the metformin treated cells, particularly in the S phase. There is a significant increase in the area of the wound of the metformin treated animals at different time points (P<0.05). There is also a significant increase in the size and wound area of the patients with diabetic foot ulcers at the time of hospitalization. A protective effect of metformin was observed for amputation, probably associated with the anti inflammatory effects reported of metformin. Metformin treatment reduces cell proliferation and reduces wound healing in an animal model and affects clinical outcomes in diabetic foot ulcer

  6. [How xenon works: neuro and cardioprotection mechanisms].

    PubMed

    Morais, Ricardo; Andrade, Luísa; Lourenço, André; Tavares, Jorge

    2014-01-01

    The Xenon, a noble gas, has anesthetics properties, associated with remarkable hemodynamic stability as well as cardioprotective, neuroprotective proprieties. Its physicochemical characteristics give him a quick induction and emergence of anesthesia, being free of deleterious effects in all organs and showing no teratogenicity. Such properties have led to a growing interest in improving the knowledge about this noble gas, in order to assess the mechanisms of neuro and cardioprotection induced and to assess the clinical indications for its use. Qualitative review of clinical trials on anesthesia with xenon. Studies were identified from MEDLINE and by hand-searching, using the following keywords: xenon, xenon anestesia, xenon neuroprotection, xenon cradioprotection. After several studies, including two randomized multicenter controlled trials, the use of xenon as an anesthetic in patients ASA I-II was approved in March 2007. However his use in clinical practice has been strongly limited by it's high price. It seems unlikely that the advantages it offers in relation to other anesthetics justify it's use in patients ASA I-II. Although, xenon may be a valuable asset in the reduction of co-morbilities and mortality in anesthesia of patients ASA III-IV, unfortunately, there are no large randomized control studies to prove it. Unfortunately, there are still no randomized or multicentric studies showing a favourable cost-benefit profile of xenon in ASA III-IV patients vs. other anaesthetics. The usefulness of xenon in Anesthesiology requires more studies to be defined.

  7. Regulation of Sirtuin-Mediated Protein Deacetylation by Cardioprotective Phytochemicals

    PubMed Central

    2017-01-01

    Modulation of posttranslational modifications (PTMs), such as protein acetylation, is considered a novel therapeutic strategy to combat the development and progression of cardiovascular diseases. Protein hyperacetylation is associated with the development of numerous cardiovascular diseases, including atherosclerosis, hypertension, cardiac hypertrophy, and heart failure. In addition, decreased expression and activity of the deacetylases Sirt1, Sirt3, and Sirt6 have been linked to the development and progression of cardiac dysfunction. Several phytochemicals exert cardioprotective effects by regulating protein acetylation levels. These effects are mainly exerted via activation of Sirt1 and Sirt3 and inhibition of acetyltransferases. Numerous studies support a cardioprotective role for sirtuin activators (e.g., resveratrol), as well as other emerging modulators of protein acetylation, including curcumin, honokiol, oroxilyn A, quercetin, epigallocatechin-3-gallate, bakuchiol, tyrosol, and berberine. Studies also point to a cardioprotective role for various nonaromatic molecules, such as docosahexaenoic acid, alpha-lipoic acid, sulforaphane, and caffeic acid ethanolamide. Here, we review the vast evidence from the bench to the clinical setting for the potential cardioprotective roles of various phytochemicals in the modulation of sirtuin-mediated deacetylation. PMID:29234485

  8. Safety and tolerability of dapagliflozin, saxagliptin and metformin in combination: Post-hoc analysis of concomitant add-on versus sequential add-on to metformin and of triple versus dual therapy with metformin.

    PubMed

    Del Prato, Stefano; Rosenstock, Julio; Garcia-Sanchez, Ricardo; Iqbal, Nayyar; Hansen, Lars; Johnsson, Eva; Chen, Hungta; Mathieu, Chantal

    2018-06-01

    The safety of triple oral therapy with dapagliflozin plus saxagliptin plus metformin versus dual therapy with dapagliflozin or saxagliptin plus metformin was compared in a post-hoc analysis of 3 randomized trials of sequential or concomitant add-on of dapagliflozin and saxagliptin to metformin. In the concomitant add-on trial, patients with type 2 diabetes on stable metformin received dapagliflozin 10 mg/d plus saxagliptin 5 mg/d. In sequential add-on trials, patients on metformin plus either saxagliptin 5 mg/d or dapagliflozin 10 mg/d received dapagliflozin 10 mg/d or saxagliptin 5 mg/d, respectively, as add-on therapy. After 24 weeks, incidences of adverse events and serious adverse events were similar between triple and dual therapy and between concomitant and sequential add-on regimens. Urinary tract infections were more common with sequential than with concomitant add-on therapy; genital infections were reported only with sequential add-on of dapagliflozin to saxagliptin plus metformin. Hypoglycaemia incidence was <2.0% across all analysis groups. In conclusion, the safety and tolerability of triple therapy with dapagliflozin, saxagliptin and metformin, as either concomitant or sequential add-on, were similar to dual therapy with either agent added to metformin. © 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

  9. Metformin Suppresses Systemic Autoimmunity in Roquinsan/san Mice through Inhibiting B Cell Differentiation into Plasma Cells via Regulation of AMPK/mTOR/STAT3.

    PubMed

    Lee, Seon-Yeong; Moon, Su-Jin; Kim, Eun-Kyung; Seo, Hyeon-Beom; Yang, Eun-Ji; Son, Hye-Jin; Kim, Jae-Kyung; Min, Jun-Ki; Park, Sung-Hwan; Cho, Mi-La

    2017-04-01

    Circulating autoantibodies and immune complex deposition are pathological hallmarks of systemic lupus erythematosus (SLE). B cell differentiation into plasma cells (PCs) and some T cell subsets that function as B cell helpers can be therapeutic targets of SLE. Mechanistic target of rapamycin (mTOR) signaling is implicated in the formation of B cells and germinal centers (GCs). We assessed the effect of metformin, which inhibits mTOR, on the development of autoimmunity using Roquin san/san mice. Oral administration of metformin inhibited the formation of splenic follicles and inflammation in kidney and liver tissues. It also decreased serum levels of anti-dsDNA Abs without affecting serum glucose levels. Moreover, metformin inhibited CD21 high CD23 low marginal zone B cells, B220 + GL7 + GC B cells, B220 - CD138 + PCs, and GC formation. A significant reduction in ICOS + follicular helper T cells was found in the spleens of the metformin-treated group compared with the vehicle-treated group. In addition, metformin inhibited Th17 cells and induced regulatory T cells. These alterations in B and T cell subsets by metformin were associated with enhanced AMPK expression and inhibition of mTOR-STAT3 signaling. Furthermore, metformin induced p53 and NF erythroid-2-related factor-2 activity in splenic CD4 + T cells. Taken together, metformin-induced alterations in AMPK-mTOR-STAT3 signaling may have therapeutic value in SLE by inhibiting B cell differentiation into PCs and GCs. Copyright © 2017 by The American Association of Immunologists, Inc.

  10. Increased risk of cognitive impairment in patients with diabetes is associated with metformin.

    PubMed

    Moore, Eileen M; Mander, Alastair G; Ames, David; Kotowicz, Mark A; Carne, Ross P; Brodaty, Henry; Woodward, Michael; Boundy, Karyn; Ellis, Kathryn A; Bush, Ashley I; Faux, Noel G; Martins, Ralph; Szoeke, Cassandra; Rowe, Christopher; Watters, David A

    2013-10-01

    To investigate the associations of metformin, serum vitamin B12, calcium supplements, and cognitive impairment in patients with diabetes. Participants were recruited from the Primary Research in Memory (PRIME) clinics study, the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, and the Barwon region of southeastern Australia. Patients with Alzheimer disease (AD) (n=480) or mild cognitive impairment (n=187) and those who were cognitively intact (n=687) were included; patients with stroke or with neurodegenerative diseases other than AD were excluded. Subgroup analyses were performed for participants who had either type 2 diabetes (n=104) or impaired glucose tolerance (n=22). Participants with diabetes (n=126) had worse cognitive performance than participants who did not have diabetes (n=1,228; adjusted odds ratio 1.51 [95% CI 1.03-2.21]). Among participants with diabetes, worse cognitive performance was associated with metformin use (2.23 [1.05-4.75]). After adjusting for age, sex, level of education, history of depression, serum vitamin B12, and metformin use, participants with diabetes who were taking calcium supplements had better cognitive performance (0.41 [0.19-0.92]). Metformin use was associated with impaired cognitive performance. Vitamin B12 and calcium supplements may alleviate metformin-induced vitamin B12 deficiency and were associated with better cognitive outcomes. Prospective trials are warranted to assess the beneficial effects of vitamin B12 and calcium use on cognition in older people with diabetes who are taking metformin.

  11. Metoprolol decreases the plasma exposure of metformin via the induction of liver, kidney and muscle uptake in rats.

    PubMed

    Ma, Yan-Rong; Shi, A-Xi; Qin, Hong-Yan; Zhang, Tiffany; Wu, Yan-Fang; Zhang, Guo-Qiang; Wu, Xin-An

    2016-12-01

    Drug interactions are one of the commonest causes of side effects, particularly in long-term therapy. The aim of the current study was to investigate the possible effects of metoprolol on the pharmacokinetics of metformin in rats and to clarify the mechanism of drug interaction. In this study, rats were treated with metformin alone or in combination with metoprolol. Plasma, urine and tissue concentrations of metformin were determined by HPLC. Western blotting and real-time qPCR were used to evaluate the expression of rOCTs and rMATE1. The results showed that, after single or 7-day repeated administration, the plasma concentrations of metformin in the co-administration group were significantly decreased compared with that in the metformin group. However, the parameter V/F of metformin in the co-administration group was markedly increased compared with that in the metformin group. The hepatic, renal and muscular K p of metformin were markedly elevated after co-administration with metoprolol. Consistently, metformin uptake in rat kidney slices was significantly induced by metoprolol. In addition, multiple administrations of metoprolol significantly reduced the expression of rMATE1 in rat kidney as well as the urinary excretion of metformin. Importantly, after long-term administration, lactic acid and uric acid levels in the co-administration group were increased by 25% and 26%, respectively, compared with that in the metformin group. These results indicate that metoprolol can decrease the plasma concentration of metformin via the induction of hepatic, renal and muscular uptake, and long-term co-administration of metformin and metoprolol can cause elevated lactic acid and uric acid levels. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  12. Variations in Metformin Prescribing for Type 2 Diabetes.

    PubMed

    Goldberg, Tiffany; Kroehl, Miranda E; Suddarth, Kathleen Heist; Trinkley, Katy E

    2015-01-01

    Reasons for suboptimal metformin prescribing are unclear, but may be due to perceived risk of lactic acidosis. The purpose of this study is to describe provider attitudes regarding metformin prescribing in various patient situations. An anonymous, electronic survey was distributed electronically to 76 health care providers across the nation. The 14-item survey contained demographic questions and questions related to prescribing of metformin for T2DM in various patient situations, including suboptimal glycemic control, alcohol use, history of lactic acidosis, and varying degrees of severity for certain health conditions, including renal and hepatic dysfunction, chronic obstructive pulmonary disease, and heart failure. There were a total of 100 respondents. For suboptimal glycemic control, most providers (75%) would increase metformin from 1500 to 2000 mg daily; however, 25% would add an alternate agent, such as a sulfonylurea (18%) or dipeptidyl peptidase-4 inhibitor (7%). Although 51% of providers would stop metformin based on serum creatinine thresholds, the remainder would rely on glomerular filtration rate thresholds of <60 mL/min (15%), <30 mL/min (33%), or <15 mL/min (1%) to determine when to stop metformin. For heart failure, 45% of providers would continue metformin as currently prescribed regardless of severity. Most providers would adjust metformin for varying severity of hepatic dysfunction (74%) and alcohol abuse (40%). Despite evidence supporting the cardiovascular benefits of metformin, provider attitudes toward prescribing metformin are suboptimal in certain patient situations and vary greatly by provider. © Copyright 2015 by the American Board of Family Medicine.

  13. The hypoglycaemic action of metformin

    PubMed Central

    Frayn, K. N.; Adnitt, P. I.; Turner, Paul

    1971-01-01

    Twenty-four-hour excretion of D-xylose after oral administration in nine diabetic patients, and of 3-0-methyl-D-glucose in six patients, showed no significant change after treatment with metformin. There was, however, a significant reduction in mean fasting blood glucose levels in thirteen patients from 160 to 115 mg/100 ml (P <0·001), and the intravenous glucose tolerance improved in twelve of these patients (P <0·01), during treatment with metformin. It is concluded that the hypoglycaemic action of metformin does not depend primarily on an intestinal effect. PMID:5138746

  14. κ-opioid receptor is involved in the cardioprotection induced by exercise training

    PubMed Central

    Li, Juan; Tian, Fei; Feng, Na; Fan, Rong; Jia, Min; Guo, Haitao; Cheng, Liang; Liu, Jincheng; Chen, Wensheng; Pei, Jianming

    2017-01-01

    The present study was designed to test the hypothesis that exercise training elicited a cardioprotective effect against ischemia and reperfusion (I/R) via the κ-opioid receptor (κ-OR)-mediated signaling pathway. Rats were randomly divided into four groups: the control group, the moderate intensity exercise (ME) group, the high intensity exercise (HE) group, and the acute exercise (AE) group. For the exercise training protocols, the rats were subjected to one week of adaptive treadmill training, while from the second week, the ME and HE groups were subjected to eight weeks of exercise training, and the AE group was subjected to three days of adaptive treadmill training and one day of vigorous exercise. After these protocols, the three exercise training groups were divided into different treatment groups, and the rats were subjected to 30 min of ischemia and 120 min of reperfusion. Changes in infarct size and serum cTnT (cardiac troponin T) caused by I/R were reduced by exercise training. Moreover, cardiac dysfunction caused by I/R was also alleviated by exercise training. These effects of exercise training were reversed by nor-BNI (a selective κ-OR antagonist), Compound C (a selective AMPK inhibitor), Akt inhibitor and L-NAME (a non-selective eNOS inhibitor). Expression of κ-OR and phosphorylation of AMPK, Akt and eNOS were significantly increased in the ME, HE and AE groups. These findings demonstrated that the cardioprotective effect of exercise training is possibly mediated by the κ-OR-AMPK-Akt-eNOS signaling pathway. PMID:28301473

  15. Parathyroid Hormone-Related Peptide: A Novel Endocrine Cardioprotective "Conditioning Mimetic".

    PubMed

    Datta, Tanuka; Przyklenk, Karin; Datta, Nabanita S

    2017-11-01

    An as-yet limited body of evidence suggests that calcium-regulating endocrine hormones-in particular, parathyroid hormone-related peptide (PTHrP)-may have unappreciated cardioprotective effects. The current review focuses on the concept that PTHrP may, via modulation of classic cardioprotective signaling pathways, provide a novel strategy to attenuate myocardial ischemia-reperfusion injury.

  16. Cardio-protection of ultrafine granular powder for Salvia miltiorrhiza Bunge against myocardial infarction.

    PubMed

    Wang, Linlin; Li, Yuanmin; Deng, Wen; Dong, Zhihui; Li, Xue; Liu, Dan; Zhao, Lijie; Fu, Weiguo; Cho, Kenka; Niu, Huaying; Guo, Dean; Cheng, Jinle; Jiang, Baohong

    2018-08-10

    Myocardial infarction (MI) is considered as the major inducer to the morbidity and mortality related to coronary occlusion. Salvia miltiorrhiza Bunge is widely applied in the clinic for the prevention and treatment of heart diseases. The preparation of traditional herb decoction (THD) is not only time consuming but also difficult to keep uniform for every time. New usage form of Salvia miltiorrhiza Bunge with characteristics of convenience, uniform and efficiency is needed. The aims of present study were to investigate the cardio-protection of ultrafine granular powder (UGP) of Salvia miltiorrhiza Bunge; and further compare the characteristics of UGP with THD. MI was induced by ligation of the left anterior descending coronary artery near the main pulmonary artery. Cardio-protection of UGP or THD was evaluated based on two sets of experiments, one was acute myocardial infarction (AMI) through 7 days preventive administration, and the other one was chronic cardiac remodeling through 28 days therapeutic administration. Hemodynamic measurement was conducted to evaluate heart function and histopathological detection was used to evaluate heart structure. No significant improvement of heart structure and function was detected for preventive administration of UGP or THD on AMI rats. While, more significant improvements on left ventricular systolic and diastolic function were detected with therapeutic treatment with 0.81 g/kg UGP than same dose of THD on rats against chronic cardiac remodeling. Both UGP and THD showed the protective effects on heart structure, especially against fibrosis with long-term therapeutic treatment. As a new usage form of Salvia miltiorrhiza Bunge, UGP showed significant cardio-protection against myocardial remodeling with therapeutic treatment. Comparing with THD, UGP also holds the advantages of uniform, convenience and efficiency. Copyright © 2018 Elsevier B.V. All rights reserved.

  17. [Treatment with metformin in type 2 diabetes mellitus - new routines when renal function is reduced and in connection with administration of iodine contrast media].

    PubMed

    Sterner, Gunnar; Frid, Anders

    2018-04-03

    Metformin is eliminated through glomerular filtration and tubular secretion in the kidneys. New guidelines recommend use of metformin down to a GFR of 30 mL/min under the condition that the dose is adjusted. As the risk of inducing lactic acidosis is very low in connection with administration of iodine contrast media, new recommendations in Sweden say that metformin must be stopped only when GFR is below 45 mL/min. Determination of metformin levels in serum is useful to guide therapeutic dose when GFR is low but also to confirm that lactic acidosis is caused by metformin.

  18. Eat healthy? Attitudes of the German population towards industrially produced cardioprotective food.

    PubMed

    Jung, F U C E; Luck-Sikorski, C; Krüger, M; Wiacek, C; Braun, P G; Engeli, S; Riedel-Heller, S G

    2018-05-01

    Cardiovascular disease (CVD) is likely to increase in incidence. Foods with cardioprotective functions, e.g. specific functional food, could reduce CVD risk factors and hence CVD incidence. Little is known about industrially modified foods with cardioprotective functions. In a large German sample (n = 1007), attitudes of consumers in Germany towards industrially produced cardioprotective food were assessed using Cluster analyses. Consumers were contacted via telephone and interviewed using questionnaires. Overall, about 25% knew about industrially produced food with cardioprotective function. Our analysis revealed a small but determined group of consumers who think very skeptical about cardioprotective products, but we also identified a favorable group. These two groups only differed in age, with the skeptical group being ten years older. The rising number of industrially modified products with potential cardioprotective benefit is met by skepticism and a lack of knowledge by German costumers. If large scale studies show health benefits of these products, these will need to be better communicated to German customers in order to address possible doubts or concerns and to encourage healthy eating habits in consumer eating behavior. Copyright © 2018 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

  19. Resistin, an adipokine, may affect the improvement of insulin sensitivity in the metabolic syndrome patient treated with metformin.

    PubMed

    Yuan, Hong; Weng, Chunyan; Yang, Youbo; Huang, Lihua; Xing, Xiaowei

    2013-12-01

    The metabolic syndrome (MS) is a cluster of metabolic disorders arising from insulin resistance, characterized by the presence of central obesity, impaired fasting glucose level, dyslipidemia and hypertension. As the first-line medication, metformin is commonly used for MS to reduce insulin resistance. Comparing with rosiglitazone, metformin does not increase cardiovascular mortality risk in patients with MS. However, metformin is not good enough in improving insulin sensitivity. Its molecular mechanism is still not clear. Recent studies have demonstrated that resistin, an adipokine, could induce IR by both AMPK-dependent and AMPK-independent pathways. Though there were conflicting findings of resistin in metabolic syndrome or type 2 diabetes mellitus in different studies, resistin was significant decreased in the rosiglitazone treated patients than in the metformin-treated patients in most of studies. Here, we hypothesized that resistin, an adipokine, may affect the improvement of insulin sensitivity in the metabolic syndrome patient treated with metformin. This hypothesis could explain why rosiglitazone is superior to metformin in enhancement of insulin sensitivity. Copyright © 2013. Published by Elsevier Ltd.

  20. Modulation of the oxidative stress by metformin in the cerebrum of rats exposed to global cerebral ischemia and ischemia/reperfusion.

    PubMed

    Abd-Elsameea, A A; Moustaf, A A; Mohamed, A M

    2014-08-01

    Oxidative stress plays a major role in the pathogenesis of ischemic and reperfusion injury to many organs, including the brain. Chronic metformin treatment is associated with a lower risk of stroke in clinical populations. The aim of the present study was to investigate the effect of metformin on the oxidative stress induced in experimental model of incomplete global cerebral ischemia and ischemia/reperfusion in adult male Wistar rats. Metformin was administered to rats orally by gavage 500 mg/kg once daily for one week before induction of cerebral ischemia (rats were subjected to 30 min of ischemia before decapitation) and ischemia/reperfusion (rats were subjected to 30 min of ischemia then 60 minutes of reperfusion before decapitation). The selected parameters for oxidative stress were the activities of the antioxidant enzymes: glutathione peroxidase (GSHPx), superoxide dismutase (SOD), and catalase as well as malondialdehyde (MDA) levels. Metformin reduced the elevated activites of GSHPx, SOD and catalase as well as MDA levels in cerebrum of rats exposed to ischemia and ischemia/reperfusion injures. Metformin improved the oxidative stress induced by ischemia and ischemia/reperfusion injuries. This may be a mechanism that explains the cerebroprotective effect of the drug.

  1. Acute metformin overdose: examining serum pH, lactate level, and metformin concentrations in survivors versus nonsurvivors: a systematic review of the literature.

    PubMed

    Dell'Aglio, Damon M; Perino, Louis J; Kazzi, Ziad; Abramson, Jerome; Schwartz, Michael D; Morgan, Brent W

    2009-12-01

    Metformin is known to cause potentially fatal metabolic acidosis with an increased lactate level in both overdose and therapeutic use. No association between mortality and serum pH, lactate level, or metformin concentrations, though intuitive, has yet been described. This systematic literature review is designed to evaluate the association between mortality and serum pH, lactate level, and metformin concentrations in acute metformin overdose. We reviewed the literature by using the MEDLINE, EMBASE, CINAHL, and TOXNET databases for cases of metformin overdose with documented mortality data and values of serum pH, lactate level, and metformin concentrations. When available, patient age, patient sex, and whether patients received intravenous sodium bicarbonate therapy or hemodialysis were also analyzed. Cases meeting inclusion criteria were analyzed to determine whether a difference in distribution of nadir serum pH, peak serum lactate level, or peak serum metformin concentrations existed between overdose survivors and nonsurvivors. We identified 10 articles that had 1 or more cases meeting our inclusion criteria. In total, there were 22 cases of metformin overdose (5/22 died) that met inclusion criteria. No intentional overdose patients died whose serum pH nadir was greater than 6.9, maximum lactate concentration less than 25 mol/L, or maximum metformin concentration less than 50 microg/mL (therapeutic range 1 to 2 microg/mL). Intentional overdose patients with a nadir serum pH less than 6.9 had 83% mortality (5/6), those with lactate concentration greater than 25 mmol/L had 83% mortality (5/6), and those with metformin concentration greater than 50 microg/mL had 38% mortality (5/12). Nadir serum pH and peak serum lactate and metformin concentration distributions in survivors and nonsurvivors revealed that survivors had a median nadir pH of 7.30, interquartile range (IQR) 7.22, 7.36; nonsurvivors, a median nadir pH of 6.71, IQR 6.71, 6.73; survivors, a median peak

  2. Metformin and the Risk of Cancer

    PubMed Central

    Suissa, Samy; Azoulay, Laurent

    2012-01-01

    OBJECTIVE Time-related biases in observational studies of drug effects have been described extensively in different therapeutic areas but less so in diabetes. Immortal time bias, time-window bias, and time-lag bias all tend to greatly exaggerate the benefits observed with a drug. RESEARCH DESIGN AND METHODS These time-related biases are described and shown to be prominent in observational studies that have associated metformin with impressive reductions in the incidence of and mortality from cancer. As a consequence, metformin received much attention as a potential anticancer agent; these observational studies sparked the conduction of randomized, controlled trials of metformin as cancer treatment. However, the spectacular effects reported in these studies are compatible with time-related biases. RESULTS We found that 13 observational studies suffered from immortal time bias; 9 studies had not considered time-window bias, whereas other studies did not consider inherent time-lagging issues when comparing the first-line treatment metformin with second- or third-line treatments. These studies, subject to time-related biases that are avoidable with proper study design and data analysis, led to illusory extraordinarily significant effects, with reductions in cancer risk with metformin ranging from 20 to 94%. Three studies that avoided these biases reported no effect of metformin use on cancer incidence. CONCLUSIONS Although observational studies are important to better understand the effects of drugs, their proper design and analysis is essential to avoid major time-related biases. With respect to metformin, the scientific evidence of its potential beneficial effects on cancer would need to be reassessed critically before embarking on further long and expensive trials. PMID:23173135

  3. Hepatotoxicity associated with metformin therapy in treatment of type 2 diabetes mellitus with nonalcoholic fatty liver disease.

    PubMed

    Cone, Catherine J; Bachyrycz, Amy M; Murata, Glen H

    2010-10-01

    To report a case of idiosyncratic hepatotoxicity associated with metformin in the treatment of type 2 diabetes with nonalcoholic fatty liver disease (NAFLD). A 61-year-old obese man presented with jaundice, nausea, fatigue, and an unintentional weight loss 2 weeks following initiation of metformin. Laboratory findings revealed aminotransferase values 10-15 times the upper limit of normal. Potential causative agents, including metformin, simvastatin, and Niaspan (extended-release niacin), were discontinued. Two months later, the patient's signs and symptoms had resolved and aminotransferase values returned to normal. An objective causality assessment revealed that the adverse reaction was probably associated with metformin. Since numerous medications and disease states can cause abnormalities in liver enzymes, it is important for providers to be able to distinguish the cause(s) and take appropriate actions. This can take a great deal of time and effort in patients with multiple medications and comorbidities. In this patient's case, viral hepatitis, worsening NAFLD, and the concomitant drugs were highly suspected. As hydroxymethylglutaryl coenzyme A reductase inhibitors offer substantial cardiovascular benefits and as metformin is a first-line agent in helping to lower blood glucose concentrations and to normalize the metabolic profile in type 2 diabetes, reintroduction of metformin and simvastatin would likely be beneficial. This is a case report of metformin-induced hepatotoxicity. As the prevalence of type 2 diabetes and subsequent metabolic effects increases in the US, metformin use will likewise increase. As potential for increased idiosyncratic hepatotoxicity associated with metformin use is likely to occur, clinicians should be vigilant.

  4. Increased Risk of Cognitive Impairment in Patients With Diabetes Is Associated With Metformin

    PubMed Central

    Moore, Eileen M.; Mander, Alastair G.; Ames, David; Kotowicz, Mark A.; Carne, Ross P.; Brodaty, Henry; Woodward, Michael; Boundy, Karyn; Ellis, Kathryn A.; Bush, Ashley I.; Faux, Noel G.; Martins, Ralph; Szoeke, Cassandra; Rowe, Christopher; Watters, David A.

    2013-01-01

    OBJECTIVE To investigate the associations of metformin, serum vitamin B12, calcium supplements, and cognitive impairment in patients with diabetes. RESEARCH DESIGN AND METHODS Participants were recruited from the Primary Research in Memory (PRIME) clinics study, the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, and the Barwon region of southeastern Australia. Patients with Alzheimer disease (AD) (n = 480) or mild cognitive impairment (n = 187) and those who were cognitively intact (n = 687) were included; patients with stroke or with neurodegenerative diseases other than AD were excluded. Subgroup analyses were performed for participants who had either type 2 diabetes (n = 104) or impaired glucose tolerance (n = 22). RESULTS Participants with diabetes (n = 126) had worse cognitive performance than participants who did not have diabetes (n = 1,228; adjusted odds ratio 1.51 [95% CI 1.03–2.21]). Among participants with diabetes, worse cognitive performance was associated with metformin use (2.23 [1.05–4.75]). After adjusting for age, sex, level of education, history of depression, serum vitamin B12, and metformin use, participants with diabetes who were taking calcium supplements had better cognitive performance (0.41 [0.19–0.92]). CONCLUSIONS Metformin use was associated with impaired cognitive performance. Vitamin B12 and calcium supplements may alleviate metformin-induced vitamin B12 deficiency and were associated with better cognitive outcomes. Prospective trials are warranted to assess the beneficial effects of vitamin B12 and calcium use on cognition in older people with diabetes who are taking metformin. PMID:24009301

  5. Metformin directly acts on mitochondria to alter cellular bioenergetics

    PubMed Central

    2014-01-01

    Background Metformin is widely used in the treatment of diabetes, and there is interest in ‘repurposing’ the drug for cancer prevention or treatment. However, the mechanism underlying the metabolic effects of metformin remains poorly understood. Methods We performed respirometry and stable isotope tracer analyses on cells and isolated mitochondria to investigate the impact of metformin on mitochondrial functions. Results We show that metformin decreases mitochondrial respiration, causing an increase in the fraction of mitochondrial respiration devoted to uncoupling reactions. Thus, cells treated with metformin become energetically inefficient, and display increased aerobic glycolysis and reduced glucose metabolism through the citric acid cycle. Conflicting prior studies proposed mitochondrial complex I or various cytosolic targets for metformin action, but we show that the compound limits respiration and citric acid cycle activity in isolated mitochondria, indicating that at least for these effects, the mitochondrion is the primary target. Finally, we demonstrate that cancer cells exposed to metformin display a greater compensatory increase in aerobic glycolysis than nontransformed cells, highlighting their metabolic vulnerability. Prevention of this compensatory metabolic event in cancer cells significantly impairs survival. Conclusions Together, these results demonstrate that metformin directly acts on mitochondria to limit respiration and that the sensitivity of cells to metformin is dependent on their ability to cope with energetic stress. PMID:25184038

  6. Cost-effectiveness of dapagliflozin (Forxiga®) added to metformin compared with sulfonylurea added to metformin in type 2 diabetes in the Nordic countries.

    PubMed

    Sabale, Ugne; Ekman, Mattias; Granström, Ola; Bergenheim, Klas; McEwan, Phil

    2015-02-01

    The aim of this study was to assess the long-term cost-effectiveness of dapagliflozin (Forxiga(®)) added to metformin, compared with sulfonylurea (SU) added to metformin, in Nordic Type 2 diabetes mellitus (T2DM) patients inadequately controlled on metformin. Data from a 52-week clinical trial comparing dapagliflozin and SU in combination with metformin was used in a Cardiff simulation model to estimate long term diabetes-related complications in a cohort of T2DM patients. Costs and QALYs were calculated from a healthcare provider perspective and estimated over a patient's lifetime. Compared with metformin+SU, the cost per QALY gained with dapagliflozin+metformin was €7944 in Denmark, €5424 in Finland, €4769 in Norway, and €6093 in Sweden. Metformin+dapagliflozin was associated with QALY gains ranging from 0.236 in Norway to 0.278 in Sweden and incremental cost ranging from €1125 in Norway to €1962 in Denmark. Results were robust across both one-way and probabilistic sensitivity analyses. Results were driven by weight changes associated with each treatment. Results indicate that metformin+dapagliflozin is associated with gains in QALY compared with metformin+SU in Nordic T2DM patients inadequately controlled on metformin. Dapagliflozin treatment is a cost-effective treatment alternative for Type 2 diabetes in all four Nordic countries. Copyright © 2014 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.

  7. Far red/near infrared light-induced cardioprotection under normal and diabetic conditions

    NASA Astrophysics Data System (ADS)

    Keszler, Agnes; Baumgardt, Shelley; Hwe, Christopher; Bienengraeber, Martin

    2015-03-01

    Far red/near infrared light (NIR) is beneficial against cardiac ischemia and reperfusion injury (I/R), although the exact underlying mechanism is unknown. Previously we established that NIR enhanced the cardioprotective effect of nitrite in the rabbit heart. Furthermore, we observed that the nitrosyl myoglobin (MbNO) level in ischemic tissue decreased upon irradiation of the heart. Our hypothesis was that protection against I/R is dependent on nitric oxide (NO)-release from heme-proteins, and remains present during diabetes. When mice were subjected to I/R NIR (660 nm) applied during the beginning of reperfusion reduced infarct size dose dependently compared to untreated animals. Similarly, the isolated (Langendorff) heart model resulted in sustained left ventricular diastolic pressure after I/R in NIR-treated hearts. NIRinduced protection was preserved in a diabetic mouse model (db/db) and during acute hyperglycemia. NIR liberated NO from nitrosyl hemoglobin (HbNO) and MbNO as well as from HbNO isolated from the blood of diabetic animals. In the Langendorff model, after application of the nitrosylated form of a hemoglobin-based oxygen carrier as an NO donor NIR induced an increase in NADH level, suggesting a mild inhibition of mitochondrial respiration by NO during reperfusion. Taken together, NIR applied during reperfusion protects the myocardium against I/R in a NO-dependent and mitochondrion-targeted manner. This unique mechanism is conserved under diabetic conditions where other protective strategies fail.

  8. Deciphering Signaling Pathway Networks to Understand the Molecular Mechanisms of Metformin Action

    PubMed Central

    Sun, Jingchun; Zhao, Min; Jia, Peilin; Wang, Lily; Wu, Yonghui; Iverson, Carissa; Zhou, Yubo; Bowton, Erica; Roden, Dan M.; Denny, Joshua C.; Aldrich, Melinda C.; Xu, Hua; Zhao, Zhongming

    2015-01-01

    A drug exerts its effects typically through a signal transduction cascade, which is non-linear and involves intertwined networks of multiple signaling pathways. Construction of such a signaling pathway network (SPNetwork) can enable identification of novel drug targets and deep understanding of drug action. However, it is challenging to synopsize critical components of these interwoven pathways into one network. To tackle this issue, we developed a novel computational framework, the Drug-specific Signaling Pathway Network (DSPathNet). The DSPathNet amalgamates the prior drug knowledge and drug-induced gene expression via random walk algorithms. Using the drug metformin, we illustrated this framework and obtained one metformin-specific SPNetwork containing 477 nodes and 1,366 edges. To evaluate this network, we performed the gene set enrichment analysis using the disease genes of type 2 diabetes (T2D) and cancer, one T2D genome-wide association study (GWAS) dataset, three cancer GWAS datasets, and one GWAS dataset of cancer patients with T2D on metformin. The results showed that the metformin network was significantly enriched with disease genes for both T2D and cancer, and that the network also included genes that may be associated with metformin-associated cancer survival. Furthermore, from the metformin SPNetwork and common genes to T2D and cancer, we generated a subnetwork to highlight the molecule crosstalk between T2D and cancer. The follow-up network analyses and literature mining revealed that seven genes (CDKN1A, ESR1, MAX, MYC, PPARGC1A, SP1, and STK11) and one novel MYC-centered pathway with CDKN1A, SP1, and STK11 might play important roles in metformin’s antidiabetic and anticancer effects. Some results are supported by previous studies. In summary, our study 1) develops a novel framework to construct drug-specific signal transduction networks; 2) provides insights into the molecular mode of metformin; 3) serves a model for exploring signaling pathways

  9. Artocarpus heterophyllus L. seed starch-blended gellan gum mucoadhesive beads of metformin HCl.

    PubMed

    Nayak, Amit Kumar; Pal, Dilipkumar; Santra, Kousik

    2014-04-01

    Jackfruit (Artocarpus heterophyllus Lam., family: Moraceae) seed starch (JFSS)-gellan gum (GG) mucoadhesive beads containing metformin HCl were developed through ionotropic gelation technique. The effect of GG to JFSS ratio and CaCl2 concentration on the drug encapsulation efficiency (DEE, %) and cumulative drug release at 10h (R10h, %) was optimized and analyzed using response surface methodology based on 3(2) factorial design. The optimized JFSS-GG beads containing metformin HCl showed DEE of 92.67±4.46%, R10h of 61.30±2.37%, and mean diameter of 1.67±0.27 mm. The optimized beads showed pH-dependent swelling and mucoadhesivity with the goat intestinal mucosa. The in vitro drug release from all these JFSS-GG beads containing metformin HCl was followed zero-order pattern (R(2)=0.9907-0.9975) with super case-II transport mechanism over a period of 10 h. The beads were also characterized by SEM and FTIR. The optimized JFSS-GG beads containing metformin HCl exhibited significant hypoglycemic effect in alloxan-induced diabetic rats over prolonged period after oral administration. Copyright © 2014 Elsevier B.V. All rights reserved.

  10. Mitochondrial events responsible for morphine's cardioprotection against ischemia/reperfusion injury

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    He, Haiyan; Department of Pharmacology, Tianjin Medical University, Tianjin 300070; Huh, Jin

    Morphine may induce cardioprotection by targeting mitochondria, but little is known about the exact mitochondrial events that mediate morphine's protection. We aimed to address the role of the mitochondrial Src tyrosine kinase in morphine's protection. Isolated rat hearts were subjected to 30 min ischemia and 2 h of reperfusion. Morphine was given before the onset of ischemia. Infarct size and troponin I release were measured to evaluate cardiac injury. Oxidative stress was evaluated by measuring mitochondrial protein carbonylation and mitochondrial ROS generation. HL-1 cells were subjected to simulated ischemia/reperfusion and LDH release and mitochondrial membrane potential (ΔΨm) were measured. Morphinemore » reduced infarct size as well as cardiac troponin I release which were aborted by the selective Src tyrosine kinase inhibitors PP2 and Src-I1. Morphine also attenuated LDH release and prevented a loss of ΔΨm at reperfusion in a Src tyrosine kinase dependent manner in HL-1 cells. However, morphine failed to reduce LDH release in HL-1 cells transfected with Src siRNA. Morphine increased mitochondrial Src phosphorylation at reperfusion and this was abrogated by PP2. Morphine attenuated mitochondrial protein carbonylation and mitochondrial superoxide generation at reperfusion through Src tyrosine kinase. The inhibitory effect of morphine on the mitochondrial complex I activity was reversed by PP2. These data suggest that morphine induces cardioprotection by preventing mitochondrial oxidative stress through mitochondrial Src tyrosine kinase. Inhibition of mitochondrial complex I at reperfusion by Src tyrosine kinase may account for the prevention of mitochondrial oxidative stress by morphine. - Highlights: • Morphine induced mito-Src phosphorylation and reduced infarct size in rat hearts. • Morphine failed to reduce I/R-induced LDH release in Src-silencing HL-1 cells. • Morphine prevented mitochondria damage caused by I/R through Src. • Morphine

  11. Is metformin poised for a second career as an antimicrobial?

    PubMed

    Malik, Faiza; Mehdi, Syed Faizan; Ali, Haroon; Patel, Priya; Basharat, Anam; Kumar, Amrat; Ashok, Fnu; Stein, Joanna; Brima, Wunnie; Malhotra, Prashant; Roth, Jesse

    2018-05-01

    Metformin, a widely used antihyperglycaemic, has a good safety profile, reasonably manageable side-effects, is inexpensive, and causes a desirable amount of weight loss. In 4 studies of patients with tuberculosis (1 prospective and 3 retrospective), metformin administration resulted in better outcomes. In mice with several models of endotoxemia, metformin diminished levels of proinflammatory cytokines and improved survival. Laboratory studies showed effectiveness of the drug on multiple pathogens, including Trichinella spiralis, Staphylococcus aureus, Pseudomonas aeruginosa, hepatitis B virus, hepatitis C virus, and human immunodeficiency virus. Metformin administration in humans and mice produced major changes in the composition of the gut microbiota. These recently discovered microbe-modulating properties of the drug have led investigators to predict wide therapeutic utility for metformin. The recent easing in United States Food and Drug Administration (FDA) guidelines regarding administration of metformin to patients with kidney disease, and reduced anxiety about patient safety in terms of lactic acidosis, increase the probability of broadening of metformin's usage as a treatment of infectious agents. In this text we review articles pertinent to metformin's effects on microorganisms, both pathogens and commensals. We highlight the possible role of metformin in a wide range of infectious diseases and a possible expansion of its therapeutic profile in this field. A systematic review was done of PubMed indexed articles that examined the effects of metformin on a wide range of pathogens. Metformin was found to have efficacy as an antimicrobial agent in patients with tuberculosis. Mice infected with Trypanosomiasis cruzi had higher survival when also treated with metformin. The drug in vitro was active against T. spiralis, S. aureus, P. aeruginosa, and hepatitis B virus. In addition there is emerging literature on its role in sepsis. We conclude that metformin may

  12. Continuation of metformin reduces early pregnancy loss in obese Pakistani women with polycystic ovarian syndrome.

    PubMed

    Nawaz, Fauzia Haq; Rizvi, Javed

    2010-01-01

    Polycystic ovarian syndrome (PCOS) is the most common cause of anovulatory infertility worldwide. In addition to a poor conception rate, pregnancy loss rates are significantly higher (30-50%) during the first trimester in women with PCOS. Insulin resistance (IR) in this syndrome is not only implicated toward early pregnancy loss (EPL) but also pathognomic for various obstetrical complications during pregnancy. We evaluated the role of Metformin in the reduction of EPL in women with PCOS who conceived spontaneously or after induction ovulation with or without Metformin. The primary objective was to evaluate the effectiveness of Metformin in the reduction of EPL in women with PCOS. Secondary outcomes like gestational diabetes, pregnancy-induced hypertension and intrauterine growth restriction were also analyzed at the end of the study. This case-control study was conducted from March 2005 to March 2008 in the infertility and antenatal clinics of the Department of Obstetrics and Gynecology of Aga Khan University Hospital, Karachi, Pakistan. A total of 197 infertile women with PCOS were included. 'Cases' were women with PCOS who conceived while taking Metformin and it whom it was continued throughout pregnancy. 'Controls' were women in whom Metformin was either stopped in first trimester after confirmation of pregnancy (by serum betaHCG or by ultrasound) or they conceived spontaneously without the use of Metformin. All 197 women in this study had a confirmed diagnosis of PCOS (Rotterdam criteria). These women were followed till the final outcome of pregnancy was achieved. Both groups were compared for risk of EPL. It was found that continuation of Metformin during pregnancy reduces EPL, i.e. 8.8 vs. 29.4% in cases and controls, respectively (p < 0.001). In the subset of women with a prior history of miscarriage, the pregnancy loss rate was 12.5% in the Metformin versus 49.4% in control group (p = 0.002). Metformin continuation during pregnancy significantly reduces EPL

  13. Metformin inhibits goitrogenous effects of type 2 diabetes.

    PubMed

    Ittermann, Till; Markus, Marcello R P; Schipf, Sabine; Derwahl, Michael; Meisinger, Christa; Völzke, Henry

    2013-07-01

    Data on the association between type 2 diabetes mellitus (T2DM) and thyroid volume are sparse. An experimental study demonstrated an inhibitory effect of metformin on the growth of human thyroid cells. So far no study on humans has investigated potentially modulating effects of metformin on the association between T2DM and thyroid volume. Therefore, we investigated these effects in a population-based cohort study. We used data from the Study of Health in Pomerania and included 2570 individuals for cross-sectional and 1088 individuals for longitudinal analyses. T2DM was defined by physician-diagnosed self-report or intake of antidiabetic medication. In the cross-sectional data, females with T2DM treated with antidiabetic medication other than metformin had a larger thyroid volume (β=4.69; 95% CI 1.87 to 7.50) and a higher odds ratio (OR) for goiter (OR=1.71; 95% CI 1.05 to 2.79) than females without T2DM, whereas in males, no such association was detected. In females or males treated with metformin, T2DM was not associated with thyroid volume or goiter. In longitudinal analyses, incident T2DM not treated with metformin was significantly associated with a higher risk for incident goiter in the total population (incidence rate ratio (IRR)=1.70; 95% CI 1.10 to 2.91). Individuals with T2DM having changed from metformin to other antidiabetic agents during follow-up also had a higher risk for incident goiter than individuals without T2DM (IRR=2.71; 95% CI 1.74 to 4.20). We demonstrate an inhibitory effect of metformin on prevalent and incident goiter. Anti-goitrogenous effects of metformin add to the general benefits of metformin treatment of T2DM.

  14. Thioredoxin 1 is Essential for Sodium Sulfide-Mediated Cardioprotection in the Setting of Heart Failure

    PubMed Central

    Nicholson, Chad K.; Lambert, Jonathan P.; Molkentin, Jeffery D.; Sadoshima, Junichi; Calvert, John W.

    2013-01-01

    Objective The aim of this study was to determine if thioredoxin-1 (Trx1) mediates the cardioprotective effects of hydrogen sulfide (H2S) in a model of ischemic-induced heart failure. Approach/Results Mice with a cardiac-specific overexpression of a dominant negative mutant of Trx1 (Tg-DN-Trx1) and wild-type littermates were subjected to ischemic-induced heart failure. Treatment with H2S as sodium sulfide (Na2S) not only increased the gene and protein expression of Trx1 in the absence of ischemia, but also augmented the heart failure-induced increase in both. Wild-type mice treated with Na2S experienced less left ventricular (LV) dilatation, improved LV function, and less cardiac hypertrophy after the induction of heart failure. In contrast, Na2S therapy failed to improve any of these parameters in the Tg-DN-Trx1 mice. Studies aimed at evaluating the underlying cardioprotective mechanisms found that Na2S therapy inhibited heart failure-induced apoptosis signaling kinase-1 (ASK1) signaling and nuclear export of histone deacetylase 4 (HDAC4) in a Trx1-dependent manner. Conclusions These findings provide novel information that the upregulation of Trx1 by Na2S therapy in the setting of heart failure sets into motion events, such as the inhibition of ASK1 signaling and HDAC4 nuclear export, which ultimately leads to the attenuation of LV remodeling. PMID:23349187

  15. Nitric oxide fails to confer endogenous antiarrhythmic cardioprotection in the primate heart in vitro.

    PubMed

    Pabla, R; Curtis, M J

    2007-04-01

    The role of nitric oxide (NO) in cardiac pathophysiology remains controversial. According to data from several studies using rat and rabbit isolated hearts, NO is an endogenous cardioprotectant against reperfusion-induced ventricular fibrillation (VF). Thus, if cardiac NO production is abolished by perfusion with L-N(G)-nitro-L-arginine methylester (L-NAME) (100 microM) there is a concomittant increase in the incidence of reperfusion-induced VF, with L-NAME's effects on NO and VF prevented by L- (but not D-) arginine co-perfusion. To make a better estimate of the clinical relevance of these findings, 100 microM L-NAME was tested in primate hearts under similar conditions. Marmoset (Callithrix jaccus) hearts, isolated and perfused, were subjected to 60 min left regional ischaemia followed by 10 min reperfusion in vitro. The ECG was recorded and NO in coronary effluent measured by chemiluminescence. L-NAME (100 micro M) decreased NO in coronary effluent throughout ischaemia and reperfusion (e.g. from 3720+/-777 pmol min(-1) g(-1) in controls to 699+/-98 pmol min(-1) g(-1) after 5 min of ischaemia) and, during ischaemia, lowered coronary flow and reduced heart rate, actions identical to those seen in rat and rabbit hearts. However, the incidence of reperfusion-induced VF was unchanged (20%, with or without L-NAME). A species difference exists in the effectiveness of endogenous NO to protect hearts against reperfusion-induced VF. The present primate data, which presumably take precedence over rat and rabbit data, cast doubt on the clinical relevance of NO as an endogenous, antiarrhythmic, cardioprotectant.

  16. Bioequivalence and food effect assessment for vildagliptin/metformin fixed-dose combination tablets relative to free combination of vildagliptin and metformin in Japanese healthy subjects.

    PubMed

    Mita, Sachiko; Chitnis, Shripad D; Kulmatycki, Kenneth; Salunke, Atish; He, Yan-Ling; Zhou, Wei; Suzuki, Hikoe

    2016-04-01

    To assess the bioequivalence of vildagliptin/metformin fixeddose combination (FDC) tablets (50/250 mg and 50/500 mg) to free combinations of vildagliptin and metformin and the effect of food on the pharmacokinetics (PK) of vildagliptin and metformin following administration of 50/500 mg FDC tablets. Two openlabel, randomized, single-center, singledose, 2-period crossover studies were conducted in Japanese healthy male volunteers. Participants were administered vildagliptin/ metformin FDC tablets (study I: 50/250 mg, study II: 50/500 mg) or their free combinations under fasted condition. Food effect (standard Japanese breakfast: fat, 20 - 30% with ~ 600 kcal in total) was assessed during an additional period in study II (50/500 mg). PK parameters (AUC, C(max), t(max), t(1/2)) were calculated for vildagliptin and metformin. In both studies, vildagliptin/metformin FDC tablets were bioequivalent to their respective free combinations. Administration of FDC tablets after meals had no effect on vildagliptin PK parameters. The rate of absorption of metformin decreased when administered under fed condition, as reflected by a prolonged t(max) (3 hours in fasted state vs. 4 hours in fed state) and decrease in C(max) by 26%, however, the extent of absorption (AUC(last)) was similar to that in the fasted state. Vildagliptin/metformin FDC tablets were bioequivalent to their free combinations. Food decreased the C(max) of metformin by 26%, while AUC(last) was unchanged, consistent with previous reports. No food effect was observed on the C(max) or AUC(last) of vildagliptin. Thus, food had no clinically relevant effects on the PK of metformin or vildagliptin.

  17. To Use or Not to Use Metformin in Cerebral Ischemia: A Review of the Application of Metformin in Stroke Rodents

    PubMed Central

    2017-01-01

    Ischemic strokes are major causes of death and disability. Searching for potential therapeutic strategies to prevent and treat stroke is necessary, given the increase in overall life expectancy. Epidemiological reports indicate that metformin is an oral antidiabetic medication that can reduce the incidence of ischemic events in patients with diabetes mellitus. Its mechanism of action has not been elucidated, but metformin pleiotropic effects involve actions in addition to glycemic control. AMPK activation has been described as one of the pharmacological mechanisms that explain the action of metformin and that lead to neuroprotective effects. Most experiments done in the cerebral ischemia model, via middle cerebral artery occlusion in rodents (MCAO), had positive results favoring metformin's neuroprotective role and involve several cellular pathways like oxidative stress, endothelial nitric oxide synthase activation, activation of angiogenesis and neurogenesis, autophagia, and apoptosis. We will review the pharmacological properties of metformin and its possible mechanisms that lead to neuroprotection in cerebral ischemia. PMID:28634570

  18. Metformin Preconditioning of Human induced Pluripotent Stem Cell-derived Neural Stem Cells Promotes Their Engraftment and Improves Post-Stroke Regeneration and Recovery.

    PubMed

    Ould-Brahim, Fares; Sarma, Sailendra Nath; Syal, Charvi; Lu, Kevin Jiaqi; Seegobin, Matthew; Carter, Anthony; Jeffers, Matthew S; Doré, Carole; Stanford, William; Corbett, Dale; Wang, Jing

    2018-06-12

    While transplantation of hiPSC-derived neural stem cells (hiPSC-NSCs) shows therapeutic potential in animal stroke models, major concerns for translating hiPSC therapy to the clinic are efficacy and safety. Therefore, there is a demand to develop an optimal strategy to enhance the engraftment and regenerative capacity of transplanted hiPSC-NSCs in order to produce fully differentiated neural cells to replace lost brain tissues. Metformin, an FDA approved drug, is an optimal neuroregenerative agent that not only promotes NSC proliferation but also drives NSC towards differentiation. In this regard, we hypothesize that preconditioning of hiPSC-NSCs with metformin before transplantation into the stroke-damaged brain will improve engraftment and regenerative capabilities of hiPSC-NSCs, ultimately enhancing functional recovery. Here we show that pretreatment of hiPSC-NSCs with metformin enhances the proliferation and differentiation of hiPSC-NSCs in culture. Furthermore, metformin-preconditioned hiPSC-NSCs show increased engraftment 1-week post-transplant in a rat endothelin-1 focal ischemic stroke model. In addition, metformin preconditioned cell grafts exhibit increased survival compared to naïve cell grafts at 7-week post-transplant. Analysis of the grafts demonstrates that metformin preconditioning enhances the differentiation of hiPSC-NSCs. As an outcome, rats receiving metformin preconditioned cells display accelerated gross motor recovery and reduced infarct volume. These studies represent a vital step forward in the optimization of hiPSC-NSC based transplantation to promote post-stroke recovery.

  19. Two new phenolic constituents from the root bark of Morus alba L. and their cardioprotective activity.

    PubMed

    Cao, Yan-Gang; Zheng, Xiao-Ke; Yang, Fang-Fang; Li, Fang; Qi, Man; Zhang, Yan-Li; Zhao, Xuan; Kuang, Hai-Xue; Feng, Wei-Sheng

    2018-02-01

    A new biphenyl-furocoumarin, named morescoumarin A (1), and a new prenylated flavanone, named morflavanone A (2) were isolated from the root bark of Morus alba L., together with four known compounds (3-6). Their structures were determined by extensive spectroscopic analyses and comparison with literature data. The cardioprotective effects of these compounds against doxorubicin-induced cell death were evaluated by MTT method.

  20. Mediterranean diet and cardioprotection: the role of nitrite, polyunsaturated fatty acids and polyphenols

    PubMed Central

    Nadtochiy, Sergiy M.; Redman, Emily K.

    2010-01-01

    The continually increasing rate of myocardial infarction (MI) in the Western world at least partly can be explained by a poor diet lacking in green vegetables, fruits, and fish, and enriched in food that contains saturated fat. In contrast, a number of epidemiological studies provide strong evidence highlighting the cardioprotective benefits of the Mediterranean diet enriched in green vegetables, fruits, fish and grape wine. Regular consumption of these products leads to an accumulation of nitrate/nitrite/NO•, polyunsaturated fatty acids (PUFA), and polyphenolic compounds, such as resveratrol, in the human body. Studies have confirmed that these constituents are bioactive exogenous mediators, which induce strong protection against MI. The aim of this review is to provide a critical, in-depth analysis of the cardioprotective pathways mediated by nitrite/NO•, PUFA, and phenolic compounds of grape wines discovered in the recent years, including cross-talk between different mechanisms and compounds. Overall, these findings may facilitate the design and synthesis of novel therapeutic tools for the treatment of MI. PMID:21454053

  1. Metformin and pioglitazone combination therapy ameliorate polycystic ovary syndrome through AMPK/PI3K/JNK pathway

    PubMed Central

    Wu, Yuanyuan; Li, Pengfen; Zhang, Dan; Sun, Yingpu

    2018-01-01

    Polycystic ovary syndrome (PCOS) is a common gynecological endocrine disorder, which results in health problems such as menstrual disorders, hyperandrogenism and persistent anovulation. Hyperandrogenism and insulin resistance are the basic characteristics of PCOS. To investigate the combined effect of metformin and pioglitazone on POCS and the potential mechanisms, a rat model of PCOS was established by intramuscular injection of estradiol valerate (EV). The effect of metformin and pioglitazone monotherapy or combination therapy in control rats and PCOS rats was evaluated, involving the testosterone level, follicular development and insulin resistance. The potential mechanism for the therapeutic effect of metformin and pioglitazone on POCS was explored through using three inhibitors of the 5′adenosine monophosphate-activated protein kinase (AMPK)/phosphoinositide-3 kinase (PI3K)/c-Jun N-terminal kinase (JNK) pathway (Compound C, Wortmannin and SP600125). The results showed that EV-induced PCOS rats demonstrated hyperandrogenemia, hyperinsulinemia and follicular dysplasia. Metformin or pioglitazone monotherapy significantly suppressed the high level of testosterone, reduced the raised percentage of cystic follicles and primary follicles, promoted the number of early antral follicles, and markedly decreased the high concentration of fasting insulin and homeostatic model assessment for insulin resistance index in PCOS rats. In addition, metformin and pioglitazone combination therapy demonstrated greater efficacy than its individual components. Furthermore, individual or joint treatment with metformin and pioglitazone affected the phosphorylation level of JNK in PCOS rats. Compound C and Wortmannin eliminated the effect of metformin and pioglitazone combination therapy on improving the follicular growth in PCOS rats, whereas SP600125 treatment enhanced this combination therapy effect. These data suggested that metformin and pioglitazone combination therapy

  2. Postmeal exercise blunts postprandial glucose excursions in people on metformin monotherapy.

    PubMed

    Erickson, Melissa L; Little, Jonathan P; Gay, Jennifer L; McCully, Kevin K; Jenkins, Nathan T

    2017-08-01

    Metformin is used clinically to reduce fasting glucose with minimal effects on postprandial glucose. Postmeal exercise reduces postprandial glucose and may offer additional glucose-lowering benefit beyond that of metformin alone, yet controversy exists surrounding exercise and metformin interactions. It is currently unknown how postmeal exercise and metformin monotherapy in combination will affect postprandial glucose. Thus, we examined the independent and combined effects of postmeal exercise and metformin monotherapy on postprandial glucose. A randomized crossover design was used to assess the influence of postmeal exercise on postprandial glucose excursions in 10 people treated with metformin monotherapy (57 ± 10 yr, HbA 1C  = 6.3 ± 0.6%). Each participant completed the following four conditions: sedentary and postmeal exercise (5 × 10-min bouts of treadmill walking at 60% V̇o 2max ) with metformin and sedentary and postmeal exercise without metformin. Peak postprandial glucose within a 2-h time window and 2-h total area under the curve was assessed after a standardized breakfast meal, using continuous glucose monitoring. Postmeal exercise significantly blunted 2-h peak ( P = 0.001) and 2-h area under the curve ( P = 0.006), with the lowest peak postprandial glucose excursion observed with postmeal exercise and metformin combined ( P < 0.05 vs. all other conditions: metformin/sedentary: 12 ± 3.4, metformin/exercise: 9.7 ± 2.3, washout/sedentary: 13.3 ± 3.2, washout/exercise: 11.1 ± 3.4 mmol/l). Postmeal exercise and metformin in combination resulted in the lowest peak postprandial glucose excursion compared with either treatment modality alone. Exercise timed to the postprandial phase may be important for optimizing glucose control during metformin monotherapy. NEW & NOTEWORTHY The interactive effects of metformin and exercise on key physiological outcomes remain an area of controversy. Findings from this study show that the combination of

  3. Bioequivalence of a fixed-dose repaglinide/metformin combination tablet and equivalent doses of repaglinide and metformin tablets
.

    PubMed

    Cho, Hea-Young; Ngo, Lien; Kim, Sang-Ki; Choi, Yoonho; Lee, Yong-Bok

    2018-06-01

    This study was conducted to determine whether a fixed-dose combination (FDC) tablet of repaglinide/metformin (2/500 mg) is equivalent to coadministration of equivalent doses of individual (EDI) tablets of repaglinide (2 mg) and metformin (500 mg) in healthy Korean male subjects. This study was conducted as an open-label, randomized, single-dose, two-period, two-sequence crossover design in 50 healthy Korean male subjects who received an FDC tablet or EDI tablets. Plasma concentrations of repaglinide and metformin were determined for up to 24 hours using a validated UPLC-MS/MS method. Bioequivalence was assessed according to current guidelines issued by the U.S. Food and Drug Administration (FDA) and Korean legislation. Tolerability was also evaluated throughout the study via subject interview, vital signs, and blood sampling. Point estimates (90% CIs) for AUC0-t, AUC0-∞, and Cmax based on EDI tablets were 110.07 (102.25 - 118.49), 109.90 (101.70 - 118.39), and 112.60 (101.49 - 124.85), respectively, for repaglinide. They were 95.18 (89.62 - 101.05), 95.00 (89.74 - 100.65), and 98.44 (92.72 - 104.50), respectively, for metformin. These results satisfied the bioequivalence criteria of 80.00 - 125.00% proposed by the FDA and Korean legislation. Results of pharmacokinetic analysis suggested that repaglinide and metformin in FDC tablets were bioequivalent to EDI tablets of repaglinide (2 mg) and metformin (500 mg) in healthy Korean male subjects. Both formulations appeared to be well tolerated.
.

  4. Cardioprotective role of G-Protein Coupled Estrogen Receptor 1 (GPER1).

    PubMed

    Koganti, Sivaramakrishna

    2015-01-01

    G-Protein Coupled Estrogen Receptor 1 (GPER1), also known as G-Protein Coupled Receptor 30 (GPR30) and initially considered an orphan receptor, has become one of the most important pharmacological targets in cardiovascular research. Since the gene encoding this putative receptor was cloned nearly 20 years ago, researchers have addressed its role in various aspects of physiology, including cardioprotection. Although extensive research has been carried out to understand the role of GPER1 as a pharmacological target to treat cardiovascular diseases, there are few current reviews addressing the overall cardioprotective benefits of this receptor and the signaling intermediates involved. This review considers the origins of GPER1, its cell biology, its physiological and pharmacological roles as a therapeutic target in cardiovascular disease, and what future research on GPER1 might entail. More specifically, the review focuses on GPER1 regulation of Angiotensin Type I Receptor (AT1R) and the role of estrogen receptors, epidermal growth factor receptor (EGFR) and matrix metalloproteinases (MMPs) in bringing about the cardioprotective effects of GPER1. Areas where improved knowledge of GPER1 biology is still needed to better understand the receptor's cardioprotective effects are also discussed.

  5. Evaluation of cardioprotective activity of Ginkgo biloba and Ocimum sanctum in rodents.

    PubMed

    Panda, Vandana S; N, Suresh R

    2009-06-01

    This study investigates the cardioprotective activity of a combined treatment of Ginkgo biloba phytosomes (GBP) and Ocimum sanctum extract (Os) in isoproterenol (ISO)-induced myocardial necrosis in rats. Significant myocardial necrosis, depletion of the endogenous antioxidants superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione (GSH), and increases in the serum marker enzymes aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK) were observed in ISO-treated rats compared with normal rats. Co-administration of GBP (100 mg per kg) with Os at two doses (50 and 75 mg per kg) for 30 days to rats treated with ISO (85 mg per kg, sc) on the 29th and 30th days demonstrated a significant decrease in ISO-induced serum marker enzyme elevations and a significant attenuation of the ISO-elevated myocardial lipid peroxidation marker malondialdehyde (MDA). A significant restoration of ISO-depleted activities and levels of AST, LDH, CPK, GSH, SOD, CAT, GPx, and GR in the hearts of the treatment groups was observed. The combination of Os 75 mg per kg and GBP 100 mg/kg elicited greater protection than the combination of Os 50 mg per kg and GBP 100 mg per kg. It may be concluded that GBP-Os oral treatment to ISO-challenged rats demonstrates significant cardiac protection, decreases lipid peroxidation, and restores antioxidant activities. However, the combined treatment failed to enhance cardioprotective activity of either herb when used alone.

  6. Metformin combined with sodium dichloroacetate promotes B leukemic cell death by suppressing anti-apoptotic protein Mcl-1

    PubMed Central

    Melloni, Elisabetta; Gilli, Paola; Bertolasi, Valerio; Casciano, Fabio; Rigolin, Gian Matteo; Zauli, Giorgio; Secchiero, Paola

    2016-01-01

    Metformin and the mitochondrial targeting dichloroacetate (DCA) have recently received attention due to their ability to inhibit anaerobic glycolysis, which renders most cancer cells resistant to apoptosis induction. We observed that Metformin alone exhibited a dose-dependent anti-leukemic activity in both B leukemic cell lines and primary B-chronic lymphocytic leukemia (B-CLL) patients' cells and its anti-leukemic activity was enhanced when used in combination with DCA. In order to overcome the problems of poor bioavailability and cellular uptake, which limit DCA efficacy, we have designed and synthetized cocrystals consisting of Metformin and DCA (Met-DCA) at different stoichiometric ratios. Of note, the MetH2++•2DCA− cocrystal exhibited enhanced in vitro anti-leukemic activity, with respect to the treatment with the mix consisting of Metformin plus DCA. In particular, the treatment with the cocrystal MetH2++•2DCA− induced a synergistic apoptotic cell death coupled to a marked down-modulation of the anti-apoptotic Mcl-1 protein. Taken together, our data emphasize that innovative compounds based on Metformin-DCA combination merit to be further evaluated as chemotherapeutic agents for the treatment of B-CLL. PMID:26959881

  7. Variation in the Glucose Transporter gene SLC2A2 is associated with glycaemic response to metformin

    PubMed Central

    Seiser, Eric L.; van Leeuwen, Nienke; Tavendale, Roger; Bennett, Amanda J; Groves, Christopher J.; Coleman, Ruth L.; van der Heijden, Amber A.; Beulens, Joline W.; de Keyser, Catherine E.; Zaharenko, Linda; Rotroff, Daniel M.; Out, Mattijs; Jablonski, Kathleen A.; Chen, Ling; Javorský, Martin; Židzik, Jozef; Levin, Albert M.; Williams, L. Keoki; Dujic, Tanja; Semiz, Sabina; Kubo, Michiaki; Chien, Huan-Chieh; Maeda, Shiro; Witte, John S.; Wu, Longyang; Tkáč, Ivan; Kooy, Adriaan; van Schaik, Ron H.N.; Stehouwer, Coen D.A.; Logie, Lisa; Sutherland, Calum; Klovins, Janis; Pirags, Valdis; Hofman, Albert; Stricker, Bruno H.; Motsinger-Reif, Alison A.; Wagner, Michael J.; Innocenti, Federico; 't Hart, Leen M.; Holman, Rury R.; McCarthy, Mark I.; Hedderson, Monique M.; Palmer, Colin N.A.; Florez, Jose C.; Giacomini, Kathleen M.; Pearson, Ewan R.

    2016-01-01

    Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear1. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C-allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (p=6.6x10-14) greater metformin induced HbA1c reduction in 10,577 participants of European ancestry. rs8192675 is the top cis-eQTL for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. In obese individuals C-allele homozygotes at rs8192675 had a 0.33% (3.6mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes.This is about half the effect seen with the addition of a DPP-4 inhibitor, and equates to a dose difference of 550mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine. PMID:27500523

  8. Loss of Eyebrows and Eyelashes During Concomitant Treatment with Sitagliptin and Metformin.

    PubMed

    Succurro, Elena; Palleria, Caterina; Ruffo, Mariafrancesca; Serra, Raffaele; Arturi, Franco; Gallelli, Luca

    2017-01-01

    The fixed dose combination of sitagliptin 50 mg and metformin 850 mg (Janumet ®), is indicated for the treatment of type 2 diabetes mellitus in addition to diet and exercise to improve glycemic control in patients treated with metformin alone. We report a 69-year-old man with type 2 diabetes that developed sudden loss of eyebrows and eyelashes about 4 months after the beginning of Janumet®. Clinical and laboratory findings excluded the presence of systemic or skin diseases able to induce these manifestations, while the Naranjo probability scale documented a possible association between the drug and the adverse drug reaction. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  9. Serum Vitamin B12 Levels in Type 2 Diabetes Patients on Metformin Compared to those Never on Metformin: A Cross-sectional Study.

    PubMed

    Raizada, Nishant; Jyotsna, Viveka P; Sreenivas, Vishnubhatla; Tandon, Nikhil

    2017-01-01

    There are limited data about the effect of metformin use on serum Vitamin B12 levels in type 2 diabetes patients from India. We studied serum Vitamin B12 levels in patients with type 2 diabetes mellitus who were receiving metformin and compared them to those never treated with metformin. A total of 183 patients ("metformin" group 121, "no metformin" group 63) of type 2 diabetes from the endocrinology clinic of a tertiary care center in North India were studied. Serum Vitamin B12 levels were measured in all patients. Diabetic neuropathy symptom score (DNS) and diabetic neuropathy examination score (DNE) were used to assess peripheral neuropathy while hemoglobin and mean corpuscular volume (MCV) were used to assess anemia. The serum Vitamin B12 levels were 267.7 ± 194.4 pmol/l in metformin group and 275.1 ± 197.2 pmol/l in the no metformin group ( P = 0.78). When adjusted for duration of diabetes, metformin use was associated with a 87.7 ± 37.7 pmol/l (95% confidence interval [CI], -162.1--3.3, P = 0.02) lower serum Vitamin B12 levels. No significant increase in the prevalence of neuropathy (DNS and DNE scores), anemia, or MCV was found in the Vitamin B12 deficient patients (levels <150 pmol/l) as compared to patients with normal Vitamin B12. However, serum Vitamin B12 levels for the entire cohort were higher by 12.2 ± 3.0 pmol/l (95% CI 6.4-18.0, P < 0.001) for every 1 year increase in the duration of diabetes. Metformin use was associated with a lower serum Vitamin B12 levels when adjusted for duration of diabetes. Increasing duration of diabetes was associated with higher serum Vitamin B12 levels.

  10. Cnidoscolus chayamansa Mc Vaugh, an important antioxidant, anti-inflammatory and cardioprotective plant used in Mexico.

    PubMed

    García-Rodríguez, Rosa Virginia; Gutiérrez-Rebolledo, Gabriel Alfonso; Méndez-Bolaina, Enrique; Sánchez-Medina, Alberto; Maldonado-Saavedra, Octavio; Domínguez-Ortiz, Miguel Ángel; Vázquez-Hernández, Maribel; Muñoz-Muñiz, Omar David; Cruz-Sánchez, Jesús Samuel

    2014-02-03

    Cnidoscolus chayamansa Mc Vaugh (Euphorbiaceae) is commonly known as 'chaya' in Central America. In South East Mexico, because of its high nutritional values, is an important part of the diet of many indigenous communities. Chaya is also used as a traditional remedy for the treatment of diabetes, rheumatism, gastrointestinal disorders and inflammation-related diseases. Although Cnidoscolus chayamansa is one of most used and valued medicinal plants, only few studies on documenting its pharmacological properties can be found. Dried leaves of Cnidoscolus chayamansa were subjected to a successive maceration using Hex, EtOAc and EtOH. The antioxidant activities of the extracts were tested using the DPPH radical scavenging, Ferric reducing/antioxidant power and total phenolic content assays. To determine the anti-inflammatory activity, the TPA-induced mouse ear edema and the carrageenan-induced mouse paw edema assays were used. The cardioprotective effects of the EtOH extract was determined using the ischemia/reperfusion (I/R) rat model. Finally, the acute toxicity was determined using Lorke's method. The results showed a similar anti-inflammatory activity (≈30%) for all extracts but only the EtOAc extract showed relevant activity when applied intraperitoneally. When tested for their antioxidant activity none of the extracts showed a significant activity suggesting that the antinflammatory activity is not related to a direct free radical scavenging of the extracts. Additionally, the EtOH extract showed a strong cardioprotective effect at 500mg/kg when given orally. Both the EtOAc and the EtOH extract have a LD50 >5g/kg, confirming their safety in acute oral administration. All these results are relevant for a better understanding of the therapeutic used of Cnidoscolus chayamansa in the Mexican traditional medicine and highlights its cardioprotective potential. © 2013 Published by Elsevier Ireland Ltd.

  11. Enhanced anti-tumor activity and cytotoxic effect on cancer stem cell population of metformin-butyrate compared with metformin HCl in breast cancer.

    PubMed

    Lee, Kyung-Min; Lee, Minju; Lee, Jiwoo; Kim, Sung Wuk; Moon, Hyeong-Gon; Noh, Dong-Young; Han, Wonshik

    2016-06-21

    Metformin, which is a drug commonly used to treat type 2 diabetes, has shown anti-tumor effects in numerous experimental, epidemiologic, observational, and clinical studies. Here, we report a new metformin derivative, metformin-butyrate (MFB). Compared to metformin-HCl, it more potently activates AMPK, inhibits mTOR, and impairs cell cycle progression at S and G2/M phases. Moreover, MFB inhibits the mammosphere formation of breast cancer cells and shows cytotoxic effects against CD44+CD24-/low populations in vitro and in vivo, indicating that it might have preferential effects on the cancer stem cell population. MFB showed synergistic cytotoxicity with docetaxel and cisplatin, and MFB pretreatment of breast cancer cells prior to their injection into the mammary fat pads of mice significantly decreased the obtained xenograft tumor volumes, compared with untreated or metformin-pretreated cells. Overall, MFB showed greater anti-neoplastic activity and greater efficacies in targeting the G2/M phase and breast cancer stem cell population, compared to metformin-HCl. This suggests that MFB may be a promising therapeutic agent against aggressive and resistant breast cancers.

  12. Metformin inhibits epithelial–mesenchymal transition in prostate cancer cells: Involvement of the tumor suppressor miR30a and its target gene SOX4

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Zhang, Jing; Shen, Chengwu; Wang, Lin

    2014-09-26

    Highlights: • Metformin inhibits TGF-β-induced EMT in prostate cancer (PCa) cells. • Metformin upregulates tumor suppressor miR30a and downregulates SOX4 in PCa cells. • SOX4 is a target gene of miR30a. - Abstract: Tumor metastasis is the leading cause of mortality and morbidity of prostate cancer (PCa) patients. Epithelial–mesenchymal transition (EMT) plays a critical role in cancer progression and metastasis. Recent evidence suggested that diabetic patients treated with metformin have lower PCa risk and better prognosis. This study was aimed to investigate the effects of metformin on EMT in PCa cells and the possible microRNA (miRNA)-based mechanisms. MiRNAs have beenmore » shown to regulate various processes of cancer metastasis. We herein showed that metformin significantly inhibits proliferation of Vcap and PC-3 cells, induces G0/G1 cell cycle arrest and inhibits invasiveness and motility capacity of Vcap cells. Metformin could inhibit TGF-β-induced EMT in Vcap cells, as manifested by inhibition of the increase of N-cadherin (p = 0.013), Vimentin (p = 0.002) and the decrease of E-cadherin (p = 0.0023) and β-catenin (p = 0.034) at mRNA and protein levels. Notably, we demonstrated significant upregulation of miR30a levels by metformin (P < 0.05) and further experiments indicated that miR30a significantly inhibits proliferation and EMT process of Vcap cells. Interestingly, we identified that SOX4, a previously reported oncogenic transcriptional factor and modulator of EMT, is a direct target gene of miR30a. Finally, we screened the expression of miR30a and SOX4 in 84 PCa cases with radical prostatectomy. Of note, SOX4 overexpression is significantly associated with decreased levels of miR30a in PCa cases. In all, our study suggested that inhibition of EMT by metformin in PCa cells may involve upregulation of miR30a and downregulation of SOX4.« less

  13. Metformin selectively affects human glioblastoma tumor-initiating cell viability

    PubMed Central

    Würth, Roberto; Pattarozzi, Alessandra; Gatti, Monica; Bajetto, Adirana; Corsaro, Alessandro; Parodi, Alessia; Sirito, Rodolfo; Massollo, Michela; Marini, Cecilia; Zona, Gianluigi; Fenoglio, Daniela; Sambuceti, Gianmario; Filaci, Gilberto; Daga, Antonio; Barbieri, Federica; Florio, Tullio

    2013-01-01

    Cancer stem cell theory postulates that a small population of tumor-initiating cells is responsible for the development, progression and recurrence of several malignancies, including glioblastoma. In this perspective, tumor-initiating cells represent the most relevant target to obtain effective cancer treatment. Metformin, a first-line drug for type II diabetes, was reported to possess anticancer properties affecting the survival of cancer stem cells in breast cancer models. We report that metformin treatment reduced the proliferation rate of tumor-initiating cell-enriched cultures isolated from four human glioblastomas. Metformin also impairs tumor-initiating cell spherogenesis, indicating a direct effect on self-renewal mechanisms. Interestingly, analyzing by FACS the antiproliferative effects of metformin on CD133-expressing subpopulation, a component of glioblastoma cancer stem cells, a higher reduction of proliferation was observed as compared with CD133-negative cells, suggesting a certain degree of cancer stem cell selectivity in its effects. In fact, glioblastoma cell differentiation strongly reduced sensitivity to metformin treatment. Metformin effects in tumor-initiating cell-enriched cultures were associated with a powerful inhibition of Akt-dependent cell survival pathway, while this pathway was not affected in differentiated cells. The specificity of metformin antiproliferative effects toward glioblastoma tumor-initiating cells was confirmed by the lack of significant inhibition of normal human stem cells (umbilical cord-derived mesenchymal stem cells) in vitro proliferation after metformin exposure. Altogether, these data clearly suggest that metformin exerts antiproliferative activity on glioblastoma cells, showing a higher specificity toward tumor-initiating cells, and that the inhibition of Akt pathway may represent a possible intracellular target of this effect. PMID:23255107

  14. Metformin Use in Prediabetes Among U.S. Adults, 2005-2012.

    PubMed

    Tseng, Eva; Yeh, Hsin-Chieh; Maruthur, Nisa M

    2017-07-01

    To determine the prevalence of and characteristics associated with metformin use among U.S. adults with prediabetes using the National Health and Nutrition Examination Survey (NHANES) 2005-2012. The American Diabetes Association's guidelines for metformin use in prediabetes have evolved, with 2017 recommendations suggesting metformin be considered in patients with prediabetes and additional risk factors (BMI ≥35 kg/m 2 , age <60 years, or prior gestational diabetes mellitus) or rising hemoglobin A 1c (HbA 1c ). We estimated the age-adjusted prevalence of metformin use among individuals with prediabetes (defined by HbA 1c 5.7-6.4%, fasting glucose 100-125 mg/dL, 2-h poststimulated glucose 140-199 mg/dL, or self-report) and used multivariate logistic regression to evaluate characteristics associated with metformin use. Of 22,174 adults, 7,652 had prediabetes. The age-adjusted prevalence of metformin use among those with prediabetes was 0.7%. Metformin use was associated with higher mean BMI (35.1 kg/m 2 vs. 29.6 kg/m 2 , P < 0.01) and higher glucose (fasting glucose 114 mg/dL vs. 105 mg/dL, P = 0.03; 2-h poststimulated glucose 155 mg/dL vs. 128 mg/dL, P = 0.003; and HbA 1c 6.0% [42 mmol/mmol] vs. 5.6% [38 mmol/mmol], P < 0.01). Metformin use was low even among those with BMI ≥35 kg/m 2 , a group for whom metformin use is recommended. Metformin use did not vary by race, poverty-to-income ratio, or education. Metformin use was <1% among U.S. adults with prediabetes and only slightly more common among those with additional risk factors for diabetes. © 2017 by the American Diabetes Association.

  15. Toxicity and toxicokinetics of metformin in rats

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Quaile, Michael P.; Melich, David H.; Jordan, Holly L.

    2010-03-15

    Metformin is a first-line drug for the treatment of type 2 diabetes (T2D) and is often prescribed in combination with other drugs to control a patient's blood glucose level and achieve their HbA1c goal. New treatment options for T2D will likely include fixed dose combinations with metformin, which may require preclinical combination toxicology studies. To date, there are few published reports evaluating the toxicity of metformin alone to aid in the design of these studies. Therefore, to understand the toxicity of metformin alone, Crl:CD(SD) rats were administered metformin at 0, 200, 600, 900 or 1200 mg/kg/day by oral gavage formore » 13 weeks. Administration of >= 900 mg/kg/day resulted in moribundity/mortality and clinical signs of toxicity. Other adverse findings included increased incidence of minimal necrosis with minimal to slight inflammation of the parotid salivary gland for males given 1200 mg/kg/day, body weight loss and clinical signs in rats given >= 600 mg/kg/day. Metformin was also associated with evidence of minimal metabolic acidosis (increased serum lactate and beta-hydroxybutyric acid and decreased serum bicarbonate and urine pH) at doses >= 600 mg/kg/day. There were no significant sex differences in mean AUC{sub 0-24} or C{sub max} nor were there significant differences in mean AUC{sub 0-24} or C{sub max} following repeated dosing compared to a single dose. The no observable adverse effect level (NOAEL) was 200 mg/kg/day (mean AUC{sub 0-24} = 41.1 mug h/mL; mean C{sub max} = 10.3 mug/mL based on gender average week 13 values). These effects should be taken into consideration when assessing potential toxicities of metformin in fixed dose combinations.« less

  16. Differential tissue-specific function of the Adora2b in cardio-protection

    PubMed Central

    Seo, Seong-wook; Koeppen, Michael; Bonney, Stephanie; Gobel, Merit; Thayer, Molly; Harter, Patrick N.; Ravid, Katya; Eltzschig, Holger K.; Mittelbronn, Michel; Walker, Lori; Eckle, Tobias

    2015-01-01

    The adenosine A2b-receptor (Adora2b) has been implicated in cardio-protection from myocardial ischemia. As such the Adora2b was found to be critical in ischemic preconditioning (IP) or ischemia reperfusion (IR) injury of the heart. While the Adora2b is present on various cells types, the tissue specific role of the Adora2b in cardio-protection is still unknown. To study the tissue specific role of Adora2b signaling on inflammatory cells, endothelia or myocytes during myocardial ischemia in vivo, we intercrossed floxed Adora2b mice with Lyz2-Cre+, VE-Cadherin-Cre+ or Myosin-Cre+ transgenic mice, respectively. Mice were exposed to 60 minutes of myocardial ischemia with or without IP (4×5min) followed by 120 minutes of reperfusion. Cardio-protection by IP was abolished in Adora2bf/f-VE-Cadherin-Cre+ or Adora2bf/f-Myosin-Cre+, indicating that Adora2bs signaling on endothelia or myocytes mediates IP. In contrast, primarily Adora2b signaling on inflammatory cells was necessary to provide cardio-protection in IR injury, indicated by significantly larger infarcts and higher troponin levels in Adora2bf/f-Lyz2-Cre+ mice only. Cytokine profiling of IR injury in Adora2bf/f-Lyz2-Cre+ mice pointed towards PMNs. Analysis of PMNs from Adora2bf/f-Lyz2-Cre+ confirmed PMNs as one source of identified tissue cytokines. Finally, adoptive transfer of Ador2b−/− PMNs revealed a critical role of the Adorab2 on PMNs in cardio-protection from IR-injury. Adora2b signaling mediates different types of cardio-protection in a tissue specific manner. These findings have implications for the use of Adora2b agonists in the treatment or prevention of myocardial injury by ischemia. PMID:26136425

  17. High Glucose-Mediated STAT3 Activation in Endometrial Cancer Is Inhibited by Metformin: Therapeutic Implications for Endometrial Cancer

    PubMed Central

    Wallbillich, John J.; Josyula, Srirama; Saini, Uksha; Zingarelli, Roman A.; Dorayappan, Kalpana Deepa Priya; Riley, Maria K.; Wanner, Ross A.; Cohn, David E.; Selvendiran, Karuppaiyah

    2017-01-01

    Objectives STAT3 is over-expressed in endometrial cancer, and diabetes is a risk factor for the development of type 1 endometrial cancer. We therefore investigated whether glucose concentrations influence STAT3 expression in type 1 endometrial cancer, and whether such STAT3 expression might be inhibited by metformin. Methods In Ishikawa (grade 1) endometrial cancer cells subjected to media with low, normal, or high concentrations of glucose, expression of STAT3 and its target proteins was evaluated by real-time quantitative PCR (qPCR). Ishikawa cells were treated with metformin and assessed with cell proliferation, survival, migration, and ubiquitin assays, as well as Western blot and qPCR. Expression of apoptosis proteins was evaluated with Western blot in Ishikawa cells transfected with a STAT3 overexpression plasmid and treated with metformin. A xenograft tumor model was used for studying the in vivo efficacy of metformin. Results Expression of STAT3 and its target proteins was increased in Ishikawa cells cultured in high glucose media. In vitro, metformin inhibited cell proliferation, survival and migration but induced apoptosis. Metformin reduced expression levels of pSTAT3 ser727, total STAT3, and its associated cell survival and anti-apoptotic proteins. Additionally, metformin treatment was associated with increased degradation of pSTAT3 ser727. No change in apoptotic protein expression was noticed with STAT3 overexpression in Ishikawa cells. In vivo, metformin treatment led to a decrease in tumor weight as well as reductions of STAT3, pSTAT3 ser727, its target proteins. Conclusions These results suggest that STAT3 expression in type 1 endometrial cancer is stimulated by a high glucose environment and inhibited by metformin. PMID:28114390

  18. Metformin decreases progerin expression and alleviates pathological defects of Hutchinson–Gilford progeria syndrome cells

    PubMed Central

    Egesipe, Anne-Laure; Blondel, Sophie; Cicero, Alessandra Lo; Jaskowiak, Anne-Laure; Navarro, Claire; Sandre-Giovannoli, Annachiara De; Levy, Nicolas; Peschanski, Marc; Nissan, Xavier

    2016-01-01

    Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disorder that causes systemic accelerated aging in children. This syndrome is due to a mutation in the LMNA gene that leads to the production of a truncated and toxic form of lamin A called progerin. Because the balance between the A-type lamins is controlled by the RNA-binding protein SRSF1, we have hypothesized that its inhibition may have therapeutic effects for HGPS. For this purpose, we evaluated the antidiabetic drug metformin and demonstrated that 48 h treatment with 5 mmol/l metformin decreases SRSF1 and progerin expression in mesenchymal stem cells derived from HGPS induced pluripotent stem cells (HGPS MSCs). The effect of metformin on progerin was then confirmed in several in vitro models of HGPS, i.e., human primary HGPS fibroblasts, LmnaG609G/G609G mouse fibroblasts and healthy MSCs previously treated with a PMO (phosphorodiamidate morpholino oligonucleotide) that induces progerin. This was accompanied by an improvement in two in vitro phenotypes associated with the disease: nuclear shape abnormalities and premature osteoblastic differentiation of HGPS MSCs. Overall, these results suggest a novel approach towards therapeutics for HGPS that can be added to the currently assayed treatments that target other molecular defects associated with the disease. PMID:28721276

  19. Metformin decreases progerin expression and alleviates pathological defects of Hutchinson-Gilford progeria syndrome cells.

    PubMed

    Egesipe, Anne-Laure; Blondel, Sophie; Cicero, Alessandra Lo; Jaskowiak, Anne-Laure; Navarro, Claire; Sandre-Giovannoli, Annachiara De; Levy, Nicolas; Peschanski, Marc; Nissan, Xavier

    2016-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder that causes systemic accelerated aging in children. This syndrome is due to a mutation in the LMNA gene that leads to the production of a truncated and toxic form of lamin A called progerin. Because the balance between the A-type lamins is controlled by the RNA-binding protein SRSF1, we have hypothesized that its inhibition may have therapeutic effects for HGPS. For this purpose, we evaluated the antidiabetic drug metformin and demonstrated that 48 h treatment with 5 mmol/l metformin decreases SRSF1 and progerin expression in mesenchymal stem cells derived from HGPS induced pluripotent stem cells (HGPS MSCs). The effect of metformin on progerin was then confirmed in several in vitro models of HGPS, i.e., human primary HGPS fibroblasts, Lmna G609G/G609G mouse fibroblasts and healthy MSCs previously treated with a PMO (phosphorodiamidate morpholino oligonucleotide) that induces progerin. This was accompanied by an improvement in two in vitro phenotypes associated with the disease: nuclear shape abnormalities and premature osteoblastic differentiation of HGPS MSCs. Overall, these results suggest a novel approach towards therapeutics for HGPS that can be added to the currently assayed treatments that target other molecular defects associated with the disease.

  20. Cardioprotective Effects of Essential Oil of Lavandula angustifolia on Isoproterenol-induced Acute Myocardial Infarction in Rat

    PubMed Central

    Ziaee, Mojtaba; Khorrami, Arash; Ebrahimi, Maryam; Nourafcan, Hassan; Amiraslanzadeh, Masoumeh; Rameshrad, Maryam; Garjani, Mehraveh; Garjani, Alireza

    2015-01-01

    Myocardial infarction (MI) is a common presentation of the ischemic heart disease. Lavandula angustifolia is an herbaceous plant with antioxidative effects. This study was designed to investigate the cardioprotective effects of lavandula angustifolia essential oil against isoproterenol-induced MI in rats. The dried sample was subjected to hydrodistillation by using a Clevenger and the oils were dried over anhydrous Na2SO4. Male Wistar rats were assigned to 6 groups of control, sham, isoproterenol and treatment with 5, 10, 20 mg/Kg of the essential oil. MI was induced by subcutaneous injection of Isoproterenol (100 mg/Kg) for 3 consecutive days at an interval of 24 h. The essential oil was given intraperitoneally every 24 h started at MI induction. Following anesthesia, hemodynamic parameters were measured. After sacrificing the animals, the hearts were removed to measure the heart to body weight ratio and histopathological examination. Myeloperoxidase (MPO) and Malondialdehyde (MDA) were measured in heart tissues for evaluating the activity of neutrophils and lipid peroxidation, respectively. The essential oil amended ECG pattern by suppressing ST-segment elevation and increasing R-amplitude. 10 mg/Kg of the essential oil significantly decreased heart to body weight ratio (P<0.001) and the elevation of MDA and MPO in myocardium, it also increased dp/dtmax from 2793 ± 210 to 4488 ± 253 mmHg/sec (P<0.001), and 20 mg/Kg of it significantly lowered LVEDP from 14 ± 3.43 to 4.3 ± 0.83 mmHg (P<0.001).The results demonstrated that L. angustifolia protects myocardium against isoproterenol-induced MI that it could be related to its antioxidant properties. PMID:25561934

  1. Epidemiology of adverse drug reactions to phenformin and metformin.

    PubMed Central

    Bergman, U; Boman, G; Wiholm, B E

    1978-01-01

    Adverse drug reactions (ADRs) to phenformin and metformin reported to the Swedish Adverse Drug Reaction Committee during 1965--77 were analysed in relation to sales and prescription data. The biguanides accounted for 0.6% of all reported adverse drug reactions but for 6% of the fatal cases (all phenformin). Sixty-four ADRs to phenformin and eight to metformin were classified as causal relation "probable" or "not excluded." Fifty-one of these reactions (71%) were lactic acidosis, all but one being reactions to phenformin. After 1973 phenformin was prescribed less in Sweden and metformin became predominant. A nationwide prescription survey during 1975--6 disclosed no differences in age and sex between patients receiving phenformin and metformin. The mean daily doses prescribed in 1976 were 74 mg of phenformin and 1.5 g of metformin. The numbers of ADRs to the two drugs reported during 1975--7 were related to use. The relative incidences of ADRs reported for phenformin and metformin did not differ. Significantly more cases of lactic acidosis and deaths were reported for phenformin. PMID:678924

  2. Repaglinide versus metformin in combination with bedtime NPH insulin in patients with type 2 diabetes established on insulin/metformin combination therapy.

    PubMed

    Furlong, Niall J; Hulme, Shirley A; O'Brien, Sarah V; Hardy, Kevin J

    2002-10-01

    To compare the effect on glycemic control and weight gain of repaglinide versus metformin combined with bedtime NPH insulin in patients with type 2 diabetes. A total of 80 subjects treated with 850 or 1,000 mg t.i.d. metformin combined with bedtime NPH insulin were randomized to 13 weeks of open-label treatment with 4 mg t.i.d. repaglinide (n = 39) or metformin (dose unchanged) (n = 41). Insulin dose was titrated at the clinician's discretion, aiming for a fasting blood glucose (FBG) < or =6.0 mmol/l. Baseline age, diabetes duration, insulin requirement, weight, BMI, FBG, and HbA(1c) (Diabetes Control and Complications Trial-aligned assay, normal range 4.6-6.2%) were similar. Glycemic control improved (nonsignificantly) with insulin/metformin by (mean) 0.4%, from 8.4 to 8.1% (P = 0.09) but deteriorated with insulin/repaglinide by (mean) 0.4%, from 8.1 to 8.6% (P = 0.03; P = 0.005 between groups). Weight gain was less with insulin/metformin: 0.9 +/- 0.4 kg (means +/- SE) (P = 0.01) versus 2.7 +/- 0.4 kg (P < 0.0001) (P = 0.002 between groups). The Diabetes Treatment Satisfaction Questionnaire score (potential range 0 [minimum] to 36 [maximum]) increased from 32.4 +/- 0.8 to 34.1 +/- 0.5 (P = 0.01) with insulin/metformin but decreased from 32.5 +/- 0.9 to 29.1 +/- 1.3 (P < 0.002) with insulin/repaglinide. Combined with bedtime NPH insulin, metformin provides superior glycemic control to repaglinide with less weight gain and improved diabetes treatment satisfaction.

  3. MicroRNA profiles following metformin treatment in a mouse model of non-alcoholic steatohepatitis

    PubMed Central

    KATSURA, AKIKO; MORISHITA, ASAHIRO; IWAMA, HISAKAZU; TANI, JOJI; SAKAMOTO, TEPPEI; TATSUTA, MIWA; TOYOTA, YUKA; FUJITA, KOJI; KATO, KIYOHITO; MAEDA, EMIKO; NOMURA, TAKAKO; MIYOSHI, HISAAKI; YONEYAMA, HIROHITO; HIMOTO, TAKASHI; FUJIWARA, SHINTARO; KOBARA, HIDEKI; MORI, HIROHITO; NIKI, TOSHIRO; ONO, MASAFUMI; HIRASHIMA, MITSUOMI; MASAKI, TSUTOMU

    2015-01-01

    Non-alcoholic steatohepatitis (NASH) is one of the most common causes of chronic liver disease and is considered to be a causative factor of cryptogenic cirrhosis and hepatocellular carcinoma. microRNAs (miRNAs) are small non-coding RNAs that negatively regulate messenger RNA (mRNA). Recently, it was demonstrated that the aberrant expression of certain miRNAs plays a pivotal role in liver disease. The aim of the present study was to evaluate changes in miRNA profiles associated with metformin treatment in a NASH model. Eight-week-old male mice were fed a methionine- and choline-deficient (MCD) diet alone or with 0.08% metformin for 15 weeks. Metformin significantly downregulated the level of plasma transaminases and attenuated hepatic steatosis and liver fibrosis. The expression of miRNA-376a, miRNA-127, miRNA-34a, miRNA-300 and miRNA-342-3p was enhanced among the 71 upregulated miRNAs, and the expression of miRNA-122, miRNA-194, miRNA-101b and miRNA-705 was decreased among 60 downregulated miRNAs in the liver of MCD-fed mice when compared with control mice. Of note, miRNA profiles were altered following treatment with metformin in MCD-fed mice. miRNA-376a, miRNA-127, miRNA-34a, miRNA-300 and miRNA-342-3p were down-regulated, but miRNA-122, miRNA-194, miRNA-101b and miRNA-705 were significantly upregulated in MCD-fed mice treated with metformin. miRNA profiles were altered in MCD-fed mice and metformin attenuated this effect on miRNA expression. Therefore, miRNA profiles are a potential tool that may be utilized to clarify the mechanism behind the metformin-induced improvement of hepatic steatosis and liver fibrosis. Furthermore, identification of targetable miRNAs may be used as a novel therapy in human NASH. PMID:25672270

  4. Metformin targets multiple signaling pathways in cancer.

    PubMed

    Lei, Yong; Yi, Yanhua; Liu, Yang; Liu, Xia; Keller, Evan T; Qian, Chao-Nan; Zhang, Jian; Lu, Yi

    2017-01-26

    Metformin, an inexpensive and well-tolerated oral agent commonly used in the first-line treatment of type 2 diabetes, has become the focus of intense research as a candidate anticancer agent. Here, we discuss the potential of metformin in cancer therapeutics, particularly its functions in multiple signaling pathways, including AMP-activated protein kinase, mammalian target of rapamycin, insulin-like growth factor, c-Jun N-terminal kinase/mitogen-activated protein kinase (p38 MAPK), human epidermal growth factor receptor-2, and nuclear factor kappaB pathways. In addition, cutting-edge targeting of cancer stem cells by metformin is summarized.

  5. Methanolic Root Extract of Rauwolfia serpentina Benth Improves the Glycemic, Antiatherogenic, and Cardioprotective Indices in Alloxan-Induced Diabetic Mice.

    PubMed

    Azmi, Muhammad Bilal; Qureshi, Shamim A

    2012-01-01

    The aim of the study was to evaluate the phytochemistry and the effect of methanolic root extract (MREt) of Rauwolfia serpentina on alloxan-induced diabetic Wister male mice. Mice were divided in control (distilled water at 1 mL/kg) and alloxan-induced diabetic mice which subdivided into diabetic (distilled water at 1 mL/kg), negative (0.05% dimethyl sulfoxide at 1 mL/kg), positive (glibenclamide at 5 mg/kg) controls, and three test groups (MREt at 10, 30, and 60 mg/kg). All treatments were given orally for 14 days. Qualitatively MREt showed the presence of alkaloids, carbohydrates, flavonoids, glycosides, cardiac glycosides, phlobatannins, resins, saponins, steroids, tannins, and triterpenoids, while quantitatively extract was rich in total phenols. The flavonoids, saponins and alkaloids were also determined in root powder. MREt found effective in improving the body weights, glucose and insulin levels, insulin/glucose ratio, glycosylated and total hemoglobin in test groups as compared to diabetic control. Similarly, significantly decreased levels of total cholesterol, triglycerides, low-density lipoprotein (LDL-c), and very low-density lipoprotein (VLDL-c) cholesterols were found in test groups. Significant lipolysis with improved glycogenesis was also found in liver tissues of all test groups. ALT levels were found normal in all groups. Thus, MREt improves the glycemic, antiatherogenic, coronary risk, and cardioprotective indices in alloxan-induced diabetic mice.

  6. Methanolic Root Extract of Rauwolfia serpentina Benth Improves the Glycemic, Antiatherogenic, and Cardioprotective Indices in Alloxan-Induced Diabetic Mice

    PubMed Central

    Azmi, Muhammad Bilal; Qureshi, Shamim A.

    2012-01-01

    The aim of the study was to evaluate the phytochemistry and the effect of methanolic root extract (MREt) of Rauwolfia serpentina on alloxan-induced diabetic Wister male mice. Mice were divided in control (distilled water at 1 mL/kg) and alloxan-induced diabetic mice which subdivided into diabetic (distilled water at 1 mL/kg), negative (0.05% dimethyl sulfoxide at 1 mL/kg), positive (glibenclamide at 5 mg/kg) controls, and three test groups (MREt at 10, 30, and 60 mg/kg). All treatments were given orally for 14 days. Qualitatively MREt showed the presence of alkaloids, carbohydrates, flavonoids, glycosides, cardiac glycosides, phlobatannins, resins, saponins, steroids, tannins, and triterpenoids, while quantitatively extract was rich in total phenols. The flavonoids, saponins and alkaloids were also determined in root powder. MREt found effective in improving the body weights, glucose and insulin levels, insulin/glucose ratio, glycosylated and total hemoglobin in test groups as compared to diabetic control. Similarly, significantly decreased levels of total cholesterol, triglycerides, low-density lipoprotein (LDL-c), and very low-density lipoprotein (VLDL-c) cholesterols were found in test groups. Significant lipolysis with improved glycogenesis was also found in liver tissues of all test groups. ALT levels were found normal in all groups. Thus, MREt improves the glycemic, antiatherogenic, coronary risk, and cardioprotective indices in alloxan-induced diabetic mice. PMID:23365565

  7. Towards natural mimetics of metformin and rapamycin.

    PubMed

    Aliper, Alexander; Jellen, Leslie; Cortese, Franco; Artemov, Artem; Karpinsky-Semper, Darla; Moskalev, Alexey; Swick, Andrew G; Zhavoronkov, Alex

    2017-11-15

    Aging is now at the forefront of major challenges faced globally, creating an immediate need for safe, widescale interventions to reduce the burden of chronic disease and extend human healthspan. Metformin and rapamycin are two FDA-approved mTOR inhibitors proposed for this purpose, exhibiting significant anti-cancer and anti-aging properties beyond their current clinical applications. However, each faces issues with approval for off-label, prophylactic use due to adverse effects. Here, we initiate an effort to identify nutraceuticals-safer, naturally-occurring compounds-that mimic the anti-aging effects of metformin and rapamycin without adverse effects. We applied several bioinformatic approaches and deep learning methods to the Library of Integrated Network-based Cellular Signatures (LINCS) dataset to map the gene- and pathway-level signatures of metformin and rapamycin and screen for matches among over 800 natural compounds. We then predicted the safety of each compound with an ensemble of deep neural network classifiers. The analysis revealed many novel candidate metformin and rapamycin mimetics, including allantoin and ginsenoside (metformin), epigallocatechin gallate and isoliquiritigenin (rapamycin), and withaferin A (both). Four relatively unexplored compounds also scored well with rapamycin. This work revealed promising candidates for future experimental validation while demonstrating the applications of powerful screening methods for this and similar endeavors.

  8. Bioequivalence of saxagliptin/metformin extended-release (XR) fixed-dose combination tablets and single-component saxagliptin and metformin XR tablets in healthy adult Chinese subjects.

    PubMed

    Gummesson, Anders; Li, Haiyan; Gillen, Michael; Xu, John; Niazi, Mohammad; Hirshberg, Boaz

    2014-11-01

    As compared with individual tablets, saxagliptin/metformin extended-release (XR) fixed-dose combination (FDC) tablets offer the potential for increased patient compliance with the convenience of once daily dosing. The aim of the present study was to show that the FDC of saxagliptin and metformin XR is bioequivalent to co-administration of the individual components when given to Chinese subjects residing in China. This was a randomized, open-label, single-dose, two-period, cross-over pharmacokinetic study in two cohorts of healthy adult Chinese male subjects (n = 32 in each cohort) under fed conditions. In cohort 1, the pharmacokinetic properties of a saxagliptin/metformin XR 5/500 mg FDC tablet were compared with those of co-administration of a 5 mg saxagliptin tablet and a 500 mg metformin XR tablet. In cohort 2, the pharmacokinetic properties of a saxagliptin/metformin XR 5/1,000 mg FDC tablet were compared with those of co-administration of a 5 mg saxagliptin tablet and 2 × 500 mg metformin XR tablets. The two cohorts were independent of each other with respect to treatment and results. The pharmacokinetic properties of the active metabolite of saxagliptin (5-hydroxy-saxagliptin), as well as the safety and tolerability of each treatment, were also evaluated. For both cohorts, saxagliptin and metformin in the FDCs were bioequivalent to the individual components, as the limits of the 90 % confidence intervals of the geometric least squares mean ratios were contained within the 80-125 % bioequivalence limits for the area under the plasma concentration-time curve parameters and within the 70-143 % bioequivalence limits for the maximum plasma concentration. Similar exposures of 5-hydroxy-saxagliptin were observed with the two treatment regimens within each cohort. Co-administration of saxagliptin and metformin XR was generally safe and well tolerated as the FDCs or as individual tablets. Saxagliptin/metformin XR 5/500 mg and saxagliptin/metformin XR 5

  9. Glycoprotein changes in non-insulin dependent diabetic rats: effect of N-benzoyl-D-phenylalanine and metformin.

    PubMed

    Pari, Leelavinothan; Ashokkumar, Natarajan

    2006-01-01

    The effect of N-benzoyl-D-phenylalanine (NBDP) and metformin on neonatal streptozotocin (nSTZ) induced diabetes has been studied on plasma and tissue glycoproteins. In some pathological conditions, such as cancer, rheumatoid arthritis and diabetes, there is an abnormal glycosylation of acute phase serum proteins. As most serum proteins are produced in the liver, we have examined glycoprotein metabolism in diabetic condition. To induce non-insulin-dependent diabetes mellitus (NIDDM) a single dose of streptozotocin (100 mg/kg body weight) was injected into two day old rats. After 10-12 weeks, rats weighing above 150 g were selected for NIDDM model. In these rat, blood glucose and plasma glycoproteins were significantly increased whereas plasma insulin was significantly decreased. There was a significant decrease in the level of sialic acid and elevated levels of hexose, hexosamine and fucose in tissues. Oral administration of NBDP and metformin to diabetic rats decreased blood glucose and plasma glycoproteins. Plasma insulin and tissue sialic acid were increased whereas tissue concentrations of hexose, hexosamine and fucose were near normal. Our study suggests that NBDP and metformin possess a significant beneficial effect on glycoproteins in addition to their antidiabetic effect.

  10. Diabetes, Metformin, and Breast Cancer in Postmenopausal Women

    PubMed Central

    Chlebowski, Rowan T.; McTiernan, Anne; Wactawski-Wende, Jean; Manson, JoAnn E.; Aragaki, Aaron K.; Rohan, Thomas; Ipp, Eli; Kaklamani, Virginia G.; Vitolins, Mara; Wallace, Robert; Gunter, Marc; Phillips, Lawrence S.; Strickler, Howard; Margolis, Karen; Euhus, David M.

    2012-01-01

    Purpose Emerging evidence suggests that metformin may reduce breast cancer incidence, but reports are mixed and few provide information on tumor characteristics. Therefore, we assessed associations among diabetes, metformin use, and breast cancer in postmenopausal women participating in Women's Health Initiative clinical trials. Patients and Methods In all, 68,019 postmenopausal women, including 3,401 with diabetes at study entry, were observed over a mean of 11.8 years with 3,273 invasive breast cancers diagnosed. Diabetes incidence status was collected throughout follow-up, with medication information collected at baseline and years 1, 3, 6, and 9. Breast cancers were confirmed by review of central medical records and pathology reports. Cox proportional hazards regression, adjusted for breast cancer risk factors, compared breast cancer incidence in women with diabetes who were metformin users or nonusers with breast cancer incidence in women without diabetes. Results Compared with that in women without diabetes, breast cancer incidence in women with diabetes differed by diabetes medication type (P = .04). Women with diabetes receiving medications other than metformin had a slightly higher incidence of breast cancer (hazard ratio [HR], 1.16; 95% CI, 0.93 to 1.45), and women with diabetes who were given metformin had lower breast cancer incidence (HR, 0.75; 95% CI, 0.57 to 0.99). The association was observed for cancers positive for both estrogen receptor and progesterone receptor and those that were negative for human epidermal growth factor receptor 2. Conclusion Metformin use in postmenopausal women with diabetes was associated with lower incidence of invasive breast cancer. These results can inform future studies evaluating metformin use in breast cancer management and prevention. PMID:22689798

  11. Past, Present, and Future Research Avenues for Metformin

    PubMed Central

    Sparkes, Steven T.; Patel, Dhiren K.

    2014-01-01

    Objective: To review why metformin is considered first-line therapy for type 2 diabetes mellitus (T2DM) and review newer avenues of research currently being evaluated. Data Sources: The Cochrane Library and Medline (to January 2014) were searched for case–control and cohort studies, clinical trials, and systematic reviews and meta-analyses involving metformin for any indication. Study Selection and Data Extraction: The literature search found 5 major avenues of research for metformin: reduction in mortality, delayed-onset or prevention of T2DM in the presence of prediabetes, nonalcoholic fatty liver disease (NAFLD), polycystic ovarian syndrome (PCOS), and decreased cancer risk. When available, multi-center, double-blind, controlled clinical trials or meta-analyses thereof were selected for review. If these types of studies did not exist, other types of studies were chosen for review. Data Synthesis: Metformin significantly decreases all-cause and diabetes-related mortality in overweight and obese patients with T2DM. It may also decrease risk of progression to T2DM in patients with prediabetes. Metformin has been studied for the treatment of NAFLD though data are limited. Metformin alone or combined with clomiphene may increase pregnancy and ovulation rates but has not yet been shown to increase live-birth rates in patients with PCOS. Metformin may decrease risk of colorectal cancer but not all-cancer risk. Conclusions: Metformin’s clinical role in T2DM and prediabetes is well established. Other avenues of research being evaluated at this time are NAFLD, PCOS, and reduced risk of cancer; more data are needed before it has a clinical role in these indications.

  12. Attenuation of oxidative stress and cardioprotective effects of zinc supplementation in experimental diabetic rats.

    PubMed

    Barman, Susmita; Srinivasan, Krishnapura

    2017-02-01

    Oxidative stress plays a major role in the pathogenesis of diabetes mellitus, which further exacerbates damage of cardiac, hepatic and other tissues. We have recently reported that Zn supplementation beneficially modulates hyperglycaemia and hypoinsulinaemia, with attendant reduction of associated metabolic abnormalities in diabetic rats. The present study assessed the potential of Zn supplementation in modulating oxidative stress and cardioprotective effects in diabetic rats. Diabetes was induced in Wistar rats with streptozotocin, and groups of diabetic rats were treated with 5- and 10-fold dietary Zn interventions (0·19 and 0·38 g Zn/kg diet) for 6 weeks. The markers of oxidative stress, antioxidant enzyme activities and concentrations of antioxidant molecules, lipid profile, and expressions of fibrosis and pro-apoptotic factors in the cardiac tissue were particularly assessed. Supplemental Zn showed significant attenuation of diabetes-induced oxidative stress in terms of altered antioxidant enzyme activities and increased the concentrations of antioxidant molecules. Hypercholesterolaemia and hyperlipidaemia were also significantly countered by Zn supplementation. Along with attenuated oxidative stress, Zn supplementation also showed significant cardioprotective effects by altering the mRNA expressions of fibrosis and pro-apoptotic factors (by >50 %). The expression of lipid oxidative marker 4-hydroxy-2-nonenal (4-HNE) protein in cardiac tissue of diabetic animals was rectified (68 %) by Zn supplementation. Elevated cardiac and hepatic markers in circulation and pathological abnormalities in cardiac and hepatic tissue architecture of diabetic animals were ameliorated by dietary Zn intervention. The present study indicates that Zn supplementation can attenuate diabetes-induced oxidative stress in circulation as well as in cardiac and hepatic tissues.

  13. Effects of metformin and sitagliptin on glycolipid metabolism in type 2 diabetic rats on different diets

    PubMed Central

    Yang, Juhong; Ba, Tu; Chen, Liming; Shan, Chunyan; Zheng, Miaoyan; Wang, Ying; Ren, Huizhu; Chen, Jingli; Xu, Jie; Han, Fei; Zhang, Yi; Yang, Xiaoyun

    2016-01-01

    Introduction The aim of the study was to investigate the effects of metformin and sitagliptin on glycolipid metabolism in type 2 diabetes after different diets. Material and methods Seventy Male Sprague Dawley rats were fed with a high fat diet followed by streptozotocin treatment to induce type 2 diabetes. Then all rats were randomly divided into a control group, a metformin group (200 mg/kg), and a sitagliptin group (10 mg/kg). Each group was further divided into 4 groups receiving one load of high carbohydrate diet (45% glucose, 4.5 ml/kg), high fat diet (20% lipid emulsion, 4.5 ml/kg), high protein diet (20% whey protein, 10 ml/kg) or mixed meal, respectively. The caloric densities were all 33 kJ/kg. Postprandial blood glucose (P2BG), triglyceride (TG), glucagon-like peptide-1 (GLP-1), glucagon and insulin levels were measured. Results In the high carbohydrate group, sitagliptin was more efficient in lowering P2BG compared with metformin (p < 0.05). In the high-fat group, metformin was more powerful in lowering TG (p < 0.05) and P2BG (p < 0.05) levels because of its improvement of insulin sensitivity. In the high protein diet group, metformin did not reduce the P2BG level (p > 0.05), although it did reduce the TG level (p < 0.05). In the mixed diet group, metformin was more efficient in lowering P2BG (p < 0.05) but had a similar effect on TG (p > 0.05) compared with sitagliptin. Conclusions In the type 2 diabetic model, metformin and sitagliptin have different effects on glycolipid metabolism after different diets. If it is proved in type 2 diabetic patients, then different medicines may be recommended according to different diets in order to improve glycolipid metabolism. PMID:27186166

  14. Cardioprotective effects of grape seed proanthocyanidin against ischemic reperfusion injury.

    PubMed

    Sato, M; Maulik, G; Ray, P S; Bagchi, D; Das, D K

    1999-06-01

    There is increasing evidence to indicate cardioprotective effects of red wine consumption. Such cardioprotective properties of wine have been attributed to certain polyphenolic constituents of grapes. The purpose of this investigation was to examine whether proanthocyanidins derived from grape seeds possess cardioprotective properties. Rats were randomly divided into two groups: grape-seed proanthocyanidin was administered orally to one group of rats (100 mg/kg/day) for 3 weeks while the other group served as control. After 3 weeks, rats were killed, hearts excised, mounted on the perfusion apparatus and perfused with Krebs-Henseleit bicarbonate (KHB) buffer. After stabilization hearts were perfused in the working mode for baseline measurements of contractile functions. Hearts were then subjected to 30 min of global ischemia followed by 2 h of reperfusion. Coronary perfusates were collected to monitor malonaldehyde formation, a presumptive marker for oxidative stress development. At the end of each experiment, the heart was processed for infarct size determination. Peroxyl radical scavenging activity of proanthocyanidin was determined by examining its ability to remove peroxyl radical generated by 2,2'-azobis (2-amidinopropane) dihydrochloride while hydroxyl radical scavenging activity was tested with its ability to reduce 7-OH.-coumarin-3-carboxylic acid. The results of our study demonstrated that proanthocyanidin-fed animals were resistant to myocardial ischemia reperfusion injury as evidenced by improved recovery of post-ischemic contractile functions. The proanthocyanidin-fed group revealed reduced extent of myocardial infarction compared to the control group. Fluorimetric study demonstrated the antioxidant property of proanthocyanidin as judged by its ability to directly scavenge peroxyl radicals. Taken together, the results of this study showed that grape seed-proanthocyanidins possess a cardioprotective effect against ischemia reperfusion injury. Such

  15. Metformin for preventing gestational diabetes in women with polycystic ovarian syndrome.

    PubMed

    Ainuddin, Jahan Ara; Kazi, Sarah; Aftab, Shazia; Kamran, Ayesha

    2015-04-01

    To assess the effect of metformin in controlling Gestational Diabetes Mellitus (GDM) in women with Polycystic Ovarian Syndrome (PCOS). Comparative cohort study. Gynecology Clinics of Mamji Hospital, Karachi, from 2008 to 2010. Patients who had been diagnosed Polycystic Ovarian Syndrome (PCOS) with hyperinsulinemia and conceived and continued pregnancy, were divided in two groups; 50 patients received metformin throughout pregnancy and 32 did not. Development of GDM was ascertained in both groups. The patients were followed throughout pregnancy and in puerperium with OGTT as per WHO criteria. Primary outcome measure was development of gestational diabetes mellitus. Comparison of continuous variables was done using student 't' test. For categorical variables, frequency and percentages are reported while, odds ratio is also estimated for GDM during pregnancy. A total of 82 women with PCOS were included in this study, out of whom, 50 patients received metformin treatment while 32 patients did not. Pregnant women with PCOS in both groups were comparable in age, weight, parity and BMI. Mean fasting insulin levels at beginning of study entry were 17.22 ± 2.3 mIU/L and 16.93 ± 2.28 mIU/L in metformin and no metformin group respectively (p=0.589). Mean fasting blood sugar levels were 94.54 mg/dl in metformin and 99.59 mg/dl in no metformin group p < 0.001. A total of 5 (10%) patients in metformin group developed GDM while 11 (34.37% OR 4.71, p = 0.01) developed GDM in no metformin group. Patients not receiving metformin were 4.7 times likely to have GDM (OR: 4.71) compared to those who received it. The frequency of gestational diabetes, was significantly higher in patients with PCOS who had not received metformin compared to those who did.

  16. Metformin Sensitizes Non-small Cell Lung Cancer Cells to an Epigallocatechin-3-Gallate (EGCG) Treatment by Suppressing the Nrf2/HO-1 Signaling Pathway.

    PubMed

    Yu, Chenxiao; Jiao, Yang; Xue, Jiao; Zhang, Qi; Yang, Hongying; Xing, Ligang; Chen, Guangxia; Wu, Jinchang; Zhang, Shuyu; Zhu, Wei; Cao, Jianping

    2017-01-01

    Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. (-)-Epigallocatechin-3-gallate (EGCG), a major polyphenol in green tea, is widely studied as a cancer chemopreventive agent with potential anti-cancer effects. The NF-E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway is considered to mediate cellular resistance to EGCG. Metformin, a classical antidiabetic drug, has been shown to prevent cancer progression. Researchers have not reported whether metformin potentiates the anti-cancer efficacy of EGCG. In this study, metformin inhibited HO-1 expression and augmented the anti-tumor effect of EGCG. Metformin also enhanced ROS (reactive oxygen species) generation induced by EGCG (100 μM), subsequently resulting in apoptosis. Based on the results of the in vivo study, size of xenografts treated with the combination of metformin and EGCG was smaller than other groups. Mechanistically, metformin modulated the EGCG-activated Nrf2/HO-1 pathway through Sirtuin 1 (SIRT1)-dependent deacetylation of Nrf2. Moreover, metformin upregulated SIRT1 expression partially through the NF-kB pathway. Comparatively, the combination of EGCG and metformin showed little impact on normal lung epithelial BEAS-2B cells. Based on our findings, metformin sensitized NSCLC cells to the EGCG treatment by suppressing the Nrf2/HO-1 signaling pathway.

  17. Metformin reduces body weight gain and improves glucose intolerance in high-fat diet-fed C57BL/6J mice.

    PubMed

    Matsui, Yukari; Hirasawa, Yasushi; Sugiura, Takahiro; Toyoshi, Tohru; Kyuki, Kohei; Ito, Mikio

    2010-01-01

    In an acute treatment experiment, metformin (150, 300 mg/kg, per os (p.o.)) markedly reduced the consumption of a high-fat diet (HFD) (45 kcal% fat-containing diet) for 2 h after the HFD was given to the fasted male C57BL/6J (B6) mice. In addition, metformin at a higher dose increased plasma active glucagon-like peptide-1 (GLP-1) levels at 1 h after the HFD was given. On the other hand, pioglitazone (12 mg/kg, p.o.) slightly increased the food intake but did not affect active GLP-1 levels when given at 6 and 12 mg/kg, p.o. In a long-team experiment for 9 weeks, metformin treatment (0.25, 0.5% in the HFD) resulted in reduction of body weight gain and HFD intake. When wet weights of various body fat pads of each mouse were measured at 9 weeks after treatment, metformin markedly decreased these weights. However, pioglitazone treatment (0.01, 0.02% in the HFD) did not have obvious effects on these parameters. Oral glucose tolerance test was carried out after 20-h fasting at 4 weeks post-treatment. Whereas metformin treatment (0.25, 0.5%) markedly improved glucose intolerance, pioglitazone treatment (0.02%) slightly improved this parameter. At 9 weeks, both metformin and pioglitazone markedly improved hyperglycemia and hyperinsulinemia. Metformin treatment also improved hyperleptinemia, whereas pioglitazone was ineffective. These results indicate that metformin reduces body weight gain and improves glucose intolerance in HFD-induced obese diabetic B6 mice.

  18. Metformin for the prevention of hypertensive disorders of pregnancy in women with gestational diabetes and obesity: a systematic review and meta-analysis.

    PubMed

    Kalafat, Erkan; Sukur, Yavuz Emre; Abdi, Abdulkadir; Thilaganathan, Basky; Khalil, Asma

    2018-05-10

    Metformin has been reported to reduce the risk of preeclampsia. It is also known to influence soluble fms-like tyrosine kinase-1 (sFlt-1) levels, which correlate significantly with the gestation of onset and severity of preeclampsia. The main aim of this systematic review and meta-analysis was to determine whether metformin use is associated with the incidence of hypertensive disorders of pregnancy (HDP). MEDLINE (1947 - September 2017), Scopus (1970 - September 2017) and the Cochrane Library (since inception - September 2017) were searched for relevant citations in English language. Randomized controlled trials on metformin use, reporting the incidence of preeclampsia or pregnancy induced hypertension were included. Studies on populations with a high probability of metformin use prior to randomization (type II diabetes or polycystic ovary syndrome) were excluded. Random-effects models with Mantel-Haenszel were used for subgroup analyses. Moreover, a Bayesian random-effects meta-regression was used to synthesize the evidence. In total, 3337 citations matched the search criteria. After evaluating the abstracts and full text review, 15 studies were included in the review. Metformin use was associated with a reduced risk of pregnancy induced hypertension when compared to insulin (RR: 0.56, 95% CI: 0.37-0.85, I^ 2 =0, 1260 women) and a non-significantly reduced risk of preeclampsia (RR: 0.83, 95% CI: 0.60-1.14, I^ 2 =0%, 1724 women). When compared to placebo, metformin use was associated with a non-significant reduction of preeclampsia (RR: 0.74, 95% CI: 0.09-6.28, I^ 2 =86%, 840 women). Metformin use was also associated with a non-significant reduction of any HDP (RR: 0.71, 95% CI: 0.41-1.25, I^ 2 =0, 556 women) when compared to glyburide. When studies were combined with Bayesian random-effects meta-regression using treatment type as a covariate, the posterior probabilities of metformin having a beneficial effect for the prevention of preeclampsia, pregnancy induced

  19. Does Metformin Reduce Cancer Risks? Methodologic Considerations.

    PubMed

    Golozar, Asieh; Liu, Shuiqing; Lin, Joeseph A; Peairs, Kimberly; Yeh, Hsin-Chieh

    2016-01-01

    The substantial burden of cancer and diabetes and the association between the two conditions has been a motivation for researchers to look for targeted strategies that can simultaneously affect both diseases and reduce their overlapping burden. In the absence of randomized clinical trials, researchers have taken advantage of the availability and richness of administrative databases and electronic medical records to investigate the effects of drugs on cancer risk among diabetic individuals. The majority of these studies suggest that metformin could potentially reduce cancer risk. However, the validity of this purported reduction in cancer risk is limited by several methodological flaws either in the study design or in the analysis. Whether metformin use decreases cancer risk relies heavily on the availability of valid data sources with complete information on confounders, accurate assessment of drug use, appropriate study design, and robust analytical techniques. The majority of the observational studies assessing the association between metformin and cancer risk suffer from methodological shortcomings and efforts to address these issues have been incomplete. Future investigations on the association between metformin and cancer risk should clearly address the methodological issues due to confounding by indication, prevalent user bias, and time-related biases. Although the proposed strategies do not guarantee a bias-free estimate for the association between metformin and cancer, they will reduce synthesis of and reporting of erroneous results.

  20. Cardioprotective activity of urocortin by preventing caspase-independent, non-apoptotic death in cultured neonatal rat cardiomyocytes exposed to ischemia

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Takatani-Nakase, Tomoka, E-mail: nakase@mukogawa-u.ac.jp; Takahashi, Koichi, E-mail: koichi@mukogawa-u.ac.jp

    Research highlights: {yields} Ischemia induces high level of iPLA{sub 2} resulting in caspase-independent myocyte death. {yields} Urocortin causes iPLA{sub 2} down-regulation leading to avoidance of non-apoptotic death. {yields} The survival-promoting effect of urocortin is abrogated by CRH receptor antagonist. -- Abstract: Caspase-independent, non-apoptotic cell death in ischemic heart disease is considered to be one of the important therapeutic targets, however, the detailed mechanisms of this cell death process are not clear. In this study, we investigated the mechanisms of non-apoptotic cell death in cultured neonatal rat cardiomyocytes during ischemia, and the cardioprotection by preventing the mechanisms. We found that ischemiamore » caused elevation of the phospholipase A{sub 2} (iPLA{sub 2}) expression in the myocytes, leading to distinctive non-apoptotic nuclear shrinkage, and cell death. Moreover, we investigated whether the potent cardioprotective corticotropin-releasing hormone (CRH), urocortin, which had been less focused on non-apoptotic cell death, inhibits the ischemic myocyte death. Ischemia-augmented nuclear shrinkage of the myocytes was suppressed by the pretreatment of {approx}10 nM urocortin before the cells were exposed to ischemia. Urocortin could significantly suppress the expression and activity of iPLA{sub 2}, resulting in preventing the ischemia-induced cell death. The survival-promoting effect of urocortin was abrogated by the CRH receptor antagonist astressin. These findings provide the first evidence linking the targets of the urocortin-mediated cardioprotection to the suppression of the caspase-independent, non-apoptotic death in cardiac myocytes exposed to ischemia.« less

  1. Adsorption of emerging contaminant metformin using graphene oxide.

    PubMed

    Zhu, Shuai; Liu, Yun-Guo; Liu, Shao-Bo; Zeng, Guang-Ming; Jiang, Lu-Hua; Tan, Xiao-Fei; Zhou, Lu; Zeng, Wei; Li, Ting-Ting; Yang, Chun-Ping

    2017-07-01

    The occurrence of emerging contaminants in our water resources poses potential threats to the livings. Due to the poor treatment in wastewater management, treatment technologies are needed to effectively remove these products for living organism safety. In this study, Graphene oxide (GO) was tested for the first time for its capacity to remove a kind of emerging wastewater contaminants, metformin. The research was conducted by using a series of systematic adsorption and kinetic experiments. The results indicated that GO could rapidly and efficiently reduce the concentration of metformin, which could provide a solution in handling this problem. The uptake of metformin on the graphene oxide was strongly dependent on temperature, pH, ionic strength, and background electrolyte. The adsorption kinetic experiments revealed that almost 80% removal of metformin was achieved within 20 min for all the doses studied, corresponding to the relatively high k 1 (0.232 min -1 ) and k 2 (0.007 g mg -1  min -1 ) values in the kinetic models. It indicated that the highest adsorption capacity in the investigated range (q m ) of GO for metformin was at pH 6.0 and 288 K. Thermodynamic study indicated that the adsorption was a spontaneous (ΔG 0  < 0) and exothermic (ΔH 0  < 0) process. The adsorption of metformin increased when the pH values changed from 4.0 to 6.0, and decreased adsorption were observed at pH 6.0-11.0. GO still exhibited excellent adsorption capacity after several desorption/adsorption cycles. Besides, both so-called π-π interactions and hydrogen bonds might be mainly responsible for the adsorption of metformin onto GO. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Metformin Use and Severe Dengue in Diabetic Adults.

    PubMed

    Htun, Htet Lin; Yeo, Tsin Wen; Tam, Clarence C; Pang, Junxiong; Leo, Yee Sin; Lye, David C

    2018-02-20

    Diabetes mellitus is a risk factor for severe dengue in adults, but few studies have examined the association between metformin use and disease severity in dengue. In addition to its effect on glucose control, metformin has been associated with pleiotropic properties in preclinical studies. Using a cohort of laboratory-confirmed adult (≥21 years) dengue patients with diabetes mellitus admitted to Tan Tock Seng Hospital, we conducted a retrospective cohort study involving 131 (58.7%) metformin users and 92 (41.3%) non-users. Dengue severity was categorized as dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS) in World Health Organization (WHO) 1997 criteria and severe dengue (SD) in WHO 2009 criteria. Multivariable Poisson regression with robust error variance was used to estimate risk ratio (RR). Compared with non-use, metformin use was associated with a decreased risk of developing severe dengue (adjusted risk ratio [aRR] = 0.60, 95% confidence interval [CI]: 0.37-0.98, P = 0.04). Additionally, there was an inverse dose-response relationship (aRR = 0.69, 95% CI: 0.49-0.98, P = 0.04) with dengue severity as classified by WHO 2009 criteria. Use of metformin, however, was not associated with dengue severity based on WHO 1997 criteria; and no dose-response relationship was noted. Our results suggest metformin use could attenuate disease severity in dengue-infected diabetes mellitus individuals.

  3. Cost-effectiveness of metformin plus vildagliptin compared with metformin plus sulphonylurea for the treatment of patients with type 2 diabetes mellitus: a Portuguese healthcare system perspective.

    PubMed

    Viriato, Daniel; Calado, Frederico; Gruenberger, Jean-Bernard; Ong, Siew Hwa; Carvalho, Davide; Silva-Nunes, José; Johal, Sukhvinder; Viana, Ricardo

    2014-07-01

    To evaluate the cost-effectiveness of vildagliptin plus metformin vs generic sulphonylurea plus metformin in patients with type 2 diabetes mellitus, not controlled with metformin, from a Portuguese healthcare system perspective. A cost-effectiveness model was constructed using risk equations from the UK Prospective Diabetes Study Outcomes Model with a 10,000-patient cohort and a lifetime horizon. The model predicted microvascular and macrovascular complications and mortality in yearly cycles. Patients entered the model as metformin monotherapy failures and switched to alternative treatments (metformin plus basal-bolus insulin and subsequently metformin plus intensive insulin) when glycated hemoglobin A1c >7.5% was reached. Baseline patient characteristics and clinical variables were derived from a Portuguese epidemiological study. Cost estimates were based on direct medical costs only. One-way and probabilistic sensitivity analyses were conducted to test the robustness of the model. There were fewer non-fatal diabetes-related adverse events (AEs) in patients treated with metformin plus vildagliptin compared with patients treated with metformin plus sulphonylurea (6752 vs 6815). Addition of vildagliptin compared with sulphonylurea led to increased drug acquisition costs but reduced costs of AEs, managing morbidities, and monitoring patients. Treatment with metformin plus vildagliptin yielded a mean per-patient gain of 0.1279 quality-adjusted life years (QALYs) and a mean per-patient increase in total cost of €1161, giving an incremental cost-effectiveness ratio (ICER) of €9072 per QALY. Univariate analyses showed that ICER values were robust and ranged from €4195 to €16,052 per QALY when different parameters were varied. The model excluded several diabetes-related morbidities, such as peripheral neuropathy and ulceration, and did not model second events. Patients were presumed to enter the model with no diabetes-related complications. Treatment with

  4. Effect of metformin on exercise capacity in metabolic syndrome.

    PubMed

    Paul, Abi Albon; Dkhar, Steven Aibor; Kamalanathan, Sadishkumar; Thabah, Molly Mary; George, Melvin; Chandrasekaran, Indumathi; Gunaseelan, Vikneswaran; Selvarajan, Sandhiya

    2017-11-01

    Metabolic syndrome is a constellation of risk factors with increased predilection towards occurrence of cardiovascular diseases. Currently physical exercise and management with metformin are the prevailing treatment modalities for metabolic syndrome. Patients with metabolic syndrome have been found to have reduced exercise capacity over a period of time. Likewise metformin has been shown to decrease exercise capacity among healthy volunteers. Hence this study aims to evaluate the effect of metformin on the exercise capacity of patients with metabolic syndrome. Prospective study with 6 weeks follow up. Newly diagnosed patients with metabolic syndrome and to be started on Table Metformin 500mg twice a day were recruited for the study after obtaining written informed consent. Cardiopulmonary Exercise Testing (CPET) was done at baseline before the subjects were started on metformin and after 6 weeks of treatment using cardiopulmonary exercise testing apparatus (ZAN600). Fifteen treatment naïve patients with metabolic syndrome completed six weeks of therapy with metformin. In these patients oxygen uptake [VO2] showed statistically significant decrease from 1.10±0.44 at baseline to 0.9±0.39 (l/min) after six weeks of treatment with metformin [mean difference of -0.20 (-0.31 to -0.09); P=0.001]. Similarly oxygen uptake/kg body weight [VO2/Kg] showed a significant decrease from 14.10±4.73 to 11.44±3.81 (mlkg -1 min -1 ) at the end of six weeks of treatment [mean difference of -2.66 (-4.06 to -1.26); P=0.001]. Six weeks of treatment with metformin significantly decreases exercise capacity in newly diagnosed patients with metabolic syndrome. Copyright © 2017 Diabetes India. Published by Elsevier Ltd. All rights reserved.

  5. The Role of Metformin in Metabolic Disturbances during Pregnancy: Polycystic Ovary Syndrome and Gestational Diabetes Mellitus

    PubMed Central

    Rojas, Joselyn; Chávez-Castillo, Mervin; Bermúdez, Valmore

    2014-01-01

    Maintenance of gestation implicates complex function of multiple endocrine mechanisms, and disruptions of the global metabolic environment prompt profound consequences on fetomaternal well-being during pregnancy and postpartum. Polycystic Ovary Syndrome (PCOS) and gestational diabetes mellitus (GDM) are very frequent conditions which increase risk for pregnancy complications, including early pregnancy loss, pregnancy-induced hypertensive disorders, and preterm labor, among many others. Insulin resistance (IR) plays a pivotal role in the pathogenesis of both PCOS and GDM, representing an important therapeutic target, with metformin being the most widely prescribed insulin-sensitizing antidiabetic drug. Although traditional views neglect use of oral antidiabetic agents during pregnancy, increasing evidence of safety during gestation has led to metformin now being recognized as a valuable tool in prevention of IR-related pregnancy complications and management of GDM. Metformin has been demonstrated to reduce rates of early pregnancy loss and onset of GDM in women with PCOS, and it appears to offer better metabolic control than insulin and other oral antidiabetic drugs during pregnancy. This review aims to summarize key aspects of current evidence concerning molecular and epidemiological knowledge on metformin use during pregnancy in the setting of PCOS and GDM. PMID:25763406

  6. Polycystic ovary syndrome (PCOS): metformin.

    PubMed

    Cahill, David J; O'Brien, Katherine

    2015-03-27

    Polycystic ovary syndrome (PCOS) is classically characterised by an accumulation of incompletely developed follicles in the ovaries due to anovulation. However, since the publication of the Rotterdam criteria, there is acceptance that menstrual cycle and endocrine dysfunction with hyperandrogenism is more important in reaching the diagnosis than ultrasound findings. It is diagnosed in up to 10% of women attending gynaecology clinics, but the prevalence in the population as a whole varies from 10% to 20%, depending on which diagnostic criteria are used. PCOS has been associated with hirsutism, infertility, acne, weight gain, type 2 diabetes, cardiovascular disease (CVD), and endometrial hyperplasia. We conducted a systematic review and aimed to answer the following clinical question: What are the effects of metformin on hirsutism and menstrual frequency in women with PCOS? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found 14 studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. In this systematic review we present information relating to the effectiveness and safety of the following interventions: metformin compared with placebo/no treatment, metformin compared with weight loss intervention, or metformin compared with cyproterone acetate-ethinylestradiol.

  7. Bis-Indole-Derived NR4A1 Ligands and Metformin Exhibit NR4A1-Dependent Glucose Metabolism and Uptake in C2C12 Cells.

    PubMed

    Mohankumar, Kumaravel; Lee, Jehoon; Wu, Chia Shan; Sun, Yuxiang; Safe, Stephen

    2018-05-01

    Treatment of C2C12 muscle cells with metformin or the NR4A1 ligand 1,1-bis(3'-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) induced NR4A1 and Glut4 messenger RNA and protein expression. Similar results were observed with buttressed (3- or 3,5-substituted) analogs of DIM-C-pPhOH, including 1,1-bis(3'-indolyl)-1-(3-chloro-4-hydroxy-5-methoxyphenyl)methane (DIM-C-pPhOH-3-Cl-5-OCH3), and the buttressed analogs were more potent than DIM-C-pPhOH NR4A1 agonists. Metformin and the bis-indole substituted analogs also induced expression of several glycolytic genes and Rab4, which has previously been linked to enhancing cell membrane accumulation of Glut4 and overall glucose uptake in C2C12 cells, and these responses were also observed after treatment with metformin and the NR4A1 ligands. The role of NR4A1 in mediating the responses induced by the bis-indoles and metformin was determined by knockdown of NR4A1, and this resulted in attenuating the gene and protein expression and enhanced glucose uptake responses induced by these compounds. Our results demonstrate that the bis-indole-derived NR4A1 ligands represent a class of drugs that enhance glucose uptake in C2C12 muscle cells, and we also show that the effects of metformin in this cell line are NR4A1-dependent.

  8. The effect of combined photobiomodulation and metformin on open skin wound healing in a non-genetic model of type II diabetes.

    PubMed

    Asghari, Mohammadali; Kanonisabet, Ali; Safakhah, Mandanad; Azimzadeh, Zahra; Mostafavinia, Ataroalsadat; Taheri, Soudabeh; Amini, Abdollah; Ghorishi, Seyed Kamran; JalaliFiroozkohi, Reza; Bayat, Sahar; Bayat, Mohammad

    2017-04-01

    This study intended to examine the combined influences of photobiomodulation (PBM) and metformin on the microbial flora and biomechanical parameters of wounds in a non-genetic model of type II diabetes mellitus (TII DM). We induced a non-genetic model of TII DM in 20 rats by feeding them a 10% fructose solution for 2weeks followed by an injection of streptozotocin (STZ, 40mg/kg). After 21days from the injection of STZ, we induced one full-thickness skin wound in each of the diabetic rats. We randomly divided the rats into four groups: i) placebo; ii) pulsed wave laser (890nm, 80Hz, 0.324J/cm 2 ); iii) metformin; and iv) laser+metformin. Rats received daily intraperitoneal injections of metformin (50mg/kg). On days 7and 15 we inspected the microbial flora of each wound. On day 15 we obtained a standard sample from each healing wound for biomechanical analyses. PBM significantly decreased colony-forming units (CFUs) 7days after wound infliction compared to the placebo group (LSD test, p=0.012). Metformin significantly enhanced the biomechanical property (stress high load) of the wounds compared to the placebo group (LSD test, p=0.028). We observed the same significant result for PBM compared to the placebo group (LSD test, p=0.047). PBM significantly accelerated the wound healing process and significantly reduced CFUs of bacteria in a non-genetic rat model of TII DM. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Metformin: A Novel Biological Modifier of Tumor Response to Radiation Therapy

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Koritzinsky, Marianne, E-mail: mkoritzi@uhnresearch.ca

    2015-10-01

    Over the last decade, evidence has emerged to support a role for the antidiabetic drug metformin in the prevention and treatment of cancer. In particular, recent studies demonstrate that metformin enhances tumor response to radiation in experimental models, and retrospective analyses have shown that diabetic cancer patients treated with radiation therapy have improved outcomes if they take metformin to control their diabetes. Metformin may therefore be of utility for nondiabetic cancer patients treated with radiation therapy. The purpose of this review is to examine the data pertaining to an interaction between metformin and radiation, highlighting the essential steps needed tomore » advance our current knowledge. There is also a focus on key biomarkers that should accompany prospective clinical trials in which metformin is being examined as a modifying agent with radiation therapy. Existing evidence supports that the mechanism underlying the ability of metformin to enhance radiation response is multifaceted, and includes direct radiosensitization as well as a reduction in tumor stem cell fraction, proliferation, and tumor hypoxia. Interestingly, metformin may enhance radiation response specifically in certain genetic backgrounds, such as in cells with loss of the tumor suppressors p53 and LKB1, giving rise to a therapeutic ratio and potential predictive biomarkers.« less

  10. Effect of hypercholesterolaemia on myocardial function, ischaemia–reperfusion injury and cardioprotection by preconditioning, postconditioning and remote conditioning

    PubMed Central

    Iliodromitis, Efstathios K; Lazou, Antigone; Görbe, Anikó; Giricz, Zoltán; Schulz, Rainer

    2017-01-01

    Hypercholesterolaemia is considered to be a principle risk factor for cardiovascular disease, having direct negative effects on the myocardium itself, in addition to the development of atherosclerosis. Since hypercholesterolaemia affects the global cardiac gene expression profile, among many other factors, it results in increased myocardial oxidative stress, mitochondrial dysfunction and inflammation triggered apoptosis, all of which may account for myocardial dysfunction and increased susceptibility of the myocardium to infarction. In addition, numerous experimental and clinical studies have revealed that hyperlcholesterolaemia may interfere with the cardioprotective potential of conditioning mechanisms. Although not fully elucidated, the underlying mechanisms for the lost cardioprotection in hypercholesterolaemic animals have been reported to involve dysregulation of the endothelial NOS‐cGMP, reperfusion injury salvage kinase, peroxynitrite‐MMP2 signalling pathways, modulation of ATP‐sensitive potassium channels and apoptotic pathways. In this review article, we summarize the current knowledge on the effect of hypercholesterolaemia on the non‐ischaemic and ischaemic heart as well as on the cardioprotection induced by drugs or ischaemic preconditioning, postconditioning and remote conditioning. Future perspectives concerning the mechanisms and the design of preclinical and clinical trials are highlighted. Linked Articles This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc PMID:28060997

  11. Metformin Does Not Suppress Serum Thyrotropin by Increasing Levothyroxine Absorption

    PubMed Central

    Al-Alusi, Mostafa A.; Du, Lin; Li, Ning; Yeh, Michael W.; He, Xuemei; Braverman, Lewis E.

    2015-01-01

    Background: Levothyroxine (LT4) absorption is affected by concomitant ingestion of certain minerals, medications, and foods. It has been hypothesized that metformin may suppress serum thyrotropin (TSH) concentrations by enhancing LT4 absorption or by directly affecting the hypothalamic–pituitary axis. This study examined the effect of metformin ingestion on LT4 absorption, as assessed by serum total thyroxine (TT4) concentrations. Methods: A modified Food and Drug Administration LT4 bioequivalence protocol was applied to healthy, metformin-naïve, euthyroid adult volunteers. Following an overnight fast, 600 μg LT4 was administered orally. Serum TT4 concentrations were measured at baseline and at 0.5, 1, 1.5, 2, 4, and 6 h following LT4 administration. Measurements were performed before and after one week of metformin ingestion (850 mg three times daily). Peak serum TT4 concentrations, time to peak TT4 concentrations, and area under the concentration-time curve (AUC) were calculated. Results: Twenty-six subjects (54% men, 27% white, age 33 ± 10 years) were studied. There were no significant differences in peak serum TT4 concentrations (p = 0.13) and time to peak TT4 concentrations (p = 0.19) before and after one week of metformin use. A trend toward reduced TT4 AUC was observed after metformin ingestion (pre-metformin 3893 ± 568 μg/dL-min, post-metformin 3765 ± 588 μg/dL-min, p = 0.09). Conclusions: LT4 absorption is unchanged by concomitant metformin ingestion. Mechanisms other than increased LT4 absorption may be responsible for the suppressed TSH concentrations observed in patients ingesting both drugs. PMID:26191653

  12. Improved glycemic control induced by both metformin and repaglinide is associated with a reduction in blood levels of 3-deoxyglucosone in nonobese patients with type 2 diabetes.

    PubMed

    Engelen, Lian; Lund, Søren S; Ferreira, Isabel; Tarnow, Lise; Parving, Hans-Henrik; Gram, Jørgen; Winther, Kaj; Pedersen, Oluf; Teerlink, Tom; Barto, Rob; Stehouwer, Coen D A; Vaag, Allan A; Schalkwijk, Casper G

    2011-03-01

    Metformin has been reported to reduce α-dicarbonyls, which are known to contribute to diabetic complications. It is unclear whether this is due to direct quenching of α-dicarbonyls or to an improvement in glycemic control. We therefore compared the effects of metformin versus repaglinide, an antihyperglycemic agent with an insulin-secreting mechanism, on the levels of the α-dicarbonyl 3-deoxyglucosone (3DG). We conducted a single-center, double-masked, double-dummy, crossover study involving 96 nonobese patients with type 2 diabetes. After a 1-month run-in on diet-only treatment, patients were randomized to either repaglinide (6 mg daily) followed by metformin (2 g daily) or vice versa each during 4 months with a 1-month washout between interventions. 3DG levels decreased after both metformin (-19.3% (95% confidence interval (CI): -23.5, -14.8)) and repaglinide (-20.8% (95% CI: -24.9, -16.3)) treatments, but no difference was found between treatments (1.8% (95% CI: -3.8, 7.8)). Regardless of the treatment, changes in glycemic variables were associated with changes in 3DG. Specifically, 3DG decreased by 22.7% (95% CI: 19.0, 26.5) per s.d. decrease in fasting plasma glucose (PG), by 20.0% (95% CI: 16.2, 23.9) per s.d. decrease in seven-point mean plasma glucose, by 22.5% (95% CI: 18.6, 26.6) per s.d. decrease in area under the curve for PG, by 17.2% (95% CI: 13.8, 20.6) per s.d. decrease in HbAlc, and by 10.9% (95% CI: 6.4, 15.5) per s.d. decrease in Amadori albumin. In addition, decreases in 3DG were associated with decreases in advanced glycation endproducts and endothelial markers. Improved glycemic control induced by both metformin and repaglinide is associated with a reduction in 3DG levels in nonobese individuals with type 2 diabetes. This may constitute a shared metabolic pathway through which both treatments have a beneficial impact on the cardiovascular risk.

  13. Metformin is a novel suppressor for transforming growth factor (TGF)-β1

    NASA Astrophysics Data System (ADS)

    Xiao, Han; Zhang, Jianshu; Xu, Zhonghe; Feng, Yenan; Zhang, Mingliang; Liu, Jianli; Chen, Ruifei; Shen, Jing; Wu, Jimin; Lu, Zhizhen; Fang, Xiaohong; Li, Jingyuan; Zhang, Youyi

    2016-06-01

    Metformin is a widely used first-line antidiabetic drug that has been shown to protect against a variety of specific diseases in addition to diabetes, including cardiovascular disorders, polycystic ovary syndrome, and cancer. However, the precise mechanisms underlying the diverse therapeutic effects of metformin remain elusive. Here, we report that transforming growth factor-β1 (TGF-β1), which is involved in the pathogenesis of numerous diseases, is a novel target of metformin. Using a surface plasmon resonance-based assay, we identified the direct binding of metformin to TGF-β1 and found that metformin inhibits [125I]-TGF-β1 binding to its receptor. Furthermore, based on molecular docking and molecular dynamics simulations, metformin was predicted to interact with TGF-β1 at its receptor-binding domain. Single-molecule force spectroscopy revealed that metformin reduces the binding probability but not the binding force of TGF-β1 to its type II receptor. Consequently, metformin suppresses type II TGF-β1 receptor dimerization upon exposure to TGF-β1, which is essential for downstream signal transduction. Thus, our results indicate that metformin is a novel TGF-β suppressor with therapeutic potential for numerous diseases in which TGF-β1 hyperfunction is indicated.

  14. Diabetes abolishes the cardioprotection induced by sevoflurane postconditioning in the rat heart in vivo: roles of glycogen synthase kinase-3β and its upstream pathways.

    PubMed

    Tai, Wenjun; Shi, Enyi; Yan, Lihui; Jiang, Xiaojing; Ma, Hong; Ai, Chunyu

    2012-11-01

    We measured the cardioprotection afforded by sevoflurane postconditioning in streptozotocin-induced diabetic rats (DRs) and determined the roles of glycogen synthase kinase (GSK), phosphatidylinositol-3-kinase/Akt, and extracellular signal-regulated kinase (ERK1/2) in such a procedure. DRs and nondiabetic rats (NDRs) were subjected to a 30-min coronary artery occlusion followed by a 120-min reperfusion. Postconditioning was achieved by inhalation of 1 minimum alveolar concentration sevoflurane at the first 5 min of reperfusion. The infarct size was determined by triphenyltetrazolium chloride staining. Expressions of GSK-3β, Akt, and ERK1/2 were measured using Western blotting. In NDRs, the infarct size was significantly decreased from 53.4% ± 7.6% to 34.9% ± 5.6% by sevoflurane postconditioning (P < 0.01). Such an anti-infarct effect was abolished completely in the DRs, as evidenced by a similar infarct size observed between the sevoflurane-treated and untreated DRs (49.3% ± 8.6% and 49.6% ± 9.3%, respectively, P > 0.05). Direct inhibition of GSK-3β by injection of SB216763 just before the start of reperfusion induced equivalent infarct-sparing effects in both NDRs (37.8% ± 3.9% and 53.4% ± 7.6% in SB216763-treated and untreated NDRs, respectively; P < 0.01) and DRs (38.8% ± 3.2% and 49.3% ± 8.6% in SB216763-treated and untreated DRs, respectively; P < 0.05). Sevoflurane postconditioning remarkably enhanced the phosphorylation of GSK-3β Ser(9), Akt Ser(473), and ERK1/2 in NDRs, which were blocked in DRs. The cardioprotection induced by sevoflurane postconditioning is abolished by diabetes. This might be due to the impairment of phosphorylation of GSK-3β and its upstream signaling pathways of phosphatidylinositol-3-kinase/Akt and ERK1/2 in the presence of diabetes. Copyright © 2012 Elsevier Inc. All rights reserved.

  15. Metformin synergizes 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) combination therapy through impairing intracellular ATP production and DNA repair in breast cancer stem cells.

    PubMed

    Soo, Jaslyn Sian-Siu; Ng, Char-Hong; Tan, Si Hoey; Malik, Rozita Abdul; Teh, Yew-Ching; Tan, Boon-Shing; Ho, Gwo-Fuang; See, Mee-Hoong; Taib, Nur Aishah Mohd; Yip, Cheng-Har; Chung, Felicia Fei-Lei; Hii, Ling-Wei; Teo, Soo-Hwang; Leong, Chee-Onn

    2015-10-01

    Metformin, an AMPK activator, has been reported to improve pathological response to chemotherapy in diabetic breast cancer patients. To date, its mechanism of action in cancer, especially in cancer stem cells (CSCs) have not been fully elucidated. In this study, we demonstrated that metformin, but not other AMPK activators (e.g. AICAR and A-769662), synergizes 5-fluouracil, epirubicin, and cyclophosphamide (FEC) combination chemotherapy in non-stem breast cancer cells and breast cancer stem cells. We show that this occurs through an AMPK-dependent mechanism in parental breast cancer cell lines. In contrast, the synergistic effects of metformin and FEC occurred in an AMPK-independent mechanism in breast CSCs. Further analyses revealed that metformin accelerated glucose consumption and lactate production more severely in the breast CSCs but the production of intracellular ATP was severely hampered, leading to a severe energy crisis and impairs the ability of CSCs to repair FEC-induced DNA damage. Indeed, addition of extracellular ATP completely abrogated the synergistic effects of metformin on FEC sensitivity in breast CSCs. In conclusion, our results suggest that metformin synergizes FEC sensitivity through distinct mechanism in parental breast cancer cell lines and CSCs, thus providing further evidence for the clinical relevance of metformin for the treatment of cancers.

  16. Effect of geraniol on rat cardiomyocytes and its potential use as a cardioprotective natural compound.

    PubMed

    Crespo, R; Wei, K; Rodenak-Kladniew, B; Mercola, M; Ruiz-Lozano, P; Hurtado, C

    2017-03-01

    Reactive oxygen species (ROS) are generated in the ischaemic myocardium especially during early reperfusion and affect myocardial function and viability. Monoterpenes have been proposed to play beneficial roles in diverse physiological systems; however, the mechanisms of action remain largely unknown. This study aims to assess the effect of monoterpene geraniol (GOH) on neonatal rat ventricular cardiomyocytes (NRVCs) subjected to oxidative stress. We used an in vitro model of hypoxia-reoxygenation. Cardioprotective (AMPK) and cardiotoxic (ERK1/2, ROS) signaling indicators were measured. Assays were performed by fluorogenic probes, MTT assays and Western-blots. We determined that the addition of GOH (5-200μM) to cultured normoxic and hypoxic-NRVCs diminished the endogenous production of ROS in stressed cardiomyocytes. We observed that GOH treatment increased pAMPK levels and decreased pERK1/2 levels in cultured NRVCs. This report suggests that GOH is a candidate cardioprotective natural compound that operates by blunting the oxidative stress signaling that is normally induced by hypoxia-reoxygenation. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Metformin preconditioned adipose derived mesenchymal stem cells is a better option for the reversal of diabetes upon transplantation.

    PubMed

    Shree, Nitya; Bhonde, Ramesh R

    2016-12-01

    Metformin is used worldwide as an insulin sensitizer. Adipose derived mesenchymal stem cells have shown promising results in the reducing hyperglycemia. We examined whether preconditioning of adipose derived mesenchymal stem cells (ASCs) with metformin could have a better therapeutic value for the reversal of type 2 diabetes. We compared the effect of metformin, ASCs and metformin preconditioned ASCs (MetASCs) in high fat diet induced C57BL/6 mice by injecting the cells intramuscularly only once where as metformin was given at a concentration of 300mg per kg body weight orally daily. Fasting glucose was measured every week for 4 weeks. At the end of the study insulin, triglycerides, IL6 and oxidised LDL were evaluated from the serum. Gene expression studies were performed for muscle (GLUT4) and liver tissues (IL6 and PAI1).There was a remarkable decrease in hyperglycemia within two weeks of injection by MetASCs as compared to metformin and ASCs alone. A significant decrement of hyperinsulinemia, triglyceridemia, serum IL6 and oxidised LDL were observed at the end of the study. Gene expression studies for muscle tissue revealed the drastic upregulation of GLUT4 gene levels in the MetASCs group indicating enhanced glucose uptake in muscle. Liver tissue analysed for the genes involved in inflammation viz. IL6 and PAI1 showed significant downregulation in the MetASCs group as compared to the other groups. This is a first report demonstrating the synergistic effect of metformin preconditioning of ASCs leading to reversal of hyperglycemia, hyperinsulinemia and triglyceridemia. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  18. Prolonged metformin treatment leads to reduced transcription of Nrf2 and neurotrophic factors without cognitive impairment in older C57BL/6J mice.

    PubMed

    Allard, Joanne S; Perez, Evelyn J; Fukui, Koji; Carpenter, Priscilla; Ingram, Donald K; de Cabo, Rafael

    2016-03-15

    Long-term use of anti-diabetic agents has become commonplace as rates of obesity, metabolic syndrome and diabetes continue to escalate. Metformin, a commonly used anti-diabetic drug, has been shown to have many beneficial effects outside of its therapeutic regulation of glucose metabolism and insulin sensitivity. Studies on metformin's effects on the central nervous system are limited and predominantly consist of in vitro studies and a few in vivo studies with short-term treatment in relatively young animals; some provide support for metformin as a neuroprotective agent while others show evidence that metformin may be deleterious to neuronal survival. In this study, we examined the effect of long-term metformin treatment on brain neurotrophins and cognition in aged male C57Bl/6 mice. Mice were fed control (C), high-fat (HF) or a high-fat diet supplemented with metformin (HFM) for 6 months. Metformin decreased body fat composition and attenuated declines in motor function induced by a HF diet. Performance in the Morris water maze test of hippocampal based memory function, showed that metformin prevented impairment of spatial reference memory associated with the HF diet. Quantitative RT-PCR on brain homogenates revealed decreased transcription of BDNF, NGF and NTF3; however protein levels were not altered. Metformin treatment also decreased expression of the antioxidant pathway regulator, Nrf2. The decrease in transcription of neurotrophic factors and Nrf2 with chronic metformin intake, cautions of the possibility that extended metformin use may alter brain biochemistry in a manner that creates a vulnerable brain environment and warrants further investigation. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. Metformin Effects on Biochemical Recurrence and Metabolic Signaling in the Prostate

    PubMed Central

    Winters, Brian; Plymate, Stephen; Zeliadt, Steven B; Holt, Sarah; Zhang, Xiaotun; Hu, Elaine; Lin, Daniel W.; Morrissey, Colm; Wooldridge, Bryan; Gore, John L; Porter, Michael P; Wright, Jonathan L

    2015-01-01

    Background Metformin has received considerable attention as a potential anti-cancer agent. Animal and in-vitro prostate cancer (PCa) models have demonstrated decreased tumor growth with metformin, however the precise mechanisms are unknown. We examine the effects of metformin on PCa biochemical recurrence (BCR) in a large clinical database followed by evaluating metabolic signaling changes in a cohort of men undergoing prostate needle biopsy (PNB). Methods Men treated for localized PCa were identified in a comprehensive clinical database between 2001 and 2010. Cox regression was performed to determine association with BCR relative to metformin use. We next identified a separate case-control cohort of men undergoing prostate needle biopsy (PNB) stratified by metformin use. Differences in mean IHC scores were compared with linear regression for phosphorylated IR, IGF-IR, AKT, and AMPK. Results 1,734 men were evaluated for BCR with mean follow up of 41 months (range 1-121 months). ‘Ever’ metformin use was not associated with BCR (HR 1.12, 0.77-1.65), however men reporting both pre/post-treatment metformin use had a 45% reduction in BCR (HR=0.55 (0.31-0.96)). For the tissue-based study, 48 metformin users and 42 controls underwent PNB. Significantly greater staining in phosphorylated nuclear (p-IR, p-AKT) and cytoplasmic (p-IR, p-IGF-1R) insulin signaling proteins were seen in patients with PCa detected compared to those with negative PNB (p-values all < 0.006). When stratified by metformin use, IGF-1R remained significantly elevated (p=0.01) in men with PCa detected whereas p-AMPK (p=0.05) was elevated only in those without PCa. Conclusion Metformin use is associated with reduced BCR after treatment of localized PCa when considering pre-diagnostic and cumulative dosing. In men with cancer detected on PNB, insulin signaling markers were significantly elevated compared to negative PNB patients. The finding of IGF-1R elevation in positive PNBs versus p-AMPK elevation

  20. Metformin inhibits heme oxygenase-1 expression in cancer cells through inactivation of Raf-ERK-Nrf2 signaling and AMPK-independent pathways

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Do, Minh Truong; Kim, Hyung Gyun; Khanal, Tilak

    2013-09-01

    Resistance to therapy is the major obstacle to more effective cancer treatment. Heme oxygenase-1 (HO-1) is often highly up-regulated in tumor tissues, and its expression is further increased in response to therapies. It has been suggested that inhibition of HO-1 expression is a potential therapeutic approach to sensitize tumors to chemotherapy and radiotherapy. In this study, we tested the hypothesis that the anti-tumor effects of metformin are mediated by suppression of HO-1 expression in cancer cells. Our results indicate that metformin strongly suppresses HO-1 mRNA and protein expression in human hepatic carcinoma HepG2, cervical cancer HeLa, and non-small-cell lung cancermore » A549 cells. Metformin also markedly reduced Nrf2 mRNA and protein levels in whole cell lysates and suppressed tert-butylhydroquinone (tBHQ)-induced Nrf2 protein stability and antioxidant response element (ARE)-luciferase activity in HepG2 cells. We also found that metformin regulation of Nrf2 expression is mediated by a Keap1-independent mechanism and that metformin significantly attenuated Raf-ERK signaling to suppress Nrf2 expression in cancer cells. Inhibition of Raf-ERK signaling by PD98059 decreased Nrf2 mRNA expression in HepG2 cells, confirming that the inhibition of Nrf2 expression is mediated by an attenuation of Raf-ERK signaling in cancer cells. The inactivation of AMPK by siRNA, DN-AMPK or the pharmacological AMPK inhibitor compound C, revealed that metformin reduced HO-1 expression in an AMPK-independent manner. These results highlight the Raf-ERK-Nrf2 axis as a new molecular target in anticancer therapy in response to metformin treatment. - Highlights: • Metformin inhibits HO-1 expression in cancer cells. • Metformin attenuates Raf-ERK-Nrf2 signaling. • Suppression of HO-1 by metformin is independent of AMPK. • HO-1 inhibition contributes to anti-proliferative effects of metformin.« less

  1. Prolonged metformin treatment leads to reduced transcription of Nrf2 and neurotrophic factors without cognitive impairment in older C57BL/6J mice

    PubMed Central

    Allard, Joanne S.; Perez, Evelyn J; Fukui, Koji; Carpenter, Priscilla; Ingram, Donald K.; de Cabo, Rafael

    2016-01-01

    Long-term use of anti-diabetic agents has become commonplace as rates of obesity, metabolic syndrome and diabetes continue to escalate. Metformin, a commonly used anti-diabetic drug, has been shown to have many beneficial effects outside of its therapeutic regulation of glucose metabolism and insulin sensitivity. Studies on metformin’s effects on the central nervous system are limited and predominantly consist of in vitro studies and a few in vivo studies with short-term treatment in relatively young animals; some provide support for metformin as a neuroprotective agent while others show evidence that metformin may be deleterious to neuronal survival. In this study, we examined the effect of long-term metformin treatment on brain neurotrophins and cognition in aged male C57Bl/6 mice. Mice were fed control (C), high-fat (HF) or a high-fat diet supplemented with metformin (HFM) for 6 months. Metformin decreased body fat composition and attenuated declines in motor function induced by a HF diet. Performance in the Morris water maze test of hippocampal based memory function, showed that metformin prevented impairment of spatial reference memory associated with the HF diet. Quantitative RT-PCR on brain homogenates revealed decreased transcription of BDNF, NGF and NTF3; however protein levels were not altered. Metformin treatment also decreased expression of the antioxidant pathway regulator, Nrf2. The decrease in transcription of neurotrophic factors and Nrf2 with chronic metformin intake, cautions of the possibility that extended metformin use may alter brain biochemistry in a manner that creates a vulnerable brain environment and warrants further investigation. PMID:26698400

  2. Vorinostat and metformin sensitize EGFR-TKI resistant NSCLC cells via BIM-dependent apoptosis induction.

    PubMed

    Chen, Hengyi; Wang, Yubo; Lin, Caiyu; Lu, Conghua; Han, Rui; Jiao, Lin; Li, Li; He, Yong

    2017-11-07

    There is a close relationship between low expression of BIM and resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Vorinostat is a pan-histone deacetylase inhibitor (HDACi) that augments BIM expression in various types of tumor cells, however, this effect is attenuated by the high expression of anti-apoptotic proteins in EGFR-TKI resistant non-small cell lung cancer (NSCLC) cells. Vorinostat in combination with metformin - a compound that can inhibit anti-apoptotic proteins expression, might cooperate to activate apoptotic signaling and overcome EGFR-TKI resistance. This study aimed to investigate the cooperative effect and evaluate possible molecular mechanisms. The results showed that vorinostat combined with gefitinib augmented BIM expression and increased the sensitivity of EGFR-TKI resistant NSCLC cells to gefitinib, adding metformin simultaneously could obviously inhibit the expression of anti-apoptotic proteins, and further increased expression levels of BIM and BAX, and as a result, further improved the sensitivity of gefitinib both on the NSCLC cells with intrinsic and acquired resistance to EGFR-TKI. In addition, autophagy induced by gefitinib and vorinostat could be significantly suppressed by metformin, which might also contribute to enhance apoptosis and improve sensitivity of gefitinib. These results suggested that the combination of vorinostat and metformin might represent a novel strategy to overcome EGFR-TKI resistance associated with BIM-dependent apoptosis in larger heterogeneous populations.

  3. Efficacy of acarbose and metformin in newly diagnosed type 2 diabetes patients stratified by HbA1c levels.

    PubMed

    Zhang, Jin-Ping; Wang, Na; Xing, Xiao-Yan; Yang, Zhao-Jun; Wang, Xin; Yang, Wen-Ying

    2016-07-01

    The aim of the present study was to investigate whether the therapeutic efficacy of acarbose and metformin is correlated with baseline HbA1c levels in Chinese patients with newly diagnosed type 2 diabetes mellitus (T2DM). Data for 711 subjects were retrieved from the MARCH (Metformin and AcaRbose in Chinese as initial Hypoglycemic treatment) trial database and reviewed retrospectively. Patients were grouped according to baseline HbA1c levels (<7%, 7%-8%, and >8%) and the results for these three groups were compared between acarbose and metformin treatments. Acarbose and metformin treatment significantly improved T2DM-associated parameters (weight, fasting plasma glucose [FPG], postprandial glucose [PPG], glucagon-like peptide-1 [GLP-1], HOMA-IR, and total cholesterol) across all HbA1c levels. Acarbose decreased PPG and HOMA-β significantly more than metformin, but only in subjects with lower baseline HbA1c (PPG in the <7% and 7%-8%, HOMA-β in the <7% groups; all P < 0.05). Acarbose decreased triglyceride (TG) levels, and the areas under the curve (AUC) for insulin and glucagon more than metformin at all HbA1c levels (P < 0.05). After 24 weeks treatment, metformin decreased FPG levels significantly more than acarbose for all baseline HbA1c groups (all P < 0.001). With the exception of FPG, PPG, and TG levels, differences between the two treatment groups observed at 24 weeks were not detected at 48 weeks. Acarbose decreased PPG and TG and spared the AUC for insulin more effectively in patients with low-to-moderate baseline HbA1c levels, whereas metformin induced greater reductions in FPG. These results may help guide selection of initial therapy based on baseline HbA1c. © 2015 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

  4. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota.

    PubMed

    Forslund, Kristoffer; Hildebrand, Falk; Nielsen, Trine; Falony, Gwen; Le Chatelier, Emmanuelle; Sunagawa, Shinichi; Prifti, Edi; Vieira-Silva, Sara; Gudmundsdottir, Valborg; Pedersen, Helle K; Arumugam, Manimozhiyan; Kristiansen, Karsten; Voigt, Anita Yvonne; Vestergaard, Henrik; Hercog, Rajna; Costea, Paul Igor; Kultima, Jens Roat; Li, Junhua; Jørgensen, Torben; Levenez, Florence; Dore, Joël; Nielsen, H Bjørn; Brunak, Søren; Raes, Jeroen; Hansen, Torben; Wang, Jun; Ehrlich, S Dusko; Bork, Peer; Pedersen, Oluf

    2015-12-10

    In recent years, several associations between common chronic human disorders and altered gut microbiome composition and function have been reported. In most of these reports, treatment regimens were not controlled for and conclusions could thus be confounded by the effects of various drugs on the microbiota, which may obscure microbial causes, protective factors or diagnostically relevant signals. Our study addresses disease and drug signatures in the human gut microbiome of type 2 diabetes mellitus (T2D). Two previous quantitative gut metagenomics studies of T2D patients that were unstratified for treatment yielded divergent conclusions regarding its associated gut microbial dysbiosis. Here we show, using 784 available human gut metagenomes, how antidiabetic medication confounds these results, and analyse in detail the effects of the most widely used antidiabetic drug metformin. We provide support for microbial mediation of the therapeutic effects of metformin through short-chain fatty acid production, as well as for potential microbiota-mediated mechanisms behind known intestinal adverse effects in the form of a relative increase in abundance of Escherichia species. Controlling for metformin treatment, we report a unified signature of gut microbiome shifts in T2D with a depletion of butyrate-producing taxa. These in turn cause functional microbiome shifts, in part alleviated by metformin-induced changes. Overall, the present study emphasizes the need to disentangle gut microbiota signatures of specific human diseases from those of medication.

  5. [Current role of metformin in treatment of diabetes mellitus type 2].

    PubMed

    Janssen, J A

    2000-09-30

    Metformin-associated lactic acidosis is not necessarily due to metformin accumulation. It appears that mortality in patients receiving metformin who develop lactic acidosis is mostly linked to underlying disease. It has been suggested that metformin should be the first-line agent for the treatment of obese type 2 diabetic patients since metformin was associated with a significant decrease in macrovascular events and a reduction of all-cause mortality in the United Kingdom Prospective Diabetes Study (UKPDS) in a substudy. However, in this substudy no significant decrease in microvascular complications was observed in obese subjects with intensive metformin therapy. In addition, the use of metformin in combination with sulfonylurea seemed to be associated with excess risk of diabetes-related and all-cause mortality in obese subjects. Due to the discrepant and contradictory nature of the results in the obese patients and a lack of power the UKPDS offered no decision for any drug for initial therapy of type 2 diabetes. The main message of the UKPDS is that lowering of the blood glucose to the normal range is beneficial irrespective of the hypoglycaemic agent used. A rational approach to therapy in a type 2 diabetes patient who fails to sufficiently lower blood sugar with diet and weight loss is to begin therapy with a sulfonylurea or metformin and to add another oral agent if the desired glycaemic control is not achieved.

  6. Health benefits of late-onset metformin treatment every other week in mice.

    PubMed

    Alfaras, Irene; Mitchell, Sarah J; Mora, Hector; Lugo, Darisbeth Rosario; Warren, Alessandra; Navas-Enamorado, Ignacio; Hoffmann, Vickie; Hine, Christopher; Mitchell, James R; Le Couteur, David G; Cogger, Victoria C; Bernier, Michel; de Cabo, Rafael

    2017-01-01

    Chronic 1% metformin treatment is nephrotoxic in mice, but this dose may nonetheless confer health benefits if given intermittently rather than continuously. Here, we examined the effects of 1% metformin given every-other week (EOW) or two consecutive weeks per month (2WM) on survival of 2-year-old male mice fed standard chow. EOW and 2WM mice had comparable life span compared with control mice. A significant reduction in body weight within the first few weeks of metformin treatment was observed without impact on food consumption and energy expenditure. Moreover, there were differences in the action of metformin on metabolic markers between the EOW and 2WM groups, with EOW metformin conferring greater benefits. Age-associated kidney lesions became more pronounced with metformin, although without pathological consequences. In the liver, metformin treatment led to an overall reduction in steatosis and was accompanied by distinct transcriptomic and metabolomic signatures in response to EOW versus 2WM regimens. Thus, the absence of adverse outcomes associated with chronic, intermittent use of 1% metformin in old mice has clinical translatability into the biology of aging in humans.

  7. A dosing algorithm for metformin based on the relationships between exposure and renal clearance of metformin in patients with varying degrees of kidney function.

    PubMed

    Duong, Janna K; Kroonen, M Y A M; Kumar, S S; Heerspink, H L; Kirkpatrick, C M; Graham, G G; Williams, K M; Day, R O

    2017-08-01

    The aims of this study were to investigate the relationship between metformin exposure, renal clearance (CL R ), and apparent non-renal clearance of metformin (CL NR /F) in patients with varying degrees of kidney function and to develop dosing recommendations. Plasma and urine samples were collected from three studies consisting of patients with varying degrees of kidney function (creatinine clearance, CL CR ; range, 14-112 mL/min). A population pharmacokinetic model was built (NONMEM) in which the oral availability (F) was fixed to 0.55 with an estimated inter-individual variability (IIV). Simulations were performed to estimate AUC 0-τ , CL R , and CL NR /F. The data (66 patients, 327 observations) were best described by a two-compartment model, and CL CR was a covariate for CL R . Mean CL R was 17 L/h (CV 22%) and mean CL NR /F was 1.6 L/h (69%).The median recovery of metformin in urine was 49% (range 19-75%) over a dosage interval. When CL R increased due to improved renal function, AUC 0-τ decreased proportionally, while CL NR /F did not change with kidney function. Target doses (mg/day) of metformin can be reached using CL CR /3 × 100 to obtain median AUC 0-12 of 18-26 mg/L/h for metformin IR and AUC 0-24 of 38-51 mg/L/h for metformin XR, with C max  < 5 mg/L. The proposed dosing algorithm can be used to dose metformin in patients with various degrees of kidney function to maintain consistent drug exposure. However, there is still marked IIV and therapeutic drug monitoring of metformin plasma concentrations is recommended.

  8. Comparative efficacy of thiazolidinediones and metformin for polycystic ovary syndrome.

    PubMed

    Du, Qiang; Wang, Yan-Jun

    2012-09-01

    To compare the efficacy of thiazolidinediones (TZDs) and metformin in polycystic ovary syndrome (PCOS) patients. This systematic review study was conducted at Shengjing Hospital of China Medical University, Shenyang, China between January and February 2012. We searched the following databases MEDLINE, EMBASE, the Cochrane Library, and Chinese National Knowledge Infrastructure until January 2012. Six randomized controlled trials records involving 267 patients were retrieved. The effect of TZDs on body mass index (BMI) was significantly lower than metformin (p=0.001; standardized mean difference [SMD] = 0.40, 95% confidence interval [CI]; 0.16-0.65). The effect of TZDs on the Homeostasis Model of Assessment-Insulin Resistance Index was not significantly different from metformin (p=0.955, SMD = 0.01, 95% CI: -0.38-0.40). The effect of TZDs on the androgen level was not significantly different from metformin (serum total testosterone: p=0.287, SMD = 0.20, 95% CI: -0.17-0.57). Compared to metformin, TZDs had the same effectiveness in treating insulin sensitivity and lowering androgen in PCOS patients, but the effect on weight loss was not as good as metformin.

  9. Saxagliptin versus glipizide as add-on therapy to metformin: assessment of hypoglycemia.

    PubMed

    Mintz, Matthew L; Minervini, Gianmaria

    2014-05-01

    To compare characteristics of hypoglycemic episodes in patients with type 2 diabetes receiving saxagliptin or glipizide add-on therapy to metformin. This was a post hoc analysis of an international, randomized, parallel-group, double-blind, active-controlled, phase 3 trial. The 52-week trial and 52-week extension were conducted from December 2007 to August 2010. Patients aged ≥18 years with glycated hemoglobin (HbA1c) >6.5% to 10.0% receiving stable metformin doses (≥1500 mg/d) were randomized 1:1 to add-on therapy with saxagliptin 5 mg/d or glipizide 5 to 20 mg/d (titrated to optimal effect or highest tolerable dose during the initial 18 weeks). Hypoglycemic episodes were recorded in patient diaries. Confirmed hypoglycemic events were defined as fingerstick glucose ≤50 mg/dL (≤2.8 mmol/L) with associated symptoms. Of 858 patients randomized, 428 received saxagliptin + metformin, and 430 received glipizide + metformin. Saxagliptin was noninferior to glipizide in lowering HbA1c. Hypoglycemia with saxagliptin + metformin and glipizide + metformin was reported by 15 (24 events) and 165 (896 events) patients, respectively, through week 104. The mean (SD) number of hypoglycemic events per patient reporting hypoglycemia was lower with saxagliptin + metformin versus glipizide + metformin through weeks 52 (1.5 [SD 0.88] vs 4.8 [SD 4.9], respectively) and 104 (1.6 [SD 0.99] vs 5.4 [SD 5.8]). Most patients receiving glipizide + metformin with hypoglycemia had multiple events (124/165 patients [75%]). Confirmed hypoglycemia, major events, and severe events occurred only with glipizide + metformin. Time to first hypoglycemic event was shorter with glipizide versus saxagliptin. Limitations of this analysis include its post hoc nature, a high rate of study discontinuation, and exclusion of patients with serious comorbidities and complications. Saxagliptin + metformin was associated with fewer patients reporting hypoglycemia

  10. An assessment of lifestyle modification versus medical treatment with clomiphene citrate, metformin, and clomiphene citrate-metformin in patients with polycystic ovary syndrome.

    PubMed

    Karimzadeh, Mohammad Ali; Javedani, Mojgan

    2010-06-01

    To compare the effect of clomiphene citrate, metformin, and lifestyle modification on treatment of patients with polycystic ovary syndrome (PCOS). Prospective randomized double-blind study. University-based infertility clinic and research center. Three hundred forty-three overweight infertile women with PCOS. The participating women were assigned to four groups: clomiphene (n = 90), metformin (n = 90), clomiphene + metformin (n = 88), and lifestyle modification (n = 75). The patients in each group received standardized dietary and exercise advice from a dietitian. The primary outcome variables were change in menstrual cycle, waist circumference measurements, endocrine parameters, and lipid profile. The main secondary outcome variable was clinical pregnancy rate. The clinical pregnancy rate was 12.2% in clomiphene group, 14.4% in metformin group, 14.8% in clomiphene + metformin group, and 20% in lifestyle modification group. Lifestyle modification group achieved a significant reduction in waist circumference, total androgen, and lipid profile. Lifestyle modification improves the lipid profile in PCOS patients. Therefore, lifestyle modification may be used as the first line of ovulation induction in PCOS patients. Copyright (c) 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  11. Comparative Study of the Antioxidant Effects of Metformin, Glibenclamide, and Repaglinide in Alloxan-Induced Diabetic Rats

    PubMed Central

    Chukwunonso Obi, Bonaventure; Chinwuba Okoye, Theophine; Okpashi, Victor Eshu; Nonye Igwe, Christiana; Olisah Alumanah, Edwin

    2016-01-01

    Diabetes mellitus is one of the serious global health problems affecting a significant proportion of both developed and developing countries. Overproduction of free radicals and oxidative stress has been associated with the development of diabetic complications. In the present study, the antioxidant effects of metformin (MET), glibenclamide (GLI), and repaglinide (REP) were evaluated in alloxan-induced diabetic rats. The findings from this study may possibly help in understanding the efficacy of these standard drugs in managing the complications arising from diabetes mellitus (DM). Alloxan (130 mg/kg BW) was administered as a single dose to induce diabetes. Four (4) groups of rats (n = 6) were used; group 1 served as diabetic control while groups 2, 3, and 4 were the diabetic test groups that received MET (25 mg/kg), GLI (2.5 mg/kg), and REP (0.5 mg/kg), respectively. The result of the study showed significant (p < 0.05) improvement in the altered antioxidant enzymes (SOD, CAT) and GSH concentration in diabetic treated rats compared with the diabetic control group. MET and REP produced significant effect on the MDA concentration while GLI showed insignificant reduction in the MDA concentration compared with the diabetic control. Findings from this study suggest that the administration of MET, GLI, and REP exerts significant antioxidant effects in alloxan-induced diabetic rats, thus contributing to the protective effect against oxidative stress-induced damage during diabetic complications. PMID:26824037

  12. Comparative Study of the Antioxidant Effects of Metformin, Glibenclamide, and Repaglinide in Alloxan-Induced Diabetic Rats.

    PubMed

    Chukwunonso Obi, Bonaventure; Chinwuba Okoye, Theophine; Okpashi, Victor Eshu; Nonye Igwe, Christiana; Olisah Alumanah, Edwin

    2016-01-01

    Diabetes mellitus is one of the serious global health problems affecting a significant proportion of both developed and developing countries. Overproduction of free radicals and oxidative stress has been associated with the development of diabetic complications. In the present study, the antioxidant effects of metformin (MET), glibenclamide (GLI), and repaglinide (REP) were evaluated in alloxan-induced diabetic rats. The findings from this study may possibly help in understanding the efficacy of these standard drugs in managing the complications arising from diabetes mellitus (DM). Alloxan (130 mg/kg BW) was administered as a single dose to induce diabetes. Four (4) groups of rats (n = 6) were used; group 1 served as diabetic control while groups 2, 3, and 4 were the diabetic test groups that received MET (25 mg/kg), GLI (2.5 mg/kg), and REP (0.5 mg/kg), respectively. The result of the study showed significant (p < 0.05) improvement in the altered antioxidant enzymes (SOD, CAT) and GSH concentration in diabetic treated rats compared with the diabetic control group. MET and REP produced significant effect on the MDA concentration while GLI showed insignificant reduction in the MDA concentration compared with the diabetic control. Findings from this study suggest that the administration of MET, GLI, and REP exerts significant antioxidant effects in alloxan-induced diabetic rats, thus contributing to the protective effect against oxidative stress-induced damage during diabetic complications.

  13. Comparison of repaglinide and metformin versus metformin alone for type 2 diabetes: a meta-analysis of randomized controlled trials.

    PubMed

    Yin, Jinjin; Deng, Houliang; Qin, Shumin; Tang, Waijiao; Zeng, Lu; Zhou, Benjie

    2014-09-01

    We conducted a meta-analysis to compare the efficacy and safety of repaglinide plus metformin with metformin alone on type 2 diabetes. Twenty-two studies were included in this meta-analysis. Results showed combination therapy was safe and could gain better outcomes in glycemic control. Well-designed studies are required to confirm this conclusion. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  14. Cardioprotective effects of 70-kDa heat shock protein in transgenic mice.

    PubMed

    Radford, N B; Fina, M; Benjamin, I J; Moreadith, R W; Graves, K H; Zhao, P; Gavva, S; Wiethoff, A; Sherry, A D; Malloy, C R; Williams, R S

    1996-03-19

    Heat shock proteins are proposed to limit injury resulting from diverse environmental stresses, but direct metabolic evidence for such a cytoprotective function in vertebrates has been largely limited to studies of cultured cells. We generated lines of transgenic mice to express human 70-kDa heat shock protein constitutively in the myocardium. Hearts isolated from these animals demonstrated enhanced recovery of high energy phosphate stores and correction of metabolic acidosis following brief periods of global ischemia sufficient to induce sustained abnormalities of these variables in hearts from nontransgenic littermates. These data demonstrate a direct cardioprotective effect of 70-kDa heat shock protein to enhance postischemic recovery of the intact heart.

  15. Prescribing Patterns of Metformin in High-risk Patients with Prediabetes.

    PubMed

    Stirling, Daniel L; Onor, Ifeanyi; Sarpong, Daniel; Rapp, Kristi Isaac; Crawford, Lori D

    2015-01-01

    The primary objective of this study is to examine the rates of metformin prescribing in patients with prediabetes who are either less than 60 years of age, have a BMI greater than 35 kg/m2, or women with a history of gestational diabetes mellitus (GDM). Secondary objectives include: 1) examination of the time from diagnosis of prediabetes to the initiation of metformin and 2) if metformin initiation status and length of time correlates to the patient having any other additional diabetes mellitus (DM) risk factors. This was a single center, retrospective cohort study. This study included all patients with prediabetes, defined as having hemoglobin A1c (HbA1c) of 39 through 46 mmol/mol (5.7-6.4 percent), who were patients at the Interim LSU Hospital and Clinics from January 2012-September 2013. There were a total of 13 patients out of 160 patients in the study population who were prescribed metformin for an overall metformin initiation rate of 8.1 percent. The metformin initiation rate for the three individual groups; history of GDM, aged less than 60 years, and BMI greater than 35 kg/m2 were 0 percent, 9.0 percent, and 17.5 percent respectively. Metformin initiation rates in patients with prediabetes are not in accordance with current recommendations, and provider education is necessary to increase rates to delay or prevent the progression of prediabetes to type 2 Diabetes Mellitus.

  16. Metformin and ascorbic acid combination therapy ameliorates type 2 diabetes mellitus and comorbid depression in rats.

    PubMed

    Shivavedi, Naveen; Kumar, Mukesh; Tej, Gullanki Naga Venkata Charan; Nayak, Prasanta Kumar

    2017-11-01

    Diabetes mellitus and depression are the common comorbid disorders affecting humans worldwide. There is an unmet need to develop therapeutic strategies to treat both diabetes mellitus and comorbid depression. The present study evaluated the effectiveness of metformin and ascorbic acid against type 2 diabetes mellitus and comorbid depression in rats. Four groups of diabetic rats were orally administered with vehicle (1mL/kg), metformin (25mg/kg), ascorbic acid (25mg/kg), or combination of metformin (25mg/kg) and ascorbic acid (25mg/kg) for 11 consecutive days. Diabetes was induced by single-dose administration of streptozotocin (65mg/kg, i.p.) with nicotinamide (120mg/kg, i.p.). Comorbid depression was induced by five inescapable foot-shocks (2mA, 2ms duration) at 10s intervals on days 1, 5, 7, and 10. One group of healthy rats received only vehicles to serve as nondiabetic control group. On day 11, animals were sacrificed, and blood and brain samples were collected from each rat following forced swim test. Plasma glucose, insulin, and corticosterone levels were estimated in plasma. The levels of monoamines, proinflammatory cytokines, and oxidative stress were measured in prefrontal cortex. The combination therapy significantly reduced immobility period, glucose, and corticosterone levels relative to diabetes with comorbid depression group. Furthermore, the combination therapy increased the levels of insulin and monoamines, and caused a significant reductions in oxidative stress and proinflammatory cytokines. In conclusion, the present study revealed that metformin and ascorbic acid combination therapy could be a potential strategy to treat type 2 diabetes mellitus and comorbid depression. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Metformin effects on biochemical recurrence and metabolic signaling in the prostate.

    PubMed

    Winters, Brian; Plymate, Stephen; Zeliadt, Steven B; Holt, Sarah; Zhang, Xiaotun; Hu, Elaine; Lin, Daniel W; Morrissey, Colm; Wooldridge, Bryan; Gore, John L; Porter, Michael P; Wright, Jonathan L

    2015-11-01

    Metformin has received considerable attention as a potential anti-cancer agent. Animal and in-vitro prostate cancer (PCa) models have demonstrated decreased tumor growth with metformin, however the precise mechanisms are unknown. We examine the effects of metformin on PCa biochemical recurrence (BCR) in a large clinical database followed by evaluating metabolic signaling changes in a cohort of men undergoing prostate needle biopsy (PNB). Men treated for localized PCa were identified in a comprehensive clinical database between 2001 and 2010. Cox regression was performed to determine association with BCR relative to metformin use. We next identified a separate case-control cohort of men undergoing prostate needle biopsy (PNB) stratified by metformin use. Differences in mean IHC scores were compared with linear regression for phosphorylated IR, IGF-IR, AKT, and AMPK. One thousand seven hundred and thirty four men were evaluated for BCR with mean follow up of 41 months (range 1-121 months). "Ever" metformin use was not associated with BCR (HR 1.12, 0.77-1.65), however men reporting both pre/post-treatment metformin use had a 45% reduction in BCR (HR = 0.55 (0.31-0.96)). For the tissue-based study, 48 metformin users and 42 controls underwent PNB. Significantly greater staining in phosphorylated nuclear (p-IR, p-AKT) and cytoplasmic (p-IR, p-IGF-1R) insulin signaling proteins were seen in patients with PCa detected compared to those with negative PNB (P-values all <0.006). When stratified by metformin use, IGF-1R remained significantly elevated (P = 0.01) in men with PCa detected whereas p-AMPK (P = 0.05) was elevated only in those without PCa. Metformin use is associated with reduced BCR after treatment of localized PCa when considering pre-diagnostic and cumulative dosing. In men with cancer detected on PNB, insulin signaling markers were significantly elevated compared to negative PNB patients. The finding of IGF-1R elevation in positive PNBs versus p

  18. Metformin affects the features of a human hepatocellular cell line (HepG2) by regulating macrophage polarization in a co-culture microenviroment.

    PubMed

    Chen, Miaojiao; Zhang, Jingjing; Hu, Fang; Liu, Shiping; Zhou, Zhiguang

    2015-11-01

    Accumulating evidence suggests an association between diabetes and cancer. Inflammation is a key event that underlies the pathological processes of the two diseases. Metformin displays anti-cancer effects, but the mechanism is not completely clear. This study investigated whether metformin regulated the microenvironment of macrophage polarization to affect the characteristics of HepG2 cells and the possible role of the Notch-signalling pathway. RAW264.7 macrophages were cultured alone or co-cultured with HepG2 cells and treated with metformin. We analysed classical (M1) and alternative (M2) gene expression in RAW264.7 cells using quantitative real-time polymerase chain reaction. Changes in mRNA and protein expressions of Notch signalling in both cell types were also detected using quantitative real-time polymerase chain reaction and Western-blotting analyses. The proliferation, apoptosis and migration of HepG2 cells were detected using Cell Titer 96 AQueous One Solution Cell Proliferation Assay (MTS) (Promega Corporation, Fitchburg, WI, USA), Annexin V-FITC/PI (7SeaPharmTech, Shanghai, China) and the cell scratch assay, respectively. Metformin induced single-cultured RAW264.7 macrophages with an M2 phenotype but attenuated the M2 macrophage differentiation and inhibited monocyte chemoattractant protein-1 (MCP-1) secretion in a co-culture system. The co-cultured group of metformin pretreatment activated Notch signalling in macrophages but repressed it inHepG2 cells. Co-culture also promoted the proliferation and migration of HepG2 cells. However, along with the enhanced apoptosis, the proliferation and the migration of HepG2 cells were remarkably inhibited in another co-culture system with metformin pretreatment. Metformin can skew RAW264.7 macrophages toward different phenotypes according to changes in the microenvironment, which may affect the inflammatory conditions mediated by macrophages, induce apoptosis and inhibit the proliferation and migration of HepG2

  19. Spectroscopic and molecular modelling studies of binding mechanism of metformin with bovine serum albumin

    NASA Astrophysics Data System (ADS)

    Sharma, Deepti; Ojha, Himanshu; Pathak, Mallika; Singh, Bhawna; Sharma, Navneet; Singh, Anju; Kakkar, Rita; Sharma, Rakesh K.

    2016-08-01

    Metformin is a biguanide class of drug used for the treatment of diabetes mellitus. It is well known that serum protein-ligand binding interaction significantly influence the biodistribution of a drug. Current study was performed to characterize the binding mechanism of metformin with serum albumin. The binding interaction of the metformin with bovine serum albumin (BSA) was examined using UV-Vis absorption spectroscopy, fluorescence, circular dichroism, density functional theory and molecular docking studies. Absorption spectra and fluorescence emission spectra pointed out the weak binding of metformin with BSA as was apparent from the slight change in absorbance and fluorescence intensity of BSA in presence of metformin. Circular dichroism study implied the significant change in the conformation of BSA upon binding with metformin. Density functional theory calculations showed that metformin has non-planar geometry and has two energy states. The docking studies evidently signified that metformin could bind significantly to the three binding sites in BSA via hydrophobic, hydrogen bonding and electrostatic interactions. The data suggested the existence of non-covalent specific binding interaction in the complexation of metformin with BSA. The present study will certainly contribute to the development of metformin as a therapeutic molecule.

  20. Comparison of acarbose and metformin therapy in newly diagnosed type 2 diabetic patients with overweight and/or obesity.

    PubMed

    Sun, Weiping; Zeng, Chunping; Liao, Lizhen; Chen, Juan; Wang, Ying

    2016-08-01

    To compare the efficacy of acarbose and metformin in overweight and/or obese patients with newly diagnosed type 2 diabetes mellitus (T2DM). A total of 108 drug-naïve patients with newly diagnosed T2DM, whose hemoglobin A1c (HbA1c) was between 7% and 10% and body mass index was greater than 24 kg/m(2), were enrolled in the First People's Hospital and Municipal Central Hospital of Xiangtan City, Xiangtan, China, from 1 February 2010 to 1 August 2011. Patients were randomly assigned to acarbose (100 mg three times a day) and metformin (1.5 g/day) groups for a predictive follow-up period of 24 weeks. Plasma glucose, insulin, and glucagons at 0, 0.5, and 2 hours after a standardized meal, and HbA1c were measured at baseline and 24 weeks. Baseline characteristics of the acarbose and metformin groups were similar. Glucose control improved significantly in both groups at 24 weeks. The percentage of patients achieving HbA1C <6.5% was comparable for acarbose and metformin therapy at 24 weeks. Body weight reduction from baseline to 24 weeks was 3.3 kg in the acarbose group and 2.7 kg in the metformin group, whereas the change in HbA1c and body weight was similar in both groups. The early-phase insulin secretion index improved only in the acarbose group at 24 weeks. After 24 weeks of therapy, fasting glucagon and 0.5 hour postprandial glucagon levels decreased markedly in the acarbose group compared to the metformin group. Twenty-four weeks of therapy with acarbose and metformin induced similar reductions in HbA1c and body weight, but acarbose showed superior efficacy in improving islet α-cell function compared with metformin in overweight/obese patients with newly diagnosed T2DM. However, more large-sample, multicenter, randomized controlled trials are needed to evaluate the efficacy, safety, cost-effectiveness, and glycemic variability of the two drugs.

  1. Variants in Pharmacokinetic Transporters and Glycemic Response to Metformin: A Metgen Meta‐Analysis

    PubMed Central

    Dujic, T; Zhou, K; Yee, SW; van Leeuwen, N; de Keyser, CE; Javorský, M; Goswami, S; Zaharenko, L; Hougaard Christensen, MM; Out, M; Tavendale, R; Kubo, M; Hedderson, MM; van der Heijden, AA; Klimčáková, L; Pirags, V; Kooy, A; Brøsen, K; Klovins, J; Semiz, S; Tkáč, I; Stricker, BH; Palmer, CNA; 't Hart, LM; Giacomini, KM

    2017-01-01

    Therapeutic response to metformin, a first‐line drug for type 2 diabetes (T2D), is highly variable, in part likely due to genetic factors. To date, metformin pharmacogenetic studies have mainly focused on the impact of variants in metformin transporter genes, with inconsistent results. To clarify the significance of these variants in glycemic response to metformin in T2D, we performed a large‐scale meta‐analysis across the cohorts of the Metformin Genetics Consortium (MetGen). Nine candidate polymorphisms in five transporter genes (organic cation transporter [OCT]1, OCT2, multidrug and toxin extrusion transporter [MATE]1, MATE2‐K, and OCTN1) were analyzed in up to 7,968 individuals. None of the variants showed a significant effect on metformin response in the primary analysis, or in the exploratory secondary analyses, when patients were stratified according to possible confounding genotypes or prescribed a daily dose of metformin. Our results suggest that candidate transporter gene variants have little contribution to variability in glycemic response to metformin in T2D. PMID:27859023

  2. Comparison of neonatal outcomes in women with gestational diabetes with moderate hyperglycaemia on metformin or glibenclamide--a randomised controlled trial.

    PubMed

    George, Anne; Mathews, Jiji E; Sam, Dibu; Beck, Manisha; Benjamin, Santosh J; Abraham, Anuja; Antonisamy, Balevendra; Jana, Atanu K; Thomas, Nihal

    2015-02-01

    Two oral hypoglycaemic agents, metformin and glibenclamide, have been compared with insulin in separate large randomised controlled trials and have been found to be as effective as insulin in gestational diabetes. However, very few trials have compared metformin with glibenclamide. Of 159 South Indian women with fasting glucose ≥5.5 mmol/l and ≤7.2 mmol/l and/or 2-h post-prandial value ≥6.7 mmol/l and ≤13.9 mmol/l after medical nutritional therapy consented to be randomised to receive either glibenclamide or metformin. 80 women received glibenclamide and 79 received metformin. Neonatal outcomes were assessed by neonatologists who were unaware that the mother was part of a study and were recorded by assessors blinded to the medication the mother was given. The primary outcome was a composite of neonatal outcomes namely macrosomia, hypoglycaemia, need for phototherapy, respiratory distress, stillbirth or neonatal death and birth trauma. Secondary outcomes were birthweight, maternal glycaemic control, pregnancy induced hypertension, preterm birth, need for induction of labour, mode of delivery and complications of delivery. Baseline characteristics were similar but for the higher fasting triglyceride levels in women on metformin. The primary outcome was seen in 35% of the glibenclamide group and 18.9% of the metformin group [95% CI 16.1 (2.5, 29.7); P = 0.02]. The difference in outcome related to a higher rate of neonatal hypoglycaemia in the glibenclamide group (12.5%) versus none in the metformin group [95% CI 12.5(5.3, 19.7); P = 0.001]. Secondary outcomes in both groups were similar. In a south Indian population with gestational diabetes, metformin was associated with better neonatal outcomes than glibenclamide. © 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.

  3. Retrospective Evaluation of Metformin and/or Metformin Plus a New Polysaccharide Complex in Treating Severe Hyperinsulinism and Insulin Resistance in Obese Children and Adolescents with Metabolic Syndrome

    PubMed Central

    Stagi, Stefano; Ricci, Franco; Bianconi, Martina; Sammarco, Maria Amina; Municchi, Giovanna; Toni, Sonia; Lenzi, Lorenzo; Verrotti, Alberto; de Martino, Maurizio

    2017-01-01

    Background: Pharmacological treatment of obesity and glucose-insulin metabolism disorders in children may be more difficult than in adults. Thus, we evaluate the effects of metformin in comparison with metformin plus a polysaccharide complex (Policaptil Gel Retard®, PGR) on body weight and metabolic parameters in obese children and adolescents with metabolic syndrome (MetS). Patients and methods: We retrospectively collected 129 children and adolescents (67 girls, 62 boys; median age 12.6 years) treated for a minimum of two years with metformin and low glycemic index (LGI) diet. Of these, 71 patients were treated with metformin plus PGR after at least 12 months of metformin alone. To minimize the confounding effect of the LGI on auxological and metabolic parameters, the patients were compared with age-, sex-, and BMI-matched control group with obesity and MetS (51 subjects; 24 males, 27 females) treated only with a LGI diet. Assessments included lipids, glucose and insulin (fasting and after oral glucose tolerance test) concentrations. The Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), Matsuda, insulinogenic and disposition indices were calculated. Results: Metformin treatment led to a significant reduction in BMI SDS (p < 0.0001), with a significant difference in ΔBMI SDS between patients and controls (p < 0.0001). Moreover, metformin treated patients showed a reduction in HOMA-IR (p < 0.0001), HbA1c levels (p < 0.0001) and a significant increase in Matsuda index (p < 0.0001) in respect to the reduction discovered in controls (p < 0.05). Moreover, in contrast to the group treated with metformin alone and controls, patients treated with metformin plus PGR showed a further reduction in BMI SDS (p < 0.0001), HOMA-IR (p < 0.0001), HbA1c (p < 0.0001), total, HDL and LDL cholesterol (p < 0.0001), as well as an increase in Matsuda (p < 0.0001), disposition (p < 0.005) and insulinogenic (respectively, p < 0.05 and p < 0.0001) indices. Conclusions

  4. Characterization and cardioprotective activity of anthocyanins from Nitraria tangutorum Bobr. by-products.

    PubMed

    Zhang, Ming; Ma, Jianbin; Bi, Hongtao; Song, Jiayin; Yang, Hongxia; Xia, Zhenghua; Du, Yuzhi; Gao, Tingting; Wei, Lixin

    2017-08-01

    The Nitraria tangutorum Bobr. fruit is an indigenous berry of the shrub belonging to the Zygophyllaceae family which grows at an altitude of over 3000 m in the Tibetan Plateau, and has been used as a native medicinal food for treating weakness of the spleen, stomach syndrome, dyspepsia, neurasthenia, dizziness, etc. for thousands of years. Nowadays, N. tangutorum industrial juice by-products generated from health food production can be a potential low cost source of some unique bioactive ingredients. In a prior study, we established a simultaneous microwave/ultrasonic assisted enzymatic extraction method for extracting antioxidant ingredients from the industrial by-products of N. tangutorum juice. In this study, these ingredients were selectively fractionated by cation-exchange resin chromatography to obtain an anthocyanin fraction namely NJBAE. NJBAE was found to be composed of 16 anthocyanins derived from six anthocyanidins by HPLC-ESI-MS, and has an appreciable cardioprotective effect on doxorubicin-induced injured H9c2 cardiomyocytes. The cardioprotective mechanism research showed that NJBAE could directly scavenge ROS, restrict further generation of ROS, promote the activity of key antioxidase, enhance glutathione redox cycling, then affect the apoptotic signaling changes in a positive way, and finally mediate caspase-dependent cell death pathways. Therefore, NJBAE has great potential to be used for preventing and treating cardiovascular disease in the food, pharmaceutical and other emerging industries.

  5. Toward Repurposing Metformin as a Precision Anti-Cancer Therapy Using Structural Systems Pharmacology

    PubMed Central

    Hart, Thomas; Dider, Shihab; Han, Weiwei; Xu, Hua; Zhao, Zhongming; Xie, Lei

    2016-01-01

    Metformin, a drug prescribed to treat type-2 diabetes, exhibits anti-cancer effects in a portion of patients, but the direct molecular and genetic interactions leading to this pleiotropic effect have not yet been fully explored. To repurpose metformin as a precision anti-cancer therapy, we have developed a novel structural systems pharmacology approach to elucidate metformin’s molecular basis and genetic biomarkers of action. We integrated structural proteome-scale drug target identification with network biology analysis by combining structural genomic, functional genomic, and interactomic data. Through searching the human structural proteome, we identified twenty putative metformin binding targets and their interaction models. We experimentally verified the interactions between metformin and our top-ranked kinase targets. Notably, kinases, particularly SGK1 and EGFR were identified as key molecular targets of metformin. Subsequently, we linked these putative binding targets to genes that do not directly bind to metformin but whose expressions are altered by metformin through protein-protein interactions, and identified network biomarkers of phenotypic response of metformin. The molecular targets and the key nodes in genetic networks are largely consistent with the existing experimental evidence. Their interactions can be affected by the observed cancer mutations. This study will shed new light into repurposing metformin for safe, effective, personalized therapies. PMID:26841718

  6. Fed and Fasted Single-dose Assessment of Bioequivalence of Dapagliflozin and Metformin Extended-release Fixed-dose Combination Tablets Relative to Single-component Dapagliflozin and Metformin Extended-release Tablets in Healthy Subjects.

    PubMed

    Boulton, David W; Chang, Ming; Griffen, Steven C; Kitaura, Catia; Lubin, Susan; Pollack, Allyson; LaCreta, Frank

    2016-01-01

    In patients with type 2 diabetes mellitus, fixed-dose combinations (FDCs) of antihyperglycemic medications may provide complementary efficacy while reducing tablet burden and improving compliance. The aim of this study was to assess the bioequivalence and tolerability of 2 FDCs of dapagliflozin and metformin extended-release (XR) versus their individual component (IC) tablets. An open-label, balanced, randomized, 2-way crossover, 4-arm study was conducted in 129 healthy Brazilian subjects (aged 18-55 years). Two oral doses of the FDCs (5 mg dapagliflozin and 500 mg metformin XR, and 10 mg dapagliflozin and 1000 mg metformin XR) were evaluated in fed and fasted states. Under fed and fasted conditions the 5 mg dapagliflozin and 500 mg metformin XR FDC showed bioequivalence to its ICs. The 10 mg dapagliflozin and 1000 mg metformin XR FDC was bioequivalent to its ICs in fed subjects. Although AUC for the 10 mg dapagliflozin and 1000 mg metformin XR FDC was bioequivalent in fasted subjects, the Cmax for metformin was not bioequivalent to its ICs in fasted subjects (upper 90% CI was 127.5%, and thus outside the 80%-125% bioequivalence interval). The small increase in the fasted state is not considered clinically meaningful due to the small magnitude of the difference (9.2%), the lack of metformin Cmax being associated with efficacy or tolerability concerns, and the fasted state not being the recommended state for dosing of metformin XR. The safety profile and tolerability of the FDCs were similar to those of their ICs and no deaths or serious adverse events were reported. Both FDCs of dapagliflozin and metformin XR were bioequivalent to their ICs in fed and fasted subjects, except for the metformin Cmax from the 10 mg dapagliflozin and 1000 mg metformin XR FDC in fasted subjects. These data support the use of a dapagliflozin and metformin XR FDC in patients with type 2 diabetes mellitus. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

  7. Histopathological study of the combination of metformin and garlic juice for the attenuation of gentamicin renal toxicity in rats

    PubMed Central

    Baradaran, Azar; Rafieian-kopaei, Mahmoud

    2013-01-01

    Introduction: Tubular toxicity is one of the most important side effects of aminoglycoside antibiotics, especially gentamicin.Objectives: We histopathologically studied the effect of garlic extract and metformin co-administration, in attenuation of genetamicin induced tubular toxicity in rats. Materials and Methods: In this study seventy rats were divided into seven equal groups and except group 1 (control) were injected 100 mg/kg/day gentamicin (GM) intraperitoneally (i.p.) for 10 days. Other than GM, group III received 20 mg/kg garlic (i.p.), group IV metformin (MF) (100 mg/kg, orally), group V a combination of MF with garlic juice (100 and 20 mg/kg/day, respectively) and group VI a combination of MF and garlic juice (50 and 10 mg/kg/day, respectively) for following 10 days. Group VII received a combination of MF and garlic juice (100 and 20 mg/kg, respectively) along with GM. Animals were sacrificed on the 20th day of the experiment and the kidneys were removed for histological examinations. Results: GM induced nephrotoxicity and garlic or MF alone and a combination of both with high doses (not low doses) significantly abolished the kidney tubular injury induced by GM. In addition, co-administration of GM, MF and garlic (group 7) prevented the GM- induced tissue damage more than the groups in which MF and garlic were injected 10 days post GM administration. Conclusion: Garlic extract and Metformin, alone or in a combination, might be safely used to ameliorate GM induced tubular toxicity. PMID:25340116

  8. Prenatal androgenization of female mice programs an increase in firing activity of gonadotropin-releasing hormone (GnRH) neurons that is reversed by metformin treatment in adulthood.

    PubMed

    Roland, Alison V; Moenter, Suzanne M

    2011-02-01

    Prenatal androgenization (PNA) of female mice with dihydrotestosterone programs reproductive dysfunction in adulthood, characterized by elevated luteinizing hormone levels, irregular estrous cycles, and central abnormalities. Here, we evaluated activity of GnRH neurons from PNA mice and the effects of in vivo treatment with metformin, an activator of AMP-activated protein kinase (AMPK) that is commonly used to treat the fertility disorder polycystic ovary syndrome. Estrous cycles were monitored in PNA and control mice before and after metformin administration. Before metformin, cycles were longer in PNA mice and percent time in estrus lower; metformin normalized cycles in PNA mice. Extracellular recordings were used to monitor GnRH neuron firing activity in brain slices from diestrous mice. Firing rate was higher and quiescence lower in GnRH neurons from PNA mice, demonstrating increased GnRH neuron activity. Metformin treatment of PNA mice restored firing activity and LH to control levels. To assess whether AMPK activation contributed to the metformin-induced reduction in GnRH neuron activity, the AMPK antagonist compound C was acutely applied to cells. Compound C stimulated cells from metformin-treated, but not untreated, mice, suggesting that AMPK was activated in GnRH neurons, or afferent neurons, in the former group. GnRH neurons from metformin-treated mice also showed a reduced inhibitory response to low glucose. These studies indicate that PNA causes enhanced firing activity of GnRH neurons and elevated LH that are reversible by metformin, raising the possibility that central AMPK activation by metformin may play a role in its restoration of reproductive cycles in polycystic ovary syndrome.

  9. Metformin increases pressure pain threshold in lean women with polycystic ovary syndrome.

    PubMed

    Kiałka, Marta; Milewicz, Tomasz; Sztefko, Krystyna; Rogatko, Iwona; Majewska, Renata

    2016-01-01

    Despite the strong preclinical rationale, there are only very few data considering the utility of metformin as a potential pain therapeutic in humans. The aim of this study was to determine the association between metformin therapy and pressure pain threshold (PPT) in lean women with polycystic ovary syndrome (PCOS). We hypothesized that metformin therapy in lean PCOS women increases PPT. Twenty-seven lean PCOS women with free androgen index phenotype >5 and 18 lean healthy controls were enrolled in the study. Fifteen of the PCOS women were randomly assigned to be treated with metformin 1,500 mg daily for 6 months. PPT and plasma β-endorphin levels were measured in all women at the beginning of the study and after 6 months of observation. We observed an increase in PPT values measured on deltoid and trapezius muscle in the PCOS with metformin group after 6 months of metformin administration (4.81±0.88 kg/cm(2), P<0.001 on deltoid muscle, and 5.71±1.16 kg/cm(2) on trapezius muscle). We did not observe any significant changes in PPT values in the PCOS without treatment group and in controls. We did not observe any significant changes in serum β-endorphin levels in any studied groups during the 6-month observation. We conclude that metformin therapy increases PPT in lean PCOS women, without affecting plasma β-endorphin concentration. Our results may suggest the potential role of metformin in pain therapy. We propose that larger, randomized studies on metformin impact on pain perception should be performed.

  10. A review of thiazolidinediones and metformin in the treatment of type 2 diabetes with focus on cardiovascular complications

    PubMed Central

    Behzad, Molavi; Negah, Rassouli; Suveer, Bagwe; Neda, Rasouli

    2007-01-01

    The rising incidence of obesity and insulin resistance to epidemic proportions has closely paralleled the surge in the prevalence of diabetes and outpaced therapeutic advances in diabetes prevention and treatment. Current evidence points to obesity induced oxidative stress and chronic inflammation as the common denominators in the evolution of insulin resistance and diabetes. Of all the hypoglycemic agents in the pharmacological arsenal against diabetes, thiazolidinediones, in particular pioglitazone, as well as metformin appear to have additional effects in ameliorating oxidative stress and inflammation; rendering them attractive tools for prevention of insulin resistance and diabetes. In addition to their hypoglycemic and lipid modifying properties, pioglitazone and metformin have been shown to exert anti-oxidative and anti-inflammatory effects in vascular beds, potentially slowing the accelerated atherosclerosis in diabetes, which is the major cause of morbidity and mortality in the affected population. The combination of pioglitazone and metformin would thus appear to be an effective pharmacological intervention in prevention and treatment of diabetes. Finally, this review will address the currently available evidence on diabetic cardiomyopathy and the potential role of combination therapy with pioglitazone and metformin. PMID:18200815

  11. Secoisolariciresinol Diglucoside Induces Neovascularization Mediated Cardioprotection against Ischemic-Reperfusion Injury In Hypercholesterolemic Myocardium

    PubMed Central

    Penumathsa, Suresh Varma; Koneru, Srikanth; Zhan, Lijun; John, Saji; Menon, Venogopal P; Prasad, Kailash; Maulik, Nilanjana

    2009-01-01

    Background Hypercholesterolemia (HC) induced endothelial cell dysfunction and decreased endothelial nitric oxide formation result in impaired angiogenesis & subsequent cardiovascular disorders. Therapeutic angiogenesis is known to be a novel strategy for treatment of those patients with ischemic heart disease. We have shown that secoisolariciresinol diglucoside (SDG) is angiogenic & cardioprotective against myocardial ischemia. In the present study we examined the efficacy of SDG in a hypercholesterolemic myocardial infarction (MI) model. Methods The rats were maintained on a normal and high cholesterol diet (2%) for 8 weeks followed by oral administration of SDG (20mg/kg) for 2 weeks. The rats were divided into 4 groups (n=12 in each): Control (C); SDG control (SDG); HC; & HC + SDG (HSDG). Isolated hearts subjected to 30 min of global ischemia followed by 120 min of reperfusion were used to measure the cardiac functions, infarct size & examine the protein expression profile. After treatment MI was induced by ligating the left anterior descending artery. Echocardiographic parameters were examined 30 days after MI. Results Significant reduction in total cholesterol, LDL-cholesterol, triglycerides and increase in HDL-cholesterol levels were observed in HSDG as compared to HC. Decreased infarct size was observed in the HSDG group (43%) compared to the HC (54%). Increased phosphorylation of endothelial nitric oxide synthase (p-eNOS) (3.1 fold), Vascular endothelial growth factor (1.9 fold) and Heme Oxygenase-1(2.3 fold) was observed in the HSDG group as compared to the HC group. Significant improvement in left ventricular functions was also observed in the HSDG group as evidenced by increased ejection fraction (55 vs 45%), fractional shortening (28 vs 22%) & decreased left ventricular inner diameter in systole (8 vs 6 mm) in HSDG compared to HC. Moreover, MI model has shown increased capillary density (2531 vs 1901) and arteriolar density (2.6 vs 1.8) in SDG treated

  12. Secoisolariciresinol diglucoside induces neovascularization-mediated cardioprotection against ischemia-reperfusion injury in hypercholesterolemic myocardium.

    PubMed

    Penumathsa, Suresh Varma; Koneru, Srikanth; Zhan, Lijun; John, Saji; Menon, Venogopal P; Prasad, Kailash; Maulik, Nilanjana

    2008-01-01

    Hypercholesterolemia (HC) induced endothelial cell dysfunction and decreased endothelial nitric oxide formation results in impaired angiogenesis and subsequent cardiovascular disorders. Therapeutic angiogenesis is known to be a novel strategy for treatment of patients with ischemic heart disease. We have shown that secoisolariciresinol diglucoside (SDG) is angiogenic as well as cardioprotective against myocardial ischemia. In the present study, we examined the efficacy of SDG in a hypercholesterolemic myocardial infarction (MI) model. The rats were maintained on a normal and high cholesterol diet (2%) for 8 weeks followed by oral administration of SDG (20 mg/kg) for 2 weeks. The rats were divided into four groups (n=24 in each): Control (C); SDG control (SDG); HC; and HC+SDG (HSDG). Isolated hearts subjected to 30 min of global ischemia followed by 120 min of reperfusion were used to measure the cardiac functions, infarct size and to examine the protein expression profile. After treatment, MI was induced by ligating the left anterior descending artery. Echocardiographic parameters were examined 30 days after MI. Significant reduction in total cholesterol, LDL-cholesterol, triglycerides and an increase in HDL-cholesterol levels were observed in HSDG as compared to the HC. Decreased infarct size was observed in the HSDG group (43%) compared to the HC (54%). Increased phosphorylation of endothelial nitric oxide synthase (p-eNOS) (3.1-fold), vascular endothelial growth factor (1.9-fold) and heme oxygenase-1 (2.3-fold) was observed in the HSDG group as compared to the HC group. Significant improvement in left ventricular functions was also observed in the HSDG group as evidenced by increased ejection fraction (55% vs. 45%), fractional shortening (28% vs. 22%) and decreased left ventricular inner diameter in systole (8 vs. 6 mm) in HSDG compared to HC. Moreover, MI model has shown increased capillary density (2531 vs. 1901) and arteriolar density (2.6 vs. 1.8) in SDG

  13. The effects of metformin in type 1 diabetes mellitus.

    PubMed

    Beysel, Selvihan; Unsal, Ilknur Ozturk; Kizilgul, Muhammed; Caliskan, Mustafa; Ucan, Bekir; Cakal, Erman

    2018-01-16

    This retrospective study investigated the effect of adding metformin to pharmacologic insulin dosing in type 1 diabetics on insulin therapy 1 year after treatment compared with patients on insulin therapy alone. Twenty-nine adults with type 1 diabetes who had metformin added to their insulin therapy for 12 months were compared with 29 adults with type 1 diabetes who remained on insulin-alone therapy. Fifty-eight patients with C peptide negative-type 1 diabetics (26 females, mean age: 29.01 ± 7.03 years, BMI: 24.18 ± 3.16 kg/m2) were analyzed. Age, sex, body weight, insulin dose requirement, plasma glucose (PG), blood pressure (BP), and lipids did not differ between groups before treatment (p > 0.05). Metabolic syndrome (44.8 vs 41.4%, p > 0.05) did not differ between the metformin-insulin and insulin alone groups before treatment. Metabolic syndrome was more decreased in the metformin-insulin group than in the insulin alone group after treatment (-8.9 ± 1.3 vs. 2.5 ± 0.6%, p = 0.028). Insulin dose requirement was lower in the metformin-insulin group than in the insulin alone group (-0.03 vs. 0.11 IU/kg/d, p = 0.006). Fasting PG (-26.9 ± 54.2 vs. 0.7 ± 29.5 mg/dL, p = 0.022) and postprandial PG (-43.1 ± 61.8 mg/dL vs. -3.1 ± 40.1 mg/dL, p = 0.010) was more decreased in the metformin-insulin group than in the insulin alone group. Body weight, lipids, and HbA1c did not differ between the groups (p > 0.05). Metformin decreased glucose concentrations, reduced metabolic syndrome, as well as insulin dose requirement more than insulin therapy alone, 1 year after treatment. These results were independent of blood lipid improvement or weight loss, although on average weight remained decreased with metformin-insulin therapy, whereas the average weight increased with insulin therapy alone.

  14. The pathophysiological basis of the protective effects of metformin in heart failure.

    PubMed

    Dziubak, Aleksandra; Wójcicka, Grażyna

    2017-08-24

    Metformin, currently recommended as the drug of first choice in type 2 diabetes mellitus (T2DM), is one of the few antihiperglycemic drugs to reduce cardiovascular risk. Nonetheless, due to the risk of lactic acidosis during metformin therapy, its usage in patients with diabetes and heart failure (HF) is still a matter of debate. The aim of this review is to present data supporting the possibility of using metformin in the treatment of diabetic patients with concomitant heart failure. In the failing heart, metformin through the mechanism related to AMP-activated protein kinase (AMPK) activity, improves free fatty acids (FFA) and glucose metabolism, mitochondrial biogenesis, as well as nitric oxide (NO)-NO synthase pathway. Metformin can also inhibit the generation and accumulation of advanced glycation end products (AGEs) and thereby prevents the development of the adverse structural and functional changes in myocardium.In summary, experimental and clinical data indicate the ability of metformin to prevent the development of the structural and functional changes in myocardium, although further basic research and clinical studies assessing benefits and safety of metformin therapy in patients with HF are required.

  15. Fixed combination of repaglinide and metformin in the management of type 2 diabetes.

    PubMed

    Moses, Robert

    2009-06-24

    Treatment to target fasting blood glucose (FBG), postprandial glucose (PPG) and HbA(1c) are essential in the management of type 2 diabetes to reduce the risk of vascular complications. Early combination therapy with oral agents is increasingly being seen as important to achieve this. Repaglinide, a rapid-acting insulin secretagogue, targets PPG, and metformin, an insulin sensitizer, targets FBG. Because of their complementary modes of action these therapies are frequently given as combination therapy in separate tablets. To overcome the issues with adherence to multiple tablets, repaglinide and metformin are now available in a fixed-dose combination (FDC). Repaglinide/metformin FDC is bioequivalent to each tablet given separately, suggesting that the efficacy and safety profile is similar. There is no effect of food on repaglinide when in the FDC. Repaglinide/metformin FDC is as effective in reducing HbA(1c) and FBG whether given twice or three times daily, with a similar safety profile. Repaglinide/metformin FDC twice daily is as effective in reducing HbA(1c) and FBG as rosiglitazone/metformin FDC with a similar safety profile, but unlike the rosiglitazone/metformin FDC, repaglinide/metformin FDC improves the lipid profile. Repaglinide/metformin FDC represents a new option in the pursuit of achieving glucose targets and reducing vascular risk in type 2 diabetes, with the advantage of improving adherence.

  16. Fixed combination of repaglinide and metformin in the management of type 2 diabetes

    PubMed Central

    Moses, Robert

    2009-01-01

    Treatment to target fasting blood glucose (FBG), postprandial glucose (PPG) and HbA1c are essential in the management of type 2 diabetes to reduce the risk of vascular complications. Early combination therapy with oral agents is increasingly being seen as important to achieve this. Repaglinide, a rapid-acting insulin secretagogue, targets PPG, and metformin, an insulin sensitizer, targets FBG. Because of their complementary modes of action these therapies are frequently given as combination therapy in separate tablets. To overcome the issues with adherence to multiple tablets, repaglinide and metformin are now available in a fixed-dose combination (FDC). Repaglinide/metformin FDC is bioequivalent to each tablet given separately, suggesting that the efficacy and safety profile is similar. There is no effect of food on repaglinide when in the FDC. Repaglinide/metformin FDC is as effective in reducing HbA1c and FBG whether given twice or three times daily, with a similar safety profile. Repaglinide/metformin FDC twice daily is as effective in reducing HbA1c and FBG as rosiglitazone/metformin FDC with a similar safety profile, but unlike the rosiglitazone/metformin FDC, repaglinide/metformin FDC improves the lipid profile. Repaglinide/metformin FDC represents a new option in the pursuit of achieving glucose targets and reducing vascular risk in type 2 diabetes, with the advantage of improving adherence. PMID:21437123

  17. Clinical Outcomes of Continuation of Metformin Titration Instructions with Electronic Prescribing.

    PubMed

    Delate, Thomas; Rader, Nathan; Rawlings, Julia E; Smith, Karen; Herner, Sheryl J

    2015-06-01

    Anecdotal evidence suggests that metformin titration instructions are not being updated and refill requests are approved without modification of the titration instructions such that the titration instructions is continued for patients newly initiated on metformin. This was a retrospective cohort analysis of adult patients who received newly initiated metformin pharmacotherapy. Patients were followed from their initial metformin purchase through two subsequent metformin refill purchases. Outcomes, including the 3-year incidence rate of patients with at least one set of continued titration instructions and proportions of patients with at least one gastrointestinal adverse effect (AE) and those with an elevated glucose measurement at follow-up, were assessed during the time period between patients' second and third metformin purchases. Analyses were performed comparing the exposure (i.e., patients with continued instructions) group to the control (i.e., patients without continued instructions) group. The exposure group had a higher mean age and chronic disease score but lower metformin starting dose than the control group (all p < 0.05). The 3-year incidence rate of patients with at least one continuation of titration instructions was 60.3 % (95 % CI 58.3-62.3). Gastrointestinal AEs were rare with equivalent proportions of patients in each group experiencing an event (p > 0.05). Control patients (48.7 % of patients with a measurement) were more likely to have had poorly controlled glucose than exposure patients (35.7 % of patients with a measurement) (p < 0.001). A high rate of continuation of titration instructions for patients newly initiated on metformin was observed; however, such continuation did not negatively affect clinical outcomes.

  18. Acute metformin intoxication: 2012 experience of Emergency Departement of Lodi, Italy.

    PubMed

    Acquistapace, Giulia; Rossi, Marco; Garbi, Mara; Cosci, Pablo; Canetta, Ciro; Manelli, Anna; Ricevuti, Giovanni

    2014-10-01

    Background: Metformin is a biguanide antihyperglycemic agent that decreases insulin resistance. It is removed through renal mechanisms and its clearance is reduced in renal failure. Metformin ingestion should always be considered in the differential diagnosis of any patient with metabolic acidosis and increased lactate level. Hemodialysis and continuous veno-venous hemofiltration (CVVH) are both efficient methods to treat metformin intoxication and correct metabolic abnormalities. Patient 1: A 63-year-old man with type 2 diabetes mellitus presented to emergency department (ED) of Lodi (Italy) for dyspnea. He also reported having diarrhea for 10 days. Initial investigations revealed metabolic acidosis with hyperlactatemia and hypoglycemia (54 mg/dL), metformin concentration was 41 μg/mL (normal value <4 μg/mL). His hemodynamic condition became rapidly unstable and hypotension worsened despite CVVH being performed. Death occurred in 24 h. Patient 2: A 76-year-old man with type 2 diabetes mellitus presented to ED of Lodi for dyspnea. He referred a recent surgery amputation of the left foot's fifth phalanx for osteomyelitis, in levofloxacin therapy. Initial investigations revealed metabolic acidosis with hyperlactatemia and severe hypoglycemia (20 mg/dL). Two hemodialysis sessions were performed with complete normalization of the serum concentration of metformin. In our two cases the genesis of metformin intoxication was clear, powered by acute renal failure, but less obvious was the etiology of acute renal damage responsible for metformin accumulation. Damage due to renal hypoperfusion or the direct toxic effect of metformin should be considered. Additionally, for the second patient, we can also hypothesize that interstitial nephritis was exacerbated by levofloxacin.

  19. Hibiscus sabdariffa (Roselle) Polyphenol-rich Extract Averts Cardiac Functional and Structural Abnormalities in Type 1 Diabetic Rats.

    PubMed

    Mohammed Yusof, Nur Liyana; Zainalabidin, Satirah; Mohd Fauzi, Norsyahida; Budin, Siti Balkis

    2018-05-04

    Diabetes mellitus is often associated with cardiac functional and structural alteration, an initial event leading to cardiovascular complications. Hibiscus sabdariffa or roselle has been widely proven as an antioxidant and recently has incited research interest for its potential in treating cardiovascular disease. Therefore, this study aimed to determine the cardioprotective effects of H. sabdariffa (roselle) polyphenol-rich extract (HPE) in type-1 induced diabetic rats. Twenty-four male Sprague-Dawley rats were randomized into four groups (n=6/group): non-diabetic (NDM), diabetic alone (DM), diabetic supplemented with HPE (DM+HPE) and metformin (DM+MET). Type-1 diabetes was induced with streptozotocin (55 mg/kg/i.p). Rats were forced-fed HPE (100 mg/kg) and metformin (150 mg/kg) daily for eight weeks. Results showed that HPE supplementation improved hyperglycemia and dyslipidemia significantly (p<0.05) in DM+HPE compared to DM group. HPE supplementation attenuated cardiac oxidative damage in DM group, indicated by low malondialdehyde and advanced oxidation protein product. As for the antioxidant status, HPE significantly (p<0.05) increased glutathione level, as well as catalase and superoxide dismutase 1 and 2 activities. These findings correlate with cardiac function, whereby HPE supplementation improved left ventricle developed pressure, coronary flow, cardiac contractility and relaxation rate significantly (p<0.05). Histological analysis showed a marked decrease in cardiomyocyte hypertrophy and fibrosis in DM+HPE compared to DM group. Ultrastructural changes and impairment of mitochondria induced by diabetes were minimized by HPE supplementation. Collectively, these findings suggest that HPE is a potential cardioprotective agent in a diabetic setting through its hypoglycemic, anti-hyperlipidemia and antioxidant properties.

  20. Synergistic Benefit of Statin and Metformin in Gastrointestinal Malignancies.

    PubMed

    Nimako, George K; Wintrob, Zachary A P; Sulik, Dmitriy A; Donato, Jennifer L; Ceacareanu, Alice C

    2017-04-01

    To evaluate whether statin use influences gastrointestinal cancer prognosis in patients with diabetes mellitus (DM). We reviewed all DM patients diagnosed at Roswell Park Cancer Institute with emergent gastrointestinal malignancy (January 2003 to December 2010) (N = 222). Baseline demographic, clinical history, and cancer outcomes were documented. Overall survival (OS) and disease-free survival (DFS) comparisons across various treatment groups were assessed by Kaplan-Meier and Cox proportional hazards. Use of statin, alone or in combination, was associated with improved OS and DFS (hazard ratio [HR] = 0.65, P = .06; HR = 0.60, P < .02). We report similar OS and DFS advantage among users of mono- or combined metformin therapy (HR = 0.55, P < .01; HR = 0.63, P < .02). Concomitant use of metformin and statin provided a synergistic OS and DFS benefit (HR = 0.42, P < .01; HR = 0.44, P < .01). Despite significant tobacco and alcohol use history, patients with upper gastrointestinal cancers derived enhanced cancer outcomes from this combination (HR = 0.34, P < .01; HR = 0.43, P < .02), while receiving a statin without metformin or metformin without a statin did not provide significant cancer-related benefits. Use of statin and metformin provides a synergistic improvement in gastrointestinal malignancies outcomes.

  1. Pregnancy outcome in women with polycystic ovary syndrome comparing the effects of laparoscopic ovarian drilling and clomiphene citrate stimulation in women pre-treated with metformin: a retrospective study.

    PubMed

    Ott, Johannes; Kurz, Christine; Nouri, Kazem; Wirth, Stefan; Vytiska-Binstorfer, Elisabeth; Huber, Johannes C; Mayerhofer, Klaus

    2010-05-13

    Ovarian stimulation in women with polycystic ovary syndrome (PCOS) increases the risk for perinatal complications. Ovulation induction by laparoscopic ovarian drilling (LOD) might improve the overall pregnancy outcomes. The aim of our study was to assess the adverse events or effects on pregnancy of LOD and clomiphene citrate (CC) stimulation in patients who received metformin. Academic research institution. We retrospectively analyzed the courses of 40 spontaneous pregnancies after LOD for CC-resistance, 40 pregnancies after CC stimulation, and 40 pregnancies after metformin treatment alone. Patients in the LOD and the CC groups had been pre-treated with Metformin. Primary outcome parameters were: the rate of multiple pregnancies; the rate of early pregnancy losses/miscarriages; the development of gestational diabetes, pregnancy-induced hypertension, and preeclampsia/HELLP-syndrome; premature delivery; and birth weight. The rate of twin pregnancies did not differ between the CC group (12.5%), the LOD group (7.5%), and the metformin only group (2.5%, p=0.239). Seventeen women suffered an early miscarriage. There were no differences with regard to the rates of gestational diabetes, pregnancy-induced hypertension, preeclampsia, and preterm delivery. By analyzing all pregnancy complications together, the overall pregnancy complication rate was highest in the CC group (70.0%, 28/40), followed by the LOD group (45.0%, 18/40), and the metformin only group (47.5%, 19/40; p=0.047). CC, but not LOD, increases the complication rate in pregnant patients who received metformin.

  2. Bioequivalence of Dapagliflozin/Metformin Extended-release Fixed-combination Drug Product and Single-component Dapagliflozin and Metformin Extended-release Tablets in Healthy Russian Subjects.

    PubMed

    Khomitskaya, Yunona; Tikhonova, Nadezhda; Gudkov, Konstantin; Erofeeva, Svetlana; Holmes, Victoria; Dayton, Brian; Davies, Nigel; Boulton, David W; Tang, Weifeng

    2018-04-01

    Fixed-combination drug products (FCDPs) combining dapagliflozin and metformin extended release (XR) may provide patients with type 2 diabetes mellitus with an alternative antihyperglycemic treatment, which could improve adherence by reducing tablet burden. This study evaluated the bioequivalence of dapagliflozin/metformin XR FCDP versus the co-administration of the individual monotherapy tablets currently available for use in the Russian Federation. Healthy subjects aged 18 to 45 years were enrolled in this randomized, open-label, 2-period crossover study, conducted in a single Russian center. Pharmacokinetic parameters (AUC 0-t , C max , and C max /AUC 0-t ) were used to assess bioequivalence of dapagliflozin/metformin XR (10/1000 mg) FCDP to the individual component tablets (dapagliflozin [10 mg] plus metformin XR [2 × 500 mg]) under standard fed conditions. Safety and tolerability were also assessed. Forty healthy subjects were included (47.5% male; mean age, 30 years; and mean body mass index, 24.2 kg/m 2 ). Dapagliflozin and metformin XR in the FCDP were bioequivalent to the individual component tablets marketed in the Russian Federation, with the 90% CIs of the geometric least-squares mean ratios for all key pharmacokinetic parameters being contained within the 80% to 125% bioequivalence limits. Both FCDP and the individual component formulations were well tolerated, with no serious adverse events. Bioequivalence of dapagliflozin/metformin XR FCDP and the individual components was established without any new safety concerns, presenting a safe alternative for patients currently receiving regimens including each component individually. ClinicalTrials.gov identifier: NCT02722239. Copyright © 2018 Elsevier HS Journals, Inc. All rights reserved.

  3. Effect of clomifene citrate plus metformin and clomifene citrate plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomised double blind clinical trial.

    PubMed

    Moll, Etelka; Bossuyt, Patrick M M; Korevaar, Johanna C; Lambalk, Cornelis B; van der Veen, Fulco

    2006-06-24

    To compare the effectiveness of clomifene citrate plus metformin and clomifene citrate plus placebo in women with newly diagnosed polycystic ovary syndrome. Randomised clinical trial. Multicentre trial in 20 Dutch hospitals. 228 women with polycystic ovary syndrome. Clomifene citrate plus metformin or clomifene citrate plus placebo. The primary outcome measure was ovulation. Secondary outcome measures were ongoing pregnancy, spontaneous abortion, and clomifene resistance. 111 women were allocated to clomifene citrate plus metformin (metformin group) and 114 women were allocated to clomifene citrate plus placebo (placebo group). The ovulation rate in the metformin group was 64% compared with 72% in the placebo group, a non-significant difference (risk difference - 8%, 95% confidence interval - 20% to 4%). There were no significant differences in either rate of ongoing pregnancy (40% v 46%; - 6%, - 20% to 7%) or rate of spontaneous abortion (12% v 11%; 1%, - 7% to 10%). A significantly larger proportion of women in the metformin group discontinued treatment because of side effects (16% v 5%; 11%, 5% to 16%). Metformin is not an effective addition to clomifene citrate as the primary method of inducing ovulation in women with polycystic ovary syndrome. Current Controlled Trials ISRCTN55906981 [controlled-trials.com].

  4. Combination of TS-021 with metformin improves hyperglycemia and synergistically increases pancreatic β-cell mass in a mouse model of type 2 diabetes.

    PubMed

    Tajima, Atsushi; Hirata, Takashi; Taniguchi, Kazuo; Kondo, Yukiko; Kato, Sota; Saito-Hori, Masako; Ishimoto, Tsuyoshi; Yamamoto, Koji

    2011-10-24

    The objectives of this study were to elucidate the effects of a potent dipeptidyl peptidase (DPP)-IV inhibitor, TS-021, combined with/without metformin on glycemic control and pathological changes in pancreatic islets in high-fat diet and streptozotocin-induced (HFD-STZ) diabetic mice. The anti-diabetic effects of TS-021 and/or metformin in HFD-STZ mice were examined in both acute and chronic treatment studies. In addition, we performed immunohistochemical analysis after repeated administration of TS-021 and/or metformin to HFD-STZ mice twice a day for 5 weeks. In the acute treatment study, TS-021 and/or metformin significantly improved glucose tolerance and glucagon-like peptide-1 (GLP-1) level, and TS-021 alone or in combination with metformin significantly increased the plasma insulin level after nutrient ingestion. In the chronic treatment study, TS-021 in combination with metformin significantly lowered the glycosylated hemoglobin level, plasma insulin level, and α-cell-to-β-cell area ratio in pancreatic islets. In particular, the combined treatment synergistically increased the insulin-positive area in pancreatic islets from 32.3% in diabetic mice treated with the vehicle to 51.1% (TS-021 alone, 35.3%; metformin alone, 30.6%). The present study demonstrated that the coadministration of TS-021 and metformin synergistically improved the islet morphology by increasing the circulating level of biologically active GLP-1, which is thought to result from two different mechanisms (namely, an increase in GLP-1 secretion and DPP-IV inhibition). These findings strongly support the rationale for combined treatment with DPP-IV inhibitors plus metformin in clinical practice by clearly demonstrating an anti-diabetic effect associated with the remarkable improvement in pancreatic β-cell morphology. Copyright © 2011 Elsevier Inc. All rights reserved.

  5. Metformin inhibition of mTORC1 activation, DNA synthesis and proliferation in pancreatic cancer cells: Dependence on glucose concentration and role of AMPK

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Sinnett-Smith, James; Kisfalvi, Krisztina; Kui, Robert

    2013-01-04

    Highlights: Black-Right-Pointing-Pointer Metformin inhibits cancer cell growth but the mechanism(s) are not understood. Black-Right-Pointing-Pointer We show that the potency of metformin is sharply dependent on glucose in the medium. Black-Right-Pointing-Pointer AMPK activation was enhanced in cancer cells incubated in physiological glucose. Black-Right-Pointing-Pointer Reciprocally, metformin potently inhibited mTORC1, DNA synthesis and proliferation. Black-Right-Pointing-Pointer Metformin, at low concentrations, inhibited DNA synthesis through AMPK. -- Abstract: Metformin, a widely used anti-diabetic drug, is emerging as a potential anticancer agent but the mechanisms involved remain incompletely understood. Here, we demonstrate that the potency of metformin induced AMPK activation, as shown by the phosphorylation ofmore » its substrates acetyl-CoA carboxylase (ACC) at Ser{sup 79} and Raptor at Ser{sup 792}, was dramatically enhanced in human pancreatic ductal adenocarcinoma (PDAC) cells PANC-1 and MiaPaCa-2 cultured in medium containing physiological concentrations of glucose (5 mM), as compared with parallel cultures in medium with glucose at 25 mM. In physiological glucose, metformin inhibited mTORC1 activation, DNA synthesis and proliferation of PDAC cells stimulated by crosstalk between G protein-coupled receptors and insulin/IGF signaling systems, at concentrations (0.05-0.1 mM) that were 10-100-fold lower than those used in most previous reports. Using siRNA-mediated knockdown of the {alpha}{sub 1} and {alpha}{sub 2} catalytic subunits of AMPK, we demonstrated that metformin, at low concentrations, inhibited DNA synthesis through an AMPK-dependent mechanism. Our results emphasize the importance of using medium containing physiological concentrations of glucose to elucidate the anticancer mechanism of action of metformin in pancreatic cancer cells and other cancer cell types.« less

  6. Cardiac-Specific SOCS3 Deletion Prevents In Vivo Myocardial Ischemia Reperfusion Injury through Sustained Activation of Cardioprotective Signaling Molecules.

    PubMed

    Nagata, Takanobu; Yasukawa, Hideo; Kyogoku, Sachiko; Oba, Toyoharu; Takahashi, Jinya; Nohara, Shoichiro; Minami, Tomoko; Mawatari, Kazutoshi; Sugi, Yusuke; Shimozono, Koutatsu; Pradervand, Sylvain; Hoshijima, Masahiko; Aoki, Hiroki; Fukumoto, Yoshihiro; Imaizumi, Tsutomu

    2015-01-01

    Myocardial ischemia reperfusion injury (IRI) adversely affects cardiac performance and the prognosis of patients with acute myocardial infarction. Although myocardial signal transducer and activator of transcription (STAT) 3 is potently cardioprotective during IRI, the inhibitory mechanism responsible for its activation is largely unknown. The present study aimed to investigate the role of the myocardial suppressor of cytokine signaling (SOCS)-3, an intrinsic negative feedback regulator of the Janus kinase (JAK)-STAT signaling pathway, in the development of myocardial IRI. Myocardial IRI was induced in mice by ligating the left anterior descending coronary artery for 1 h, followed by different reperfusion times. One hour after reperfusion, the rapid expression of JAK-STAT-activating cytokines was observed. We precisely evaluated the phosphorylation of cardioprotective signaling molecules and the expression of SOCS3 during IRI and then induced myocardial IRI in wild-type and cardiac-specific SOCS3 knockout mice (SOCS3-CKO). The activation of STAT3, AKT, and ERK1/2 rapidly peaked and promptly decreased during IRI. This decrease correlated with the induction of SOCS3 expression up to 24 h after IRI in wild-type mice. The infarct size 24 h after reperfusion was significantly reduced in SOCS3-CKO compared with wild-type mice. In SOCS3-CKO mice, STAT3, AKT, and ERK1/2 phosphorylation was sustained, myocardial apoptosis was prevented, and the expression of anti-apoptotic Bcl-2 family member myeloid cell leukemia-1 (Mcl-1) was augmented. Cardiac-specific SOCS3 deletion led to the sustained activation of cardioprotective signaling molecules including and prevented myocardial apoptosis and injury during IRI. Our findings suggest that SOCS3 may represent a key factor that exacerbates the development of myocardial IRI.

  7. Cardiac-Specific SOCS3 Deletion Prevents In Vivo Myocardial Ischemia Reperfusion Injury through Sustained Activation of Cardioprotective Signaling Molecules

    PubMed Central

    Nagata, Takanobu; Yasukawa, Hideo; Kyogoku, Sachiko; Oba, Toyoharu; Takahashi, Jinya; Nohara, Shoichiro; Minami, Tomoko; Mawatari, Kazutoshi; Sugi, Yusuke; Shimozono, Koutatsu; Pradervand, Sylvain; Hoshijima, Masahiko; Aoki, Hiroki; Fukumoto, Yoshihiro; Imaizumi, Tsutomu

    2015-01-01

    Myocardial ischemia reperfusion injury (IRI) adversely affects cardiac performance and the prognosis of patients with acute myocardial infarction. Although myocardial signal transducer and activator of transcription (STAT) 3 is potently cardioprotective during IRI, the inhibitory mechanism responsible for its activation is largely unknown. The present study aimed to investigate the role of the myocardial suppressor of cytokine signaling (SOCS)-3, an intrinsic negative feedback regulator of the Janus kinase (JAK)-STAT signaling pathway, in the development of myocardial IRI. Myocardial IRI was induced in mice by ligating the left anterior descending coronary artery for 1 h, followed by different reperfusion times. One hour after reperfusion, the rapid expression of JAK-STAT–activating cytokines was observed. We precisely evaluated the phosphorylation of cardioprotective signaling molecules and the expression of SOCS3 during IRI and then induced myocardial IRI in wild-type and cardiac-specific SOCS3 knockout mice (SOCS3-CKO). The activation of STAT3, AKT, and ERK1/2 rapidly peaked and promptly decreased during IRI. This decrease correlated with the induction of SOCS3 expression up to 24 h after IRI in wild-type mice. The infarct size 24 h after reperfusion was significantly reduced in SOCS3-CKO compared with wild-type mice. In SOCS3-CKO mice, STAT3, AKT, and ERK1/2 phosphorylation was sustained, myocardial apoptosis was prevented, and the expression of anti-apoptotic Bcl-2 family member myeloid cell leukemia-1 (Mcl-1) was augmented. Cardiac-specific SOCS3 deletion led to the sustained activation of cardioprotective signaling molecules including and prevented myocardial apoptosis and injury during IRI. Our findings suggest that SOCS3 may represent a key factor that exacerbates the development of myocardial IRI. PMID:26010537

  8. Cardioprotective effects of 70-kDa heat shock protein in transgenic mice.

    PubMed Central

    Radford, N B; Fina, M; Benjamin, I J; Moreadith, R W; Graves, K H; Zhao, P; Gavva, S; Wiethoff, A; Sherry, A D; Malloy, C R; Williams, R S

    1996-01-01

    Heat shock proteins are proposed to limit injury resulting from diverse environmental stresses, but direct metabolic evidence for such a cytoprotective function in vertebrates has been largely limited to studies of cultured cells. We generated lines of transgenic mice to express human 70-kDa heat shock protein constitutively in the myocardium. Hearts isolated from these animals demonstrated enhanced recovery of high energy phosphate stores and correction of metabolic acidosis following brief periods of global ischemia sufficient to induce sustained abnormalities of these variables in hearts from nontransgenic littermates. These data demonstrate a direct cardioprotective effect of 70-kDa heat shock protein to enhance postischemic recovery of the intact heart. Images Fig. 1 Fig. 3 PMID:8637874

  9. Metformin use in kidney transplant recipients in the United States: an observational study.

    PubMed

    Stephen, Jenise; Anderson-Haag, Teresa L; Gustafson, Sally; Snyder, Jon J; Kasiske, Bertram L; Israni, Ajay K

    2014-01-01

    Although metformin is contraindicated in patients with increased serum creatinine levels (≥1.5 mg/dl in men, ≥1.4 mg/dl in women) in the United States, its use has not been systematically examined in kidney transplant recipients. We aimed to determine the frequency of metformin use and its associations among kidney transplant recipients, and to assess allograft and patient survival associated with metformin use. In this retrospective cohort study, we linked Scientific Registry of Transplant Recipients data for all incident kidney transplants 2001-2012 and national pharmacy claims (n = 46,914). We compared recipients having one or more pharmacy claims for a metformin-containing product (n = 4,609) and recipients having one or more claims for a non-metformin glucose-lowering agent (n = 42,305). On average, metformin claims were filled later after transplant and were associated with higher estimated glomerular filtration rates before the first claim. Median serum creatinine (mg/dl) levels before the first claim were lower in recipients with metformin claims than in those with non-metformin claims (1.3 [interquartile range 1.0-1.7] vs. 1.6 [1.2-2.5], respectively; p < 0.0001). Metformin was associated with lower adjusted hazards for living donor (0.55, 95% confidence interval 0.38-0.80; p = 0.002) and deceased donor (0.55, 0.44-0.70; p < 0.0001) allograft survival at 3 years posttransplant, and with lower mortality. Despite metformin being contraindicated in renal dysfunction, many kidney transplant recipients receive it, and it is not associated with worse patient or allograft survival. © 2015 S. Karger AG, Basel.

  10. Cardioprotective effects of fatty acid amide hydrolase inhibitor URB694, in a rodent model of trait anxiety

    PubMed Central

    Carnevali, Luca; Vacondio, Federica; Rossi, Stefano; Macchi, Emilio; Spadoni, Gilberto; Bedini, Annalida; Neumann, Inga D.; Rivara, Silvia; Mor, Marco; Sgoifo, Andrea

    2015-01-01

    In humans, chronic anxiety represents an independent risk factor for cardiac arrhythmias and sudden death. Here we evaluate in male Wistar rats bred for high (HAB) and low (LAB) anxiety-related behavior, as well as non-selected (NAB) animals, the relationship between trait anxiety and cardiac electrical instability and investigate whether pharmacological augmentation of endocannabinoid anandamide-mediated signaling exerts anxiolytic-like and cardioprotective effects. HAB rats displayed (i) a higher incidence of ventricular tachyarrhythmias induced by isoproterenol, and (ii) a larger spatial dispersion of ventricular refractoriness assessed by means of an epicardial mapping protocol. In HAB rats, acute pharmacological inhibition of the anandamide-degrading enzyme, fatty acid amide hydrolase (FAAH), with URB694 (0.3 mg/kg), (i) decreased anxiety-like behavior in the elevated plus maze, (ii) increased anandamide levels in the heart, (iii) reduced isoproterenol-induced occurrence of ventricular tachyarrhythmias, and (iv) corrected alterations of ventricular refractoriness. The anti-arrhythmic effect of URB694 was prevented by pharmacological blockade of the cannabinoid type 1 (CB1), but not of the CB2, receptor. These findings suggest that URB694 exerts anxiolytic-like and cardioprotective effects in HAB rats, the latter via anandamide-mediated activation of CB1 receptors. Thus, pharmacological inhibition of FAAH might be a viable pharmacological strategy for the treatment of anxiety-related cardiac dysfunction. PMID:26656183

  11. Metformin blocks mitochondrial membrane potential and inhibits sperm motility in fresh and refrigerated boar spermatozoa.

    PubMed

    Hurtado de Llera, A; Martin-Hidalgo, D; Garcia-Marin, L J; Bragado, M J

    2018-06-01

    Metformin is clinically used to treat diabetes. Given its role-impacting metabolism, metformin has been also added to semen cryopreservation media showing specie-dependent effects. We aimed to investigate metformin effects in both fresh (38.5°C for 2, 24 hr) and refrigerated (17°C for 10 days) boar spermatozoa. Metformin (2 hr) does not affect fresh sperm viability, membrane lipid organization nor acrosome integrity. However, metformin (24 hr) blocks sperm ΔΨm and significantly reduces % motile spermatozoa (65%), % progressive spermatozoa (50%), % rapid (100%), velocities VCL (69%), VSL (86%), VAP (78%) and motility coefficients. Metformin-including extender does not modify sperm viability, membrane lipid organization or acrosome integrity. Furthermore, it significantly reduces high ΔΨ-population spermatozoa at refrigeration day 4. Metformin also significantly reduces sperm motility during refrigeration. Summarizing, metformin inhibits both boar sperm ΔΨ and motility in any sperm condition studied: fresh and refrigerated. These findings dissuade metformin as an additive to improve boar sperm quality. © 2018 Blackwell Verlag GmbH.

  12. Houttuynia cordata Facilitates Metformin on Ameliorating Insulin Resistance Associated with Gut Microbiota Alteration in OLETF Rats.

    PubMed

    Wang, Jing-Hua; Bose, Shambhunath; Lim, Soo-Kyoung; Ansari, AbuZar; Chin, Young-Won; Choi, Han Seok; Kim, Hojun

    2017-09-22

    Metformin and Houttuynia cordata are representative anti-diabetic therapeutics in western and oriental medicine, respectively. The current study examined the synergistic anti-diabetic effect of Houttuynia cordata extraction (HCE) and metformin combination in Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Fecal microbiota were analyzed by denaturing gradient gel electrophoresis (DGGE) and real-time PCR. Combining HCE + metformin resulted in significantly ameliorated glucose tolerance (oral glucose tolerance test (OGTT))-the same as metformin alone. Particularly, results of the insulin tolerance test (ITT) showed that combining HCE + metformin dramatically improved insulin sensitivity as compared to metformin treatment alone. Both fecal and serum endotoxin, as well as cytokines (tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6)) were significantly ameliorated by HCE + metformin compared to metformin alone. Meanwhile, the activation of AMPK (adenosine monophosphate-activated protein kinase) by metformin was distinctly enhanced by HCE. Both of HCE and metformin evidently changed the gut microbiota composition, causing the alteration of bacterial metabolite, like short-chain fatty acids. H. cordata , together with metformin, exerts intensive sensibilization to insulin; the corresponding mechanisms are associated with alleviation of endotoxemia via regulation of gut microbiota, particularly Roseburia , Akkermansia , and Gram-negative bacterium.

  13. Houttuynia cordata Facilitates Metformin on Ameliorating Insulin Resistance Associated with Gut Microbiota Alteration in OLETF Rats

    PubMed Central

    Bose, Shambhunath; Lim, Soo-Kyoung; Ansari, AbuZar; Chin, Young-Won; Choi, Han Seok; Kim, Hojun

    2017-01-01

    Metformin and Houttuynia cordata are representative anti-diabetic therapeutics in western and oriental medicine, respectively. The current study examined the synergistic anti-diabetic effect of Houttuynia cordata extraction (HCE) and metformin combination in Otsuka Long–Evans Tokushima Fatty (OLETF) rats. Fecal microbiota were analyzed by denaturing gradient gel electrophoresis (DGGE) and real-time PCR. Combining HCE + metformin resulted in significantly ameliorated glucose tolerance (oral glucose tolerance test (OGTT))—the same as metformin alone. Particularly, results of the insulin tolerance test (ITT) showed that combining HCE + metformin dramatically improved insulin sensitivity as compared to metformin treatment alone. Both fecal and serum endotoxin, as well as cytokines (tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6)) were significantly ameliorated by HCE + metformin compared to metformin alone. Meanwhile, the activation of AMPK (adenosine monophosphate-activated protein kinase) by metformin was distinctly enhanced by HCE. Both of HCE and metformin evidently changed the gut microbiota composition, causing the alteration of bacterial metabolite, like short-chain fatty acids. H. cordata, together with metformin, exerts intensive sensibilization to insulin; the corresponding mechanisms are associated with alleviation of endotoxemia via regulation of gut microbiota, particularly Roseburia, Akkermansia, and Gram-negative bacterium. PMID:28937612

  14. Metformin, Lifestyle Intervention, and Cognition in the Diabetes Prevention Program Outcomes Study.

    PubMed

    Luchsinger, José A; Ma, Yong; Christophi, Costas A; Florez, Hermes; Golden, Sherita H; Hazuda, Helen; Crandall, Jill; Venditti, Elizabeth; Watson, Karol; Jeffries, Susan; Manly, Jennifer J; Pi-Sunyer, F Xavier

    2017-07-01

    We examined the association of the Diabetes Prevention Program (DPP) intervention arms (lifestyle intervention, metformin, and placebo) with cognition in the Diabetes Prevention Program Outcomes Study (DPPOS). We also examined metformin use, incident type 2 diabetes, and glycemia as exposures. The DPP lasted 2.8 years, followed by a 13-month bridge to DPPOS. Cognition was assessed in DPPOS years 8 and 10 (12 and 14 years after randomization) with the Spanish English Verbal Learning Test (SEVLT), letter fluency and animal fluency tests, Digit Symbol Substitution Test (DSST), and a composite cognitive score. A total of 2,280 participants (749 lifestyle, 776 metformin, and 755 placebo) aged 63.1 ± 10.7 years underwent cognitive assessments; 67.7% women, 54.6% non-Hispanic white, 20.7% non-Hispanic black, 14.6% Hispanic, 5.5% American Indian, and 4.6% Asian; 26.6% were homozygous or heterozygous for APOE-ε4. At the time of cognitive assessment, type 2 diabetes was higher in the placebo group (57.9%; P < 0.001) compared with lifestyle (47.0%) and metformin (50.4%). Metformin exposure was higher in the metformin group (8.72 years; P < 0.001) compared with placebo (1.43 years) and lifestyle (0.96 years). There were no differences in cognition across intervention arms. Type 2 diabetes was not related to cognition, but higher glycated hemoglobin at year 8 was related to worse cognition after confounder adjustment. Cumulative metformin exposure was not related to cognition. Exposure to intensive lifestyle intervention or metformin was not related to cognition among DPPOS participants. Higher glycemia was related to worse cognitive performance. Metformin seemed cognitively safe among DPPOS participants. © 2017 by the American Diabetes Association.

  15. The Efficacy and Safety of Saxagliptin When Added to Metformin Therapy in Patients With Inadequately Controlled Type 2 Diabetes With Metformin Alone

    PubMed Central

    DeFronzo, Ralph A.; Hissa, Miguel N.; Garber, Alan J.; Luiz Gross, Jorge; Yuyan Duan, Raina; Ravichandran, Shoba; Chen, Roland S.

    2009-01-01

    OBJECTIVE This 24-week trial assessed the efficacy and safety of saxagliptin as add-on therapy in patients with type 2 diabetes with inadequate glycemic control with metformin alone. RESEARCH DESIGN AND METHODS This was a randomized, double-blind, placebo-controlled study of saxagliptin (2.5, 5, or 10 mg once daily) or placebo plus a stable dose of metformin (1,500–2,500 mg) in 743 patients (A1C ≥7.0 and ≤10.0%). Efficacy analyses were performed using an ANCOVA model using last observation carried forward methodology on primary (A1C) and secondary (fasting plasma glucose [FPG] and postprandial glucose [PPG] area under the curve [AUC]) end points. RESULTS Saxagliptin (2.5, 5, and 10 mg) plus metformin demonstrated statistically significant adjusted mean decreases from baseline to week 24 versus placebo in A1C (−0.59, −0.69, and −0.58 vs. +0.13%; all P < 0.0001), FPG (−14.31, −22.03, and −20.50 vs. +1.24 mg/dl; all P < 0.0001), and PPG AUC (−8,891, −9,586, and −8,137 vs. −3,291 mg · min/dl; all P < 0.0001). More than twice as many patients achieved A1C <7.0% with 2.5, 5, and 10 mg saxagliptin versus placebo (37, 44, and 44 vs. 17%; all P < 0.0001). β-Cell function and postprandial C-peptide, insulin, and glucagon AUCs improved in all saxagliptin treatment groups at week 24. Incidence of hypoglycemic adverse events and weight reductions were similar to those with placebo. CONCLUSIONS Saxagliptin once daily added to metformin therapy was generally well tolerated and led to statistically significant improvements in glycemic indexes versus placebo added to metformin in patients with type 2 diabetes inadequately controlled with metformin alone. PMID:19478198

  16. Metformin in gestational diabetes: An emerging contender

    PubMed Central

    Singh, Awadhesh Kumar; Singh, Ritu

    2015-01-01

    Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance occurring first time during pregnancy. Its prevalence is simultaneously increasing with the global rise of diabesity. GDM commonly develops, when maternal glucose metabolism is unable to compensate for the progressive development of insulin resistance, arising primarily from the consistently rising diabetogenic placental hormones. It classically develops during the second or third trimester. Theoretically, insulin sensitizers should have been the ideal agent in its treatment, given the insulin resistance, the major culprit in its pathogenesis. Fortunately, majority of women can be treated satisfactorily with lifestyle modification, and approximately 20% requires more intensive treatment. For several decades, insulin has been the most reliable treatment strategy and the gold standard in GDM. Metformin is effective insulin sensitizing agent and an established first line drug in type 2 diabetes currently. As it crosses the placenta, a safety issue remains an obstacle and, therefore, metformin is currently not recommended in the treatment of GDM. Nevertheless, given the emerging clinically equivalent safety and efficacy data of metformin compared to insulin, it appears that it may perhaps open a rather new door in managing GDM. The aim of this review is to critically analyze, the safety and efficacy data of metformin regarding its use in GDM and pregnant mothers with polycystic ovarian disease, which has emerged in past decades. PMID:25729685

  17. Trace Element Determination and Cardioprotection of Terminalia pallida Fruit Ethanolic Extract in Isoproterenol Induced Myocardial Infarcted Rats by ICP-MS.

    PubMed

    Althaf Hussain, Shaik; Kareem, Mohammed Abdul; Rasool, Shaik Nayab; Al Omar, Suliman Yousef; Saleh, Alwasel; Al-Fwuaires, Manal Abdulrahman; Daddam, Jayasimha Rayalu; Devi, Kodidhela Lakshmi

    2018-01-01

    The trace elements and minerals in Terminalia pallida fruit ethanolic extract (TpFE) were determined by the instrument inductively coupled plasma-mass spectrometry (ICP-MS), and the cardioprotection of TpFE against isoproterenol (ISO)-administered rats was studied. Rats were pretreated with TpFE (100, 300, and 500 mg/kg bw) for 30 days, with concurrent administration of ISO (85 mg/kg bw) for two consecutive days. The levels of trace elements and minerals in TpFE were below the permitted limits of World Health Organization standards. ISO administration significantly increased the heart weight and cardiac marker enzymes in serum, xanthine oxidase, sodium, and calcium in the heart, whereas significantly decreased body weight, reduced glutathione, glutathione-S-transferase, superoxide dismutase, and potassium in the heart. Oral pretreatment of TpFE significantly prevented the ISO-induced alterations. This is the first report that revealed the determination of trace elements and mineral nutrients of TpFE by ICP-MS which plays a principal role in the herbal drug discovery for the treatment of cardiovascular diseases.

  18. Metformin Treatment May Increase Omentin-1 Levels in Women With Polycystic Ovary Syndrome

    PubMed Central

    Tan, Bee K.; Adya, Raghu; Farhatullah, Syed; Chen, Jing; Lehnert, Hendrik; Randeva, Harpal S.

    2010-01-01

    OBJECTIVE Polycystic ovary syndrome (PCOS) is associated with the metabolic syndrome. Decreased omentin-1 levels are associated with obesity and diabetes. To study the effects of metformin treatment on omentin-1 levels in PCOS subjects and effects of omentin-1 on in vitro migration and angiogenesis. RESEARCH DESIGN AND METHODS Serum omentin-1 was measured by ELISA. Angiogenesis was assessed by studying capillary tube formation in human microvascular endothelial cells (HMEC-1) on growth factor reduced Matrigel. Endothelial cell migration assay was performed in a modified Boyden chamber. Nuclear factor-κB (NF-κB) was studied by stably transfecting HMEC-1 cells with a cis-reporter plasmid containing luciferase reporter gene linked to five repeats of NF-κB binding sites. Akt phosphorylation was assessed by Western blotting. RESULTS Serum omentin-1 was significantly lower in PCOS women (P < 0.05). After 6 months of metformin treatment, there was a significant increase in serum omentin-1 (P < 0.01). Importantly, changes in hs-CRP were significantly negatively correlated with changes in serum omentin-1 (P = 0.036). In vitro migration and angiogenesis were significantly increased in serum from PCOS women (P < 0.01) compared with matched control subjects; these effects were significantly attenuated by metformin treatment (P < 0.01) plausibly through the regulation of omentin-1 levels via NF-κB and Akt pathways. CRP and VEGF induced in vitro migration, and angiogenesis was significantly decreased by omentin-1. CONCLUSIONS Increases in omentin-1 levels may play a role but are not sufficient to explain the decreased inflammatory and angiogenic effects of sera from metformin-treated PCOS women. PMID:20852028

  19. Body weight reduction and metformin: Roles in polycystic ovary syndrome.

    PubMed

    Al-Nozha, Omar; Habib, Fawziah; Mojaddidi, Moaz; El-Bab, Mohamed Fath

    2013-04-01

    Polycystic ovary syndrome (PCOS) is a common problem in women at fertile age. A prospective study was conducted to clarify the pathophysiological responses during an application of insulin sensitizer, metformin and weight reduction therapy at the Gynecology Center in Ohud hospital, in AL-Madinah AL-Munawarah, Kingdom of Saudi Arabia. Twenty healthy women served as controls and 180 PCOS women divided into three groups participated in the study. First group was treated with Clomid citrate 100mg/day from the 2nd day of menses to the 6th day plus gonadotrophin from day three to the 13th. Group II was treated as group I plus 850mg metformin twice a day and group III was treated as group I plus weight reduction. Clinical symptoms, menstrual pattern, hirsutism, blood glucose, body mass index, waist-to-hip ratio, insulin, hormonal, and lipid profiles were assessed pre- and post treatment. Insulin resistance was calculated. PCOS women had significantly higher values than the healthy women in most of the measurements. Metformin and weight reduction therapy resulted in a significant decrease in the fasting insulin, glucose/insulin ratio and HOMA-IR. Metformin and weight reduction therapy resulted in a significant decrease in the lipid parameters, testosterone, LH/FSH ratio, SHBG, and prolactin levels. HOMA-IR was significantly higher in women with PCOS. HOMA-IR was positively correlated with testosterone, estradiol, TG, total cholesterol and LDL-cholesterol parameters, and negatively correlated with HDL-cholesterol and FSH levels. Metformin therapy and weight reduction had favorable influences on the basic metabolic and hormonal profiles in women with PCOS and that metformin and lifestyle modification (weight reduction via diet restriction or exercise) resulted in a significantly greater weight loss than hormonal therapy alone. Metformin and weight reduction therapy decreased also hyperandrogenism and insulin resistance. Copyright © 2013 Elsevier Ireland Ltd. All rights

  20. Metformin effectiveness and safety in the management of overweight/obese nondiabetic children and adolescents: metabolic benefits of the continuous exposure to metformin at 12 and 24 months.

    PubMed

    Marques, Pedro; Limbert, Catarina; Oliveira, Laura; Santos, Maria Inês; Lopes, Lurdes

    2016-02-19

    Childhood obesity prevalence is rising and new therapeutical approaches are needed. Metformin is likely beneficial in obese and/or insulin-resistant children/adolescents, but its role in this setting is still unclear. We aimed to evaluate the effectiveness, in terms of weight loss and insulin resistance, and safety of metformin in nondiabetic overweight/obese children and adolescents. We retrospectively reviewed clinical records of 78 nondiabetic obese/overweight [body mass index (BMI)≥85th/95th percentile for age and sex] children and adolescents. Anthropometric and metabolic outcomes of 39 patients treated with metformin (mean daily dose: 1.3±0.5 g) were analyzed and compared to lifestyle intervention alone at different follow-up times (12 and 24 months). The mean age of the 78 patients was 13.3 years, 41 were females and mean BMI and BMI-SDS were 32.8 kg/m2 and 3.1, respectively. There was a decrease in mean BMI-SDS within each treatment group in all periods, except at 24 months for lifestyle intervention. However, the change in BMI-SDS was not significantly superior in the metformin group when compared to lifestyle intervention. Metformin had greater effectiveness over lifestyle intervention alone in reducing fasting insulin levels and homeostasis model assessment for insulin-resistance index (HOMA-IR) at both 12 and 24 months. Five patients had gastrointestinal adverse effects (12.8%), four requiring dose reduction, but metformin could be resumed in all. Metformin for nondiabetic obese/overweight children and adolescents resulted in a noteworthy insulin resistance improvement, without significant BMI advantage when compared to lifestyle intervention. Metformin metabolic and anthropometric effects appear to be beneficial up to 24 months, without relevant adverse effects, highlighting its potential long-term benefits.

  1. Cardioprotective Effects of Quercetin in Cardiomyocyte under Ischemia/Reperfusion Injury

    PubMed Central

    Chen, Yi-Wen; Chou, Hsiu-Chuan; Lin, Szu-Ting; Chen, You-Hsuan; Chang, Yu-Jung; Chen, Linyi; Chan, Hong-Lin

    2013-01-01

    Quercetin, a polyphenolic compound existing in many vegetables, fruits, has antiinflammatory, antiproliferation, and antioxidant effect on mammalian cells. Quercetin was evaluated for protecting cardiomyocytes from ischemia/reperfusion injury, but its protective mechanism remains unclear in the current study. The cardioprotective effects of quercetin are achieved by reducing the activity of Src kinase, signal transducer and activator of transcription 3 (STAT3), caspase 9, Bax, intracellular reactive oxygen species production, and inflammatory factor and inducible MnSOD expression. Fluorescence two-dimensional differential gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) can reveal the differentially expressed proteins of H9C2 cells treated with H2O2 or quercetin. Although 17 identified proteins were altered in H2O2-induced cells, these proteins such as alpha-soluble NSF attachment protein (α-SNAP), Ena/VASP-like protein (Evl), and isopentenyl-diphosphate delta-isomerase 1 (Idi-1) were reverted by pretreatment with quercetin, which correlates with kinase activation, DNA repair, lipid, and protein metabolism. Quercetin dephosphorylates Src kinase in H2O2-induced H9C2 cells and likely blocks the H2O2-induced inflammatory response through STAT3 kinase modulation. This probably contributes to prevent ischemia/reperfusion injury in cardiomyocytes. PMID:23573126

  2. Metformin Treatment Inhibits Motility and Invasion of Glioblastoma Cancer Cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Al Hassan, Marwa; Fakhoury, Isabelle; El Masri, Zeinab

    Glioblastoma multiforme (GBM) is one of the most common and deadliest cancers of the central nervous system (CNS). GBMs high ability to infiltrate healthy brain tissues makes it difficult to remove surgically and account for its fatal outcomes. To improve the chances of survival, it is critical to screen for GBM-targeted anticancer agents with anti-invasive and antimigratory potential. Metformin, a commonly used drug for the treatment of diabetes, has recently emerged as a promising anticancer molecule. This prompted us, to investigate the anticancer potential of metformin against GBMs, specifically its effects on cell motility and invasion. The results show amore » significant decrease in the survival of SF268 cancer cells in response to treatment with metformin. Furthermore, metformin’s efficiency in inhibiting 2D cell motility and cell invasion in addition to increasing cellular adhesion was also demonstrated in SF268 and U87 cells. Finally, AKT inactivation by downregulation of the phosphorylation level upon metformin treatment was also evidenced. In conclusion, this study provides insights into the anti-invasive antimetastatic potential of metformin as well as its underlying mechanism of action.« less

  3. Metformin Treatment Inhibits Motility and Invasion of Glioblastoma Cancer Cells

    DOE PAGES

    Al Hassan, Marwa; Fakhoury, Isabelle; El Masri, Zeinab; ...

    2018-06-26

    Glioblastoma multiforme (GBM) is one of the most common and deadliest cancers of the central nervous system (CNS). GBMs high ability to infiltrate healthy brain tissues makes it difficult to remove surgically and account for its fatal outcomes. To improve the chances of survival, it is critical to screen for GBM-targeted anticancer agents with anti-invasive and antimigratory potential. Metformin, a commonly used drug for the treatment of diabetes, has recently emerged as a promising anticancer molecule. This prompted us, to investigate the anticancer potential of metformin against GBMs, specifically its effects on cell motility and invasion. The results show amore » significant decrease in the survival of SF268 cancer cells in response to treatment with metformin. Furthermore, metformin’s efficiency in inhibiting 2D cell motility and cell invasion in addition to increasing cellular adhesion was also demonstrated in SF268 and U87 cells. Finally, AKT inactivation by downregulation of the phosphorylation level upon metformin treatment was also evidenced. In conclusion, this study provides insights into the anti-invasive antimetastatic potential of metformin as well as its underlying mechanism of action.« less

  4. TGF-α equalizes age disparities in stem cell-mediated cardioprotection.

    PubMed

    Herrmann, Jeremy L; Fiege, Jeremy W; Abarbanell, Aaron M; Weil, Brent R; Wang, Yue; Poynter, Jeffrey A; Manukyan, Mariuxi C; Brewster, Benjamin D; Meldrum, Daniel R

    2012-08-01

    Neonatal mesenchymal stem cells exhibit less cardioprotective potential than their adult counterparts. Transforming growth factor-α (TGF-α) has been shown to stimulate adult stem cell VEGF production, however, it remains unknown whether it may augment neonatal stem cell paracrine function. We hypothesized that TGF-α would equalize adult and neonatal stem cell paracrine function and cardioprotection during acute ischemia/reperfusion. Bone marrow mesenchymal stem cells isolated from adult and 2.5 wk-old mice were treated with TGF-α (250 ng/mL) for 24 h. VEGF, HGF, IGF-1, IL-1β, and IL-6 production were measure in vitro, and cells were infused via an intracoronary route using a model of isolated heart perfusion. TGF-α equalized adult and neonatal stem cell VEGF production but did not affect production of HGF, IGF-1, IL-1β, or IL-6. ERK, p38 MAPK, and JNK phosphorylation were greater in adult cells in response to TGF-α. Whereas infusion of adult but not neonatal stem cells was associated with improved myocardial functional recovery during reperfusion, infusions of either TGF-α-pretreated cell group were associated with the greatest functional recovery. TGF-α equalizes adult and neonatal mesenchymal stem cell VEGF production and cardioprotection in association with differential regulation of ERK, p38 MAPK, and JNK phosphorylation. Copyright © 2012. Published by Elsevier Inc.

  5. Proton Pump Inhibitors Inhibit Metformin Uptake by Organic Cation Transporters (OCTs)

    PubMed Central

    Nies, Anne T.; Hofmann, Ute; Resch, Claudia; Schaeffeler, Elke; Rius, Maria; Schwab, Matthias

    2011-01-01

    Metformin, an oral insulin-sensitizing drug, is actively transported into cells by organic cation transporters (OCT) 1, 2, and 3 (encoded by SLC22A1, SLC22A2, or SLC22A3), which are tissue specifically expressed at significant levels in various organs such as liver, muscle, and kidney. Because metformin does not undergo hepatic metabolism, drug-drug interaction by inhibition of OCT transporters may be important. So far, comprehensive data on the interaction of proton pump inhibitors (PPIs) with OCTs are missing although PPIs are frequently used in metformin-treated patients. Using in silico modeling and computational analyses, we derived pharmacophore models indicating that PPIs (i.e. omeprazole, pantoprazole, lansoprazole, rabeprazole, and tenatoprazole) are potent OCT inhibitors. We then established stably transfected cell lines expressing the human uptake transporters OCT1, OCT2, or OCT3 and tested whether these PPIs inhibit OCT-mediated metformin uptake in vitro. All tested PPIs significantly inhibited metformin uptake by OCT1, OCT2, and OCT3 in a concentration-dependent manner. Half-maximal inhibitory concentration values (IC50) were in the low micromolar range (3–36 µM) and thereby in the range of IC50 values of other potent OCT drug inhibitors. Finally, we tested whether the PPIs are also transported by OCTs, but did not identify PPIs as OCT substrates. In conclusion, PPIs are potent inhibitors of the OCT-mediated metformin transport in vitro. Further studies are needed to elucidate the clinical relevance of this drug-drug interaction with potential consequences on metformin disposition and/or efficacy. PMID:21779389

  6. Metformin treatment after the hypoxia-ischemia attenuates brain injury in newborn rats

    PubMed Central

    Fang, Mingchu; Jiang, Huai; Ye, Lixia; Cai, Chenchen; Hu, Yingying; Pan, Shulin; Li, Peijun; Xiao, Jian; Lin, Zhenlang

    2017-01-01

    Neonatal hypoxic-ischemic (HI) brain injury is a devastating disease that often leads to death and detrimental neurological deficits. The present study was designed to evaluate the ability of metformin to provide neuroprotection in a model of neonatal hypoxic-ischemic brain injury and to study the associated molecular mechanisms behind these protective effects. Here, we found that metformin treatment remarkably attenuated brain infarct volumes and brain edema at 24 h after HI injury, and the neuroprotection of metformin was associated with inhibition of neuronal apoptosis, suppression of the neuroinflammation and amelioration of the blood brain barrier breakdown. Additionally, metformin treatment conferred long-term protective against brain damage at 7 d after HI injury. Our study indicates that metformin treatment protects against neonatal hypoxic-ischemic brain injury and thus has potential as a therapy for this disease. PMID:29088867

  7. Recurrent lactic acidosis and hypoglycemia with inadvertent metformin use: a case of look-alike pills.

    PubMed

    Jacob, Tess; Garrick, Renee; Goldberg, Michael D

    2018-01-01

    Metformin is recommended as the first-line agent for the treatment of type 2 diabetes. Although this drug has a generally good safety profile, rare but potentially serious adverse effects may occur. Metformin-associated lactic acidosis, although very uncommon, carries a significant risk of mortality. The relationship between metformin accumulation and lactic acidosis is complex and is affected by the presence of comorbid conditions such as renal and hepatic disease. Plasma metformin levels do not reliably correlate with the severity of lactic acidosis. We present a case of inadvertent metformin overdose in a patient with both renal failure and hepatic cirrhosis, leading to two episodes of lactic acidosis and hypoglycemia. The patient was successfully treated with hemodialysis both times and did not develop any further lactic acidosis or hypoglycemia, after the identification of metformin tablets accidentally mixed in with his supply of sevelamer tablets. Early initiation of renal replacement therapy is key in decreasing lactic acidosis-associated mortality. When a toxic ingestion is suspected, direct visualization of the patient's pills is advised in order to rule out the possibility of patient- or pharmacist-related medication errors.Though sending a specimen for determination of the plasma metformin concentration is important when a metformin-treated patient with diabetes presents with lactic acidosis, complex relationships exist between metformin accumulation, hyperlactatemia and acidosis, and the drug may not always be the precipitating factor.Intermittent hemodialysis is recommended as the first-line treatment for metformin-associated lactic acidosis (MALA).An investigational delayed-release form of metformin with reduced systemic absorption may carry a lower risk for MALA in patients with renal insufficiency, in whom metformin therapy may presently be contraindicated.

  8. Metformin improves defective hematopoiesis and delays tumor formation in Fanconi anemia mice.

    PubMed

    Zhang, Qing-Shuo; Tang, Weiliang; Deater, Matthew; Phan, Ngoc; Marcogliese, Andrea N; Li, Hui; Al-Dhalimy, Muhsen; Major, Angela; Olson, Susan; Monnat, Raymond J; Grompe, Markus

    2016-12-15

    Fanconi anemia (FA) is an inherited bone marrow failure disorder associated with a high incidence of leukemia and solid tumors. Bone marrow transplantation is currently the only curative therapy for the hematopoietic complications of this disorder. However, long-term morbidity and mortality remain very high, and new therapeutics are badly needed. Here we show that the widely used diabetes drug metformin improves hematopoiesis and delays tumor formation in Fancd2 -/- mice. Metformin is the first compound reported to improve both of these FA phenotypes. Importantly, the beneficial effects are specific to FA mice and are not seen in the wild-type controls. In this preclinical model of FA, metformin outperformed the current standard of care, oxymetholone, by improving peripheral blood counts in Fancd2 -/- mice significantly faster. Metformin increased the size of the hematopoietic stem cell compartment and enhanced quiescence in hematopoietic stem and progenitor cells. In tumor-prone Fancd2 -/- Trp53 +/- mice, metformin delayed the onset of tumors and significantly extended the tumor-free survival time. In addition, we found that metformin and the structurally related compound aminoguanidine reduced DNA damage and ameliorated spontaneous chromosome breakage and radials in human FA patient-derived cells. Our results also indicate that aldehyde detoxification might be one of the mechanisms by which metformin reduces DNA damage in FA cells. © 2016 by The American Society of Hematology.

  9. Asymptomatic chronic gastritis decreases metformin tolerance in patients with type 2 diabetes.

    PubMed

    Huang, Y; Sun, J; Wang, X; Tao, X; Wang, H; Tan, W

    2015-08-01

    Digestive disorders represent the most common metformin side effects for type 2 diabetes. The mechanism of these metformin side effects is unclear. The aim of this study was to assess whether asymptomatic chronic gastritis could influence metformin tolerance in patients with type 2 diabetes. Demographic, anthropometric, ultrasound and laboratory data were obtained from 144 metformin naïve patients with diabetes. The diagnosis of chronic gastritis was based on endoscopic and histopathological examination, and H. pylori infection was assessed based on (13) C urea breath test (UBT). All subjects started metformin at 500 mg/day and increasing progressively to 1500 mg/day over 4 weeks. A score of gastrointestinal side effects (abdominal pain, diarrhoea, nausea, vomiting, bloating and anorexia) was assessed each week, and metformin dose was adjusted as appropriate. Based on endoscopy, 64 patients were categorized as non-gastritis subjects and 80 as chronic gastritis subjects. At baseline, there is no statistical difference in gastrointestinal symptoms between two groups. With metformin, the mean scores for gastrointestinal symptoms in the non-gastritis and gastritis subjects were 1·02 ± 1·71 vs. 2·18 ± 2·05 (P = 0·001), 0·20 ± 0·65 vs. 0·50 ± 0·89 (P = 0·022), 0 vs. 0·06 ± 0·24 (P = 0·024) and 1·08 ± 1·03 vs. 1·71 ± 1·66 (P = 0·028). The mean final metformin dose used by gastritis subjects was 706·24 ± 568·90 mg, significantly less than the mean dose used by non-gastritis subjects (1101·56 ± 578·58 mg, P = 0·001). After adjustment for age and sex, the odds ratio (OR) for a final metformin dose of less than 1500 mg/day was found to be 2·76 (95% CI 1·38-5·53, P = 0·004) for chronic gastritis subjects. The OR for a final metformin dose of less than 1000 mg/day was found to be 3·98 (95% CI 1·91-8·27, P = 0·001) for chronic gastritis subjects. Our data suggest that pre-existing non-symptomatic gastritis was associated with metformin

  10. Pregnancy outcome in women with polycystic ovary syndrome comparing the effects of laparoscopic ovarian drilling and clomiphene citrate stimulation in women pre-treated with metformin: a retrospective study

    PubMed Central

    2010-01-01

    Background Ovarian stimulation in women with polycystic ovary syndrome (PCOS) increases the risk for perinatal complications. Ovulation induction by laparoscopic ovarian drilling (LOD) might improve the overall pregnancy outcomes. The aim of our study was to assess the adverse events or effects on pregnancy of LOD and clomiphene citrate (CC) stimulation in patients who received metformin. Methods Setting: Academic research institution. We retrospectively analyzed the courses of 40 spontaneous pregnancies after LOD for CC-resistance, 40 pregnancies after CC stimulation, and 40 pregnancies after metformin treatment alone. Patients in the LOD and the CC groups had been pre-treated with Metformin. Primary outcome parameters were: the rate of multiple pregnancies; the rate of early pregnancy losses/miscarriages; the development of gestational diabetes, pregnancy-induced hypertension, and preeclampsia/HELLP-syndrome; premature delivery; and birth weight. Results The rate of twin pregnancies did not differ between the CC group (12.5%), the LOD group (7.5%), and the metformin only group (2.5%, p = 0.239). Seventeen women suffered an early miscarriage. There were no differences with regard to the rates of gestational diabetes, pregnancy-induced hypertension, preeclampsia, and preterm delivery. By analyzing all pregnancy complications together, the overall pregnancy complication rate was highest in the CC group (70.0%, 28/40), followed by the LOD group (45.0%, 18/40), and the metformin only group (47.5%, 19/40; p = 0.047). Conclusions CC, but not LOD, increases the complication rate in pregnant patients who received metformin. PMID:20465786

  11. Oral metformin treatment prevents enhanced insulin demand and placental dysfunction in the pregnant rat fed a fructose-rich diet.

    PubMed

    Alzamendi, Ana; Del Zotto, Hector; Castrogiovanni, Daniel; Romero, Jose; Giovambattista, Andres; Spinedi, Eduardo

    2012-01-01

    The intake of a fructose-rich diet (FRD) in the normal female rat induces features similar to those observed in the human metabolic syndrome phenotype. We studied the impact of FRD administration to mothers on pregnancy outcome. On gestational day (Gd) zero rats were assigned to either group: ad libitum drinking tap water alone (normal diet, ND) or containing fructose (10% w/vol; FRD) through pregnancy; all rats were fed a Purina chow diet ad libitum ND and FRD rats were daily cotreated or not with metformin (60 mg/Kg/day oral; ND + MF and FRD + MF) and submitted to a high glucose load test on Gd 14. Additionally, placentas from different groups were studied on Gd 20. Data indicated that: (1) although FRD rats well tolerated glucose overload, their circulating levels of insulin were significantly higher than in ND rats; (2) the mesometrial triangle blood vessel area was significantly lower in placentas from FRD than ND dams; (3) the detrimental effects of FRD administration to mothers were ameliorated by metformin cotreatment. Our study suggests that excessive intake of fructose during pregnancy enhanced the risk for developing gestational diabetes and subsequent preeclampsia, and that metformin prevented the poor pregnancy outcome induced by FRD.

  12. Oral Metformin Treatment Prevents Enhanced Insulin Demand and Placental Dysfunction in the Pregnant Rat Fed a Fructose-Rich Diet

    PubMed Central

    Alzamendi, Ana; Del Zotto, Hector; Castrogiovanni, Daniel; Romero, Jose; Giovambattista, Andres; Spinedi, Eduardo

    2012-01-01

    The intake of a fructose-rich diet (FRD) in the normal female rat induces features similar to those observed in the human metabolic syndrome phenotype. We studied the impact of FRD administration to mothers on pregnancy outcome. On gestational day (Gd) zero rats were assigned to either group: ad libitum drinking tap water alone (normal diet, ND) or containing fructose (10% w/vol; FRD) through pregnancy; all rats were fed a Purina chow diet ad libitum ND and FRD rats were daily cotreated or not with metformin (60 mg/Kg/day oral; ND + MF and FRD + MF) and submitted to a high glucose load test on Gd 14. Additionally, placentas from different groups were studied on Gd 20. Data indicated that: (1) although FRD rats well tolerated glucose overload, their circulating levels of insulin were significantly higher than in ND rats; (2) the mesometrial triangle blood vessel area was significantly lower in placentas from FRD than ND dams; (3) the detrimental effects of FRD administration to mothers were ameliorated by metformin cotreatment. Our study suggests that excessive intake of fructose during pregnancy enhanced the risk for developing gestational diabetes and subsequent preeclampsia, and that metformin prevented the poor pregnancy outcome induced by FRD. PMID:22957268

  13. Metformin and phenformin deplete tricarboxylic acid cycle and glycolytic intermediates during cell transformation and NTPs in cancer stem cells

    PubMed Central

    Janzer, Andreas; German, Natalie J.; Gonzalez-Herrera, Karina N.; Asara, John M.; Haigis, Marcia C.; Struhl, Kevin

    2014-01-01

    Metformin, a first-line diabetes drug linked to cancer prevention in retrospective clinical analyses, inhibits cellular transformation and selectively kills breast cancer stem cells (CSCs). Although a few metabolic effects of metformin and the related biguanide phenformin have been investigated in established cancer cell lines, the global metabolic impact of biguanides during the process of neoplastic transformation and in CSCs is unknown. Here, we use LC/MS/MS metabolomics (>200 metabolites) to assess metabolic changes induced by metformin and phenformin in an Src-inducible model of cellular transformation and in mammosphere-derived breast CSCs. Although phenformin is the more potent biguanide in both systems, the metabolic profiles of these drugs are remarkably similar, although not identical. During the process of cellular transformation, biguanide treatment prevents the boost in glycolytic intermediates at a specific stage of the pathway and coordinately decreases tricarboxylic acid (TCA) cycle intermediates. In contrast, in breast CSCs, biguanides have a modest effect on glycolytic and TCA cycle intermediates, but they strongly deplete nucleotide triphosphates and may impede nucleotide synthesis. These metabolic profiles are consistent with the idea that biguanides inhibit mitochondrial complex 1, but they indicate that their metabolic effects differ depending on the stage of cellular transformation. PMID:25002509

  14. Metformin and phenformin deplete tricarboxylic acid cycle and glycolytic intermediates during cell transformation and NTPs in cancer stem cells.

    PubMed

    Janzer, Andreas; German, Natalie J; Gonzalez-Herrera, Karina N; Asara, John M; Haigis, Marcia C; Struhl, Kevin

    2014-07-22

    Metformin, a first-line diabetes drug linked to cancer prevention in retrospective clinical analyses, inhibits cellular transformation and selectively kills breast cancer stem cells (CSCs). Although a few metabolic effects of metformin and the related biguanide phenformin have been investigated in established cancer cell lines, the global metabolic impact of biguanides during the process of neoplastic transformation and in CSCs is unknown. Here, we use LC/MS/MS metabolomics (>200 metabolites) to assess metabolic changes induced by metformin and phenformin in an Src-inducible model of cellular transformation and in mammosphere-derived breast CSCs. Although phenformin is the more potent biguanide in both systems, the metabolic profiles of these drugs are remarkably similar, although not identical. During the process of cellular transformation, biguanide treatment prevents the boost in glycolytic intermediates at a specific stage of the pathway and coordinately decreases tricarboxylic acid (TCA) cycle intermediates. In contrast, in breast CSCs, biguanides have a modest effect on glycolytic and TCA cycle intermediates, but they strongly deplete nucleotide triphosphates and may impede nucleotide synthesis. These metabolic profiles are consistent with the idea that biguanides inhibit mitochondrial complex 1, but they indicate that their metabolic effects differ depending on the stage of cellular transformation.

  15. Effect of clomifene citrate plus metformin and clomifene citrate plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomised double blind clinical trial

    PubMed Central

    Moll, Etelka; Bossuyt, Patrick M M; Korevaar, Johanna C; Lambalk, Cornelis B; van der Veen, Fulco

    2006-01-01

    Objective To compare the effectiveness of clomifene citrate plus metformin and clomifene citrate plus placebo in women with newly diagnosed polycystic ovary syndrome. Design Randomised clinical trial. Setting Multicentre trial in 20 Dutch hospitals. Participants 228 women with polycystic ovary syndrome. Interventions Clomifene citrate plus metformin or clomifene citrate plus placebo. Main outcome measure The primary outcome measure was ovulation. Secondary outcome measures were ongoing pregnancy, spontaneous abortion, and clomifene resistance. Results 111 women were allocated to clomifene citrate plus metformin (metformin group) and 114 women were allocated to clomifene citrate plus placebo (placebo group). The ovulation rate in the metformin group was 64% compared with 72% in the placebo group, a non-significant difference (risk difference - 8%, 95% confidence interval - 20% to 4%). There were no significant differences in either rate of ongoing pregnancy (40% v 46%; - 6%, - 20% to 7%) or rate of spontaneous abortion (12% v 11%; 1%, - 7% to 10%). A significantly larger proportion of women in the metformin group discontinued treatment because of side effects (16% v 5%; 11%, 5% to 16%). Conclusion Metformin is not an effective addition to clomifene citrate as the primary method of inducing ovulation in women with polycystic ovary syndrome. Trial registration Current Controlled Trials ISRCTN55906981 [controlled-trials.com]. PMID:16769748

  16. Parkinson's disease proteins: Novel mitochondrial targets for cardioprotection

    PubMed Central

    Mukherjee, Uma A.; Ong, Sang-Bing; Ong, Sang-Ging; Hausenloy, Derek J.

    2015-01-01

    Ischemic heart disease (IHD) is the leading cause of death and disability worldwide. Therefore, novel therapeutic targets for protecting the heart against acute ischemia/reperfusion injury (IRI) are required to attenuate cardiomyocyte death, preserve myocardial function, and prevent the onset of heart failure. In this regard, a specific group of mitochondrial proteins, which have been linked to familial forms of Parkinson's disease (PD), may provide novel therapeutic targets for cardioprotection. In dopaminergic neurons of the substantia nigra, these PD proteins, which include Parkin, PINK1, DJ-1, LRRK2, and α-synuclein, play essential roles in preventing cell death—through maintaining normal mitochondrial function, protecting against oxidative stress, mediating mitophagy, and preventing apoptosis. These rare familial forms of PD may therefore provide important insights into the pathophysiology underlying mitochondrial dysfunction and the development of PD. Interestingly, these PD proteins are also present in the heart, but their role in myocardial health and disease is not clear. In this article, we review the role of these PD proteins in the heart and explore their potential as novel mitochondrial targets for cardioprotection. PMID:26481155

  17. Cardioprotective Action of Ginkgo biloba Extract against Sustained β-Adrenergic Stimulation Occurs via Activation of M2/NO Pathway.

    PubMed

    Mesquita, Thássio R R; de Jesus, Itamar C G; Dos Santos, Jucilene F; de Almeida, Grace K M; de Vasconcelos, Carla M L; Guatimosim, Silvia; Macedo, Fabrício N; Dos Santos, Robervan V; de Menezes-Filho, José E R; Miguel-Dos-Santos, Rodrigo; Matos, Paulo T D; Scalzo, Sérgio; Santana-Filho, Valter J; Albuquerque-Júnior, Ricardo L C; Pereira-Filho, Rose N; Lauton-Santos, Sandra

    2017-01-01

    Ginkgo biloba is the most popular phytotherapic agent used worldwide for treatment of several human disorders. However, the mechanisms involved in the protective actions of Ginkgo biloba on cardiovascular diseases remain poorly elucidated. Taking into account recent studies showing beneficial actions of cholinergic signaling in the heart and the cholinergic hypothesis of Ginkgo biloba -mediated neuroprotection, we aimed to investigate whether Ginkgo biloba extract (GBE) promotes cardioprotection via activation of cholinergic signaling in a model of isoproterenol-induced cardiac hypertrophy. Here, we show that GBE treatment (100 mg/kg/day for 8 days, v.o.) reestablished the autonomic imbalance and baroreflex dysfunction caused by chronic β-adrenergic receptor stimulation (β-AR, 4.5 mg/kg/day for 8 days, i.p.). Moreover, GBE prevented the upregulation of muscarinic receptors (M 2 ) and downregulation of β 1 -AR in isoproterenol treated-hearts. Additionally, we demonstrated that GBE prevents the impaired endothelial nitric oxide synthase activity in the heart. GBE also prevented the pathological cardiac remodeling, electrocardiographic changes and impaired left ventricular contractility that are typical of cardiac hypertrophy. To further investigate the mechanisms involved in GBE cardioprotection in vivo , we performed in vitro studies. By using neonatal cardiomyocyte culture we demonstrated that the antihypertrophic action of GBE was fully abolished by muscarinic receptor antagonist or NOS inhibition. Altogether, our data support the notion that antihypertrophic effect of GBE occurs via activation of M 2 /NO pathway uncovering a new mechanism involved in the cardioprotective action of Ginkgo biloba .

  18. Houttuynia cordata extract increased systemic exposure and liver concentrations of metformin through OCTs and MATEs in rats.

    PubMed

    You, Byoung Hoon; Chin, Young-Won; Kim, Hojun; Choi, Han Seok; Choi, Young Hee

    2018-06-01

    The synergistic activity of Houttuynia cordata ethanol extract (HCT) and metformin combination in diabetic rats has been previously reported, but the fundamental causes remain unsolved. Organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs) transport metformin to the liver and kidneys. Therefore, pharmacological activity and systemic exposure of metformin in HCT-metformin combination were determined from pharmacokinetic change and glucose-lowering activity using in vitro HEK-293 cells expressing human OCTs or human MATEs and in vivo rats. HCT inhibited human OCT2 and human MATE1-mediated metformin transports in vitro. In in vivo rats, treatment with HCT and metformin for 28 days in rats (28MH rats) reduced the rat Oct2-mediated renal excretion of metformin and thereby the increased systemic exposure of metformin compared with only metformin-treated rats for 28 days (28M rats). In 28MH rats, rat Oct1-mediated metformin uptake into the liver was enhanced, leading to an improved glucose-lowering effect without hypoglycaemia compared with 28M rats. There was no impairment of renal function in HCT and metformin treatments. These results suggest that HCT-metformin combination therapy is applicable in terms of efficacy and safety. Copyright © 2018 John Wiley & Sons, Ltd.

  19. Effect of N-benzoyl-D-phenylalanine and metformin on carbohydrate metabolic enzymes in neonatal streptozotocin diabetic rats.

    PubMed

    Ashokkumar, Natarajan; Pari, Leelavinothan

    2005-01-01

    The effect of N-benzoyl-D-phenylalanine (NBDP) and metformin was studied on the activities of carbohydrate metabolic enzymes in neonatal streptozotocin (nSTZ) non-insulin-dependent diabetic rats. To induce non-insulin-dependent diabetes mellitus (NIDDM), single dose injection of streptozotocin (STZ; 100 mg/kg body weight; i.p.) was given to 2-day old rats. After 10-12 weeks, rats weighing >150 g were selected for screening in NIDDM model, they were checked for fasting blood glucose concentrations to conform the status of NIDDM. NBDP (50,100 and 200 mg/kg body weight) was administered orally for 6 weeks into the confirmed diabetic rats. The activities of gluconeogenic enzymes were significantly increased, whereas the activities of hexokinase and glucose-6-phosphate dehydrogenase were significantly decreased in nSTZ diabetic rats. Both NBDP and metformin were able to restore the altered enzyme activities to almost control concentrations. Combination treatment was more effective than either drug alone. The administration of NBDP along with metformin to nSTZ diabetic rats normalizes blood glucose and causes marked improvement of altered carbohydrate metabolic enzymes during diabetes.

  20. Investigation of Risk Factors Affecting Lactate Levels in Japanese Patients Treated with Metformin.

    PubMed

    Yokoyama, Shota; Tsuji, Hideyuki; Hiraoka, Sachiko; Nishihara, Masayuki

    2016-01-01

    Metformin is a biguanaide antidiabetic drug used worldwide, and its effectiveness and benefits have already been established. However, the safety of high doses of metformin in Japanese patients, especially in elderly patients with a decreased renal function, remains unclear. Among the side effects of metformin, lactate acidosis is the most problematic due to a high mortality rate. Therefore, we assessed plasma lactate levels in metformin-treated patients to identify independent risk factors for hyperlactemia. 290 outpatients receiving various doses of metformin at our hospital were enrolled between March and July 2014. Serum electrolytes, Cre (creatinine), BUN (blood urea nitrogen), UA (uric acid), HbA1c (hemoglobin A1c), and lactate levels were investigated. Lactate levels did not significantly differ between the elderly (≥75 years) and non-elderly (<75 years) groups. Patients in the elderly group had a significantly lower daily metformin dose and estimated glomerular filtration rate (eGFR), compared with the non-elderly group (both p<0.005). Between with and without hyperlactemia groups, no significant differences were observed in either Cre or age. On the other hand, patients with hyperlactemia had a significantly higher dose of metformin than those without hyperlactemia (p<0.05). In this study, we found that old age and mildly impaired kidney function were not associated with increased lactate levels, and that a higher dose of metformin may be an independent risk factor for elevated lactate levels in Japanese patients.

  1. Metformin treatment of type 2 diabetes mellitus in pregnancy: update on safety and efficacy.

    PubMed

    Polasek, Thomas M; Doogue, Matthew P; Thynne, Tilenka R J

    2018-06-01

    With the increasing prevalence of type 2 diabetes mellitus (T2DM) in women of childbearing age, prescribing antidiabetic medications in first-trimester pregnancy is becoming more common. Metformin treatment during this time is usually avoided in countries with well-resourced healthcare. This is based on historical concerns about safety to the foetus and the widespread availability of insulin. However, there is now increasing interest in the potential benefits of metformin in pregnant women with T2DM. In this commentary, the main evidence supporting metformin safety in pregnancy is summarized, with an emphasis on the first trimester. Based on a structured literature search, the recent randomized controlled trials comparing metformin and insulin are reviewed. We then show that prescribing advice for metformin in pregnancy is inconsistent and product information/package inserts (PI) are universally out of date. This causes confusion and pushes some women and their clinicians to change from metformin to insulin. The potential advantages of metformin in pregnant women with T2DM are then discussed, including oral dosing and improved acceptability, lower resource utilization and cost, decreased insulin requirements, less maternal weight gain and less risk of maternal and neonatal hypoglycaemia. The conclusion is that metformin is a cheap and efficacious antidiabetic medication for many pregnant women with T2DM, with reasonable evidence for safety. Drug information resources should be updated so that metformin can be considered more broadly in women with T2DM who present for antenatal care.

  2. Cardioprotective Effect of Aloe vera Biomacromolecules Conjugated with Selenium Trace Element on Myocardial Ischemia-Reperfusion Injury in Rats.

    PubMed

    Yang, Yang; Yang, Ming; Ai, Fen; Huang, Congxin

    2017-06-01

    The present study was undertaken to evaluate the cardioprotection potential and underlying molecular mechanism afforded by a selenium (Se) polysaccharide (Se-AVP) from Aloe vera in the ischemia-reperfusion (I/R) model of rats in vivo. Myocardial I/R injury was induced by occluding the left anterior descending coronary artery (LAD) for 30 min followed by 2-h continuous reperfusion. Pretreatment with Se-AVP (100, 200, and 400 mg/kg) attenuated myocardial damage, as evidenced by reduction of the infarct sizes, increase in serum and myocardial endogenous antioxidants (superoxide dismutase (SOD), glutathione peroxidase (GSH), and catalase (CAT)), and decrease in the malondialdehyde (MDA) level in the rats suffering I/R injury. This cardioprotective activity afforded by Se-AVP is further supported by the decreased levels of cardiac marker enzymes creatine kinase (CK) and lactate dehydrogenase (LDH), as well as the rise of myocardial Na + -K + -ATPase and Ca 2+ -Mg 2+ -ATPase activities in I/R rats. Additionally, cardiomyocytic apoptosis was measured by terminal-deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) staining and the result showed that the percent of TUNEL-positive cells in myocardium of Se-AVP-treated groups was lower than I/R rats. In conclusion, we clearly demonstrated that Se-AVP had a protective effect against myocardial I/R injury in rats by augmenting endogenous antioxidants and protecting rat hearts from oxidative stress-induced myocardial apoptosis.

  3. Twenty years of ovulation induction with metformin for PCOS; what is the best available evidence?

    PubMed

    Abu Hashim, Hatem

    2016-01-01

    The potential reproductive benefits of metformin, a drug endowed with the capacity to ameliorate insulin resistance in polycystic ovary syndrome (PCOS), has garnered much interest over the past 2 decades. In this review, randomized-controlled trials (RCT) and meta-analyses of RCT comparing metformin are critically appraised and summarized. PubMed and CENTRAL databases were consulted. Evidence is insufficient to favour the use of metformin or metformin plus clomiphene citrate instead of clomiphene citrate for ovulation induction in women with newly diagnosed PCOS. Evidence is also insufficient to recommend metformin as a primary treatment for non-obese women with PCOS. Metformin plus clomiphene citrate should be considered as an effective option in clomiphene citrate-resistant PCOS. In women with PCOS undergoing gonadotrophin ovulation induction, metformin significantly increased pregnancy and live birth rates (P < 0.0001 and P = 0.020, respectively) with reduced risk of cancelled cycles. A beneficial effect of metformin co-treatment in increasing clinical pregnancy rates and reducing the risk of OHSS in PCOS patients undergoing assisted reproduction techniques has been shown. No evidence was found of reduced risk of spontaneous abortion or increased risk of major anomalies in women with PCOS taking metformin during the first trimester. Copyright © 2015 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

  4. Metformin in Gestational Diabetes: The Offspring Follow-Up (MiG TOFU)

    PubMed Central

    Rowan, Janet A.; Rush, Elaine C.; Obolonkin, Victor; Battin, Malcolm; Wouldes, Trecia; Hague, William M.

    2011-01-01

    OBJECTIVE In women with gestational diabetes mellitus, who were randomized to metformin or insulin treatment, pregnancy outcomes were similar (Metformin in Gestational diabetes [MiG] trial). Metformin crosses the placenta, so it is important to assess potential effects on growth of the children. RESEARCH DESIGN AND METHODS In Auckland, New Zealand, and Adelaide, Australia, women who had participated in the MiG trial were reviewed when their children were 2 years old. Body composition was measured in 154 and 164 children whose mothers had been randomized to metformin and insulin, respectively. Children were assessed with anthropometry, bioimpedance, and dual energy X-ray absorptiometry (DEXA), using standard methods. RESULTS The children were similar for baseline maternal characteristics and pregnancy outcomes. In the metformin group, compared with the insulin group, children had larger mid-upper arm circumferences (17.2 ± 1.5 vs. 16.7 ± 1.5 cm; P = 0.002) and subscapular (6.3 ± 1.9 vs. 6.0 ± 1.7 mm; P = 0.02) and biceps skinfolds (6.03 ± 1.9 vs. 5.6 ± 1.7 mm; P = 0.04). Total fat mass and percentage body fat assessed by bioimpedance (n = 221) and DEXA (n = 114) were not different. CONCLUSIONS Children exposed to metformin had larger measures of subcutaneous fat, but overall body fat was the same as in children whose mothers were treated with insulin alone. Further follow-up is required to examine whether these findings persist into later life and whether children exposed to metformin will develop less visceral fat and be more insulin sensitive. If so, this would have significant implications for the current pandemic of diabetes. PMID:21949222

  5. Combined metformin and clomiphene citrate versus laparoscopic ovarian diathermy for ovulation induction in clomiphene-resistant women with polycystic ovary syndrome: a randomized controlled trial.

    PubMed

    Abu Hashim, Hatem; El Lakany, Naser; Sherief, Lotfy

    2011-03-01

    To compare the effect of combined metformin and clomiphene citrate (CC) with laparoscopic ovarian diathermy (LOD) meant for ovulation induction in CC-resistant women with polycystic ovary syndrome (PCOS). Two-hundred and eighty-two anovulatory women with CC-resistant PCOS were selected in this randomized controlled trial. Patients (n = 138) received combined metformin-CC for up to six cycles or underwent LOD (n = 144) with six months follow up. The outcome measures were: ovulation rate, midcycle endometrial thickness, pregnancy and miscarriage rates. Ovulation occurred in 386/576 cycles (67%) in the combined metformin-CC group and 381/558 cycles (68.2%) in LOD group without a significant difference between the groups. Resumption of regular menstruation was similar in both groups. A significant increase in midcycle endometrial thickness was observed in the combined metformin-CC group (9.2 ± 1.2 mm vs 7.6 ± 1.1 mm) (P < 0.05). The pregnancy rate was similar in both groups (15.4% vs 17%), and there were no statistically significant differences regarding the miscarriage rate between both groups. Four twin pregnancies occurred in the metformin-CC group. No ovarian hyperstimulation occurred in either group. Combined metformin-CC and LOD are equally effective for inducing ovulation and achieving pregnancy in CC-resistant PCOS patients. © 2010 The Authors. Journal of Obstetrics and Gynaecology Research © 2010 Japan Society of Obstetrics and Gynecology.

  6. Metformin versus dietary treatment in nonalcoholic hepatic steatosis: a randomized study.

    PubMed

    Garinis, G A; Fruci, B; Mazza, A; De Siena, M; Abenavoli, S; Gulletta, E; Ventura, V; Greco, M; Abenavoli, L; Belfiore, A

    2010-08-01

    We aimed at evaluating whether the addition of low-dose metformin to dietary treatment could be an effective approach in nondiabetic patients with nonalcoholic fatty liver disease (NAFLD). We carried out a 6-month prospective study in a series of overweight or obese patients with ultrasonographic diagnosis of hepatic steatosis. In total, 50 patients were enrolled and randomized into two groups: the first group (n=25) was given metformin (1 g per day) plus dietary treatment and the second group (n=25) was given dietary treatment alone. At the end of the study, the proportion of patients with echographic evidence of fatty liver was reduced in both the metformin (P<0.0001) and the diet group (P=0.029). Moreover, patient body mass index and waist circumference significantly decreased in both groups (P<0.001). Fasting glucose, insulin resistance (evaluated as homeostasis model assessment of insulin resistance (HOMA-IR)) and serum adiponectin decreased in both groups, although these changes reached statistical significance only in the metformin group. In this group, HOMA-IR decreased from 3.3+/-1.6 to 2.4+/-1.2 (P=0.003), whereas it decreased from 3.2+/-1.6 to 2.8+/-1.1 (not significant, NS) in the diet group. Similarly, the proportion of patients with impaired fasting glucose declined from 35 to 5% (P=0.04) in the metformin and from 32 to 12% (NS) in the diet group. At baseline, approximately 40% of patients in both groups met the diagnostic criteria of metabolic syndrome. This proportion decreased to 20% in the metformin group (P=0.008) and to 32% in the diet group (NS). In our 6-month prospective study, both low-dose metformin and dietary treatment alone ameliorated liver steatosis and metabolic derangements in patients with NAFLD. However, metformin was more effective than dietary treatment alone in normalizing several metabolic parameters in these patients.

  7. Metformin plus oral contraceptive may decrease plasma sCD40 ligand in women with PCOS patients.

    PubMed

    Kebapcilar, Levent; Kebapcilar, Ayse Gul; Bilgir, Oktay; Taner, Cuneyt Eftal; Bozkaya, Giray; Yildiz, Yasar; Sari, Ismail

    2011-02-01

    To evaluate sCD40L levels in women with polycystic ovary syndrome (PCOS) who use combination therapy with metformin and oral contraceptives. Total of 60 patients with PCOS was studied to evaluate and compare with a non-PCOS group consisting of 30 subjects. A low-dose oral contraceptive containing ethinyl oestradiol-cyproterone acetate (EE/CA) and metformin (M; 850 mg metformin twice a day) were given for three cycles. Plasma sCD40L was measured before and after the treatment of 3 months. At baseline, the sCD40L levels of the patients with PCOS was significantly higher than those of control subjects (3.1 ± 2.0 vs. 2.05 ± 1.0, respectively; p=0.002). An average of 3 months of EE/CA-M therapy induced a significant decrease of sCD40L levels in the PCOS group (3.1 ± 2.0 vs. 2.5 ± 1.0; p=0.026). After having treated patients with PCOS, the sCD40L level was not completely normalised when compared to the healthy controls (2.5 ± 1.0 vs. 2.05 ± 1.0; p=0.039). PCOS is associated with elevated levels of sCD40L. Adding metformin therapy to EE/CA may decrease sCD40L levels in women PCOS. However, after the treatment for PCOS subjects, the sCD40L was not completely normalised when compared patients to healthy controls.

  8. Metformin effects on the heart and the cardiovascular system: A review of experimental and clinical data.

    PubMed

    Nesti, L; Natali, A

    2017-08-01

    Metformin, the eldest and most widely used glucose lowering drug, is likely to be effective also on cardiac and vascular disease prevention. Nonetheless, uncertainty still exists with regard to its effects on the cardiovascular system as a whole and specifically on the myocardium, both at the organ and cellular levels. We reviewed the available data on the cardiac and vascular effects of metformin, encompassing both in vitro, either tissue or isolated organ, and in vivo studies in experimental animals and humans, as well as the evidence generated by major clinical trials. At the cellular level metformin's produces both AMP-activated kinase (AMPK) dependent and independent effects. At the systemic level, possibly also through other pathways, this drug improves endothelial function, protects from oxidative stress and inflammation, and from the negative effects of angiotensin II. On the myocardium it attenuates ischemia-reperfusion injury and prevents adverse remodeling induced by humoral and hemodynamic factors. The effects on myocardial cell metabolism and contractile function being not evident at rest or in more advanced stages of cardiac dysfunction, could be relevant during transient ischemia, during an acute increase in workload and in the early stages of diabetic/hypertensive cardiomyopathy as confirmed by few small clinical trials and some observational studies. The overall evidence emerging from both clinical trials and real world registry is in favor of a protective effect of metformin with respect to both coronary events and progression to heart failure. Given this potential, its efficacy and its safety (and also its low cost) metformin remains the central pillar of the therapy of diabetes. Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

  9. DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action in human liver cancer cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Obara, Akio; Fujita, Yoshihito; Abudukadier, Abulizi

    Metformin, one of the most commonly used drugs for patients with type 2 diabetes, recently has received much attention regarding its anti-cancer action. It is thought that the suppression of mTOR signaling is involved in metformin's anti-cancer action. Although liver cancer is one of the most responsive types of cancer for reduction of incidence by metformin, the molecular mechanism of the suppression of mTOR in liver remains unknown. In this study, we investigated the mechanism of the suppressing effect of metformin on mTOR signaling and cell proliferation using human liver cancer cells. Metformin suppressed phosphorylation of p70-S6 kinase, and ribosomemore » protein S6, downstream targets of mTOR, and suppressed cell proliferation. We found that DEPTOR, an endogenous substrate of mTOR suppression, is involved in the suppressing effect of metformin on mTOR signaling and cell proliferation in human liver cancer cells. Metformin increases the protein levels of DEPTOR, intensifies binding to mTOR, and exerts a suppressing effect on mTOR signaling. This increasing effect of DEPTOR by metformin is regulated by the proteasome degradation system; the suppressing effect of metformin on mTOR signaling and cell proliferation is in a DEPTOR-dependent manner. Furthermore, metformin exerts a suppressing effect on proteasome activity, DEPTOR-related mTOR signaling, and cell proliferation in an AMPK-dependent manner. We conclude that DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action in liver, and could be a novel target for anti-cancer therapy. - Highlights: • We elucidated a novel pathway of metformin's anti-cancer action in HCC cells. • DEPTOR is involved in the suppressing effect of metformin on mTOR signaling. • Metformin increases DEPTOR protein levels via suppression of proteasome activity. • DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action.« less

  10. Ischemic postconditioning provides cardioprotective and antiapoptotic effects against ischemia-reperfusion injury through iNOS inhibition in hyperthyroid rats.

    PubMed

    Zaman, Jalal; Jeddi, Sajad; Daneshpour, Maryam Sadat; Zarkesh, Maryam; Daneshian, Zahra; Ghasemi, Asghar

    2015-10-10

    Ischemic postconditioning (IPost) is a strategy to provide protection against ischemia-reperfusion (IR) injury. The cardioprotective effects of IPost in cases of ischemic heart disease along with co-morbidities like hyperthyroidism remain unknown. The aim of this study was to investigate the effects of IPost on expression of eNOS, iNOS, Bax, and Bcl-2 genes in hyperthyroid male rats, subjected to myocardial IR. Hyperthyroidism was induced by adding thyroxine to drinking water for a period of 21 days. Using the Langendorff device hearts were perfused, then subjected to a 30-minute global ischemia which was followed by 120 min of reperfusion; subsequently IPost was induced immediately after ischemia. Results indicated that following IR, expression of eNOS and Bcl-2 decreased, whereas expression of iNOS and Bax increased in both the control and hyperthyroid groups. In hyperthyroid animals, IPost significantly increased expression of eNOS by 3.19 fold and Bcl-2 by 3.66 fold; it also decreased expression of Bax by 51%, and reduced IR-induced DNA laddering pattern and infarct size (45.7 ± 1.82% vs. 59.3 ± 1.83%, p<0.05) in the presence of aminoguanidine (AG), a selective iNOS inhibitor. In conclusion, IPost per se could not provide cardioprotection against myocardial ischemia in hyperthyroid rats, a loss of which however was restored by the combination of IPost and iNOS inhibition that acts by a decrease in Bax and an increase in both eNOS and Bcl-2 expression. Copyright © 2015 Elsevier B.V. All rights reserved.

  11. Missing the Benefit of Metformin in Acute Myeloid Leukemia: A Problem of Contrast?

    PubMed

    Ceacareanu, Alice C; Nimako, George K; Wintrob, Zachary A P

    2017-01-01

    To evaluate whether metformin's cancer-related benefits reported in patients with solid tumors (ST) are also present in acute myeloid leukemia (AML) patients. Baseline demographic and clinical history for all diabetes mellitus patients newly diagnosed with AML or cancer of the breast, ovary, prostate, gastrointestinal tract, lung, or kidney at Roswell Park Cancer Institute in Buffalo, NY (January 2003-December 2010, n = 924) was collected. Overall survival (OS) and disease-free survival (DFS) were assessed by Kaplan-Meier (KM) analysis and Cox proportional hazards regression (hazard ratio [HR]). Baseline metformin use provided significant OS and DFS benefit in ST but not in AML (KM: P ST-OS = 0.003; P ST-DFS = 0.002; P AML-OS = 0.961; P AML-DFS = 0.943). AML median survival was slightly better with metformin use, but users derived no relapse benefit. In ST, metformin nonusers had shorter median survival, 57.7 versus 86 months, and poorer outcomes (HR ST-OS = 1.33; P ST-OS = 0.002; HR ST-DFS = 1.32; P ST-DFS = 0.002). These findings remained significant in age-adjusted models (HR ST-OS = 1.21; P ST-OS = 0.039; HR ST-DFS = 1.23; P ST-DFS = 0.02) but not fully adjusted models (HR ST-OS = 0.96; P ST-OS = 0.688; HR ST-DFS = 1.0; P ST-DFS = 0.94). Higher mortality was noted in AML patients taking insulin versus oral diabetes pharmacotherapy at baseline (HR AML-OS = 2.03; P AML-OS = 0.04). Lack of metformin benefit in AML could be due to advanced age at cancer diagnosis. Metformin substitution with insulin before computed tomography scans with contrast - a frequent AML assessment practice - may also explain the lack of subsequent benefit despite taking metformin at baseline. A temporary metformin substitution is recommended by the package insert due to a possible drug interaction with the contrast dye. Our data suggest that metformin substitution was permanent in many patients. Nonetheless, the observed benefit in other malignancies warrants further investigation of

  12. Hybrid drug combination: Combination of ferulic acid and metformin as anti-diabetic therapy.

    PubMed

    Nankar, Rakesh; Prabhakar, P K; Doble, Mukesh

    2017-12-15

    Ferulic acid, an anti-oxidant phytochemical present in several dietary components, is known to produce wide range of pharmacological effects. It is approved for use in food industry as a preservative and in sports food. Previous reports from our lab have shown synergistic interaction of ferulic acid with metformin in cell lines and diabetic rats. The purpose of this review is to compile information about anti-diabetic activity of ferulic acid in in vitro and in vivo models with special emphasis on activity of ferulic acid when combined with metformin. The mechanism of synergistic interaction between ferulic acid and metformin is also proposed after carefully studying effects of these compounds on molecules involved in glucose metabolism. Scientific literature for the purpose of this review was collected using online search engines and databases such as ScienceDirect, Scopus, PubMed and Google scholar. Ferulic acid forms resonance stabilized phenoxyl radical which scavenges free radicals and reduce oxidative stress. It improves glucose and lipid profile in diabetic rats by enhancing activities of antioxidant enzymes, superoxide dismutase and catalase in the pancreatic tissue. Combining ferulic acid with metformin improves both, in vitro glucose uptake activity and in vivo hypoglycemic activity of the latter. It is possible to reduce the dose of metformin by four folds (from 50 to 12.5 mg/kg body weight) by combining it with 10 mg of ferulic acid/kg body weight in diabetic rats. Ferulic acid improves glucose uptake through PI3-K pathway whereas metformin activates AMPK pathway to improve glucose uptake. The synergistic interaction of ferulic acid and metformin is due their action on parallel pathways which are involved in glucose uptake. Due to synergistic nature of their interaction, it is possible to reduce the dose of metformin (by combining with ferulic acid) required to achieve normoglycemia. Since the dose of metformin is reduced, the dose associated side

  13. Missing the Benefit of Metformin in Acute Myeloid Leukemia: A Problem of Contrast?

    PubMed Central

    Ceacareanu, Alice C.; Nimako, George K.; Wintrob, Zachary A. P.

    2017-01-01

    Objective: To evaluate whether metformin's cancer-related benefits reported in patients with solid tumors (ST) are also present in acute myeloid leukemia (AML) patients. Methods: Baseline demographic and clinical history for all diabetes mellitus patients newly diagnosed with AML or cancer of the breast, ovary, prostate, gastrointestinal tract, lung, or kidney at Roswell Park Cancer Institute in Buffalo, NY (January 2003–December 2010, n = 924) was collected. Overall survival (OS) and disease-free survival (DFS) were assessed by Kaplan–Meier (KM) analysis and Cox proportional hazards regression (hazard ratio [HR]). Findings: Baseline metformin use provided significant OS and DFS benefit in ST but not in AML (KM: PST-OS= 0.003; PST-DFS= 0.002; PAML-OS= 0.961; PAML-DFS= 0.943). AML median survival was slightly better with metformin use, but users derived no relapse benefit. In ST, metformin nonusers had shorter median survival, 57.7 versus 86 months, and poorer outcomes (HRST-OS= 1.33; PST-OS= 0.002; HRST-DFS= 1.32; PST-DFS= 0.002). These findings remained significant in age-adjusted models (HRST-OS= 1.21; PST-OS= 0.039; HRST-DFS= 1.23; PST-DFS= 0.02) but not fully adjusted models (HRST-OS= 0.96; PST-OS= 0.688; HRST-DFS= 1.0; PST-DFS= 0.94). Higher mortality was noted in AML patients taking insulin versus oral diabetes pharmacotherapy at baseline (HRAML-OS= 2.03; PAML-OS= 0.04). Conclusion: Lack of metformin benefit in AML could be due to advanced age at cancer diagnosis. Metformin substitution with insulin before computed tomography scans with contrast – a frequent AML assessment practice – may also explain the lack of subsequent benefit despite taking metformin at baseline. A temporary metformin substitution is recommended by the package insert due to a possible drug interaction with the contrast dye. Our data suggest that metformin substitution was permanent in many patients. Nonetheless, the observed benefit in other malignancies warrants further

  14. Retrospective chart review of children with type 2 diabetes mellitus evaluating the efficacy of metformin vs. insulin vs. combination insulin/metformin.

    PubMed

    Meyer, Stacy L; Hoffman, Robert P

    2011-10-01

    Type 2 diabetes mellitus is a growing problem in pediatrics and there is no consensus on the best treatment. We conducted this chart review on newly diagnosed pediatric patients with type 2 diabetes mellitus to compare the effect of treatment regimen on body mass index (BMI) and hemoglobin A1c over a 6-month period. We conducted a retrospective chart review on patients with type 2 DM who presented to Nationwide Children's Hospital. Data were collected on therapy type, BMI, and hemoglobin A1c over a 6-month follow-up. Therapy type was divided into metformin, insulin, or combination insulin and metformin. 1,997 charts were reviewed for inclusion based on ICD-9 codes consistent with a diagnosis of diabetes, abnormal oral glucose tolerance test, or insulin resistance. Of the 47 charts eligible for the review, 26 subjects were treated with metformin 1000-1500 mg daily, 14 patients were treated with insulin therapy, and 7 patients were treated with a combination of insulin and metformin therapy. At baseline, the only significant difference among groups was A1c (P = 0.012). In regression analysis with baseline A1c as a covariate, the only predictor of change in A1c over time was the A1c at onset (P < 0.001). Therapy type was not predictive of change (P = 0.905). Regression analysis showed a greater BMI at onset predicted a greater decrease in BMI (P = 0.006), but therapy type did not predict a change (P = 0.517). Metformin may be as effective as insulin or combination therapy for treatment of diabetes from onset to 6-month follow-up.

  15. Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk

    PubMed Central

    Lien, Fleur; Berthier, Alexandre; Bouchaert, Emmanuel; Gheeraert, Céline; Alexandre, Jeremy; Porez, Geoffrey; Prawitt, Janne; Dehondt, Hélène; Ploton, Maheul; Colin, Sophie; Lucas, Anthony; Patrice, Alexandre; Pattou, François; Diemer, Hélène; Van Dorsselaer, Alain; Rachez, Christophe; Kamilic, Jelena; Groen, Albert K.; Staels, Bart; Lefebvre, Philippe

    2014-01-01

    The nuclear bile acid receptor farnesoid X receptor (FXR) is an important transcriptional regulator of bile acid, lipid, and glucose metabolism. FXR is highly expressed in the liver and intestine and controls the synthesis and enterohepatic circulation of bile acids. However, little is known about FXR-associated proteins that contribute to metabolic regulation. Here, we performed a mass spectrometry–based search for FXR-interacting proteins in human hepatoma cells and identified AMPK as a coregulator of FXR. FXR interacted with the nutrient-sensitive kinase AMPK in the cytoplasm of target cells and was phosphorylated in its hinge domain. In cultured human and murine hepatocytes and enterocytes, pharmacological activation of AMPK inhibited FXR transcriptional activity and prevented FXR coactivator recruitment to promoters of FXR-regulated genes. Furthermore, treatment with AMPK activators, including the antidiabetic biguanide metformin, inhibited FXR agonist induction of FXR target genes in mouse liver and intestine. In a mouse model of intrahepatic cholestasis, metformin treatment induced FXR phosphorylation, perturbed bile acid homeostasis, and worsened liver injury. Together, our data indicate that AMPK directly phosphorylates and regulates FXR transcriptional activity to precipitate liver injury under conditions favoring cholestasis. PMID:24531544

  16. Cardioprotective properties of Crataegus oxycantha extract against ischemia-reperfusion injury

    PubMed Central

    Swaminathan, Jayachandran Kesavan; Khan, Mahmood; Mohan, Iyappu K; Selvendiran, Karuppaiyah; Devaraj, S. Niranjali; Rivera, Brian K.; Kuppusamy, Periannan

    2010-01-01

    The aim of the study was to investigate the cardioprotective effect and mechanism of Crataegus oxycantha (COC) extract, a well-known natural antioxidant-based cardiotonic, against ischemia/reperfusion (I/R) injury. Electron paramagnetic resonance studies showed that COC extract was capable of scavenging superoxide, hydroxyl, and peroxyl radicals, in vitro. The cardioprotective efficacy of the extract was studied in a crystalloid perfused heart model of I/R injury. Hearts were subjected to 30 min of global ischemia followed by 45 min of reperfusion. During reperfusion, COC extract was infused at a dose rate of 1 mg/ml/min for 10 min. Hearts treated with COC extract showed a significant recovery in cardiac contractile function, reduction in infarct size, and decrease in creatine kinase and lactate dehydrogenase activities. The expressions of xanthine oxidase and NADPH oxidase were significantly reduced in the treated group. A significant upregulation of the anti-apoptotic proteins Bcl-2 and Hsp70 with simultaneous downregulation of the pro-apoptotic proteins cytochrome c and cleaved caspase-3 was observed. The molecular signaling cascade including phospho-Akt (ser-473) and HIF-1α that lead to the activation or suppression of apoptotic pathway also showed a significant protective role in the treatment group. No significant change in phospho-p38 levels was observed. The results suggested that the COC extract may reduce the oxidative stress in the reperfused myocardium, and play a significant role in the inhibition of apoptotic pathways leading to cardioprotection. PMID:20171068

  17. Metformin use and risk of prostate cancer: results from the REDUCE study.

    PubMed

    Feng, Tom; Sun, Xizi; Howard, Lauren E; Vidal, Adriana C; Gaines, Alexis R; Moreira, Daniel M; Castro-Santamaria, Ramiro; Andriole, Gerald L; Freedland, Stephen J

    2015-11-01

    The role of metformin in prostate cancer chemoprevention remains unclear. REDUCE, which followed biopsy-negative men with protocol-dictated PSA-independent biopsies at 2- and 4-years, provides an opportunity to evaluate the link between metformin use and prostate cancer diagnosis with minimal confounding from screening biases. In diabetic men from REDUCE, we tested the association between metformin use, use of other antidiabetic medications, versus no antidiabetic medication use, and prostate cancer diagnosis as well as prostate cancer grade (low-grade Gleason 4-6 and high-grade Gleason 7-10) using logistic regression. Of the 540 diabetic men with complete data, 205 (38%) did not report use of any antidiabetic medications, 141 (26%) reported use of at least one antidiabetic medication other than metformin, and 194 (36%) reported use of metformin. During the 4-year study, 122 men (23%) were diagnosed with prostate cancer. After adjusting for various clinical and demographic characteristics, we found that metformin use was not significantly associated with total (OR, 1.19; P = 0.50), low- (OR, 1.01; P = 0.96), or high-grade (OR, 1.83; P = 0.19) prostate cancer diagnosis. Likewise, there was no significant association between the use of non-metformin antidiabetic medications and prostate cancer risk in both crude (OR, 1.02; P = 0.95) and multivariable analysis (OR, 0.85; P = 0.56). Furthermore, the interactions between antidiabetic medication use and BMI, geographic location, coronary artery disease, smoking, and treatment group were not significant (all P > 0.05). Among diabetic men with a negative prestudy biopsy who all underwent biopsies largely independent of PSA, metformin use was not associated with reduced risk of prostate cancer diagnosis. ©2015 American Association for Cancer Research.

  18. Ursodeoxycholic acid protects cardiomyocytes against cobalt chloride induced hypoxia by regulating transcriptional mediator of cells stress hypoxia inducible factor 1α and p53 protein.

    PubMed

    Mohamed, Anis Syamimi; Hanafi, Noorul Izzati; Sheikh Abdul Kadir, Siti Hamimah; Md Noor, Julina; Abdul Hamid Hasani, Narimah; Ab Rahim, Sharaniza; Siran, Rosfaiizah

    2017-10-01

    In hepatocytes, ursodeoxycholic acid (UDCA) activates cell signalling pathways such as p53, intracellular calcium ([Ca 2+ ] i ), and sphingosine-1-phosphate (S1P)-receptor via Gα i -coupled-receptor. Recently, UDCA has been shown to protect the heart against hypoxia-reoxygenation injury. However, it is not clear whether UDCA cardioprotection against hypoxia acts through a transcriptional mediator of cells stress, HIF-1α and p53. Therefore, in here, we aimed to investigate whether UDCA could protect cardiomyocytes (CMs) against hypoxia by regulating expression of HIF-1α, p53, [Ca 2+ ] i , and S1P-Gα i -coupled-receptor. Cardiomyocytes were isolated from newborn rats (0-2 days), and hypoxia was induced by using cobalt chloride (CoCl 2 ). Cardiomyocytes were treated with UDCA and cotreated with either FTY720 (S1P-receptor agonist) or pertussis toxin (PTX; Gα i inhibitor). Cells were subjected for proliferation assay, beating frequency, QuantiGene Plex assay, western blot, immunofluorescence, and calcium imaging. Our findings showed that UDCA counteracted the effects of CoCl 2 on cell viability, beating frequency, HIF-1α, and p53 protein expression. We found that these cardioprotection effects of UDCA were similar to FTY720, S1P agonist. Furthermore, we observed that UDCA protects CMs against CoCl 2 -induced [Ca 2+ ] i dynamic alteration. Pharmacological inhibition of the Gα i -sensitive receptor did not abolish the cardioprotection of UDCA against CoCl 2 detrimental effects, except for cell viability and [Ca 2+ ] i . Pertussis toxin is partially effective in inhibiting UDCA protection against CoCl 2 effects on CM cell viability. Interestingly, PTX fully inhibits UDCA cardioprotection on CoCl 2 -induced [Ca 2+ ] i dynamic changes. We conclude that UDCA cardioprotection against CoCl 2 -induced hypoxia is similar to FTY720, and its actions are not fully mediated by the Gα i -coupled protein sensitive pathways. Ursodeoxycholic acid is the most hydrophilic bile

  19. Metformin combined with aspirin significantly inhibit pancreatic cancer cell growth in vitro and in vivo by suppressing anti-apoptotic proteins Mcl-1 and Bcl-2

    PubMed Central

    Yue, Wen; Zheng, Xi; Lin, Yong; Yang, Chung S.; Xu, Qing; Carpizo, Darren; Huang, Huarong; DiPaola, Robert S.; Tan, Xiang-Lin

    2015-01-01

    Metformin and aspirin have been studied extensively as cancer preventive or therapeutic agents. However, the effects of their combination on pancreatic cancer cells have not been investigated. Herein, we evaluated the effects of metformin and aspirin, alone or in combination, on cell viability, migration, and apoptosis as well as the molecular changes in mTOR, STAT3 and apoptotic signaling pathways in PANC-1 and BxPC3 cells. Metformin and aspirin, at relatively low concentrations, demonstrated synergistically inhibitory effects on cell viability. Compared to the untreated control or individual drug, the combination of metformin and aspirin significantly inhibited cell migration and colony formation of both PANC-1 and BxPC-3 cells. Metformin combined with aspirin significantly inhibited the phosphorylation of mTOR and STAT3, and induced apoptosis as measured by caspase-3 and PARP cleavage. Remarkably, metformin combined with aspirin significantly downregulated the anti-apoptotic proteins Mcl-1 and Bcl-2, and upregulated the pro-apoptotic proteins Bim and Puma, as well as interrupted their interactions. The downregulation of Mcl-1 and Bcl-2 was independent of AMPK or STAT3 pathway but partially through mTOR signaling and proteasome degradation. In a PANC-1 xenograft mouse model, we demonstrated that the combination of metformin and aspirin significantly inhibited tumor growth and downregulated the protein expression of Mcl-1 and Bcl-2 in tumors. Taken together, the combination of metformin and aspirin significantly inhibited pancreatic cancer cell growth in vitro and in vivo by regulating the pro- and anti-apoptotic Bcl-2 family members, supporting the continued investigation of this two drug combination as chemopreventive or chemotherapeutic agents for pancreatic cancer. PMID:26056043

  20. Acarbose plus metformin fixed-dose combination outperforms acarbose monotherapy for type 2 diabetes.

    PubMed

    Wang, Jun-Sing; Huang, Chien-Ning; Hung, Yi-Jen; Kwok, Ching-Fai; Sun, Jui-Hung; Pei, Dee; Yang, Chwen-Yi; Chen, Ching-Chu; Lin, Ching-Ling; Sheu, Wayne Huey-Herng

    2013-10-01

    To compare the efficacy and safety of acarbose plus metformin fixed-dose combination (FDC) versus acarbose monotherapy for type 2 diabetes (T2D). Eligible T2D patients undergoing treatment with diet control only or oral antidiabetic medications were run-in on acarbose 50mg thrice-daily for 4 weeks, then randomised either to continue this monotherapy, or to acarbose 50mg plus metformin hydrochloride 500mg FDC (acarbose/metformin FDC), each thrice-daily for 16 weeks. Acarbose/metformin FDC therapy significantly reduced HbA1c, fasting plasma glucose (FPG), and postprandial plasma glucose (PPG) from baseline (all p<0.0001) with superior efficacy compared with acarbose monotherapy (between-group differences; HbA1c -1.35%; FPG -29.5mg/dl; PPG -41.6mg/dl; all p<0.0001). Proportionally more patients treated with acarbose/metformin FDC achieved HbA1c <7.0% (47.8% vs. 10.7%, p<0.0001). Both treatments reduced bodyweight (p<0.0001), with a significant between-group difference (-0.6kg, p<0.01) favouring acarbose/metformin FDC. Hypoglycaemia was not reported with either treatment, and the incidence of other adverse events did not differ significantly between the groups. Compared with acarbose monotherapy, acarbose/metformin FDC has superior antihyperglycaemic efficacy, brings proportionally more T2D patients to HbA1c goal, and further reduces bodyweight. Acarbose/metformin FDC is well-tolerated without significant risk of hypoglycaemia and is a potentially advantageous therapy for T2D. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  1. Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis.

    PubMed

    Naderpoor, Negar; Shorakae, Soulmaz; de Courten, Barbora; Misso, Marie L; Moran, Lisa J; Teede, Helena J

    2015-01-01

    Polycystic ovary syndrome (PCOS) is a common endocrine disorder with diverse reproductive and metabolic features. It is underpinned by insulin resistance that is exacerbated by obesity. Lifestyle modification is the first line treatment in PCOS, but it is associated with low adherence and sustainability. In small studies, metformin improves outcomes such as hyperinsulinaemia, ovulation and menstrual cyclicity. We conducted a systematic review and meta-analysis to compare the effect of lifestyle modification + metformin with lifestyle modification ± placebo, and of metformin alone with lifestyle modification ± placebo in PCOS on anthropometric, metabolic, reproductive and psychological outcomes. Databases including MEDLINE, EMBASE, Pubmed, Scopus, Cochrane, PsycINFO, CINAHL, Clinical Trials registry and ANZCTR were searched for RCTs conducted on humans and published in English up to August 2014. Inclusion criteria were diagnosis of PCOS based on Rotterdam criteria (inclusive of National Institutes of Health criteria) at any age and with any BMI. Interventions of interest included lifestyle + metformin (with any dose and any duration) or metformin alone compared with lifestyle ± placebo. Of 2372 identified studies, 12 RCTs were included for analysis comprising 608 women with PCOS. Lifestyle + metformin were associated with lower BMI (mean difference (MD) -0.73 kg/m(2), 95% confidence intervals (CI) -1.14, -0.32, P = 0.0005) and subcutaneous adipose tissue (MD -92.49 cm(2), 95% CI -164.14, -20.84, P = 0.01) and increased number of menstrual cycles (MD 1.06, 95% CI 0.30, 1.82, P = 0.006) after 6 months compared with lifestyle ± placebo. There were no differences in other anthropometric, metabolic (surrogate markers of insulin resistance, fasting and area under the curve glucose, lipids and blood pressure), reproductive (clinical and biochemical hyperandrogenism), and psychological (quality of life) outcomes after 6 months between lifestyle + metformin compared with

  2. Cardioprotective Effects of Astragalin against Myocardial Ischemia/Reperfusion Injury in Isolated Rat Heart.

    PubMed

    Qu, Daoxu; Han, Jichun; Ren, Huanhuan; Yang, Wenxiao; Zhang, Xinjie; Zheng, Qiusheng; Wang, Dong

    2016-01-01

    This study aims to evaluate the cardioprotective effects of astragalin against myocardial ischemia/reperfusion (I/R) injury in isolated rat heart. The cardioprotective effects of astragalin on myocardial I/R injury were investigated on Langendorff apparatus. Adult male Sprague-Dawley rats were randomly divided into five groups. The results showed that astragalin pretreatment improved myocardial function. Compared with I/R group, lactate dehydrogenase (LDH) and creatine kinase (CK) activities in coronary flow decreased in astragalin pretreatment groups, whereas superoxide dismutase (SOD) activity and glutathione/glutathione disulfide (GSH/GSSG) ratio significantly increased. The levels of malondialdehyde (MDA), intracellular reactive oxygen species (ROS), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) decreased in astragalin-treated groups. The infarct size (IS) and apoptosis rate in hearts from astragalin-treated groups were lower than those in hearts from the I/R group. Western blot analysis also revealed that astragalin preconditioning significantly reduced Bax level, whereas Bcl-2 was increased in the myocardium. Therefore, astragalin exhibited cardioprotective effects via its antioxidative, antiapoptotic, and anti-inflammatory activities.

  3. Cardioprotective Effects of Astragalin against Myocardial Ischemia/Reperfusion Injury in Isolated Rat Heart

    PubMed Central

    Qu, Daoxu; Ren, Huanhuan; Yang, Wenxiao; Zhang, Xinjie; Zheng, Qiusheng; Wang, Dong

    2016-01-01

    This study aims to evaluate the cardioprotective effects of astragalin against myocardial ischemia/reperfusion (I/R) injury in isolated rat heart. The cardioprotective effects of astragalin on myocardial I/R injury were investigated on Langendorff apparatus. Adult male Sprague-Dawley rats were randomly divided into five groups. The results showed that astragalin pretreatment improved myocardial function. Compared with I/R group, lactate dehydrogenase (LDH) and creatine kinase (CK) activities in coronary flow decreased in astragalin pretreatment groups, whereas superoxide dismutase (SOD) activity and glutathione/glutathione disulfide (GSH/GSSG) ratio significantly increased. The levels of malondialdehyde (MDA), intracellular reactive oxygen species (ROS), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) decreased in astragalin-treated groups. The infarct size (IS) and apoptosis rate in hearts from astragalin-treated groups were lower than those in hearts from the I/R group. Western blot analysis also revealed that astragalin preconditioning significantly reduced Bax level, whereas Bcl-2 was increased in the myocardium. Therefore, astragalin exhibited cardioprotective effects via its antioxidative, antiapoptotic, and anti-inflammatory activities. PMID:26788251

  4. Cardioprotective effects of calcitonin gene-related peptide in isolated rat heart and in H9c2 cells via redox signaling.

    PubMed

    Tullio, Francesca; Penna, Claudia; Cabiale, Karine; Femminò, Saveria; Galloni, Marco; Pagliaro, Pasquale

    2017-06-01

    The calcitonin-gene-related-peptide (CGRP) release is coupled to the signaling of Angeli's salt in determining vasodilator effects. However, it is unknown whether CGRP is involved in Angeli's salt cardioprotective effects and which are the mechanisms of protection. We aimed to determine whether CGRP is involved in myocardial protection induced by Angeli's salt. We also analyzed the intracellular signaling pathway activated by CGRP. Isolated rat hearts were pre-treated with Angeli's salt or Angeli's salt plus CGRP 8-37 , a specific CGRP-receptor antagonist, and subjected to ischemia (30-min) and reperfusion (120-min). Moreover, we studied CGRP-induced protection during oxidative stress (H 2 O 2 ) and hypoxia/reoxygenation protocols in H9c2 cardiomyocytes. Cell vitality and mitochondrial membrane potential (ΔYm, MMP) were measured using MTT and JC-1 dyes. Angeli's salt reduced infarct size and ameliorated post-ischemic cardiac function via a CGRP-receptor-dependent mechanism. Pre-treatment with CGRP increased H9c2 survival upon challenging with either H 2 O 2 (redox stress) or hypoxia/reoxygenation (H/R stress). Under these stress conditions, reduction in MMP and cell death were partly prevented by CGRP. These CGRP beneficial effects were blocked by CGRP 8-37. During H/R stress, pre-treatment with either CGRP-receptor, protein kinase C (PKC) or mitochondrial K ATP channel antagonists, and pre-treatment with an antioxidant (2-mercaptopropionylglycine) blocked the protection mediated by CGRP. In conclusion, CGRP is involved in the cardioprotective effects of Angeli's salt. In H9c2 cardiomyocytes, CGRP elicits PKC-dependent and mitochondrial-K ATP -redox-dependent mechanisms. Hence, CGRP is an important factor in the redox-sensible cardioprotective effects of Angeli's salt. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  5. Effects of metformin on energy intake and satiety in obese children.

    PubMed

    Adeyemo, M A; McDuffie, J R; Kozlosky, M; Krakoff, J; Calis, K A; Brady, S M; Yanovski, J A

    2015-04-01

    To investigate the effects of metformin on appetite and energy intake in obese children with hyperinsulinaemia. We conducted a 6-month randomized, double-blind, placebo-controlled trial to evaluate the effects of metformin 1000 mg twice daily on body weight and energy balance in 100 obese children with hyperinsulinaemia aged 6-12 years. The children ate ad libitum from standardized food arrays on two separate occasions before and after 6 months of study medication. The first test meal was consumed after an overnight fast. The second was preceded by a pre-meal load. For each test meal, energy intake was recorded, and the children completed scales of hunger, fullness and desire to eat. Data from the meal studies at baseline and after treatment with study medication were available for 84 children (metformin-treated, n = 45; placebo-treated, n = 39). Compared with placebo, metformin treatment elicited significant reductions from baseline in adjusted mean ± standard error of the mean energy intake after the pre-meal load (metformin: -104.7 ± 83.8 kcal vs. placebo: +144.2 ± 96.9 kcal; p = 0.034) independently of changes in body composition. Metformin also significantly decreased ratings of hunger (-1.5 ± 5.6 vs. +18.6 ± 6.3; p = 0.013) and increased ratings of fullness (+10.1 ± 6.2 vs. -12.8 ± 7.0; p = 0.01) after the pre-meal load. These data suggest that decreased perceived hunger resulting in diminished food intake are among the mechanisms by which metformin treatment reduces body weight in overweight children with hyperinsulinaemia. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

  6. Opioid receptors and cardioprotection – ‘opioidergic conditioning’ of the heart

    PubMed Central

    Headrick, John P; See Hoe, Louise E; Du Toit, Eugene F; Peart, Jason N

    2015-01-01

    Ischaemic heart disease (IHD) remains a major cause of morbidity/mortality globally, firmly established in Westernized or ‘developed’ countries and rising in prevalence in developing nations. Thus, cardioprotective therapies to limit myocardial damage with associated ischaemia–reperfusion (I–R), during infarction or surgical ischaemia, is a very important, although still elusive, clinical goal. The opioid receptor system, encompassing the δ (vas deferens), κ (ketocyclazocine) and μ (morphine) opioid receptors and their endogenous opioid ligands (endorphins, dynorphins, enkephalins), appears as a logical candidate for such exploitation. This regulatory system may orchestrate organism and organ responses to stress, induces mammalian hibernation and associated metabolic protection, triggers powerful adaptive stress resistance in response to ischaemia/hypoxia (preconditioning), and mediates cardiac benefit stemming from physical activity. In addition to direct myocardial actions, central opioid receptor signalling may also enhance the ability of the heart to withstand I–R injury. The δ- and κ-opioid receptors are strongly implicated in cardioprotection across models and species (including anti-infarct and anti-arrhythmic actions), with mixed evidence for μ opioid receptor-dependent protection in animal and human tissues. A small number of clinical trials have provided evidence of cardiac benefit from morphine or remifentanil in cardiopulmonary bypass or coronary angioplasty patients, although further trials of subtype-specific opioid receptor agonists are needed. The precise roles and utility of this GPCR family in healthy and diseased human myocardium, and in mediating central and peripheral survival responses, warrant further investigation, as do the putative negative influences of ageing, IHD co-morbidities, and relevant drugs on opioid receptor signalling and protective responses. PMID:25521834

  7. Major malformation risk, pregnancy outcomes, and neurodevelopmental outcomes associated with metformin use during pregnancy.

    PubMed

    Andrade, Chittaranjan

    2016-04-01

    There are several reasons why metformin treatment may be considered for women in neuropsychiatric practice. These include prevention or attenuation of antipsychotic-associated weight gain, prevention or treatment of gestational diabetes mellitus (GDM), treatment of type 2 diabetes mellitus, and improvement of conception chances and pregnancy outcomes in the presence of polycystic ovarian disease (PCOD). This article examines the benefits and risks associated with metformin use during pregnancy. The available data suggest that metformin exposure during the first trimester is not associated with major congenital malformations; that metformin reduces the risk of early pregnancy loss, preeclampsia, preterm delivery, and GDM in women with PCOD; that metformin is associated with at least comparable benefits relative to insulin treatment in women with mild GDM; and that neurodevelopmental outcomes at age 1.5-2.5 years are comparable after gestational exposure to metformin and insulin. Whereas study designs were not always ideal and sample sizes were mostly small to modest, the study findings are more encouraging than discouraging and can guide shared decision-making in women who are receiving or may need metformin during pregnancy. © Copyright 2016 Physicians Postgraduate Press, Inc.

  8. Cardioprotective effects of red wine and vodka in a model of endothelial dysfunction

    PubMed Central

    Lassaletta, Antonio D; Chu, Louis M; Elmadhun, Nassrene Y; Burgess, Thomas A; Feng, Jun; Robich, Michael P; Sellke, Frank W

    2012-01-01

    Background Moderate alcohol consumption is largely believed to be cardioprotective, while red wine is hypothesized to offer benefit in part due to the pro-angiogenic and antioxidant properties of polyphenols. We investigated the cardiovascular effects of both red wine and vodka in a swine model of endothelial dysfunction. Methods Twenty-seven male Yorkshire swine fed a high-fat/cholesterol diet were divided into three groups and received either no alcohol (Control), red wine, or vodka. After seven weeks, myocardial perfusion was measured, and ventricular tissue was analyzed for microvascular reactivity, and immunohistochemical studies. Results There were no differences in myocardial perfusion, in arteriolar or capillary density, or in VEGF expression among groups. Total protein oxidation as well as expression of superoxide dismutase-1 and -2 (SOD1, SOD2) and NADPH-oxidase (NOX2) was decreased in both treatment groups compared to controls. Endothelium-dependent microvessel relaxation, however, was significantly improved only in the red wine-supplemented group. Conclusions Supplementation with both red wine and vodka decreased oxidative stress by several measures, implicating the effects of ethanol in reducing oxidative stress in the myocardium. However, it was only in the red wine-supplemented group that an improvement in microvessel function was observed. This suggests that a component of red wine, independent of ethanol, possibly a polyphenol such as resveratrol, may confer cardioprotection by normalizing endothelial dysfunction induced by an atherogenic diet. PMID:22748601

  9. Acidosis in the hospital setting: is metformin a common precipitant?

    PubMed

    Scott, K A; Martin, J H; Inder, W J

    2010-05-01

    Acidosis is commonly seen in the acute hospital setting, and carries a high mortality. Metformin has been associated with lactic acidosis, but it is unclear how frequently this is a cause of acidosis in hospitalized inpatients. The aim of this study is to explore the underlying comorbidities and acute precipitants of acidosis in the hospital setting, including the relationship between type 2 diabetes (T2DM) and metformin use. Retrospective review. Cases of acidosis were identified using the hospital discharge code for acidosis for a 3-month period: October-December 2005. A total of 101 episodes of acidosis were identified: 29% had isolated respiratory acidosis, 31% had metabolic acidosis and 40% had a mixed respiratory and metabolic acidosis. There were 28 cases of confirmed lactic acidosis. Twenty-nine patients had T2DM, but only five of the subjects with T2DM had lactic acidosis; two were on metformin. The major risk factors for development of lactic acidosis were hepatic impairment (OR 33.8, P = 0.01), severe left ventricular dysfunction (OR 25.3, P = 0.074) and impaired renal function (OR 9.7, P = 0.09), but not metformin use. Most cases of metabolic and lactic acidosis in the hospital setting occur in patients not taking metformin. Hepatic, renal and cardiac dysfunction are more important predictors for the development of acidosis.

  10. Cardioprotective effect of zingerone against oxidative stress, inflammation, and apoptosis induced by cisplatin or gamma radiation in rats.

    PubMed

    Soliman, Ahmed F; Anees, Lobna M; Ibrahim, Doaa M

    2018-05-07

    Despite their clinical benefits in cancer treatment, the deleterious effects on heart following chemo/radiotherapy are of increasing importance. Zingerone, a natural polyphenol, possesses multiple biological activities, such as antioxidant and anti-inflammatory. Thus, the current study was designed to assess the potential cardioprotective effects of zingerone against cisplatin or γ-radiation. Zingerone was given by intragastric intubation (25 mg/kg) daily for three successive weeks prior to the induction of cardiotoxicity using a single dose of cisplatin (20 mg/kg, i.p.) or a whole body γ-irradiation at a single dose of 6 Gy. Zingerone pre-treatment significantly reduced the abnormalities in heart histology and the increase in the cardiotoxicity indices, serum lactate dehydrogenase, and creatine kinase-MB activities, as well as plasma cardiac troponin T and B-natriuretic peptide, induced by cisplatin or γ-radiation. Further, zingerone, except for superoxide dismutase, notably ameliorated the state of oxidative stress as evidenced by a significant decrease in malondialdehyde level accompanied with a significant increase in the reduced glutathione content and catalase activity. Additionally, zingerone mitigated the increase in the inflammatory markers including serum level of tumor necrosis factor-alpha, cardiac myeloperoxidase activity, and cyclooxygenase-2 protein expression. Moreover, zingerone alleviated the elevation of caspase-3 gene expression and the prominent nuclear DNA fragmentation and attenuated the decrease in mitochondrial complexes' activities. This study sheds the light on a probable protective role of zingerone as an antioxidant, anti-inflammatory, and antiapoptotic agent against cisplatin- or γ-radiation-induced cardiotoxicity and holds a potential in regard to therapeutic intervention for chemo/radiotherapy mediated cardiac damage.

  11. Does Metformin Treatment During Pregnancy Modify the Future Metabolic Profile in Women With PCOS?

    PubMed

    Underdal, Maria Othelie; Stridsklev, Solhild; Oppen, Ingrid Hennum; Høgetveit, Kristin; Andersen, Marianne Skovsager; Vanky, Eszter

    2018-06-01

    Worldwide, metformin is prescribed to improve pregnancy outcome in polycystic ovary syndrome (PCOS). Metformin may also benefit future health by modulating increased metabolic stress during pregnancy. To investigate whether metformin during pregnancy modified future metabolic health in women with PCOS. Follow-up study of a randomized controlled trial that compared metformin with placebo in women with PCOS. Mean follow-up period was 7.7 years (range, 5 to 11 years). Three university hospitals, seven local hospitals, and one gynecological specialist practice. Women with PCOS according to Rotterdam criteria; all former participants in the Metformin in Pregnant PCOS Women Study. Metformin 2000 mg daily or placebo from first trimester to delivery in the original study. No intervention in the present follow-up study. Main outcome measure was weight gain in the follow-up period. Weight, body mass index (BMI), waist and hip circumferences, and blood pressure (BP) were registered. Body composition was assessed by bioelectrical impedance analysis, and fasting lipids, glucose, and insulin were analyzed. Of 239 invited women, 131 (55%) participated in the follow-up. Weight gain was similar in women given metformin (2.1 ± 10.5 kg) and women given placebo (1.8 ± 11.2 kg) at 7.7 years' follow-up after pregnancy (P = 0.834). No difference was found in BMI, waist/hip ratio, BP, body composition, lipids, glucose and insulin levels, or prevalence of metabolic syndrome at follow-up between those treated with metformin and those treated with placebo during pregnancy. Metformin treatment during pregnancy did not influence the metabolic profile in women with PCOS at 7.7 years of follow-up.

  12. Trimethoprim–metformin interaction and its genetic modulation by OCT2 and MATE1 transporters

    PubMed Central

    Grün, Barbara; Kiessling, Michael K; Burhenne, Jürgen; Riedel, Klaus-Dieter; Weiss, Johanna; Rauch, Geraldine; Haefeli, Walter E; Czock, David

    2013-01-01

    Aims Metformin pharmacokinetics depends on the presence and activity of membrane-bound drug transporters and may be affected by transport inhibitors. The aim of this study was to investigate the effects of trimethoprim on metformin pharmacokinetics and genetic modulation by organic cation transporter 2 (OCT2) and multidrug and toxin extrusion 1 (MATE1) polymorphisms. Methods Twenty-four healthy volunteers received metformin 500 mg three times daily for 10 days and trimethoprim 200 mg twice daily from day 5 to 10. Effects of trimethoprim on steady-state metformin pharmacokinetics were analysed. Results In the population as a whole, trimethoprim significantly reduced the apparent systemic metformin clearance (CL/F) from 74 to 54 l h−1 and renal metformin clearance from 31 to 21 l h−1, and prolonged half-life from 2.7 to 3.6 h (all P < 0.01). This resulted in an increase in the maximal plasma concentration by 38% and in the area under the plasma concentration–time curve by 37%. In volunteers polymorphic for both OCT2 and MATE1, trimethoprim had no relevant inhibitory effects on metformin kinetics. Trimethoprim was associated with a decrease in creatinine clearance from 133 to 106 ml min−1 (P < 0.01) and an increase in plasma lactate from 0.94 to 1.2 mmol l−1 (P = 0.016). Conclusions The extent of inhibition by trimethoprim was moderate, but might be clinically relevant in patients with borderline renal function or high-dose metformin. PMID:23305245

  13. Cardioprotective Action of Ginkgo biloba Extract against Sustained β-Adrenergic Stimulation Occurs via Activation of M2/NO Pathway

    PubMed Central

    Mesquita, Thássio R. R.; de Jesus, Itamar C. G.; dos Santos, Jucilene F.; de Almeida, Grace K. M.; de Vasconcelos, Carla M. L.; Guatimosim, Silvia; Macedo, Fabrício N.; dos Santos, Robervan V.; de Menezes-Filho, José E. R.; Miguel-dos-Santos, Rodrigo; Matos, Paulo T. D.; Scalzo, Sérgio; Santana-Filho, Valter J.; Albuquerque-Júnior, Ricardo L. C.; Pereira-Filho, Rose N.; Lauton-Santos, Sandra

    2017-01-01

    Ginkgo biloba is the most popular phytotherapic agent used worldwide for treatment of several human disorders. However, the mechanisms involved in the protective actions of Ginkgo biloba on cardiovascular diseases remain poorly elucidated. Taking into account recent studies showing beneficial actions of cholinergic signaling in the heart and the cholinergic hypothesis of Ginkgo biloba-mediated neuroprotection, we aimed to investigate whether Ginkgo biloba extract (GBE) promotes cardioprotection via activation of cholinergic signaling in a model of isoproterenol-induced cardiac hypertrophy. Here, we show that GBE treatment (100 mg/kg/day for 8 days, v.o.) reestablished the autonomic imbalance and baroreflex dysfunction caused by chronic β-adrenergic receptor stimulation (β-AR, 4.5 mg/kg/day for 8 days, i.p.). Moreover, GBE prevented the upregulation of muscarinic receptors (M2) and downregulation of β1-AR in isoproterenol treated-hearts. Additionally, we demonstrated that GBE prevents the impaired endothelial nitric oxide synthase activity in the heart. GBE also prevented the pathological cardiac remodeling, electrocardiographic changes and impaired left ventricular contractility that are typical of cardiac hypertrophy. To further investigate the mechanisms involved in GBE cardioprotection in vivo, we performed in vitro studies. By using neonatal cardiomyocyte culture we demonstrated that the antihypertrophic action of GBE was fully abolished by muscarinic receptor antagonist or NOS inhibition. Altogether, our data support the notion that antihypertrophic effect of GBE occurs via activation of M2/NO pathway uncovering a new mechanism involved in the cardioprotective action of Ginkgo biloba. PMID:28553225

  14. Heritability of variation in glycaemic response to metformin: a genome-wide complex trait analysis

    PubMed Central

    Zhou, Kaixin; Donnelly, Louise; Yang, Jian; Li, Miaoxin; Deshmukh, Harshal; Van Zuydam, Natalie; Ahlqvist, Emma; Spencer, Chris C; Groop, Leif; Morris, Andrew D; Colhoun, Helen M; Sham, Pak C; McCarthy, Mark I; Palmer, Colin N A; Pearson, Ewan R

    2014-01-01

    Summary Background Metformin is a first-line oral agent used in the treatment of type 2 diabetes, but glycaemic response to this drug is highly variable. Understanding the genetic contribution to metformin response might increase the possibility of personalising metformin treatment. We aimed to establish the heritability of glycaemic response to metformin using the genome-wide complex trait analysis (GCTA) method. Methods In this GCTA study, we obtained data about HbA1c concentrations before and during metformin treatment from patients in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) study, which includes a cohort of patients with type 2 diabetes and is linked to comprehensive clinical databases and genome-wide association study data. We applied the GCTA method to estimate heritability for four definitions of glycaemic response to metformin: absolute reduction in HbA1c; proportional reduction in HbA1c; adjusted reduction in HbA1c; and whether or not the target on-treatment HbA1c of less than 7% (53 mmol/mol) was achieved, with adjustment for baseline HbA1c and known clinical covariates. Chromosome-wise heritability estimation was used to obtain further information about the genetic architecture. Findings 5386 individuals were included in the final dataset, of whom 2085 had enough clinical data to define glycaemic response to metformin. The heritability of glycaemic response to metformin varied by response phenotype, with a heritability of 34% (95% CI 1–68; p=0·022) for the absolute reduction in HbA1c, adjusted for pretreatment HbA1c. Chromosome-wise heritability estimates suggest that the genetic contribution is probably from individual variants scattered across the genome, which each have a small to moderate effect, rather than from a few loci that each have a large effect. Interpretation Glycaemic response to metformin is heritable, thus glycaemic response to metformin is, in part, intrinsic to individual biological variation

  15. Heritability of variation in glycaemic response to metformin: a genome-wide complex trait analysis.

    PubMed

    Zhou, Kaixin; Donnelly, Louise; Yang, Jian; Li, Miaoxin; Deshmukh, Harshal; Van Zuydam, Natalie; Ahlqvist, Emma; Spencer, Chris C; Groop, Leif; Morris, Andrew D; Colhoun, Helen M; Sham, Pak C; McCarthy, Mark I; Palmer, Colin N A; Pearson, Ewan R

    2014-06-01

    Metformin is a first-line oral agent used in the treatment of type 2 diabetes, but glycaemic response to this drug is highly variable. Understanding the genetic contribution to metformin response might increase the possibility of personalising metformin treatment. We aimed to establish the heritability of glycaemic response to metformin using the genome-wide complex trait analysis (GCTA) method. In this GCTA study, we obtained data about HbA1c concentrations before and during metformin treatment from patients in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) study, which includes a cohort of patients with type 2 diabetes and is linked to comprehensive clinical databases and genome-wide association study data. We applied the GCTA method to estimate heritability for four definitions of glycaemic response to metformin: absolute reduction in HbA1c; proportional reduction in HbA1c; adjusted reduction in HbA1c; and whether or not the target on-treatment HbA1c of less than 7% (53 mmol/mol) was achieved, with adjustment for baseline HbA1c and known clinical covariates. Chromosome-wise heritability estimation was used to obtain further information about the genetic architecture. 5386 individuals were included in the final dataset, of whom 2085 had enough clinical data to define glycaemic response to metformin. The heritability of glycaemic response to metformin varied by response phenotype, with a heritability of 34% (95% CI 1-68; p=0·022) for the absolute reduction in HbA1c, adjusted for pretreatment HbA1c. Chromosome-wise heritability estimates suggest that the genetic contribution is probably from individual variants scattered across the genome, which each have a small to moderate effect, rather than from a few loci that each have a large effect. Glycaemic response to metformin is heritable, thus glycaemic response to metformin is, in part, intrinsic to individual biological variation. Further genetic analysis might enable us to make better

  16. Association of oral contraceptive and metformin did not improve insulin resistance in women with polycystic ovary syndrome.

    PubMed

    Iwata, Margareth Chiharu; Porquere, Livia; Sorpreso, Isabel C Espósito; Baracat, Edmund C; Soares Júnior, José Maria

    2015-01-01

    to compare clinical and laboratory parameters in women with polycystic ovary syndrome (PCOS) using metformin or combined oral contraceptive (COC) after 6 months. retrospective study analyzing records of patients with PCOS using the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society criteria. The groups were: I-COC (21 tablets, pause of 7 days; n=16); II-metformin (850 mg 12/12h, n=16); III-COC plus metformin (n=9). Body mass index (BMI), acne (% of improvement), modified Ferriman-Gallway index and menstrual cycle index (MCI), luteinizing hormone (LH), follicle-stimulating hormone (FSH), total testosterone (TT), androstenedione (A) and homeostasis model assessment: insulin resistance (HOMA-IR) index were assessed Results: isolated use of COC compared to metformin was better regarding to acne, Ferriman index, MCI, LH, TT and A levels. On the other hand, metformin was better in the HOMA-IR index (4.44 and 1.67 respectively, p=0.0007). The association COC plus metformin, compared to metformin alone shows the maintenance of improvement of acne, Ferriman index, MCI, and testosterone levels. The HOMA-IR index remained lower in the metformin alone group (4.19 and 1.67, respectively; p=0,046). The comparison between COC plus metformin and COC alone, in turn, shows no difference in the improvement of acne, Ferriman index, MCI, LH, TT and A levels, indicating that the inclusion of metformin did not lead to additional benefits in these parameters. Still, the HOMA-IR index was similar in both groups (4.19 and 4.44 respectively; p=0.75), showing that the use of metformin associated with COC may not improve insulin resistance as much as it does if used alone. our data suggest that the combination of metformin and contraceptive does not improve insulin resistance as observed with metformin alone.

  17. Roll Compaction and Tableting of High Loaded Metformin Formulations Using Efficient Binders.

    PubMed

    Arndt, Oscar-Rupert; Kleinebudde, Peter

    2018-04-23

    Metformin has a poor tabletability and flowability. Therefore, metformin is typically wet granulated with a binder before tableting. To save production costs, it would be desirable to implement a roll compaction/dry granulation (RCDG) process for metformin instead of using wet granulation. In order to implement RCDG, the efficiency of dry binders is crucial to ensure a high drug load and suitable properties of dry granules and tablets. This study evaluates dry granules manufactured by RCDG and subsequently tableting of high metformin content formulations (≥ 87.5%). Based on previous results, fine particle grades of hydroxypropylcellulose and copovidone in different fractions were compared as dry binders. The formulations are suitable for RCDG and tableting. Furthermore, results can be connected to in-die and out-of-die compressibility analysis. The addition of 7% of dry binder is a good compromise to generate sufficient mechanical properties on the one hand, but also to save resources and ensure a high metformin content on the other hand. Hydroxypropylcellulose was more efficient in terms of granule size, tensile strength and friability. Three percent croscarmellose was added to reach the specifications of the US Pharmacopeia regarding dissolution. The final formulation has a metformin content of 87.5%. A loss in tabletability does not occur for granules compressed at different specific compaction forces, which displays a robust tensile strength of tablets independent of the granulation process.

  18. Statin and Metformin Use Prolongs Survival in Patients With Resectable Pancreatic Cancer.

    PubMed

    Kozak, Margaret M; Anderson, Eric M; von Eyben, Rie; Pai, Jonathan S; Poultsides, George A; Visser, Brendan C; Norton, Jeffrey A; Koong, Albert C; Chang, Daniel T

    2016-01-01

    The aim of this study was to investigate the impact of statin and metformin therapy on disease outcome for patients with pancreatic ductal adenocarcinoma (PDAC). This retrospective study included 171 PDAC patients who underwent surgical resection at the Stanford Cancer Institute between 1998 and 2013. No patients received neoadjuvant therapy. Statin and metformin use was defined as use during initial consult and continuing upon discharge from the hospital after surgery. Dose of each medication was recorded, as was the type of statin taken. The median follow-up for all patients was 11.23 months (range, 0.2-105.0 months). Among the 171 patients included in our analysis, 18 patients (10.5%) took metformin and 34 patients (19.9%) took statins. Statin use was associated with better overall survival (OS) in patients with PDAC (P = 0.011). Metformin use was also associated with better OS (P = 0.035). The use of statins remained significant on multivariate analysis for OS (P = 0.014; hazards ratio, 0.33; 95% confidence interval, 0.139-0.799), but metformin use did not (P = 0.33; hazards ratio 0.60, 95% confidence interval, 0.211-1.675). Statin and metformin use is associated with improved OS in patients with resectable PDAC. These medications should be further investigated for possible long-term use in the general population.

  19. Mitochondrial permeability transition in cardiac ischemia–reperfusion: whether cyclophilin D is a viable target for cardioprotection?

    PubMed Central

    Jang, Sehwan; Parodi-Rullan, Rebecca; Khuchua, Zaza; Kuznetsov, Andrey V.

    2018-01-01

    Growing number of studies provide strong evidence that the mitochondrial permeability transition pore (PTP), a non-selective channel in the inner mitochondrial membrane, is involved in the pathogenesis of cardiac ischemia–reperfusion and can be targeted to attenuate reperfusion-induced damage to the myocardium. The molecular identity of the PTP remains unknown and cyclophilin D is the only protein commonly accepted as a major regulator of the PTP opening. Therefore, cyclophilin D is an attractive target for pharmacological or genetic therapies to reduce ischemia–reperfusion injury in various animal models and humans. Most animal studies demonstrated cardioprotective effects of PTP inhibition; however, a recent large clinical trial conducted by international groups demonstrated that cyclosporine A, a cyclophilin D inhibitor, failed to protect the heart in patients with myocardial infarction. These studies, among others, raise the question of whether cyclophilin D, which plays an important physiological role in the regulation of cell metabolism and mitochondrial bioenergetics, is a viable target for cardioprotection. This review discusses previous studies to provide comprehensive information on the physiological role of cyclophilin D as well as PTP opening in the cell that can be taken into consideration for the development of new PTP inhibitors. PMID:28378042

  20. Comparison of the effects of sibutramine versus sibutramine plus metformin in obese women.

    PubMed

    Sari, Ramazan; Eray, Esin; Ozdem, Sabahat; Akbas, Halide; Coban, Erkan

    2010-09-01

    Sibutramine and metformin are drugs commonly used to obtain weight loss. We aimed to compare the effects of sibutramine alone with that of sibutramine plus metformin combination on weight loss, insulin sensitivity, leptin and C reactive protein in obese women. Seventy obese women were included. After a diet period of month (baseline), each individual was randomly assigned to receive 15 mg sibutramine (sibutramine group; n = 36) or 15 mg sibutramine plus 1,700 mg metformin per day (sibutramine plus metformin group; n = 34) during the next 12 months. Body weight, insulin resistance by the homeostasis model assessment model (HOMA-IR), leptin and C reactive protein were measured at baseline, after 3 months and after 12 months. Mean weight losses in sibutramine and sibutramine plus metformin groups were 5.3 +/- 4.0% (P < 0.001) and 6.8 +/- 3.9% (P < 0.001) after 3 months, and 10.5 +/- 4.4% (P < 0.001) and 15.7 +/- 4.6% (P = 0.007) after 12 months, respectively. HOMA-IR value also decreased in both sibutramine (P = 0.045 and P = 0.002) and sibutramine plus metformin groups (P = 0.04 and P = 0.015) after 3 and 12 months, respectively. Similarly, serum leptin levels decreased in both sibutramine (P = 0.04, P = 0.01) and sibutramine plus metformin groups (P = 0.023, P = 0.025) after 3 and 12 months, respectively. There was also significant reductions in serum C reactive protein levels in both sibutramine (P = 0.045, P = 0.02) and sibutramine plus metformin groups (P = 0.007, P = 0.001) after 3 and 12 months, respectively. These decrements of body weight, HOMA-IR, serum leptin and C reactive protein levels were not statistical significance between these two groups both after 3 and 12 months (P > 0.05). Combination of sibutramine with metformin did not result in any further effects on weight loss, insulin resistance, leptin and C reactive protein levels when compared to sibutramine alone.

  1. Metformin for Clozapine Associated Obesity: A Systematic Review and Meta-Analysis.

    PubMed

    Siskind, Dan J; Leung, Janni; Russell, Anthony W; Wysoczanski, Daniel; Kisely, Steve

    2016-01-01

    Although clozapine is the gold-standard for treatment refractory schizophrenia, it has the worst metabolic profile of all antipsychotics. This is partly mediated by clozapine's impact on glucagon-like peptide (GLP-1). There is an absence of robust evidence for effective treatments for clozapine associated weight gain and metabolic syndrome. Metformin, with its role in increasing GLP-1 may aid weight loss among people on clozapine. We conducted a systematic-review and meta-analysis of metformin versus placebo for change in weight and metabolic syndrome for people on clozapine without diabetes mellitus. We searched the Cochrane Schizophrenia Group's trial register, Pubmed and Embase, as well as the following Chinese databases: the Chinese Biomedical Literature Service System and China Knowledge Resource Integrated Database. This was supplemented by hand searches of key papers. Eight studies, of which three were from Chinese databases, with 478 participants were included. We found that metformin was superior to placebo in terms of weight loss (-3.12kg, 95%CI -4.88kg to -1.37kg) and BMI (-1.18kg/m2, 95%CI -1.76kg/m2 to -0.61kg/m2). Metformin significantly improved three of the five components of metabolic syndrome; waist circumference, fasting glucose and triglycerides. Sensitivity analysis on study quality and duration did not greatly impact results. Metformin led to clinically meaningful weight loss among people on clozapine, and may reduce the rates of metabolic syndrome. Inclusion of metformin into the treatment protocols of people on clozapine, as tolerated, should be considered. PROSPERO registration number: CRD42015029723.

  2. Efficacy and safety of metformin or oral contraceptives, or both in polycystic ovary syndrome.

    PubMed

    Yang, Young-Mo; Choi, Eun Joo

    2015-01-01

    Polycystic ovary syndrome (PCOS) is an endocrinopathy that affects approximately 10% of reproductive-aged women throughout their lives. Women with PCOS present with heterogeneous symptoms including ovulatory dysfunction, hyperandrogenism, and polycystic ovaries. Therefore, lifelong individualized management should be considered. Pharmacological agents commonly used to manage the symptoms are metformin and oral contraceptive pills. Although these medications have been beneficial in treating PCOS symptoms, their efficacy and safety are still not entirely elucidated. This study aimed to report the efficacy and safety of metformin, oral contraceptives, or their combination in the treatment of PCOS and to define their specific individual roles. A literature search of original studies published in PubMed and Scopus was conducted to identify studies comparing metformin with oral contraceptives or evaluating the combination of both in PCOS. Eight clinical trials involving 313 patients were examined in the review. The intervention dosage of metformin ranged from 1,000 to 2,000 mg/d and that of oral contraceptives was ethinylestradiol 35 µg and cyproterone acetate 2 mg. Lower body mass index was observed with regimens including metformin, but increased body mass index was observed in monotherapy with oral contraceptives. Administration of metformin or oral contraceptives, especially as monotherapy, had a negative effect on lipid profiles. In addition, there are still uncertainties surrounding the effects of metformin or oral contraceptives in the management of insulin level, although they improved total testosterone and sex hormone-binding globulin levels. In the included studies, significant side effects due to metformin or oral contraceptives were not reported. The clinical trials suggest that metformin or oral contraceptives are at least patient convenient, efficacious, and safe for the treatment of PCOS. However, well-designed, prospective, long-term, large

  3. Efficacy and safety of metformin or oral contraceptives, or both in polycystic ovary syndrome

    PubMed Central

    Yang, Young-Mo; Choi, Eun Joo

    2015-01-01

    Background Polycystic ovary syndrome (PCOS) is an endocrinopathy that affects approximately 10% of reproductive-aged women throughout their lives. Women with PCOS present with heterogeneous symptoms including ovulatory dysfunction, hyperandrogenism, and polycystic ovaries. Therefore, lifelong individualized management should be considered. Pharmacological agents commonly used to manage the symptoms are metformin and oral contraceptive pills. Although these medications have been beneficial in treating PCOS symptoms, their efficacy and safety are still not entirely elucidated. This study aimed to report the efficacy and safety of metformin, oral contraceptives, or their combination in the treatment of PCOS and to define their specific individual roles. Methods A literature search of original studies published in PubMed and Scopus was conducted to identify studies comparing metformin with oral contraceptives or evaluating the combination of both in PCOS. Results Eight clinical trials involving 313 patients were examined in the review. The intervention dosage of metformin ranged from 1,000 to 2,000 mg/d and that of oral contraceptives was ethinylestradiol 35 µg and cyproterone acetate 2 mg. Lower body mass index was observed with regimens including metformin, but increased body mass index was observed in monotherapy with oral contraceptives. Administration of metformin or oral contraceptives, especially as monotherapy, had a negative effect on lipid profiles. In addition, there are still uncertainties surrounding the effects of metformin or oral contraceptives in the management of insulin level, although they improved total testosterone and sex hormone-binding globulin levels. In the included studies, significant side effects due to metformin or oral contraceptives were not reported. Conclusion The clinical trials suggest that metformin or oral contraceptives are at least patient convenient, efficacious, and safe for the treatment of PCOS. However, well

  4. Cardioprotective effects of BMS-180448, a prototype mitoK(ATP) channel opener, and the role of salvage kinases, in the rat model of global ischemia and reperfusion heart injury.

    PubMed

    Lee, Ju-Han; Jung, In-Sang; Lee, Sung-Hun; Yang, Min-Kyu; Hwang, Ji-Hye; Lee, Hak-Dong; Cho, Yu-Sun; Song, Min-Jin; Yi, Kyu-Yang; Yoo, Sung-Eun; Kwon, Suk-Hyung; Kim, Bokyung; Lee, Chang-Soo; Shin, Hwa-Sup

    2007-05-01

    To investigate the involvement of reperfusion-induced salvage kinases (RISK) as possible signaling molecules for the cardioprotective effects of BMS-180448, a prototype mitochondrial ATP-sensitive K+ (mitoK(ATP)) channel opener, we measured its cardioprotective effects in a rat model of ischemia/reperfusion (I/R) heart injury, together with western blotting analysis of five different signaling proteins. In isolated rat hearts subjected to 30-min global ischemia followed by 30-min reperfusion, BMS-180448 (1, 3 and 10 microM) significantly increased reperfusion left ventricular developed pressure (LVDP) and 30-min reperfusion double product (heart rate x LVDP) in a concentration-dependent manner, while decreasing left ventricular end-diastolic pressure (LVEDP) throughout reperfusion period in a concentration-dependent manner. SDS-PAGE/western blotting analysis of left ventricle reperfused for 30 min revealed that BMS-180448 significantly decreased phospho-GSK3beta at high concentration, whereas it tended to increase slightly phospho-eNOS and phospho-p70S6K with concentration. However, BMS-180448 had no effect on phospho-Akt and phospho-Bad. These results suggest that the cardioprotective effects of BMS-180448 against I/R heart injury may result from direct activation of mitoK(ATP) channel in cardiomyocytes, with the minimal role of RISK pathway in the activation of this channel and the cardioprotective effects of BMS-180448.

  5. Cardioprotective properties of Crataegus oxycantha extract against ischemia-reperfusion injury.

    PubMed

    Swaminathan, J K; Khan, M; Mohan, I K; Selvendiran, K; Niranjali Devaraj, S; Rivera, B K; Kuppusamy, P

    2010-08-01

    The aim of the study was to investigate the cardioprotective effect and mechanism of Crataegus oxycantha (COC) extract, a well-known natural antioxidant-based cardiotonic, against ischemia/reperfusion (I/R) injury. Electron paramagnetic resonance studies showed that COC extract was capable of scavenging superoxide, hydroxyl, and peroxyl radicals, in vitro. The cardioprotective efficacy of the extract was studied in a crystalloid perfused heart model of I/R injury. Hearts were subjected to 30min of global ischemia followed by 45min of reperfusion. During reperfusion, COC extract was infused at a dose rate of 1mg/ml/min for 10min. Hearts treated with COC extract showed a significant recovery in cardiac contractile function, reduction in infarct size, and decrease in creatine kinase and lactate dehydrogenase activities. The expressions of xanthine oxidase and NADPH oxidase were significantly reduced in the treated group. A significant upregulation of the anti-apoptotic proteins Bcl-2 and Hsp70 with simultaneous downregulation of the pro-apoptotic proteins cytochrome c and cleaved caspase-3 was observed. The molecular signaling cascade including phospho-Akt (ser-473) and HIF-1alpha that lead to the activation or suppression of apoptotic pathway also showed a significant protective role in the treatment group. No significant change in phospho-p38 levels was observed. The results suggested that the COC extract may reduce the oxidative stress in the reperfused myocardium, and play a significant role in the inhibition of apoptotic pathways leading to cardioprotection. 2010 Elsevier GmbH. All rights reserved.

  6. Metformin confers risk reduction for developing hepatocellular carcinoma recurrence after liver resection.

    PubMed

    Chan, Kun-Ming; Kuo, Chang-Fu; Hsu, Jun-Te; Chiou, Meng-Jiun; Wang, Yu-Chao; Wu, Tsung-Han; Lee, Chen-Fang; Wu, Ting-Jung; Chou, Hong-Shiue; Lee, Wei-Chen

    2017-03-01

    Hepatocellular carcinoma recurrence following liver resection remains a great concern. The study aims to examine the chemopreventive effect of metformin in patients undergoing liver resection for hepatocellular carcinoma from a population-based study. All patients registered as having hepatocellular carcinoma between January 1995 and December 2011 in a nationwide database were retrospectively analysed. Outcomes related to liver resection and the presence of diabetes mellitus were assessed. Prognosis in terms of the use of metformin was further explored, in which only patients in the long-term follow-up starting at 2 years were included for analysis. Patients with diabetes mellitus had a significantly poorer outcome than patients without diabetes mellitus. Among diabetes mellitus patients, metformin users had significantly better survival curves in both recurrence-free survival (P<.0001) and overall survival (P<.0001) after liver resection. The hazard ratio of metformin use in hepatocellular carcinoma patients with diabetes mellitus was 0.65 (P<.05, 95% CI=0.60-0.72) for hepatocellular carcinoma recurrence and 0.79 (P<.05, 95% CI=0.72-0.88) for overall survival after liver resection. The risk reduction in hepatocellular carcinoma recurrence after liver resection was significantly associated with a dose/duration dependent of accumulated metformin usage. Diabetes mellitus has an adverse effect on patients with hepatocellular carcinoma regardless of treatment modality. The use of metformin significantly reduces the risk of hepatocellular carcinoma recurrence and improves the overall outcome of patients after liver resection if patients survives the initial 2 years. Nonetheless, a prospective controlled study is recommended for validating the metformin use on preventing postoperative hepatocellular carcinoma recurrence. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Metformin as add-on to intensive insulin therapy in type 1 diabetes mellitus.

    PubMed

    Staels, Frederik; Moyson, Carolien; Mathieu, Chantal

    2017-10-01

    We aimed to evaluate the effect of adjuvant metformin to intensive insulin therapy in patients with type 1 diabetes mellitus (T1DM). A 10-year retrospective study in 2 cohorts was performed: the MET cohort (n = 181) consisted of patients with T1DM on adjuvant metformin for ≥6 months and the CTR cohort (n = 62) consisted of patients with T1DM who refused metformin (n = 25) or adhered to metformin for <6 months (n = 36). Data on glycated haemoglobin (HbA1c), body mass index (BMI) and daily insulin dose were recorded yearly. A third cross-sectional cohort, the REF cohort (n = 961), consisting of patients with T1DM not offered adjuvant metformin, was used as a reference for baseline comparison. At the study start, BMI was significantly higher and insulin doses were lower in patients in the MET cohort, while HbA1c levels were similar. In the first years of metformin therapy, small but non-significant decreases were seen in BMI and insulin dose in patients in the MET cohort, while after 10 years no persistent effect on HbA1c, insulin dose or BMI was seen. In conclusion, although metformin may have short-term effects on BMI and insulin dose when used as adjunct therapy in patients with T1DM, no long-term beneficial effects were observed when patients were followed for 10 years. © 2017 John Wiley & Sons Ltd.

  8. Low Concentrations of Metformin Suppress Glucose Production in Hepatocytes through AMP-activated Protein Kinase (AMPK)*♦

    PubMed Central

    Cao, Jia; Meng, Shumei; Chang, Evan; Beckwith-Fickas, Katherine; Xiong, Lishou; Cole, Robert N.; Radovick, Sally; Wondisford, Fredric E.; He, Ling

    2014-01-01

    Metformin is a first-line antidiabetic agent taken by 150 million people across the world every year, yet its mechanism remains only partially understood and controversial. It was proposed that suppression of glucose production in hepatocytes by metformin is AMPK-independent; however, unachievably high concentrations of metformin were employed in these studies. In the current study, we find that metformin, via an AMP-activated protein kinase (AMPK)-dependent mechanism, suppresses glucose production and gluconeogenic gene expression in primary hepatocytes at concentrations found in the portal vein of animals (60–80 μm). Metformin also inhibits gluconeogenic gene expression in the liver of mice administered orally with metformin. Furthermore, the cAMP-PKA pathway negatively regulates AMPK activity through phosphorylation at Ser-485/497 on the α subunit, which in turn reduces net phosphorylation at Thr-172. Because diabetic patients often have hyperglucagonemia, AMPKα phosphorylation at Ser-485/497 is a therapeutic target to improve metformin efficacy. PMID:24928508

  9. [Vitamin B12 deficiency associated with high doses od metformin in older people diabetic].

    PubMed

    Sánchez, Hugo; Masferrer, Dominique; Lera, Lydia; Arancibia, Estrella; Angel, Barbara; Albala, Cecilia

    2014-06-01

    The aim of the study was to estimate if B12 deficiency is associated with the use of metformin in the elderly diabetics. Case-control study in diabetic OP. Cases (n = 137) were defined as elderly with B12 < 221 pmol/L and controls (n = 279) elderly with B12 > 221 pmol/L. Four categories of metformin use were defined: non-users, ≤850 mg/day, > 850 and < 2,550 mg/day and ≥2,550 mg/day. Metformin ≥2,550 mg/day was high doses considered. The crude OR for B12 deficiency and consumption of Metformin were calculated. Logistic regression models were developed to explore the association between B12 deficiency and metformin dose. The research protocol was approved by the Ethics Committee of INTA. The age of cases and controls was (70.2 years vs 68.6 years (p < 0.05). The 62% were women in cases vs 74.9% in controls (p < 0.05). The 73% of cases and 76% of controls used metformin (p < 0.05) the average consumption of metformin was de 1,954.3 mg/day (SD: 1,063.2) in cases and 1,696.6 mg/day (SD: 1,074.4) in controls (p < 0.05). The use of 2,550 mg/day was observed in 29.2% of cases and 19.3% for controls (p < 0.05). It was observed that OP who consumed high doses of metformin had 1.9 times the risk of B12 deficiency (OR: 1.9; 95%CI: 1,08- 3,30). These results show a strong association between high doses of metformin and low levels of vitamin B12 in diabetic elderly. This project was funded by FONIS SA11I2092. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

  10. Cardioprotective Effects of Total Flavonoids Extracted from Xinjiang Sprig Rosa rugosa against Acute Ischemia/Reperfusion-Induced Myocardial Injury in Isolated Rat Heart.

    PubMed

    Hou, Xuejiao; Han, Jichun; Yuan, Changsheng; Ren, Huanhuan; Zhang, Ya; Zhang, Tao; Xu, Lixia; Zheng, Qiusheng; Chen, Wen

    2016-01-01

    This study evaluated the antioxidative and cardioprotective effects of total flavonoids extracted from Xinjiang sprig Rosa rugosa on ischemia/reperfusion (I/R) injury using an isolated Langendorff rat heart model. The possible mechanism of Xinjiang sprig rose total flavonoid (XSRTF) against I/R injury was also studied. XSRTF (5, 10, and 20 µg/mL) dissolved in Krebs-Henseleit buffer was administered to isolated rat heart. The XSRTF showed remarkable scavenging effects against 1,1-diphenyl-2-picrylhydrazyl, hydroxyl, and superoxide anion radicals in vitro. XSRTF pretreatment improved the heart rate, increased LVDP, and decreased CK and LDH levels in coronary flow. This pretreatment also increased SOD activity and GSH/GSSG ratio but decreased MDA, TNF-α, and CRP levels and IL-8 and IL-6 activities. The infarct size and cell apoptosis in the hearts from the XSRTF-treated group were lower than those in the hearts from the I/R group. Therefore, the cardioprotective effects of XSRTF may be attributed to its antioxidant, antiapoptotic, and anti-inflammatory activities.

  11. [Metformin-associated lactic acidosis in a patient with pre-existing risk factors].

    PubMed

    Becker, C; Luginbühl, A; Pittl, U; Schlienger, R

    2005-09-07

    Lactic acidosis is a serious clinical situation associated with a high case fatality rate. Lactic acidosis is particularly found in conditions with an insufficient supply of oxigen in the tissue. Other causes for lactic acidosis can be hepatic or renal insufficiency. For the therapy of overweight patients with type 2 diabetes metformin is the first choice if diet and physical training have been ineffective. Metformin, however, has the potential to increase serumlactate. Therefore its ability to cause lactic acidosis is controversely discussed. We present a 64-year-old female patient with metformin-associated lactic acidosis. She had several pre-existing risk factors to develop a lactic acidosis. On her referral to the hospital she suffered from acute renal failure which is considered to be a contraindication for the use of metformin.

  12. Metformin for weight loss and metabolic control in overweight outpatients with schizophrenia and schizoaffective disorder.

    PubMed

    Jarskog, L Fredrik; Hamer, Robert M; Catellier, Diane J; Stewart, Dawn D; Lavange, Lisa; Ray, Neepa; Golden, Lauren H; Lieberman, Jeffrey A; Stroup, T Scott

    2013-09-01

    The purpose of this study was to determine whether metformin promotes weight loss in overweight outpatients with chronic schizophrenia or schizoaffective disorder. In a double-blind study, 148 clinically stable, overweight (body mass index [BMI] ≥27) outpatients with chronic schizophrenia or schizoaffective disorder were randomly assigned to receive 16 weeks of metformin or placebo. Metformin was titrated up to 1,000 mg twice daily, as tolerated. All patients continued to receive their prestudy medications, and all received weekly diet and exercise counseling. The primary outcome measure was change in body weight from baseline to week 16. Fifty-eight (77.3%) patients who received metformin and 58 (81.7%) who received placebo completed 16 weeks of treatment. Mean change in body weight was -3.0 kg (95% CI=-4.0 to -2.0) for the metformin group and -1.0 kg (95% CI=-2.0 to 0.0) for the placebo group, with a between-group difference of -2.0 kg (95% CI=-3.4 to -0.6). Metformin also demonstrated a significant between-group advantage for BMI (-0.7; 95% CI=-1.1 to -0.2), triglyceride level (-20.2 mg/dL; 95% CI=-39.2 to -1.3), and hemoglobin A1c level (-0.07%; 95% CI=-0.14 to -0.004). Metformin-associated side effects were mostly gastrointestinal and generally transient, and they rarely led to treatment discontinuation. Metformin was modestly effective in reducing weight and other risk factors for cardiovascular disease in clinically stable, overweight outpatients with chronic schizophrenia or schizoaffective disorder over 16 weeks. A significant time-by-treatment interaction suggests that benefits of metformin may continue to accrue with longer treatment. Metformin may have an important role in diminishing the adverse consequences of obesity and metabolic impairments in patients with schizophrenia.

  13. The cardioprotective effect of wine on human blood chemistry.

    PubMed

    van Velden, David P; Mansvelt, Erna P G; Fourie, Elba; Rossouw, Marietjie; Marais, A David

    2002-05-01

    We investigated the in vivo effects of regular consumption of red and white wine on the serum lipid profile, plasma plasminogen activator-1, homocysteine levels, and total antioxidant status. This study confirmed that moderate consumption of wine, red more than white, exerts cardioprotective effects through beneficial changes in lipid profiles and plasma total antioxidant status.

  14. Genetic Variants in Transcription Factors Are Associated With the Pharmacokinetics and Pharmacodynamics of Metformin

    PubMed Central

    Goswami, S; Yee, SW; Stocker, S; Mosley, JD; Kubo, M; Castro, R; Mefford, JA; Wen, C; Liang, X; Witte, J; Brett, C; Maeda, S; Simpson, MD; Hedderson, MM; Davis, RL; Roden, DM; Giacomini, KM; Savic, RM

    2014-01-01

    One-third of type 2 diabetes patients do not respond to metformin. Genetic variants in metformin transporters have been extensively studied as a likely contributor to this high failure rate. Here, we investigate, for the first time, the effect of genetic variants in transcription factors on metformin pharmacokinetics (PK) and response. Overall, 546 patients and healthy volunteers contributed their genome-wide, pharmacokinetic (235 subjects), and HbA1c data (440 patients) for this analysis. Five variants in specificity protein 1 (SP1), a transcription factor that modulates the expression of metformin transporters, were associated with changes in treatment HbA1c (P < 0.01) and metformin secretory clearance (P < 0.05). Population pharmacokinetic modeling further confirmed a 24% reduction in apparent clearance in homozygous carriers of one such variant, rs784888. Genetic variants in other transcription factors, peroxisome proliferator–activated receptor-α and hepatocyte nuclear factor 4-α, were significantly associated with HbA1c change only. Overall, our study highlights the importance of genetic variants in transcription factors as modulators of metformin PK and response. PMID:24853734

  15. Phytochemical screening and evaluation of cardioprotective activity of ethanolic extract of Ocimum basilicum L. (basil) against isoproterenol induced myocardial infarction in rats

    PubMed Central

    2012-01-01

    Background and the purpose of the study The objectives of the present study were phytochemical screening and study of the effects of ethanolic extract of aerial parts of Ocimum basilicum (basil) on cardiac functions and histopathological changes in isoproterenol-induced myocardial infarction (MI). Methods The leaves of the plant were extracted with ethanol by maceration and subjected to colorimetry to determine flavonoids and phenolic compounds. High-performance TLC analysis and subsequent CAMAG's TLC scanning were performed to quantify rosmarinic acid content. Wistar rats were assigned to 6 groups of normal control, sham, isoproterenol, and treatment with 10, 20, and 40 mg/kg of the extract two times per day concurrent with MI induction. A subcutaneous injection of isoproterenol (100 mg/kg/day) for 2 consecutive days was used to induce MI. Results Phytochemical screening indicated the presence of phenolic compounds (5.36%) and flavonoids (1.86%). Rosmarinic acid was the principal phenolic compound with a 15.74% existence. The ST-segment elevation induced by isoproterenol was significantly suppressed by all doses of the extract. A severe myocardial necrosis and fibrosis with a sharp reduction in left ventricular contractility and a marked increase in left ventricular end-diastolic pressure were seen in the isoproterenol group, all of which were significantly improved by the extract treatment. In addition to in-vitro antioxidant activity, the extract significantly suppressed the elevation of malondialdehyde levels both in the serum and the myocardium. Conclusion The results of the study demonstrate that Ocimum basilicum strongly protected the myocardium against isoproterenol-induced infarction and suggest that the cardioprotective effects could be related to antioxidative activities. PMID:23351503

  16. Sex-dependent difference in the effect of metformin on colorectal cancer-specific mortality of diabetic colorectal cancer patients

    PubMed Central

    Park, Jung Won; Lee, Jin Ha; Park, Ye Hyun; Park, Soo Jung; Cheon, Jae Hee; Kim, Won Ho; Kim, Tae Il

    2017-01-01

    AIM To assess factors associated with the higher effect of metformin on mortality in diabetic colorectal cancer (CRC) patients, since the factors related to the effectiveness of metformin have not been identified yet. METHODS Between January 2000 and December 2010, 413 patients diagnosed with both stage 3/4 CRC and diabetes mellitus were identified. Patients’ demographics and clinical characteristics were analyzed. The effect of metformin on CRC-specific mortality and the interactions between metformin and each adjusted factor were evaluated. RESULTS Total follow-up duration was median 50 mo (range: 1-218 mo). There were 85 deaths (45.9%) and 72 CRC-specific deaths (38.9%) among 185 patients who used metformin, compared to 130 total deaths (57.0%) and 107 CRC-specific deaths (46.9%) among 228 patients who did not use metformin. In multivariate analysis, survival benefit associated with metformin administration was identified (HR = 0.985, 95%CI: 0.974-0.997, P = 0.012). Interaction test between metformin and sex after adjustment for relevant factors revealed that female CRC patients taking metformin exhibited a significantly lower CRC-specific mortality rate than male CRC patients taking metformin (HR = 0.369, 95%CI: 0.155-0.881, P = 0.025). Furthermore, subgroup analysis revealed significant differences in CRC-specific mortality between the metformin and non-metformin groups in female patients (HR = 0.501, 95%CI: 0.286-0.879, P = 0.013) but not male patients (HR = 0.848, 95%CI: 0.594-1.211, P = 0.365). There were no significant interactions between metformin and other adjusted factors on CRC-specific mortality. CONCLUSION We showed a strong sex-dependent difference in the effect of metformin on CRC-specific mortality in advanced stage CRC patients with diabetes. PMID:28811714

  17. Mechanism of metformin action in MCF-7 and MDA-MB-231 human breast cancer cells involves oxidative stress generation, DNA damage, and transforming growth factor β1 induction.

    PubMed

    Marinello, Poliana Camila; da Silva, Thamara Nishida Xavier; Panis, Carolina; Neves, Amanda Fouto; Machado, Kaliana Larissa; Borges, Fernando Henrique; Guarnier, Flávia Alessandra; Bernardes, Sara Santos; de-Freitas-Junior, Júlio Cesar Madureira; Morgado-Díaz, José Andrés; Luiz, Rodrigo Cabral; Cecchini, Rubens; Cecchini, Alessandra Lourenço

    2016-04-01

    The participation of oxidative stress in the mechanism of metformin action in breast cancer remains unclear. We investigated the effects of clinical (6 and 30 μM) and experimental concentrations of metformin (1000 and 5000 μM) in MCF-7 and in MDA-MB-231 cells, verifying cytotoxicity, oxidative stress, DNA damage, and intracellular pathways related to cell growth and survival after 24 h of drug exposure. Clinical concentrations of metformin decreased metabolic activity of MCF-7 cells in the MTT assay, which showed increased oxidative stress and DNA damage, although cell death and impairment in the proliferative capacity were observed only at higher concentrations. The reduction in metabolic activity and proliferation in MDA-MB-231 cells was present only at experimental concentrations after 24 h of drug exposition. Oxidative stress and DNA damage were induced in this cell line at experimental concentrations. The drug decreased cytoplasmic extracellular signal-regulated kinases 1 and 2 (ERK1/2) and AKT and increased nuclear p53 and cytoplasmic transforming growth factor β1 (TGF-β1) in both cell lines. These findings suggest that metformin reduces cell survival by increasing reactive oxygen species, which induce DNA damage and apoptosis. A relationship between the increase in TGF-β1 and p53 levels and the decrease in ERK1/2 and AKT was also observed. These findings suggest the mechanism of action of metformin in both breast cancer cell lineages, whereas cell line specific undergoes redox changes in the cells in which proliferation and survival signaling are modified. Taken together, these results highlight the potential clinical utility of metformin as an adjuvant during the treatment of luminal and triple-negative breast cancer.

  18. Metformin Has a Positive Therapeutic Effect on Prostate Cancer in Diabetes Mellitus 2 Patients

    PubMed Central

    Chong, R. William; Vasudevan, Vijaya; Zuber, Jeffrey; Solomon, Solomon S.

    2016-01-01

    Objective Prostate cancer and type 2 diabetes mellitus are both common diseases found in the elderly male population. The diabetic drug, metformin, has been shown to have anti-neoplastic properties and demonstrated better treatment outcomes when used as adjuvant therapy in breast cancer patients. The hormonally-sensitive cancer analogous to breast in men is prostate. We investigated improved survival, lower risks of recurrences, and lower, more stable levels of prostate specific antigen (PSA) in DM2 patients with prostate cancer on metformin. Methods Prostate cancer patients with type 2 diabetes that remained on metformin were compared to controls not on metformin matched by age, weight, race, and Gleason score cancer staging. The endpoints of our study included final PSA values, number of recurrences, metastases and number living for each group. Results There were significantly fewer deaths (23% vs 10%), fewer recurrences (15% vs 8%), and fewer metastases (5% vs 0%), and fewer secondary cancers (17% vs 6%) in the metformin group (p<0.004). The final PSA value was lower in the metformin-treated group with a result approaching significance (p=0.067). The primary treatments for prostate cancer (i.e. surgery, radiation, androgen depletion) were found to be comparable in both groups. Conclusions Our retrospective study shows that adjuvant metformin therapy leads to a better prognosis in prostate cancer. Not only are PSA levels controlled for several years, but there are significantly fewer cancer recurrences in metformin treated patients. Overall, these results are promising and should be followed up with a prospective study to assess long-term survival. PMID:27079349

  19. Trimethoprim-metformin interaction and its genetic modulation by OCT2 and MATE1 transporters.

    PubMed

    Grün, Barbara; Kiessling, Michael K; Burhenne, Jürgen; Riedel, Klaus-Dieter; Weiss, Johanna; Rauch, Geraldine; Haefeli, Walter E; Czock, David

    2013-11-01

    Metformin pharmacokinetics depends on the presence and activity of membrane-bound drug transporters and may be affected by transport inhibitors. The aim of this study was to investigate the effects of trimethoprim on metformin pharmacokinetics and genetic modulation by organic cation transporter 2 (OCT2) and multidrug and toxin extrusion 1 (MATE1) polymorphisms. Twenty-four healthy volunteers received metformin 500 mg three times daily for 10 days and trimethoprim 200 mg twice daily from day 5 to 10. Effects of trimethoprim on steady-state metformin pharmacokinetics were analysed. In the population as a whole, trimethoprim significantly reduced the apparent systemic metformin clearance (CL/F) from 74 to 54 l h(-1) and renal metformin clearance from 31 to 21 l h(-1) , and prolonged half-life from 2.7 to 3.6 h (all P < 0.01). This resulted in an increase in the maximal plasma concentration by 38% and in the area under the plasma concentration-time curve by 37%. In volunteers polymorphic for both OCT2 and MATE1, trimethoprim had no relevant inhibitory effects on metformin kinetics. Trimethoprim was associated with a decrease in creatinine clearance from 133 to 106 ml min(-1) (P < 0.01) and an increase in plasma lactate from 0.94 to 1.2 mmol l(-1) (P = 0.016). The extent of inhibition by trimethoprim was moderate, but might be clinically relevant in patients with borderline renal function or high-dose metformin. © 2013 The Authors. British Journal of Clinical Pharmacology © 2013 The British Pharmacological Society.

  20. Effects of Metformin on Endocrine and Metabolic Parameters in Patients with Polycystic Ovary Syndrome.

    PubMed

    Zahra, M; Shah, M; Ali, A; Rahim, R

    2017-02-01

    The present study was designed to evaluate the effects of metformin on metabolic and endocrine parameters in patients with polycystic ovary syndrome (PCOS). The study included 40 patients with PCOS. Patients were divided into 2 groups based on whether they will receive metformin (500 mg 3 times a day, n=20) or placebo (n=20) for 3 consecutive months. Serum concentrations of fasting blood glucose, insulin, HOMA-IR, INSL-3, visfatin, FSH, and LH were measured at baseline and after 3 months of therapy. The key endocrine and metabolic parameters significantly changed after metformin treatment. The systolic and diastolic blood pressures were significantly reduced in the metformin group after treatment compared to placebo (p<0.001). A significant reduction in the size of the right ovary was observed after metformin treatment (p=0.05), while no change was found in the size of left ovary (p>0.12). Moreover, a significant reduction was observed in the serum levels of FSH (p>0.01), LH (p>0.001), and visfatin (p>0.001) after metformin treatment. However, HOMA-IR (which is used to assess insulin resistance) failed to reach the statistical significance (p=0.20). We conclude that metformin treatment in females with PCOS showed significant improvement in systolic and diastolic blood pressures. In addition, an improvement in the hormonal profile in the form of reduction in LH, FSH, and visfatin levels was observed. Thus, therapeutic intervention with metformin could be of clinical importance in high-risk group of young females with PCOS. © Georg Thieme Verlag KG Stuttgart · New York.

  1. Antihypertensive and cardioprotective effects of pumpkin seed oil.

    PubMed

    El-Mosallamy, Aliaa E M K; Sleem, Amany A; Abdel-Salam, Omar M E; Shaffie, Nermeen; Kenawy, Sanaa A

    2012-02-01

    Pumpkin seed oil is a natural product commonly used in folk medicine for treatment of prostatic hypertrophy. In the present study, the effects of treatment with pumpkin seed oil on hypertension induced by the nitric oxide synthase inhibitor N(ω)-nitro-L-arginine methyl ester hydrochloride (L-NAME) (50 mg /kg/day) in rats were studied and compared with those of the calcium channel blocker amlodipine. Pumpkin seed oil (40 or 100 mg/kg), amlodipine (0.9 mg/kg), or vehicle (control) was given once daily orally for 6 weeks. Arterial blood pressure (BP), heart rate, electrocardiogram (ECG) changes, levels of serum nitric oxide (NO) (the concentrations of nitrite/nitrate), plasma malondialdehyde (MDA), blood glutathione, and erythrocytic superoxide dismutase activity were measured. Histopathological examination of heart and aorta was conducted as well. L-NAME administration resulted in a significant increase in BP starting from the second week. Pumpkin seed oil or amlodipine treatment significantly reduced the elevation in BP by L-NAME and normalized the L-NAME-induced ECG changes-namely, prolongation of the RR interval, increased P wave duration, and ST elevation. Both treatments significantly decreased the elevated levels of MDA and reversed the decreased levels of NO metabolites to near normal values compared with the L-NAME-treated group. Amlodipine also significantly increased blood glutathione content compared with normal (but not L-NAME-treated) rats. Pumpkin seed oil as well as amlodipine treatment protected against pathological alterations in heart and aorta induced by L-NAME. In conclusion, this study has shown that pumpkin seed oil exhibits an antihypertensive and cardioprotective effects through a mechanism that may involve generation of NO.

  2. Clomiphene citrate combined with metformin versus letrozole for induction of ovulation in clomiphene-resistant polycystic ovary syndrome: a randomized clinical trial.

    PubMed

    Rezk, Mohamed; Shaheen, Abd-Elhamid; Saif El-Nasr, Ibrahim

    2018-04-01

    A total of 202 patients with clomiphene citrate (CC) -resistant polycystic ovary syndrome (PCOS) were randomly allocated into two arms of induction of ovulation; the first group (n = 102) received CC 100 mg and metformin 500 mg while the second group (n = 100) received letrozole 2.5 mg with ovulation rate, clinical pregnancy rate, adverse effects, and acceptability were assessed. Patients in the letrozole arm experienced higher rate of ovulation (82% versus 43.1%, p < .001), more dominant follicles (p < .05), better endometrial thickness (p < .001), higher clinical pregnancy rate (36% versus 9.8%, p < .001), higher multiple pregnancy rate (p < .05), lesser adverse effects (p < .05) and higher acceptability (p < .001) compared to patients in the CC and metformin arm. In conclusion; letrozole is better and more acceptable than combined CC and metformin for inducing ovulation in patients with CC-resistant PCOS with higher clinical pregnancy rate and unexpectedly higher multiple pregnancy rate.

  3. Oxytocin and cardioprotection in diabetes and obesity.

    PubMed

    Jankowski, Marek; Broderick, Tom L; Gutkowska, Jolanta

    2016-06-07

    Oxytocin (OT) emerges as a drug for the treatment of diabetes and obesity. The entire OT system is synthesized in the rat and human heart. The direct myocardial infusion with OT into an ischemic or failing heart has the potential to elicit a variety of cardioprotective effects. OT treatment attenuates cardiomyocyte (CMs) death induced by ischemia-reperfusion by activating pro-survival pathways within injured CMs in vivo and in isolated cells. OT treatment reduces cardiac apoptosis, fibrosis, and hypertrophy. The OT/OT receptor (OTR) system is downregulated in the db/db mouse model of type 2 diabetes which develops genetic diabetic cardiomyopathy (DC) similar to human disease. We have shown that chronic OT treatment prevents the development of DC in the db/db mouse. In addition, OT stimulates glucose uptake in both cardiac stem cells and CMs, and increases cell resistance to diabetic conditions. OT may help replace lost CMs by stimulating the in situ differentiation of cardiac stem cells into functional mature CMs. Lastly, adult stem cells amenable for transplantation such as MSCs could be preconditioned with OT ex vivo and implanted into the injured heart to aid in tissue regeneration through direct differentiation, secretion of protective and cardiomyogenic factors and/or their fusion with injured CMs.

  4. Metformin impacts cecal bile acid profiles in mice.

    PubMed

    Sillner, Nina; Walker, Alesia; Koch, Wendelin; Witting, Michael; Schmitt-Kopplin, Philippe

    2018-04-15

    Bile acids (BAs) are major components of bile synthesized from cholesterol and take part in the digestion of dietary lipids, as well as having signaling functions. They undergo extensive microbial metabolism inside the gastrointestinal tract. Here, we present a method of ultra-high pressure liquid chromatography coupled to ion trap mass spectrometry for quantification of 45 BAs in mouse cecum. The system was validated in regard to sensitivity with limits of detection and quantification (0.6-24.9 nM), interday accuracy (102.4%), interday precision (15.2%), recovery rate (74.7%), matrix effect (98.2%) and carry-over effect (<1.1%). Afterwards, we applied our method to investigate the effect of metformin on BA profiles. Diabetic mice were treated with metformin for 1 day or 14 days. One day of treatment resulted in a significant increase of total BA concentration (2.7-fold increase; db/db metformin 5.32 μmol/g, db/db control mice 1.95 μmol/g), most notable in levels of 7-oxodeoxycholic, 3-dehydrocholic and cholic acid. We observed only minor impact on BA metabolism after 14 days of metformin treatment, compared to the single treatment. Furthermore, healthy wild type mice had elevated concentrations of allocholic and ω-muricholic acid compared to diabetic mice. Our method proved the applicability of profiling BAs in cecum to investigate intestinal BA metabolism in diabetes and pharmacological applications. Copyright © 2018 Elsevier B.V. All rights reserved.

  5. Pioglitazone metabolic effect in metformin-intolerant obese patients treated with sibutramine.

    PubMed

    Derosa, Giuseppe; Mereu, Roberto; Salvadeo, Sibilla A T; D'Angelo, Angela; Ciccarelli, Leonardina; Piccinni, Mario N; Ferrari, Ilaria; Gravina, Alessia; Maffioli, Pamela; Cicero, Arrigo F G

    2009-01-01

    Metformin is the drug of choice to treat obese type 2 diabetes patients because it reduces either insulin-resistance and body weight. We aimed to comparatively test the efficacy and tolerability of pioglitazone and sibutramine in metformin-intolerant obese type 2 diabetic patients treated with sibutramine. Five hundred and seventy-six consecutive Caucasian obese type 2 diabetic patients were evaluated during a 12-months period and fifty-two patients were resulted intolerant to metformin at maximum dosage (3,000 mg/day). All intolerant patients to metformin received a treatment with pioglitazone (45 mg/day) and sibutramine (10 mg/day) and they were compared with fifty-three patients treated with metformin (3,000 mg/day) and sibutramine (10 mg/day) for 6 months in a single-blind controlled trial. We assessed body mass index, waist circumference, glycated hemoglobin, Fasting Plasma glucose, postprandial plasma glucose, fasting plasma insulin, postprandial plasma insulin, lipid profile, systolic blood pressure, diastolic blood pressure and heart rate at baseline and after 3, and 6 months. No body mass index change was observed at 3, and 6 months in pioglitazone + sibutramine group, while a significant reduction of body mass index and waist circumference was observed after 6 months in metformin + sibutramine group (p<0.05). A significant decrease of glycated hemoglobin, Fasting Plasma glucose, postprandial plasma glucose, fasting plasma insulin, postprandial plasma insulin and HOMA index was observed after 3, and 6 months in both groups (p<0.05, and p<0.01, respectively). A significant Tg reduction was present after 6 months (p<0.05) in both groups respect to the baseline values. No systolic blood pressure, diastolic blood pressure and heart rate change was obtained after 3, and 6 months in both groups. Pioglitazone and sibutramine combination appears to be a short-term equally efficacious and well-tolerated therapeutic alternative respect to metformin-intolerant obese

  6. The effect of metformin on the recurrence of colorectal adenoma in diabetic patients with previous colorectal adenoma.

    PubMed

    Han, Min Seok; Lee, Hyun Jung; Park, Soo Jung; Hong, Sung Pil; Cheon, Jae Hee; Kim, Won Ho; Kim, Tae Il

    2017-08-01

    Existing studies suggest that metformin lowers the risk and mortality of colorectal cancer. However, the effect of metformin on the suppression and prevention of colorectal adenomas is not clear. The aim of this study was to evaluate the effect of metformin on the recurrence of colorectal adenoma in diabetic patients with previous colorectal adenoma. Among 423 diabetic patients who underwent surveillance colonoscopy after resection of colorectal adenoma between 2005 and 2011, 257 patients were retrospectively reviewed. The patients were divided into two groups: one group comprising 106 patients who took metformin and another group comprising 151 patients who did not take metformin. The clinical characteristics, colorectal adenoma recurrence, and valuable factors for adenoma recurrence were analyzed. At surveillance colonoscopy after colonoscopic polypectomy for adenoma, 38 patients (35.8%) exhibited colorectal adenoma among 106 patients who took metformin, compared with 85 patients (56.3%) with colorectal adenoma among 151 patients who did not take metformin (odds ratio 0.434, 95% confidence interval 0.260-0.723, P = 0.001). Multivariate Cox analysis showed that metformin was associated with decreased recurrence of colorectal adenoma (hazard ratio 0.572, 95% confidence interval 0.385-0.852, P = 0.006) in diabetic patients with previous colorectal adenoma. The cumulative probability of colorectal adenoma recurrence was significantly lower in the metformin group than in the non-metformin group (P = 0.001). Metformin use in diabetic patients with previous colorectal adenoma is associated with a lower risk of colorectal adenoma recurrence.

  7. Pharmacokinetic and pharmacodynamic interaction between nifedipine and metformin in rats: competitive inhibition for metabolism of nifedipine and metformin by each other via CYP isozymes.

    PubMed

    Choi, Young H; Lee, Myung G

    2012-05-01

    It has been reported that hypertension exponentially increases in the patients with type 2 diabetes mellitus. Thus, this study was performed to investigate the pharmacokinetic and pharmacodynamic interactions between nifedipine and metformin, since both drugs were commonly metabolized via hepatic CYP2C and 3A subfamilies in rats. Nifedipine (3 mg/kg) and metformin (100 mg/kg) were simultaneously administered intravenously or orally to rats. Concentrations (I) of each drug in the liver and intestine, maximum velocity (V(max)), Michaelis-Menten constant (K(m)), and intrinsic clearance (CL(int)) for the disappearance of each drug, apparent inhibition constant (K(i)) and [I]/K(i) ratios of each drug in liver and intestine were determined. Also the metabolism of each drug in rat and human CYPs and blood pressure were also measured. After the simultaneous single intravenous administration of both drugs together, the AUCs of each drug were significantly greater than that in each drug alone due to the competitive inhibition for the metabolism of nifedipine by metformin via hepatic CYP3A1/2 and of metformin by nifedipine via hepatic CYP2C6 and 3A1/2. After the simultaneous single oral administration of both drugs, the significantly greater AUCs of each drug than that in each drug alone could have mainly been due to the competitive inhibition for the metabolism of nifedipine and metformin by each other via intestinal CYP3A1/2 in addition to competitive inhibition for the hepatic metabolism of each drug as same as the intravenous study.

  8. A phase Ib study of everolimus combined with metformin for patients with advanced cancer.

    PubMed

    Molenaar, Remco J; van de Venne, Tim; Weterman, Mariëtte J; Mathot, Ron A; Klümpen, Heinz-Josef; Richel, Dick J; Wilmink, Johanna W

    2018-02-01

    Background The efficacy to monotherapy with the mTOR inhibitor everolimus in advanced cancer is often limited due to therapy resistance. Combining everolimus with metformin may decrease the chance of therapy resistance. Methods Patients received everolimus and metformin in a 3 + 3 dose-escalation scheme. Objectives were to determine the dose-limiting toxicities (DLTs), maximum tolerated dose, toxic effects, pharmacokinetics and anti-tumour efficacy. Results 9 patients received study treatment for a median duration of 48 days (range: 4-78). 6 patients discontinued due to toxicity and 3 patients because of progressive disease. At the starting dose level of 10 mg everolimus qd and 500 mg metformin bid, 3 out of 5 patients experienced a DLT. After de-escalation to 5 mg everolimus qd and 500 mg metformin bid, considerable toxicity was still observed and patient enrollment was terminated. In pharmacokinetic analyses, metformin was eliminated slower when co-administered with everolimus than as single-agent. After 9 weeks of treatment, 3 patients were still on study and all had stable disease. Conclusion The combination of everolimus and metformin is poorly tolerated in patients with advanced cancer. The pharmacokinetic interaction between everolimus and metformin may have implications for diabetic cancer patients that are treated with these drugs. Our results advocate for future clinical trials with combinations of other mTOR inhibitors and biguanides.

  9. Metformin augments doxorubicin cytotoxicity in mammary carcinoma through activation of adenosine monophosphate protein kinase pathway.

    PubMed

    El-Ashmawy, Nahla E; Khedr, Naglaa F; El-Bahrawy, Hoda A; Abo Mansour, Hend E

    2017-05-01

    Since the incidence of breast cancer increases dramatically all over the world, the search for effective treatment is an urgent need. Metformin has demonstrated anti-tumorigenic effect both in vivo and in vitro in different cancer types. This work was designed to examine on molecular level the mode of action of metformin in mice bearing solid Ehrlich carcinoma and to evaluate the use of metformin in conjunction with doxorubicin as a combined therapy against solid Ehrlich carcinoma. Ehrlich ascites carcinoma cells were inoculated in 60 female mice as a model of breast cancer. The mice were divided into four equal groups: Control tumor, metformin, doxorubicin, and co-treatment. Metformin (15 mg/kg) and doxorubicin (4 mg/kg) were given intraperitoneally (i.p.) for four cycles every 5 days starting on day 12 of inoculation. The anti-tumorigenic effect of metformin was mediated by enhancement of adenosine monophosphate protein kinase activity and elevation of P53 protein as well as the suppression of nuclear factor-kappa B, DNA contents, and cyclin D1 gene expression. Metformin and doxorubicin mono-treatments exhibited opposing action regarding cyclin D1 gene expression, phosphorylated adenosine monophosphate protein kinase, and nuclear factor-kappa B levels. Co-treatment markedly decreased tumor volume, increased survival rate, and improved other parameters compared to doxorubicin group. In parallel, the histopathological findings demonstrated enhanced apoptosis and absence of necrosis in tumor tissue of co-treatment group. Metformin proved chemotherapeutic effect which could be mediated by the activation of adenosine monophosphate protein kinase and related pathways. Combining metformin and doxorubicin, which exhibited different mechanisms of action, produced greater efficacy as anticancer therapeutic regimen.

  10. Anti-cancer Effects of Metformin: Recent Evidences for its Role in Prevention and Treatment of Cancer.

    PubMed

    Kheirandish, Masoumeh; Mahboobi, Hamidreza; Yazdanparast, Maryam; Kamal, Warda; Kamal, Mohammad A

    2018-04-16

    Metformin is widely used for the management of type 2 diabetes mellitus (T2DM). Recently growing evidence has shown its anti-cancer effects. The results are mainly obtained from observational studies and thus, little information is available concerning the mechanisms of action. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) plays an important role in the mechanism of action of metformin. The anti-cancer mechanisms of metformin include direct and indirect effects. The direct effects of metformin include AMPK-independent and AMPK-dependent effects, whereas the decrease in glucose level, hyperinsulinemia, and Insulin-like growth factor 1 (IGF-1) level was considered its indirect effects. Metformin also decreases both pro-inflammatory cytokines and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and improves the immune response to cancer cells. Although the results of recent trials confirm the efficacy of metformin in prevention and treatment of different cancers, the evidence is not adequate enough. This paper reviews recently available evidence on anti-cancer effects of metformin. The effects of metformin in specific cancers including colorectal, prostate, pancreatic, renal, cervical, endometrial, gastric, lung, breast, and ovarian cancer are also reviewed in this paper. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  11. Effect of metformin treatment during pregnancy on women with PCOS: a systematic review and meta-analysis.

    PubMed

    Tan, Xingrong; Li, Shengbing; Chang, Ying; Fang, Chao; Liu, Hua; Zhang, Xingping; Wang, Yi

    2016-09-11

    Some previous studies have found that continued metformin use is beneficial in the management of polycystic ovary syndrome (PCOS) in pregnant women. A systemic review and meta-analysis were needed to more fully assess the effects of metformin on pregnant PCOS patients. The literature was fully searched using MEDLINE, EMBASE, SCOPUS, and COCHRANE for continued metformin use during pregnancy in women with PCOS. A systematic review and meta-analysis were performed to evaluate the comprehensive effects of continued metformin treatment on pregnancy-related outcomes in these women. Eleven eligible studies out of 127 relevant publications were included in meta-analysis. The rates of early pregnancy loss and preterm delivery were found to be significantly decreased in metformin-treated PCOS women. A non-significant difference was found in fetal abnormality and fetal birth weight between the metformin-treated and the non-treated groups. The incidence of gestational diabetes mellitus (GDM) and hypertension/preeclampsia were not significantly different in the two groups, probably because of inconsistent results in the subgroup analysis. Our results showed that continued use during of metformin, during pregnancy in women with PCOS, had no effect on incidence of fetal abnormalities or fetal birth weight. The effects of metformin on GDM and hypertension/preeclampsia should be determined through high-quality randomized controlled trials.

  12. Chitosan-poly (lactide-co-glycolide) (CS-PLGA) nanoparticles containing metformin HCl: preparation and in vitro evaluation.

    PubMed

    Gundogdu, Nuran; Cetin, Meltem

    2014-11-01

    In this study, the preparation and in vitro characterisation of metformin HCl-loaded CS-PLGA nanoparticles (NPs) were aimed. The prepared nanoparticles (blank nanoparticles (C-1), 50 mg of metformin HCl loaded nanoparticles (C-2) and 75 mg of metformin HCl loaded nanoparticles (C-3) ranged in size from 506.67±13.61 to 516.33±16.85 nm and had surface charges of 22.57±1.21 to 32.37±0.57 mV. Low encapsulation efficiency was observed for both nanoparticle formulations due to the leakage of metformin HCl to the external medium during preparation of nanoparticles. Nanoparticle formulations showed highly reproducible drug release profiles. ~20% of metformin HCl was released within 30 minutes and approximately 98% of the loaded metformin HCl was released at 144 hours in a phosphate buffer (PB; pH 6.8). No statistically significant difference was noted between the in vitro release profiles of the nanoparticles (C-2 and C-3) containing metformin HCl. Also, nanoparticles were characterised using FT-IR and DSC.

  13. Evaluation of the potential cardioprotective activity of some Saudi plants against doxorubicin toxicity.

    PubMed

    Ashour, Osama M; Abdel-Naim, Ashraf B; Abdallah, Hossam M; Nagy, Ayman A; Mohamadin, Ahmed M; Abdel-Sattar, Essam A

    2012-01-01

    Doxorubicin (DOX) is an anthracycline antibiotic widely used as a chemotherapeutic agent in the treatment of several tumours. However, its cardiac toxicity limits its use at maximum therapeutic doses. Most studies implicated increased oxidative stress as the major determinant of DOX cardiotoxicity. The local Saudi flora is very rich in a variety of plants of quite known folkloric or traditional medicinal uses. Tribulus macropterus Boiss., Olea europaea L. subsp. africana (Mill.) P. S. Green, Tamarix aphylla (L.) H. Karst., Cynomorium coccineum L., Cordia myxa L., Calligonum comosum L' Hér, and Withania somnifera (L.) Dunal are Saudi plants known to have antioxidant activities. The aim of the current study was to explore the potential protective effects of methanolic extracts of these seven Saudi plants against DOX-induced cardiotoxicity in rats. Two plants showed promising cardioprotective potential in the order Calligonum comosum > Cordia myxa. The two plant extracts showed potent in vitro radical scavenging and antioxidant properties. They significantly protected against DOX-induced alterations in cardiac oxidative stress markers (GSH and MDA) and cardiac serum markers (CK-MB and LDH activities). Additionally, histopathological examination indicated a protection against DOX-induced cardiotoxicity. In conclusion, C. comosum and C. myxa exerted protective activity against DOX-induced cardiotoxicity, which is, at least partly, due to their antioxidant effect.

  14. Metformin compared with glyburide for the management of gestational diabetes.

    PubMed

    Silva, Jean Carl; Pacheco, Carina; Bizato, Juliana; de Souza, Bárbara Vicente; Ribeiro, Thaís Engel; Bertini, Anna Maria

    2010-10-01

    To assess blood glucose control and neonatal outcomes when women with gestational diabetes mellitus (GDM) were treated with metformin or glyburide. When an appropriate diet was insufficient to control their blood glucose levels, women with GDM were randomized to a glyburide or a metformin treatment group. If the maximum dose was reached, the assessed drug was replaced by insulin. The primary outcome measures analyzed were maternal glucose levels during pregnancy, birth weight, and neonatal glucose levels. The only significant difference in outcome between the 2 treatment drugs was that maternal weight gain during pregnancy was less in the metformin (n=40) than in the glyburide group (n=32) (10.3 kg vs 7.6 kg; P=0.02). No differences were found in treatment failure, mean level of fasting or postprandial plasma glucose, rate of participants with glycated hemoglobin, birth weight, rate of large-for-gestational-age newborns, or newborns with hypoglycemia. The treatment of GDM with metformin or glyburide was found to be equivalent for both women and newborns. Copyright © 2010 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

  15. Metformin and Its Sulfenamide Prodrugs Inhibit Human Cholinesterase Activity.

    PubMed

    Markowicz-Piasecka, Magdalena; Sikora, Joanna; Mateusiak, Łukasz; Mikiciuk-Olasik, Elżbieta; Huttunen, Kristiina M

    2017-01-01

    The results of epidemiological and pathophysiological studies suggest that type 2 diabetes mellitus (T2DM) may predispose to Alzheimer's disease (AD). The two conditions present similar glucose levels, insulin resistance, and biochemical etiologies such as inflammation and oxidative stress. The diabetic state also contributes to increased acetylcholinesterase (AChE) activity, which is one of the factors leading to neurodegeneration in AD. The aim of this study was to assess in vitro the effects of metformin, phenformin, and metformin sulfenamide prodrugs on the activity of human AChE and butyrylcholinesterase (BuChE) and establish the type of inhibition. Metformin inhibited 50% of the AChE activity at micromolar concentrations (2.35  μ mol/mL, mixed type of inhibition) and seemed to be selective towards AChE since it presented low anti-BuChE activity. The tested metformin prodrugs inhibited cholinesterases (ChE) at nanomolar range and thus were more active than metformin or phenformin. The cyclohexyl sulfenamide prodrug demonstrated the highest activity towards both AChE (IC 50  = 890 nmol/mL, noncompetitive inhibition) and BuChE (IC 50  = 28 nmol/mL, mixed type inhibition), while the octyl sulfenamide prodrug did not present anti-AChE activity, but exhibited mixed inhibition towards BuChE (IC 50  = 184 nmol/mL). Therefore, these two bulkier prodrugs were concluded to be the most selective compounds for BuChE over AChE. In conclusion, it was demonstrated that biguanides present a novel class of inhibitors for AChE and BuChE and encourages further studies of these compounds for developing both selective and nonselective inhibitors of ChEs in the future.

  16. A RETINOIC ACID β2-RECEPTOR AGONIST EXERTS CARDIOPROTECTIVE EFFECTS.

    PubMed

    Marino, Alice; Sakamoto, Takuya; Tang, Xiao-Han; Gudas, Lorraine J; Levi, Roberto

    2018-06-15

    We previously discovered that oral treatment with AC261066, a synthetic selective agonist for the retinoic acid β2-receptor (RARβ2), decreases oxidative stress in the liver, pancreas, and kidney of mice fed a high-fat diet (HFD). Since hyperlipidemic states are causally associated with myocardial ischemia and oxidative stress, we have now investigated the effects of AC261066 in an ex-vivo ischemia/reperfusion (I/R) injury model in hearts of two prototypic dysmetabolic mice. We found that a 6-week oral treatment with AC261066 in both genetically hypercholesterolemic (ApoE-/-) and obese (HFD-fed) wild-type mice exerts protective effects when their hearts are subsequently subjected to I/R ex vivo in the absence of added drug. In ApoE-/- mice this cardioprotection ensued without hyperlipidemic changes. Cardioprotection consisted of an attenuation of infarct size, diminution of norepinephrine (NE) spillover, and alleviation of reperfusion arrhythmias. This cardioprotection was associated with a reduction in oxidative stress and mast cell (MC) degranulation. We suggest that the reduction in myocardial injury and adrenergic activation, and the antiarrhythmic effects result from decreased formation of oxygen radicals and toxic aldehydes known to elicit the release of MC-derived renin, promoting the activation of local renin-angiotensin system (RAS) leading to enhanced NE release and reperfusion arrhythmias. Because these beneficial effects of AC261066 occurred at the ex-vivo level following oral drug treatment, our data suggest that AC261066 could be viewed as a therapeutic means to reduce I/R injury of the heart, and potentially also considered in the treatment of other cardiovascular ailments such as chronic arrhythmias, and cardiac failure. The American Society for Pharmacology and Experimental Therapeutics.

  17. The protective effect of 1alpha, 25-dihydroxyvitamin d3 and metformin on liver in type 2 diabetic rats.

    PubMed

    Elattar, Samah; Estaphan, Suzanne; Mohamed, Enas A; Elzainy, Ahmed; Naguib, Mary

    2017-10-01

    There is an accumulating evidence suggesting an immunomodulatory role of 1α,25(OH) 2 D3. Altered 1α,25(OH) 2 D3 level may play a role in the development of T2DM and contribute to the pathogenesis of liver diseases. Our study was designed to study and compare the effect of metformin and 1α,25(OH) 2 D3 supplementation on liver injury in type 2 diabetic rat. Sixty male Albino rats were divided into 5 groups; group 1: control rats. the remaining rats were fed high fat diet for 2 weeks and injected with streptozotocin (35mg/kg BW, i.p.) to induce T2DM and were divided into: group 2: untreated diabetic rats, group 3: diabetic rats treated by metformin (100mg/kgBW/d, orally), group 4: diabetic rats supplemented by 1α,25(OH) 2 D3 (0.5μg/kg BW, i.p.) 3 times weekly and group 5: supplemented by both 1α,25(OH) 2 D3 and metformin. Eight weeks later, serum glucose and insulin levels were measured, HOMA IR was calculated, lipid profile, Ca2+, ALT and AST were estimated. Liver specimens were taken to investigate PPAR-α (regulator of lipid metabolism), NF-κB p65, caspase 3 and PCNA (proliferating cell nuclear antigen) and for histological examination. The liver enzymes were elevated in the diabetic rats and the histological results revealed an injurious effect of diabetes on the liver. 1α,25(OH) 2 D3, metformin and both drugs treatment significantly improved liver enzymes as compared to the untreated rats. The improvement was associated with a significant improvement in the glycemic control, lipid profile and serum Ca2+ with a significant reduction in NF-κB p65 and caspase 3 and increased PPAR-α, and PCNA expression as compared to the untreated group. 1α,25(OH) 2 D3 induced a slightly better effect as compared to metformin. Both agents together had a synergistic action and almost completely protected the liver. Histological results confirmed the biochemical findings. Our results showed a protective effect of 1α,25(OH) 2 D3 and metformin on liver in diabetic rats as

  18. Targeted deletion of NF-κB p50 diminishes the cardioprotection of histone deacetylase inhibition

    PubMed Central

    Zhang, L. X.; Zhao, Y.; Cheng, G.; Guo, T. L.; Chin, Y. E.; Liu, P. Y.

    2010-01-01

    We have recently demonstrated that the inhibition of histone deacetylases (HDAC) protects the heart against ischemia-reperfusion (I/R) injury. The mechanism by which HDAC inhibition confers myocardial protection remains unknown. The purpose of this study is to investigate whether the disruption of NF-κB p50 would eliminate the protective effects of HDAC inhibition. Wild-type and NF-κB p50-deficient mice were treated with trichostatin A (TSA; 0.1 mg/kg ip), a potent inhibitor of HDACs. Twenty-four hours later, the hearts were perfused in Langendorff model and subjected to 30 min of ischemia and 30 min of reperfusion. Inhibition of HDACs by TSA in wild-type mice produced marked improvements in left ventricular end-diastolic pressure, left ventricular rate pressure product, and the reduction of infarct size compared with non-TSA-treated group. TSA-induced cardioprotection in wild-type animals was absent with genetic deletion of NF-κB p50 subunit. Notably, Western blot displayed a significant increase in nuclear NF-κB p50 and the immunoprecipitation demonstrated a remarkable acetylation of NF-κB p50 at lysine residues following HDAC inhibition. EMSA exhibited a subsequent increase in NF-κB DNA binding activity. Luciferase assay demonstrated an activation of NF-κB by HDAC inhibition. The pretreatment of H9c2 cardiomyoblasts with TSA (50 nmol/l) decreased cell necrosis and increased in cell viability in simulated ischemia. The resistance of H9c2 cardiomyoblasts to simulated ischemia by HDAC inhibition was eliminated by genetic knockdown of NF-κB p50 with transfection of NF-κB p50 short interfering RNA but not scrambled short interfering RNA. These results suggest that NF-κB p50 acetylation and activation play a pivotal role in HDAC inhibition-induced cardioprotection. PMID:20382965

  19. Effects of metformin on metabolite profiles and LDL cholesterol in patients with type 2 diabetes.

    PubMed

    Xu, Tao; Brandmaier, Stefan; Messias, Ana C; Herder, Christian; Draisma, Harmen H M; Demirkan, Ayse; Yu, Zhonghao; Ried, Janina S; Haller, Toomas; Heier, Margit; Campillos, Monica; Fobo, Gisela; Stark, Renee; Holzapfel, Christina; Adam, Jonathan; Chi, Shen; Rotter, Markus; Panni, Tommaso; Quante, Anne S; He, Ying; Prehn, Cornelia; Roemisch-Margl, Werner; Kastenmüller, Gabi; Willemsen, Gonneke; Pool, René; Kasa, Katarina; van Dijk, Ko Willems; Hankemeier, Thomas; Meisinger, Christa; Thorand, Barbara; Ruepp, Andreas; Hrabé de Angelis, Martin; Li, Yixue; Wichmann, H-Erich; Stratmann, Bernd; Strauch, Konstantin; Metspalu, Andres; Gieger, Christian; Suhre, Karsten; Adamski, Jerzy; Illig, Thomas; Rathmann, Wolfgang; Roden, Michael; Peters, Annette; van Duijn, Cornelia M; Boomsma, Dorret I; Meitinger, Thomas; Wang-Sattler, Rui

    2015-10-01

    Metformin is used as a first-line oral treatment for type 2 diabetes (T2D). However, the underlying mechanism is not fully understood. Here, we aimed to comprehensively investigate the pleiotropic effects of metformin. We analyzed both metabolomic and genomic data of the population-based KORA cohort. To evaluate the effect of metformin treatment on metabolite concentrations, we quantified 131 metabolites in fasting serum samples and used multivariable linear regression models in three independent cross-sectional studies (n = 151 patients with T2D treated with metformin [mt-T2D]). Additionally, we used linear mixed-effect models to study the longitudinal KORA samples (n = 912) and performed mediation analyses to investigate the effects of metformin intake on blood lipid profiles. We combined genotyping data with the identified metformin-associated metabolites in KORA individuals (n = 1,809) and explored the underlying pathways. We found significantly lower (P < 5.0E-06) concentrations of three metabolites (acyl-alkyl phosphatidylcholines [PCs]) when comparing mt-T2D with four control groups who were not using glucose-lowering oral medication. These findings were controlled for conventional risk factors of T2D and replicated in two independent studies. Furthermore, we observed that the levels of these metabolites decreased significantly in patients after they started metformin treatment during 7 years' follow-up. The reduction of these metabolites was also associated with a lowered blood level of LDL cholesterol (LDL-C). Variations of these three metabolites were significantly associated with 17 genes (including FADS1 and FADS2) and controlled by AMPK, a metformin target. Our results indicate that metformin intake activates AMPK and consequently suppresses FADS, which leads to reduced levels of the three acyl-alkyl PCs and LDL-C. Our findings suggest potential beneficial effects of metformin in the prevention of cardiovascular disease. © 2015 by the American

  20. Metformin for Weight Loss and Metabolic Control in Overweight Outpatients With Schizophrenia and Schizoaffective Disorder

    PubMed Central

    Jarskog, L. Fredrik; Hamer, Robert M.; Catellier, Diane J.; Stewart, Dawn D.; LaVange, Lisa; Ray, Neepa; Golden, Lauren H.; Lieberman, Jeffrey A.; Stroup, T. Scott

    2013-01-01

    Objective The purpose of this study was to determine whether metformin promotes weight loss in overweight out-patients with chronic schizophrenia or schizoaffective disorder. Method In a double-blind study, 148 clinically stable, overweight (body mass index [BMI] ≥27) outpatients with chronic schizophrenia or schizoaffective disorder were randomly assigned to receive 16 weeks of metformin or placebo. Metformin was titrated up to 1,000 mg twice daily, as tolerated. All patients continued to receive their prestudy medications, and all received weekly diet and exercise counseling. The primary outcome measure was change in body weight from baseline to week 16. Results Fifty-eight (77.3%) patients who received metformin and 58 (81.7%) who received placebo completed 16 weeks of treatment. Mean change in body weight was −3.0 kg (95% CI=−4.0 to −2.0) for the metformin group and −1.0 kg (95% CI= −2.0 to 0.0) for the placebo group, with a between-group difference of −2.0 kg (95% CI=−3.4 to −0.6). Metformin also demonstrated a significant between-group advantage for BMI (−0.7; 95% CI=−1.1 to −0.2), triglyceride level (−20.2 mg/dL; 95% CI=−39.2 to −1.3), and hemoglobin A1c level (−0.07%; 95% CI=−0.14 to −0.004). Metformin-associated side effects were mostly gastrointestinal and generally transient, and they rarely led to treatment discontinuation. Conclusions Metformin was modestly effective in reducing weight and other risk factors for cardiovascular disease in clinically stable, overweight outpatients with chronic schizophrenia or schizoaffective disorder over 16 weeks. A significant time-by-treatment interaction suggests that benefits of metformin may continue to accrue with longer treatment. Metformin may have an important role in diminishing the adverse consequences of obesity and metabolic impairments in patients with schizophrenia. PMID:23846733

  1. Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: a systematic review and meta-analysis

    PubMed Central

    Balsells, Montserrat; García-Patterson, Apolonia; Solà, Ivan; Roqué, Marta; Gich, Ignasi

    2015-01-01

    Objective To summarize short term outcomes in randomized controlled trials comparing glibenclamide or metformin versus insulin or versus each other in women with gestational diabetes requiring drug treatment. Design Systematic review and meta-analysis. Eligibility criteria for selecting studies Randomized controlled trials that fulfilled all the following: (1) published as full text; (2) addressed women with gestational diabetes requiring drug treatment; (3) compared glibenclamide v insulin, metformin v insulin, or metformin v glibenclamide; and (4) provided information on maternal or fetal outcomes. Data sources Medline, CENTRAL, and Embase were searched up to 20 May 2014. Outcomes measures We considered 14 primary outcomes (6 maternal, 8 fetal) and 16 secondary (5 maternal, 11 fetal) outcomes. Results We analyzed 15 articles, including 2509 subjects. Significant differences for primary outcomes in glibenclamide v insulin were obtained in birth weight (mean difference 109 g (95% confidence interval 35.9 to 181)), macrosomia (risk ratio 2.62 (1.35 to 5.08)), and neonatal hypoglycaemia (risk ratio 2.04 (1.30 to 3.20)). In metformin v insulin, significance was reached for maternal weight gain (mean difference −1.14 kg (−2.22 to −0.06)), gestational age at delivery (mean difference −0.16 weeks (−0.30 to −0.02)), and preterm birth (risk ratio 1.50 (1.04 to 2.16)), with a trend for neonatal hypoglycaemia (risk ratio 0.78 (0.60 to 1.01)). In metformin v glibenclamide, significance was reached for maternal weight gain (mean difference −2.06 kg (−3.98 to −0.14)), birth weight (mean difference −209 g (−314 to −104)), macrosomia (risk ratio 0.33 (0.13 to 0.81)), and large for gestational age newborn (risk ratio 0.44 (0.21 to 0.92)). Four secondary outcomes were better for metformin in metformin v insulin, and one was worse for metformin in metformin v glibenclamide. Treatment failure was higher with metformin than with glibenclamide. Conclusions At

  2. PHO-ERK1/2 interaction with mitochondria regulates the permeability transition pore in cardioprotective signaling.

    PubMed

    Hernández-Reséndiz, Sauri; Zazueta, Cecilia

    2014-07-11

    The molecular mechanism(s) by which extracellular signal-regulated kinase 1/2 (ERK1/2) and other kinases communicate with downstream targets have not been fully determined. Multiprotein signaling complexes undergoing spatiotemporal redistribution may enhance their interaction with effector proteins promoting cardioprotective response. Particularly, it has been proposed that some active kinases in association with caveolae may converge into mitochondria. Therefore, in this study we investigate if PHO-ERK1/2 interaction with mitochondria may provide a mechanistic link in the regulation of these organelles in cardioprotective signaling. Using a model of dilated cardiomyopathy followed by ischemia-reperfusion injury, we determined ERK1/2 signaling at the level of mitochondria and evaluated its effect on the permeability transition pore. The most important finding of the present study is that, under cardioprotective conditions, a subpopulation of activated ERK1/2 was directed to the mitochondrial membranes through vesicular trafficking, concurring with increased phosphorylation of mitochondrial proteins and inhibition of the mitochondrial permeability transition pore opening. In addition, our results suggest that vesicles enriched with caveolin-3 could form structures that may drive ERK1/2, GSK3β and Akt to mitochondria. Signaling complexes including PHO-ERK, PHO-Akt, PHO-eNOS and caveolin-3 contribute to cardioprotection by directly targeting the mitochondrial proteome and regulating the opening of the permeability transition pore in this model. Copyright © 2013 Elsevier Inc. All rights reserved.

  3. Metformin downregulates the insulin/IGF-I signaling pathway and inhibits different uterine serous carcinoma (USC) cells proliferation and migration in p53-dependent or -independent manners.

    PubMed

    Sarfstein, Rive; Friedman, Yael; Attias-Geva, Zohar; Fishman, Ami; Bruchim, Ilan; Werner, Haim

    2013-01-01

    Accumulating epidemiological evidence shows that obesity is associated with an increased risk of several types of adult cancers, including endometrial cancer. Chronic hyperinsulinemia, a typical hallmark of diabetes, is one of the leading factors responsible for the obesity-cancer connection. Numerous cellular and circulating factors are involved in the biochemical chain of events leading from hyperinsulinemia and insulin resistance to increased cancer risk and, eventually, tumor development. Metformin is an oral anti-diabetic drug of the biguanide family used for treatment of type 2 diabetes. Recently, metformin was shown to exhibit anti-proliferative effects in ovarian and Type I endometrial cancer, although the mechanisms responsible for this non-classical metformin action remain unclear. The insulin-like growth factors (IGFs) play a prominent role in cancer biology and their mechanisms of action are tightly interconnected with the insulin signaling pathways. Given the cross-talk between the insulin and IGF signaling pathways, the aim of this study was to examine the hypothesis that the anti-proliferative actions of metformin in uterine serous carcinoma (USC) are potentially mediated via suppression of the IGF-I receptor (IGF-IR) pathway. Our results show that metformin interacts with the IGF pathway, and induces apoptosis and inhibition of proliferation and migration of USC cell lines with both wild type and mutant p53. Taken together, our results suggest that metformin therapy could be a novel and attractive therapeutic approach for human USC, a highly aggressive variant of endometrial cancer.

  4. Effect of repaglinide addition to metformin monotherapy on glycemic control in patients with type 2 diabetes.

    PubMed

    Moses, R; Slobodniuk, R; Boyages, S; Colagiuri, S; Kidson, W; Carter, J; Donnelly, T; Moffitt, P; Hopkins, H

    1999-01-01

    To compare the effect of repaglinide in combination with metformin with monotherapy of each drug on glycemic control in patients with type 2 diabetes. A total of 83 patients with type 2 diabetes who had inadequate glycemic control (HbA1c > 7.1%) when receiving the antidiabetic agent metformin were enrolled in this multicenter, double-blind trial. Subjects were randomized to continue with their prestudy dose of metformin (n = 27), to continue with their prestudy dose of metformin with the addition of repaglinide (n = 27), or to receive repaglinide alone (n = 29). For patients receiving repaglinide, the optimal dose was determined during a 4- to 8-week titration and continued for a 3-month maintenance period. In subjects receiving combined therapy, HbA1c was reduced by 1.4 +/- 0.2%, from 8.3 to 6.9% (P = 0.0016) and fasting plasma glucose by 2.2 mmol/l (P = 0.0003). No significant changes were observed in subjects treated with either repaglinide or metformin monotherapy in HbA1c (0.4 and 0.3% decrease, respectively) or fasting plasma glucose (0.5 mmol/l increase and 0.3 mmol/l decrease respectively). Subjects receiving repaglinide either alone or in combination with metformin, had an increase in fasting levels of insulin between baseline and the end of the trial of 4.04 +/- 1.56 and 4.23 +/- 1.50 mU/l, respectively (P < 0.02). Gastrointestinal adverse events were common in the metformin group. An increase in body weight occurred in the repaglinide and combined therapy groups (2.4 +/- 0.5 and 3.0 +/- 0.5 kg, respectively; P < 0.05). Combined metformin and repaglinide therapy resulted in superior glycemic control compared with repaglinide or metformin monotherapy in patients with type 2 diabetes whose glycemia had not been well controlled on metformin alone. Repaglinide monotherapy was as effective as metformin monotherapy.

  5. Metformin for Reducing Racial/Ethnic Difference in Prostate Cancer Incidence for Men with Type II Diabetes.

    PubMed

    Wang, Chen-Pin; Lehman, Donna M; Lam, Yui-Wing F; Kuhn, John G; Mahalingam, Devalingam; Weitman, Steven; Lorenzo, Carlos; Downs, John R; Stuart, Elizabeth A; Hernandez, Javier; Thompson, Ian M; Ramirez, Amelie G

    2016-10-01

    Racial/ethnic disparity in prostate cancer is under studied in men with diabetes who are at a higher risk of aggressive prostate cancer. This study assessed the race/ethnic disparity in prostate cancer incidence for men with type II diabetes (T2D) and whether the impact of metformin on prostate cancer incidence varied by race/ethnicity. We conducted a retrospective study in 76,733 male veterans with T2D during 2003 to 2012. Cox proportional hazards model adjusting for covariates and propensity scores of metformin use and race/ethnic group membership was utilized to compute the HR of prostate cancer incidence associated with race/ethnicity and compare HR associated with metformin use between race/ethnic groups. Mean follow-up was 6.4 ± 2.8 years; 7% were Hispanics; 17% were African Americans (AA); mean age was 67.8 ± 9.8 years; 5.2% developed prostate cancer; and 38.9% used metformin. Among these diabetic men without metformin use, prostate cancer incidence was higher in Hispanics and AA than in non-Hispanic White (NHW). Use of metformin alone or metformin + statins was associated with a greater prostate cancer incidence reduction in Hispanics compared with NHW, but not between AA and NHW. Use of metformin + finasteride was associated with a greater prostate cancer incidence reduction in Hispanics and AA compared with NHW. Our results suggested that metformin treatment could be a potential strategy to reduce prostate cancer incidence in the minority populations who are at high risk for fatal prostate cancer. It will be important to further examine the pleiotropic effects of metformin in multi-race/ethnic prospective studies to better inform clinical management and potentially reduce racial/ethnic disparity in prostate cancer incidence among diabetic men. Cancer Prev Res; 9(10); 779-87. ©2016 AACR. ©2016 American Association for Cancer Research.

  6. The cardioprotective power of leaves

    PubMed Central

    Boncler, Magdalena; Watala, Cezary

    2015-01-01

    Lack of physical activity, smoking and/or inappropriate diet can contribute to the increase of oxidative stress, in turn affecting the pathophysiology of cardiovascular diseases. Strong anti-oxidant properties of plant polyphenolic compounds might underlie their cardioprotective activity. This paper reviews recent findings on the anti-oxidant activity of plant leaf extracts and emphasizes their effects on blood platelets, leukocytes and endothelial cells – the targets orchestrating the development and progression of cardiovascular diseases. We also review the evidence linking supplementation with plant leaf extracts and the risk factors defining the metabolic syndrome. The data point to the importance of leaves as an alternative source of polyphenolic compounds in the human diet and their role in the prevention of cardiovascular diseases. PMID:26322095

  7. Cardioprotective effect of magnetic hydrogel nanocomposite loaded N,α-L-rhamnopyranosyl vincosamide isolated from Moringa oleifera leaves against doxorubicin-induced cardiac toxicity in rats: in vitro and in vivo studies.

    PubMed

    Cheraghi, Mostafa; Namdari, Mehrdad; Daraee, Hadis; Negahdari, Babak

    2017-06-01

    Cardioprotective effect of N, α-L-rhamnopyranosyl vincosamide (VR), isolated from the leaves of Moringa oleifera plant in doxorubicin (Dox)-induced cardiac toxicity rats was evaluated. Twelve (12) rats were randomly selected into three groups; two rats received distilled water in the control group, five rats in group I received varying concentration of VR treatment, and group II containing five rats received varying concentration of VR-loaded magnetic hydrogel nanocomposite. Malondialdehyde (MDA), glutathione peroxidase (GSH) and superoxide dismutase (SOD) enzymes activities level were analysed after two weeks. In addition, the expression of three heart failure markers; beta major histocompatibility complex (β-MHC), atrial natriuretic peptide (ANP), and B type natriuretic peptide (BNP) were also evaluated. It was observed that the level of these markers expression decreases with an increase in VR concentration (p < 0.05). The reduced GSH and SOD level were increased after VR administration, this extract also reduced the initially increased MDA level in cardiac tissue. Pharmacokinetic parameters evaluation showed that nanogel treated rats possesses a significantly increased VR plasma concentration, C max , K el , t ½(a), t ½(el), K a and AUC. The result of this study indicated that VR may help to lower the dosage level, and reduces the treatment course in cardiovascular diseases (CVD). Our conclusion proposes the cardio-protective ability of the isolated VR and its beneficial effect via free radical scavenging properties.

  8. Metformin in severe exacerbations of chronic obstructive pulmonary disease: a randomised controlled trial.

    PubMed

    Hitchings, Andrew W; Lai, Dilys; Jones, Paul W; Baker, Emma H

    2016-07-01

    Severe exacerbations of COPD are commonly associated with hyperglycaemia, which predicts adverse outcomes. Metformin is a well-established anti-hyperglycaemic agent in diabetes mellitus, possibly augmented with anti-inflammatory effects, but its effects in COPD are unknown. We investigated accelerated metformin therapy in severe COPD exacerbations, primarily to confirm or refute an anti-hyperglycaemic effect, and secondarily to explore its effects on inflammation and clinical outcome. This was a multicentre, randomised, double-blind, placebo-controlled trial testing accelerated metformin therapy in non-diabetic patients, aged ≥35 years, hospitalised for COPD exacerbations. Participants were assigned in a 2:1 ratio to 1 month of metformin therapy, escalated rapidly to 2 g/day, or matched placebo. The primary end point was mean in-hospital blood glucose concentration. Secondary end points included the concentrations of fructosamine and C reactive protein (CRP), and scores on the COPD Assessment Test and Exacerbations of Chronic Pulmonary Disease Tool. 52 participants (mean (±SD) age 67±9 years) were randomised (34 to metformin, 18 to placebo). All were included in the primary end point analysis. The mean blood glucose concentrations in the metformin and placebo groups were 7.1±0.9 and 8.0±3.3 mmol/L, respectively (difference -0.9 mmol/L, 95% CI -2.1 to +0.3; p=0.273). No significant between-group differences were observed on any of the secondary end points. Adverse reactions, particularly gastrointestinal effects, were more common in metformin-treated participants. Metformin did not ameliorate elevations in blood glucose concentration among non-diabetic patients admitted to hospital for COPD exacerbations, and had no detectable effect on CRP or clinical outcomes. ISRCTN66148745 and NCT01247870. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  9. Transitory Activation of AMPK at Reperfusion Protects the Ischaemic-Reperfused Rat Myocardium Against Infarction

    PubMed Central

    Paiva, Marta A.; Gonçalves, Lino M.; Providência, Luis A.; Davidson, Sean M.; Yellon, Derek M.; Mocanu, Mihaela M.

    2010-01-01

    Purpose AMPK plays a crucial role in the regulation of the energy metabolism of the heart. During ischaemia, AMPK activation is a known adaptative prosurvival mechanism that helps to maintain the energy levels of the myocardium. However, it still remains unclear if activation of AMPK during reperfusion is beneficial for the heart. Two known AMPK activators (metformin and AICAR) were used to verify the hypothesis that a transitory activation of AMPK at reperfusion may exert cardioprotection, as reflected in a reduction in myocardial infarct size. Methods Perfused rat hearts were subjected to 35 min ischaemia and 120 min reperfusion. Metformin (50 μM) or AICAR (0.5 mM) were added for 15 min at the onset of reperfusion alone or with Compound C (CC, 10 μM), an AMPK inhibitor. Infarct size and α-AMPK phosphorylation were measured. Results Metformin significantly reduced infarct size from 47.8±1.7% in control to 31.4±2.9%, an effect abolished by CC when the drugs were given concomitantly. Similarly, AICAR also induced a significant reduction in infarct size to 32.3±4.8%, an effect also abrogated by CC. However, metformin's protection was not abolished if CC was administered later in reperfusion. In addition, α-AMPK phosphorylation was significantly increased in the metformin treated group during the initial 30 min of reperfusion. Conclusions Our data demonstrated that, in our ex vivo model of myocardial ischaemia-reperfusion injury, AMPK activation in early reperfusion is associated with a reduction in infarct size. PMID:20229055

  10. Multivitamin Use and Serum Vitamin B12 Concentrations in Older-Adult Metformin Users in REGARDS, 2003-2007.

    PubMed

    Kancherla, Vijaya; Garn, Joshua V; Zakai, Neil A; Williamson, Rebecca S; Cashion, Winn T; Odewole, Oluwaseun; Judd, Suzanne E; Oakley, Godfrey P

    2016-01-01

    Metformin, an insulin-sensitizing drug, is a first line treatment for type 2 diabetes. Long-term use of metformin has been associated with subsequent reductions in vitamin B12 concentrations. The objective of our study was to determine whether metformin use is associated with lower serum vitamin B12 concentrations in older adults, and whether concurrent use of multivitamins modifies this association. We examined 2,510 participants aged 50 years and over, participating in the national population-based Reasons for Geographic And Racial Differences in Stroke (REGARDS) Study. Multivariable linear and logistic regression models were used to assess associations between multivitamin use and serum vitamin B12 concentrations. We estimated adjusted odds ratios (aOR)s and confidence intervals (CI)s. Results were stratified by three metformin/diabetes sub-groups: 1) participants with diabetes who were metformin users; 2) participants with diabetes who were not metformin users; and 3) participants without diabetes. We found that diabetic metformin users had significantly lower geometric mean serum B12 concentrations (409 pmol/L) than the group with diabetes not taking metformin (485 pmol/L; P<0.01), and the group without diabetes (445 pmol/L; P = 0.02). The geometric mean serum B12 concentrations were greater for multivitamin users (509 pmol/L) compared to those who did not use multivitamins (376 pmol/L; p<0.01). Among the participants with diabetes who were on metformin therapy, multivitamin use was associated with geometric mean serum vitamin B12 concentrations that were 50% (or 161 pmol/L) higher, compared to those not using multivitamins. Among metformin users, multivitamin use was associated with lower prevalence of combined low and borderline vitamin B12 concentrations (aOR = 0.14; 95% CI = 0.04, 0.54) compared to those not using multivitamins. In conclusion, metformin use was associated with lower geometric mean serum vitamin B12 concentrations among diabetic older

  11. The cardioprotective and antiarrhythmic effects of Nardostachys chinensis in animal and cell experiments.

    PubMed

    Li, Min; Xu, Xue; Yang, Xinyu; Kwong, Joey S W; Shang, Hongcai

    2017-08-10

    Cardiovascular disease (CVD) is the leading cause of premature death throughout the world. An estimated 17.5 million people died from CVD in 2012, representing 31% of all global deaths. Nardostachys chinensis (NC), a typical traditional Chinese medicine (TCM), plays a crucial role in the management of patients with CVD, especially for those with cardiac arrhythmia. The purpose of this study was to evaluate the cardioprotective and antiarrhythmic effects of NC in animal and cell experiments. To review the cardioprotective and antiarrhythmic effects of NC, studies of NC on cardiovascular diseases in animal and cell experiments were identified from five databases through April 2016. Two investigators independently conducted the literature search, study selection, and data extraction. A total of 16 studies were identified, including five animal experiments and eleven cell experiments. Four studies showed significant effects of NC on myocardial protection by inhibiting myocardial apoptosis, inflammation and oxidative stress. Twelve studies indicated significant beneficial effects of NC in cardiac arrhythmia primarily through the modulation of ion channels (I k , I k1 , I Na , I Ca-L , I to ). The above findings showed the possible efficacy of NC via its cardioprotective and antiarrhythmic effects, but the results should be interpreted with caution due to the limitations and the deficiencies in the studies.

  12. A randomized controlled trial of clomifene citrate, metformin, and pioglitazone versus letrozole, metformin, and pioglitazone for clomifene-citrate-resistant polycystic ovary syndrome.

    PubMed

    El-khayat, Waleed; Abdel Moety, Ghada; Al Mohammady, Maged; Hamed, Dalia

    2016-02-01

    To examine the efficacy of clomifene citrate, metformin, and pioglitazone versus letrozole, metformin, and pioglitazone among women with polycystic ovary syndrome (PCOS) resistant to clomifene citrate. A prospective double-blind randomized controlled trial of women younger than 40 years who had primary/secondary infertility associated with PCOS and had not ovulated in response to clomifene citrate regimens previously was conducted at a center in Cairo, Egypt, between August 1, 2013, and December 31, 2014. Computer-generated random number tables and opaque envelopes were used to assign participants to group A or group B. Participants allocated to group A received 100mg clomifene citrate daily for 5 days from the third day of the menstrual cycle, whereas those in group B received 5mg letrozole daily in the same regimen. All patients received 850 mg metformin and 15 mg pioglitazone for 10 days from the first day of the menstrual cycle. The primary outcome was cumulative ovulation rate. Analyses were by intention to treat. Fifty women were assigned to each group. Ovulation occurred in 108 (92.3%) of 117 cycles in group A and 93 (86.9%) of 107 cycles in Group B (P=0.184). Combined treatment with letrozole, metformin, and pioglitazone was efficacious among women with PCOS resistant to clomifene citrate. ClinicalTrials.gov: NCT01909141. Copyright © 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

  13. Fetal Growth and Birth Anthropometrics in Metformin-Exposed Offspring Born to Mothers With PCOS.

    PubMed

    Hjorth-Hansen, Anna; Salvesen, Øyvind; Engen Hanem, Liv Guro; Eggebø, Torbjørn; Salvesen, Kjell Å; Vanky, Eszter; Ødegård, Rønnaug

    2018-02-01

    Metformin is used in an attempt to reduce pregnancy complications associated with polycystic ovary syndrome (PCOS). Little is known about the effect of metformin on fetal development and growth. To compare the effect of metformin versus placebo on fetal growth and birth anthropometrics in PCOS offspring compared with a reference population in relation to maternal body mass index (BMI). Post hoc analysis of a randomized controlled trial. Double-blind, placebo-controlled, multicenter study. 258 offspring born to mothers with PCOS. 2000 mg metformin (n = 131) or placebo (n = 121) from first trimester to delivery. Mean abdominal diameter and biparietal diameter (BPD) at gestational weeks 19 and 32. Head circumference (HC), birth length, and weight related to a reference population of healthy offspring, expressed as gestational age- and sex-adjusted z-scores. Metformin- versus placebo-exposed offspring had larger heads at gestational week 32 (BPD, 86.1 mm versus 85.2 mm; P = 0.03) and at birth (HC, 35.6 cm versus 35.1 cm; P < 0.01). Analyses stratified by maternal prepregnancy BMI, larger heads were observed only among offspring of overweight/obese mothers. Among normal-weight mothers, the effect of metformin compared with placebo was reduced length (z-score = -0.96 versus -0.42, P = 0.04) and weight (z-score = -0.44 versus 0.02; P = 0.03). Compared with the reference population, offspring born to PCOS mothers (placebo group) had reduced length (z-score = -0.40; 95% confidence interval, -0.60 to -0.40), but similar birth weight and HC. Metformin exposure resulted in larger head size in offspring of overweight mothers, traceable already in utero. Maternal prepregnancy BMI modified the effect of metformin on offspring anthropometrics. Anthropometrics of offspring born to PCOS mothers differed from those of the reference population. Copyright © 2017 Endocrine Society

  14. A PET Tracer for Renal Organic Cation Transporters, ¹¹C-Metformin: Radiosynthesis and Preclinical Proof-of-Concept Studies.

    PubMed

    Jakobsen, Steen; Busk, Morten; Jensen, Jonas Brorson; Munk, Ole Lajord; Zois, Nora Elisabeth; Alstrup, Aage K O; Jessen, Niels; Frøkiær, Jørgen

    2016-04-01

    Organic cation transporters (OCTs) in the kidney proximal tubule (PT) participate in renal excretion of drugs and endogenous compounds. PT function is commonly impaired in kidney diseases, and consequently quantitative measurement of OCT function may provide an important estimate of kidney function. Metformin is a widely used drug and targets OCT type 2 located in the PT. Thus, we hypothesized that (11)C-labeled metformin would be a suitable PET tracer for quantification of renal function. (11)C-metformin was prepared by (11)C-methylation of 1-methylbiguanide. In vitro cell uptake of (11)C-metformin was studied in LLC-PK1 cells in the presence of increasing doses of unlabeled metformin. In vivo small-animal PET studies in Sprague-Dawley rats were performed at baseline and after treatment with OCT inhibitors to evaluate renal uptake of (11)C-metformin. Kidney and liver pharmacokinetics of (11)C-metformin was investigated in vivo by dynamic (11)C-metformin PET/CT in 6 anesthetized pigs, and renal clearance of (11)C-metformin was compared with renal clearance of (51)Cr-ethylenediaminetetraacetic acid (EDTA). Formation of (11)C metabolites was investigated by analysis of blood and urine samples. The radiochemical yield of (11)C-metformin was 15% ± 3% (n= 40, decay-corrected), and up to 1.5 GBq of tracer were produced with a radiochemical purity greater than 95% in less than 30 min. Dose-dependent uptake of (11)C-metformin in LLC-PK1 cells was rapid. Rat small-animal PET images showed (11)C-metformin uptake in the kidney and liver, the kinetics of which were changed after challenging animals with OCT inhibitors. In pigs, 80% of the injected metformin dose was rapidly present in the kidney, and a high dose of metformin caused a delayed renal uptake and clearance compared with baseline consistent with transporter-mediated competition. Renal clearance of (11)C-metformin was approximately 3 times the renal clearance of (51)Cr-EDTA. We successfully synthesized an (11)C-metformin

  15. A retrospective study on the role of diabetes and metformin in colorectal cancer disease survival

    PubMed Central

    Ramjeesingh, R.; Orr, C.; Bricks, C.S.; Hopman, W.M.; Hammad, N.

    2016-01-01

    Background Recent studies have suggested an effect of metformin on mortality for patients with both diabetes and colorectal cancer (crc). However, the literature is contradictory, with both positive and negative effects being identified. We set out to determine the effect of metformin with respect to prognosis in crc patients. Methods After a retrospective chart review of crc patients treated at the Cancer Centre of Southeastern Ontario, Kaplan–Meier analyses and Cox proportional hazards regression models were used to compare overall survival (os) in patients with and without diabetes. Results We identified 1304 crc patients treated at the centre. No significant differences between the diabetic and nondiabetic groups were observed with respect to tumour pathology, extent of metastatic disease, time or toxicity of chemotherapy, and the os rate (1-year os: 85.6% vs. 86.4%, p = 0.695; 2-year os: 73.6% vs. 77.0%, p = 0.265). In subgroup analysis, diabetic patients taking metformin survived significantly longer than their counterparts taking other diabetes treatments (os for the metformin group: 91% at 1 year; 80.5% at 2 years; os for the group taking other treatments, including diet control: 80.6% at 1 year, 67.4% at 2 years). Multivariate analysis suggests that patients with diabetes taking treatments other than metformin experience worse survival (p = 0.025). Conclusions Our results suggest that crc patients with diabetes, excluding those taking metformin, might have a worse crc prognosis. Taking metformin appears to have a positive association with prognosis. The protective nature of metformin needs further evaluation in prospective analyses. PMID:27122979

  16. Nightmare and Abnormal Dreams: Rare Side Effects of Metformin?

    PubMed Central

    Yanto, Theo Audi; Kosasih, Felicia Nathania

    2018-01-01

    Background Metformin is widely known as an antidiabetic agent which has significant gastrointestinal side effects, but nightmares and abnormal dreams as its adverse reactions are not well reported. Case Presentation Herein we present a case of 56-year-old male patient with no known history of recurrent nightmares and sleep disorder, experiencing nightmare and abnormal dreams directly after consumption of 750 mg extended release metformin. He reported his dream as an unpleasant experience which awakened him at night with negative feelings. The nightmare only lasted for a night, but his dreams every night thereafter seemed abnormal. The dreams were vivid and indescribable. The disappearance and occurrence of abnormal dreams ensued soon after the drug was discontinued and rechallenged. The case was assessed using Naranjo Adverse Drug Reaction (ADR) probability scale and resulted as probable causality. Conclusion Metformin might be the underlying cause of nightmare and abnormal dreams in this patient. More studies are needed to confirm the association and causality of this findings. PMID:29581904

  17. A novel description of FDG excretion in the renal system: application to metformin-treated models

    NASA Astrophysics Data System (ADS)

    Garbarino, S.; Caviglia, G.; Sambuceti, G.; Benvenuto, F.; Piana, M.

    2014-05-01

    This paper introduces a novel compartmental model describing the excretion of 18F-fluoro-deoxyglucose (FDG) in the renal system and a numerical method based on the maximum likelihood for its reduction. This approach accounts for variations in FDG concentration due to water re-absorption in renal tubules and the increase of the bladder’s volume during the FDG excretion process. From the computational viewpoint, the reconstruction of the tracer kinetic parameters is obtained by solving the maximum likelihood problem iteratively, using a non-stationary, steepest descent approach that explicitly accounts for the Poisson nature of nuclear medicine data. The reliability of the method is validated against two sets of synthetic data realized according to realistic conditions. Finally we applied this model to describe FDG excretion in the case of animal models treated with metformin. In particular we show that our approach allows the quantitative estimation of the reduction of FDG de-phosphorylation induced by metformin.

  18. Blends of jackfruit seed starch-pectin in the development of mucoadhesive beads containing metformin HCl.

    PubMed

    Nayak, Amit Kumar; Pal, Dilipkumar

    2013-11-01

    In this work, calcium pectinate-jackfruit (Artocarpus heterophyllus Lam.) seed starch (JFSS) mucoadhesive beads containing metformin HCl were developed through ionotropic-gelation. Effects of pectin and JFSS amounts on drug encapsulation efficiency (DEE), and cumulative drug release after 10 h (R10 h) were optimized using 3(2) factorial design. The optimized calcium pectinate-JFSS beads containing metformin HCl showed DEE of 94.11 ± 3.92%, R10 h of 48.88 ± 2.02%, and mean diameter of 2.06 ± 0.20 mm. The in vitro drug release from these beads was followed controlled-release (zero-order) pattern with super case-II transport mechanism. The beads were also characterized by SEM and FTIR. The pH of test mediums was found critical for swelling and mucoadhesion of these beads. The optimized calcium pectinate-JFSS beads also exhibited good mucoadhesivity and significant hypoglycemic effect in alloxan-induced diabetic rats over prolonged period after oral administration. Copyright © 2013 Elsevier B.V. All rights reserved.

  19. Clinical, endocrine and metabolic effects of metformin added to ethinyl estradiol-cyproterone acetate in non-obese women with polycystic ovarian syndrome: a randomized controlled study.

    PubMed

    Elter, Koray; Imir, Gonca; Durmusoglu, Fatih

    2002-07-01

    Oral contraceptive pills (OC) are usually the first choice of treatment for polycystic ovarian syndrome (PCOS), when fertility is not desired. However, they do not improve, or may even further induce impairment of insulin sensitivity, which is already impaired in women with PCOS. In this prospective, randomized study, we analysed the additional benefits of adding metformin to the OC treatment in non-obese women with PCOS. After a baseline work-up including body mass index (BMI), waist:hip ratio (WHR), Ferriman-Gallwey score, ovarian volume, serum gonadotrophin, androgen and sex hormone-binding globulin (SHBG) levels, and fasting lipid, glucose and insulin levels, 40 non-obese women with PCOS were assigned either to the OC or to the OC + metformin treatment by computer-assisted randomization. At the end of the 4 month follow-up period, subjects were re-evaluated. The two groups were similar at baseline. After treatment, women in the OC + metformin group had significant decreases in BMI and WHR, and a significant increase in insulin sensitivity, in contrast to those in the OC group, who had insignificant changes in these parameters. Adding metformin also caused significant improvements in serum androstenedione and SHBG levels compared with the OC treatment alone. Adding metformin to the OC treatment may improve the insulin sensitivity, and may further suppress the hyperandrogenaemia in non-obese women with PCOS.

  20. The MATE1 rs2289669 polymorphism affects the renal clearance of metformin following ranitidine treatment.

    PubMed

    Cho, Sung Kweon; Chung, Jae-Yong

    2016-04-01

    Human multidrug and toxin extrusion member 1 (MATE1, SLC47A1) and Organic Cation Transporter 2 (OCT2, SLC22A2) play important roles in the renal elimination of various pharmacologic agents, including the anti-diabetic drug metformin. The goal of this study was to determine the association between metformin's pharmacokinetics and pharmacodynamics and the genetic variants of MATE1 (rs2289669) and OCT2 (rs316019) before and after treatment with the potential MATE inhibitor, ranitidine. We recruited 26 healthy Koreans balanced across the OCT2 and MATE1 genetic variants, and conducted a prospective clinical trial to investigate their effects on metformin's pharmacokinetics and pharmacodynamics before and after ranitidine treatment. Neither MATE1 rs2289669 nor OCT2 rs316019 affected metformin's pharmacokinetics and pharmacodynamics before ranitidine treatment. However, the renal clearance of metformin was significantly higher (15.2%) after ranitidine treatment in the MATE1 GG group compared with the MATE1 GA + AA group. Only the effect of MATE1 on the renal clearance of metformin after ranitidine treatment was significant (b = -0.465, p ≤ 0.05) after including demographic data and the OCT2 genotype in the model. Our study suggests that MATE1 rs2289669 may be a significant determinant in the renal clearance of metformin in the case of transporter-mediated drug interactions.