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  1. Cinnamaldehyde impairs high glucose-induced hypertrophy in renal interstitial fibroblasts.

    PubMed

    Chao, Louis Kuoping; Chang, Wen-Teng; Shih, Yuan-Wei; Huang, Jau-Shyang

    2010-04-15

    Cinnamaldehyde is a major and a bioactive compound isolated from the leaves of Cinnamomum osmophloeum kaneh. To explore whether cinnamaldehyde was linked to altered high glucose (HG)-mediated renal tubulointerstitial fibrosis in diabetic nephropathy (DN), the molecular mechanisms of cinnamaldehyde responsible for inhibition of HG-induced hypertrophy in renal interstitial fibroblasts were examined. We found that cinnamaldehyde caused inhibition of HG-induced cellular mitogenesis rather than cell death by either necrosis or apoptosis. There were no changes in caspase 3 activity, cleaved poly(ADP-ribose) polymerase (PARP) protein expression, and mitochondrial cytochrome c release in HG or cinnamaldehyde treatments in these cells. HG-induced extracellular signal-regulated kinase (ERK)/c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) (but not the Janus kinase 2/signal transducers and activators of transcription) activation was markedly blocked by cinnamaldehyde. The ability of cinnamaldehyde to inhibit HG-induced hypertrophy was verified by the observation that it significantly decreased cell size, cellular hypertrophy index, and protein levels of collagen IV, fibronectin, and alpha-smooth muscle actin (alpha-SMA). The results obtained in this study suggest that cinnamaldehyde treatment of renal interstitial fibroblasts that have been stimulated by HG reduces their ability to proliferate and hypertrophy through mechanisms that may be dependent on inactivation of the ERK/JNK/p38 MAPK pathway.

  2. High glucose-induced barrier impairment of human retinal pigment epithelium is ameliorated by treatment with Goji berry extracts through modulation of cAMP levels.

    PubMed

    Pavan, Barbara; Capuzzo, Antonio; Forlani, Giuseppe

    2014-03-01

    Human retinal pigment epithelium cells were used to investigate the mechanisms underlying blood-retinal barrier disruption under conditions of chronic hyperglycemia. The treatment with 25 mM glucose caused a rapid drop in the transepithelial electrical resistance (TEER), which was reversed by the addition of either a methanolic extract from Goji (Lycium barbarum L.) berries or its main component, taurine. Intracellular cAMP levels increased concurrently with the high glucose-induced TEER decrease, and were correlated to an increased activity of the cytosolic isoform of the enzyme adenylyl cyclase. The treatment with plant extract or taurine restored control levels. Data are discussed in view of a possible prevention approach for diabetic retinopathy.

  3. Fructose impairs glucose-induced hepatic triglyceride synthesis.

    PubMed

    Huang, Danshan; Dhawan, Tania; Young, Stephen; Yong, William H; Boros, Laszlo G; Heaney, Anthony P

    2011-01-24

    Obesity, type 2 diabetes and hyperlipidemia frequently coexist and are associated with significantly increased morbidity and mortality. Consumption of refined carbohydrate and particularly fructose has increased significantly in recent years and has paralled the increased incidence of obesity and diabetes. Human and animal studies have demonstrated that high dietary fructose intake positively correlates with increased dyslipidemia, insulin resistance, and hypertension. Metabolism of fructose occurs primarily in the liver and high fructose flux leads to enhanced hepatic triglyceride accumulation (hepatic steatosis). This results in impaired glucose and lipid metabolism and increased proinflammatory cytokine expression. Here we demonstrate that fructose alters glucose-stimulated expression of activated acetyl CoA carboxylase (ACC), pSer hormone sensitive lipase (pSerHSL) and adipose triglyceride lipase (ATGL) in hepatic HepG2 or primary hepatic cell cultures in vitro. This was associated with increased de novo triglyceride synthesis in vitro and hepatic steatosis in vivo in fructose- versus glucose-fed and standard-diet fed mice. These studies provide novel insight into the mechanisms involved in fructose-mediated hepatic hypertriglyceridemia and identify fructose-uptake as a new potential therapeutic target for lipid-associated diseases.

  4. Myeloperoxidase amplified high glucose-induced endothelial dysfunction in vasculature: Role of NADPH oxidase and hypochlorous acid.

    PubMed

    Tian, Rong; Ding, Yun; Peng, Yi-Yuan; Lu, Naihao

    2017-03-11

    Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived reactive oxygen species (ROS) such as superoxide and hydrogen peroxide (H2O2), have emerged as important molecules in the pathogenesis of diabetic endothelial dysfunction. Additionally, neutrophils-derived myeloperoxidase (MPO) and MPO-catalyzed hypochlorous acid (HOCl) play important roles in the vascular injury. However, it is unknown whether MPO can use vascular-derived ROS to induce diabetic endothelial dysfunction. In the present study, we demonstrated that NADPH oxidase was the main source of ROS formation in high glucose-cultured human umbilical vein endothelial cells (HUVECs), and played a critical role in high glucose-induced endothelial dysfunction such as cell apoptosis, loss of cell viability and reduction of nitric oxide (NO). However, the addition of MPO could amplify the high glucose-induced endothelial dysfunction which was inhibited by the presence of apocynin (NADPH oxidase inhibitor), catalase (H2O2 scavenger), or methionine (HOCl scavenger), demonstrating the contribution of NADPH oxidase-H2O2-MPO-HOCl pathway in the MPO/high glucose-induced vascular injury. In high glucose-incubated rat aortas, MPO also exacerbated the NADPH oxidase-induced impairment of endothelium-dependent relaxation. Consistent with these in vitro data, in diabetic rat aortas, both MPO expresion and NADPH oxidase activity were increased while the endothelial function was simultaneously impaired. The results suggested that vascular-bound MPO could amplify high glucose-induced vascular injury in diabetes. MPO-NADPH oxidase-HOCl may represent an important pathogenic pathway in diabetic vascular diseases.

  5. NLRP3 Inflammasome Expression and Signaling in Human Diabetic Wounds and in High Glucose Induced Macrophages

    PubMed Central

    Zhang, Xiaotian; Dai, Jiezhi; Li, Li

    2017-01-01

    Introduction. To investigate the contribution and mechanism of NLRP3 inflammasome expression in human wounds in diabetes mellitus and in high glucose induced macrophages. Methods. In the present study, we compared the expression of NLRP3 inflammasome in debridement wound tissue from diabetic and nondiabetic patients. We also examined whether high glucose induces NLRP3 inflammasome expression in cultures THP-1-derived macrophages and the influence on IL-1β expression. Results. The expressions of NLRP3, caspase1, and IL-1β, at both the mRNA and protein level, were significantly higher in wounds of diabetic patients compared with nondiabetic wounds (P < 0.05). High glucose induced a significant increase in NLRP3 inflammasome and IL-1β expression in THP-1-derived macrophages. M1 macrophage surface marker with CCR7 was significantly upregulated after high glucose stimulation. SiRNA-mediated silencing of NLRP3 expression downregulates the expression of IL-1β. Conclusion. The higher expression of NLRP3, caspase1, and secretion of IL-1β, signaling, and activation might contribute to the hyperinflammation in the human diabetic wound and in high glucose induced macrophages. It may be a novel target to treat the DM patients with chronic wound. PMID:28164132

  6. Punicalagin exerts protective effect against high glucose-induced cellular stress and neural tube defects.

    PubMed

    Zhong, Jianxiang; Reece, E Albert; Yang, Peixin

    2015-11-13

    Maternal diabetes-induced birth defects remain a significant health problem. Studying the effect of natural compounds with antioxidant properties and minimal toxicities on diabetic embryopathy may lead to the development of new and safe dietary supplements. Punicalagin is a primary polyphenol found in pomegranate juice, which possesses antioxidant, anti-inflammatory and anti-tumorigenic properties, suggesting a protective effect of punicalagin on diabetic embryopathy. Here, we examined whether punicalagin could reduce high glucose-induced neural tube defects (NTDs), and if this rescue occurs through blockage of cellular stress and caspase activation. Embryonic day 8.5 (E8.5) mouse embryos were cultured for 24 or 36 h with normal (5 mM) glucose or high glucose (16.7 mM), in presence or absence of 10 or 20 μM punicalagin. 10 μM punicalagin slightly reduced NTD formation under high glucose conditions; however, 20 μM punicalagin significantly inhibited high glucose-induced NTD formation. Punicalagin suppressed high glucose-induced lipid peroxidation marker 4-hydroxynonenal, nitrotyrosine-modified proteins, and lipid peroxides. Moreover, punicalagin abrogated endoplasmic reticulum stress by inhibiting phosphorylated protein kinase ribonucleic acid (RNA)-like ER kinase (p-PERK), phosphorylated inositol-requiring protein-1α (p-IRE1α), phosphorylated eukaryotic initiation factor 2α (p-eIF2α), C/EBP-homologous protein (CHOP), binding immunoglobulin protein (BiP) and x-box binding protein 1 (XBP1) mRNA splicing. Additionally, punicalagin suppressed high glucose-induced caspase 3 and caspase 8 cleavage. Punicalagin reduces high glucose-induced NTD formation by blocking cellular stress and caspase activation. These observations suggest punicalagin supplements could mitigate the teratogenic effects of hyperglycemia in the developing embryo, and possibly prevent diabetes-induced NTDs.

  7. Punicalagin exerts protective effect against high glucose-induced cellular stress and neural tube defects

    PubMed Central

    Zhong, Jianxiang; Reece, E. Albert; Yang, Peixin

    2015-01-01

    Maternal diabetes-induced birth defects remain a significant health problem. Studying the effect of natural compounds with antioxidant properties and minimal toxicities on diabetic embryopathy may lead to the development of new and safe dietary supplements. Punicalagin is a primary polyphenol found in pomegranate juice, which possesses antioxidant, anti-inflammatory and anti-tumorigenic properties, suggesting a protective effect of punicalagin on diabetic embryopathy. Here, we examined whether punicalagin could reduce high glucose-induced neural tube defects (NTDs), and if this rescue occurs through blockage of cellular stress and caspase activation. Embryonic day 8.5 (E8.5) mouse embryos were cultured for 24 or 36 hours with normal (5 mM) glucose or high glucose (16.7 mM), in presence or absence of 10 or 20 µM punicalagin. 10 µM punicalagin slightly reduced NTD formation under high glucose conditions; however, 20 µM punicalagin significantly inhibited high glucose-induced NTD formation. Punicalagin suppressed high glucose-induced lipid peroxidation marker 4-hydroxynonenal, nitrotyrosine-modified proteins, and lipid peroxides. Moreover, punicalagin abrogated endoplasmic reticulum stress by inhibiting phosphorylated protein kinase ribonucleic acid (RNA)-like ER kinase (p-PERK), phosphorylated inositol-requiring protein-1α (p-IRE1α), phosphorylated eukaryotic initiation factor 2α (p-eIF2α), C/EBP-homologous protein (CHOP), binding immunoglobulin protein (BiP) and x-box binding protein 1 (XBP1) mRNA splicing. Additionally, punicalagin suppressed high glucose-induced caspase 3 and caspase 8 cleavage. Punicalagin reduces high glucose-induced NTD formation by blocking cellular stress and caspase activation. These observations suggest punicalagin supplements could mitigate the teratogenic effects of hyperglycemia in the developing embryo, and possibly prevent diabetesinduced NTDs. PMID:26453010

  8. Coenzyme Q10 prevents high glucose-induced oxidative stress in human umbilical vein endothelial cells.

    PubMed

    Tsuneki, Hiroshi; Sekizaki, Naoto; Suzuki, Takashi; Kobayashi, Shinjiro; Wada, Tsutomu; Okamoto, Tadashi; Kimura, Ikuko; Sasaoka, Toshiyasu

    2007-07-02

    Hyperglycemia-induced oxidative stress plays a crucial role in the pathogenesis of vascular complications in diabetes. Although some clinical evidences suggest the use of an antioxidant reagent coenzyme Q10 in diabetes with hypertension, the direct effect of coenzyme Q10 on the endothelial functions has not been examined. In the present study, we therefore investigated the protective effect of coenzyme Q10 against high glucose-induced oxidative stress in human umbilical vein endothelial cells (HUVEC). HUVEC exposed to high glucose (30 mM) exhibited abnormal properties, including the morphological and biochemical features of apoptosis, overproduction of reactive oxygen species, activation of protein kinase Cbeta2, and increase in endothelial nitric oxide synthase expression. Treatment with coenzyme Q10 strongly inhibited these changes in HUVEC under high glucose condition. In addition, coenzyme Q10 inhibited high glucose-induced cleavage of poly(ADP-ribose) polymerase, an endogenous caspase-3 substrate. These results suggest that coenzyme Q10 prevents reactive oxygen species-induced apoptosis through inhibition of the mitochondria-dependent caspase-3 pathway. Moreover, consistent with previous reports, high glucose caused upregulation of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) in HUVEC, and promoted the adhesion of U937 monocytic cells. Coenzyme Q10 displayed potent inhibitory effects against these endothelial abnormalities. Thus, we provide the first evidence that coenzyme Q10 has a beneficial effect in protecting against the endothelial dysfunction by high glucose-induced oxidative stress in vitro.

  9. Oxidative stress plays a role in high glucose-induced activation of pancreatic stellate cells

    SciTech Connect

    Ryu, Gyeong Ryul; Lee, Esder; Chun, Hyun-Ji; Yoon, Kun-Ho; Ko, Seung-Hyun; Ahn, Yu-Bae; Song, Ki-Ho

    2013-09-20

    Highlights: •High glucose increased production of reactive oxygen species in cultured pancreatic stellate cells. •High glucose facilitated the activation of these cells. •Antioxidant treatment attenuated high glucose-induced activation of these cells. -- Abstract: The activation of pancreatic stellate cells (PSCs) is thought to be a potential mechanism underlying islet fibrosis, which may contribute to progressive β-cell failure in type 2 diabetes. Recently, we demonstrated that antioxidants reduced islet fibrosis in an animal model of type 2 diabetes. However, there is no in vitro study demonstrating that high glucose itself can induce oxidative stress in PSCs. Thus, PSCs were isolated and cultured from Sprague Dawley rats, and treated with high glucose for 72 h. High glucose increased the production of reactive oxygen species. When treated with high glucose, freshly isolated PSCs exhibited myofibroblastic transformation. During early culture (passage 1), PSCs treated with high glucose contained an increased number of α-smooth muscle actin-positive cells. During late culture (passages 2–5), PSCs treated with high glucose exhibited increases in cell proliferation, the expression of fibronectin and connective tissue growth factor, release of interleukin-6, transforming growth factor-β and collagen, and cell migration. Finally, the treatment of PSCs with high glucose and antioxidants attenuated these changes. In conclusion, we demonstrated that high glucose increased oxidative stress in primary rat PSCs, thereby facilitating the activation of these cells, while antioxidant treatment attenuated high glucose-induced PSC activation.

  10. Nrf2 is critical in defense against high glucose-induced oxidative damage in cardiomyocytes.

    PubMed

    He, Xiaoqing; Kan, Hong; Cai, Lu; Ma, Qiang

    2009-01-01

    Exposure to high levels of glucose induces the production of reactive oxygen species (ROS) in cardiomyocytes that may contribute to the development of cardiomyopathy in diabetes. Nuclear factor erythroid 2-related factor 2 (Nrf2) controls the antioxidant response element (ARE)-dependent gene regulation in response to oxidative stress. The role of Nrf2 in defense against high glucose-induced oxidative damage in cardiomyocytes was investigated. Glucose at high concentrations induced ROS production in both primary neonatal and adult cardiomyocytes from the Nrf2 wild type (WT) mouse heart, whereas, in Nrf2 knockout (KO) cells, ROS was significantly higher under basal conditions and high glucose markedly further increased ROS production in concentration and time-dependent manners. Concomitantly, high glucose induced significantly higher levels of apoptosis at lower concentrations and in shorter time in Nrf2 KO cells than in WT cells. Primary adult cardiomyocytes from control and diabetic mice also showed dependence on Nrf2 function for isoproterenol-stimulated contraction. Additionally, cardiomyocytes from Nrf2 KO mice exhibited increased sensitivity to 3-nitropropionic acid, an inhibitor of mitochondrial respiratory complex II, for both ROS production and apoptosis compared with Nrf2 WT cells, further emphasizing the role of Nrf2 in ROS defense in the cells. Mechanistically, Nrf2 was shown to mediate the basal expression and induction of ARE-controlled cytoprotective genes, Nqo1 and Ho1, at both mRNA and protein levels in cardiomyocytes, as both the basal and inducible expressions of the genes were lost in Nrf2 KO cells or largely reduced by Nrf2 SiRNA. The findings, for the first time, established Nrf2 as a critical regulator of defense against ROS in normal and diabetic hearts.

  11. Proanthocyanidins Prevent High Glucose-Induced Eye Malformation by Restoring Pax6 Expression in Chick Embryo

    PubMed Central

    Tan, Rui-Rong; Zhang, Shi-Jie; Li, Yi-Fang; Tsoi, Bun; Huang, Wen-Shan; Yao, Nan; Hong, Mo; Zhai, Yu-Jia; Mao, Zhong-Fu; Tang, Lu-Ping; Kurihara, Hiroshi; Wang, Qi; He, Rong-Rong

    2015-01-01

    Gestational diabetes mellitus (GDM) is one of the leading causes of offspring malformations, in which eye malformation is an important disease. It has raised demand for therapy to improve fetal outcomes. In this study, we used chick embryo to establish a GDM model to study the protective effects of proanthocyanidins on eye development. Chick embryos were exposed to high glucose (0.2 mmol/egg) on embryo development day (EDD) 1. Proanthocyanidins (1 and 10 nmol/egg) were injected into the air sac on EDD 0. Results showed that both dosages of proanthocyanidins could prevent the eye malformation and rescue the high glucose-induced oxidative stress significantly, which the similar effects were showed in edaravone. However, proanthocyanidins could not decrease the glucose concentration of embryo eye. Moreover, the key genes regulating eye development, Pax6, was down-regulated by high glucose. Proanthocyanidins could restore the suppressed expression of Pax6. These results indicated proanthocyanidins might be a promising natural agent to prevent high glucose-induced eye malformation by restoring Pax6 expression. PMID:26262640

  12. Proanthocyanidins Prevent High Glucose-Induced Eye Malformation by Restoring Pax6 Expression in Chick Embryo.

    PubMed

    Tan, Rui-Rong; Zhang, Shi-Jie; Li, Yi-Fang; Tsoi, Bun; Huang, Wen-Shan; Yao, Nan; Hong, Mo; Zhai, Yu-Jia; Mao, Zhong-Fu; Tang, Lu-Ping; Kurihara, Hiroshi; Wang, Qi; He, Rong-Rong

    2015-08-07

    Gestational diabetes mellitus (GDM) is one of the leading causes of offspring malformations, in which eye malformation is an important disease. It has raised demand for therapy to improve fetal outcomes. In this study, we used chick embryo to establish a GDM model to study the protective effects of proanthocyanidins on eye development. Chick embryos were exposed to high glucose (0.2 mmol/egg) on embryo development day (EDD) 1. Proanthocyanidins (1 and 10 nmol/egg) were injected into the air sac on EDD 0. Results showed that both dosages of proanthocyanidins could prevent the eye malformation and rescue the high glucose-induced oxidative stress significantly, which the similar effects were showed in edaravone. However, proanthocyanidins could not decrease the glucose concentration of embryo eye. Moreover, the key genes regulating eye development, Pax6, was down-regulated by high glucose. Proanthocyanidins could restore the suppressed expression of Pax6. These results indicated proanthocyanidins might be a promising natural agent to prevent high glucose-induced eye malformation by restoring Pax6 expression.

  13. Nanoceria Attenuated High Glucose-Induced Oxidative Damage in HepG2 Cells

    PubMed Central

    Shokrzadeh, Mohammad; Abdi, Hakimeh; Asadollah-Pour, Azin; Shaki, Fatemeh

    2016-01-01

    Objective Hyperglycemia, a common metabolic disorder in diabetes, can lead to oxidative damage. The use of antioxidants can benefit the control and prevention of diabetes side effects. This study aims to evaluate the effect of nanoceria particles, as an antioxidant, on glucose induced cytotoxicity, reactive oxygen species (ROS), lipid peroxidation (LPO) and glutathione (GSH) content in a human hepatocellular liver carcinoma cell line (HepG2) cell line. Materials and Methods In this experimental study, we divided HepG2 cells into these groups: i. Cells treated with 5 mM D-glucose (control), ii. Cells treated with 45 mM D- mannitol+5 mM D-glucose (osmotic control), iii. Cells treated with 50 mM D-glucose (high glucose), and iv. Cells treated with 50 mM D-glucose+nanoceria. Cell viability, ROS formation, LPO and GSH were measured and analyzed statistically. Results High glucose (50 mM) treatment caused significant cell death and increased oxidative stress markers in HepG2 cells. Interestingly, nanoceria at a concentration of 50 mM significantly decreased the high glucose-induced cytotoxicity, ROS formation and LPO. This concentration of nanoceria increased the GSH content in HepG2 cells (P<0.05). Conclusion The antioxidant feature of nanoceria particles makes it an attractive candidate for attenuation of hyperglycemia oxidative damage in different organs. PMID:27054124

  14. Thymol, a monoterpene, inhibits aldose reductase and high-glucose-induced cataract on isolated goat lens

    PubMed Central

    Kanchan, Divya M.; Kale, Smita S.; Somani, Gauresh S.; Kaikini, Aakruti A.; Sathaye, Sadhana

    2016-01-01

    Background: Overactivation of aldose reductase (AR) enzyme has been implicated in the development of various diabetic complications. In the present study, the inhibitory effect of thymol was investigated on AR enzyme and its anti-cataract activity was also examined on isolated goat lens. Materials and Methods: Various concentrations of thymol were incubated with AR enzyme prepared from isolated goat lens. Molecular docking studies were carried out using Schrodinger software to verify the binding of thymol with AR as well as to understand their binding pattern. Further, thymol was evaluated for its anti-cataract activity in high-glucose-induced cataract in isolated goat lens in vitro. Quercetin was maintained as standard (positive control) throughout the study. Results: Thymol showed potent inhibitory activity against goat lens AR enzyme with an IC50 value of 0.65 μg/ml. Docking studies revealed that thymol binds with AR in similar binding pattern as that of quercetin. The high–glucose-induced cataract in isolated goat lens was also improved by thymol treatment. Thymol was also able to significantly (P < 0.001) reduce the oxidative stress associated with cataract. Conclusion: The results suggest that thymol may be a potential therapeutic approach in the prevention of diabetic complications through its AR inhibitory and antioxidant activities. PMID:28216950

  15. Erythropoietin (EPO) protects against high glucose-induced apoptosis in retinal ganglional cells.

    PubMed

    Wang, Yunxiao; Zhang, Hui; Liu, Yanping; Li, Ping; Cao, Zhihong; Cao, Yu

    2015-03-01

    The aim of this study was to investigate the protective effect and mechanism of EPO on the apoptosis induced by high levels of glucose in retinal ganglial cells (RGCs). High glucose-induced apoptosis model was established in RGCs isolated from SD rats (1-3 days old) and identified with Thy1.1 mAb and MAP-2 pAb. The apoptosis was determined by Hochest assay. The levels of ROS were quantitated by staining the cells with dichloro-dihydro-fluorescein diacetate (DCFH-DA) and measure by flow cytometry. The SOD, GSH-Px, CAT activities, and levels of T-AOC and MDA were determined by ELISA. Change in mitochondrial membrane potential (Δψm) was also assessed by flow cytometry, and expressions of Bcl-2, Bax, caspase-3, caspase-9, and cytochrome C were assessed by western blotting. The RGCs treated with high glucose levels exhibited significantly increased apoptotic rate and concentrations of ROS and MDA. Pretreatment of the cells with EPO caused a significant blockade of the high glucose-induced increase in ROS and MDA levels and apoptotic rate. EPO also increased the activities of SOD, GSH-Px, and CAT, and recovered the levels of T-AOC levels. As a consequence, the mitochondrial membrane potential was improved and Cyt c release into the cytoplasm was prevented which led to significantly suppressed up-regulation of Bax reducing the Bax/Bcl-2 ratio. The expressions of caspase-3 and caspase-9 induced by high glucose exposure were also ameliorated in the RGCs treated with EPO. The protective effect of EPO against apoptosis was mediated through its antioxidant action. Thus, it blocked the generation of pro-apoptotic proteins and apoptotic degeneration of the RGCs by preventing the mitochondrial damage.

  16. Volume-sensitive outwardly rectifying chloride channel blockers protect against high glucose-induced apoptosis of cardiomyocytes via autophagy activation.

    PubMed

    Wang, Lin; Shen, Mingzhi; Guo, Xiaowang; Wang, Bo; Xia, Yuesheng; Wang, Ning; Zhang, Qian; Jia, Lintao; Wang, Xiaoming

    2017-03-16

    Hyperglycemia is a well-characterized contributing factor for cardiac dysfunction and heart failure among diabetic patients. Apoptosis of cardiomyocytes plays a major role during the onset and pathogenesis of diabetic cardiomyopathy (DCM). Nonetheless, the molecular machinery underlying hyperglycemia-induced cardiac damage and cell death remains elusive. In the present study, we found that chloride channel blockers, 4,4'-diisothiocya-natostilbene-2,2'- disulfonic acid (DIDS) and 4-(2-butyl-6,7-dichlor-2-cyclopentyl-indan-1-on-5-yl) oxybutyric acid (DCPIB), inhibited high glucose-activated volume-sensitive outwardly rectifying (VSOR) Cl(-) channel and improved the viability of cardiomyocytes. High glucose induced cardiomyocyte apoptosis by suppressing the autophagic stress, which can be reversed via blockade of VSOR Cl(-) channel. VSOR activation in high glucose-treated cardiomyocytes was attributed to increased intracellular levels of reactive oxygen species (ROS). Taken together, our study unraveled a role of VSOR chloride currents in impaired autophagy and increased apoptosis of high glucose-exposed cardiomyocyte, and has implications for a therapeutic potential of VSOR chloride channel blockers in DCM.

  17. Volume-sensitive outwardly rectifying chloride channel blockers protect against high glucose-induced apoptosis of cardiomyocytes via autophagy activation

    PubMed Central

    Wang, Lin; Shen, Mingzhi; Guo, Xiaowang; Wang, Bo; Xia, Yuesheng; Wang, Ning; Zhang, Qian; Jia, Lintao; Wang, Xiaoming

    2017-01-01

    Hyperglycemia is a well-characterized contributing factor for cardiac dysfunction and heart failure among diabetic patients. Apoptosis of cardiomyocytes plays a major role during the onset and pathogenesis of diabetic cardiomyopathy (DCM). Nonetheless, the molecular machinery underlying hyperglycemia-induced cardiac damage and cell death remains elusive. In the present study, we found that chloride channel blockers, 4,4′-diisothiocya-natostilbene-2,2′- disulfonic acid (DIDS) and 4-(2-butyl-6,7-dichlor-2-cyclopentyl-indan-1-on-5-yl) oxybutyric acid (DCPIB), inhibited high glucose-activated volume-sensitive outwardly rectifying (VSOR) Cl− channel and improved the viability of cardiomyocytes. High glucose induced cardiomyocyte apoptosis by suppressing the autophagic stress, which can be reversed via blockade of VSOR Cl− channel. VSOR activation in high glucose-treated cardiomyocytes was attributed to increased intracellular levels of reactive oxygen species (ROS). Taken together, our study unraveled a role of VSOR chloride currents in impaired autophagy and increased apoptosis of high glucose-exposed cardiomyocyte, and has implications for a therapeutic potential of VSOR chloride channel blockers in DCM. PMID:28300155

  18. High glucose-induced cytoplasmic translocation of Dnmt3a contributes to CTGF hypo-methylation in mesangial cells

    PubMed Central

    Zhang, Hao; Li, Aimei; Zhang, Wei; Huang, Zhijun; Wang, Jianwen; Yi, Bin

    2016-01-01

    Connective tissue growth factor (CTGF) plays an essential role in the pathogenesis of diabetic nephropathy and we have previously identified that high glucose induced the expression of CTGF by decreasing DNA methylation. The aim of the present study was to investigate the underlying mechanisms of the high glucose-induced CTGF hypo-methylation. Human glomerular mesangial cells (hMSCs) were treated with low glucose (5 mM), mannitol (30 mM) or high glucose (30 mM) respectively. Immunofluorescence staining, real-time quantitative PCR and western blotting were performed to determine the subcellular distribution and expression of CTGF and Dnmt3a. ChIP-PCR assay was applied to investigate the capability of Dnmt3a to bind the CpG island of CTGF. Our results showed that high glucose induced both mRNA and protein expressions of CTGF, and led to increased cytoplasmic translocation of Dnmt3a in cultured hMSCs. The nuclear Dnmt3a protein was significantly reduced after high glucose treatment, although the expression of total Dnmt3a protein was not altered. We further discovered that ERK/MAPK signalling contributed to the high glucose-induced cytoplasmic translocation of Dnmt3a. Consequently, less Dnmt3a protein was bound to the CpG island of CTGF promoter, which induced an increase in CTGF expression by epigenetic regulation in the presence of high glucose. In conclusion, high glucose induces cytoplasmic translocation of Dnmt3a, possibly through activating ERK/MAPK signalling pathway, which contributes to the decreased binding of Dnmt3a on CTGF promoter and the subsequent CTGF hypo-methylation in diabetic nephropathy. PMID:27364355

  19. Effects of hydrogen sulfide on high glucose-induced glomerular podocyte injury in mice.

    PubMed

    Liu, Ye; Zhao, Huichen; Qiang, Ye; Qian, Guanfang; Lu, Shengxia; Chen, Jicui; Wang, Xiangdong; Guan, Qingbo; Liu, Yuantao; Fu, Yuqin

    2015-01-01

    The aim of this study was to assess the effects of hydrogen sulfide on high glucose-induced mouse podocyte (MPC) injury and the underlying mechanisms. Mouse podocytes were randomly divided into 4 groups, including high glucose (HG), normal glucose (NG), normal glucose + DL-propargylglycine (PPG), and high glucose + NaHS (HG + NaHS) groups for treatment. Then, ZO-2, nephrin, β-catenin, and cystathionine γ-lyase (CSE) protein expression levels were determined by western blot. We found that high glucose significantly reduced nephrin, ZO-2, and CSE expression levels (P<0.05), and overtly elevated β-catenin amounts (P<0.05), in a time-dependent manner. Likewise, PPG at different concentrations in normal glucose resulted in significantly lower CSE, ZO-2, and nephrin levels (P<0.05), and increased β-catenin amounts (P<0.05). Interestingly, significantly increased ZO-2 and nephrin levels, and overtly reduced β-catenin amounts were observed in the HG + NaHS group compared with HG treated cells (P<0.01). Compared with NG treated cells, decreased ZO-2 and nephrin levels and higher β-catenin amounts were obtained in the HG + NaHS group. In conclusion,CSE downregulation contributes to hyperglycemia induced podocyte injury, which is alleviated by exogenous H2S possibly through ZO-2 upregulation and the subsequent suppression of Wnt/β-catenin pathway.

  20. Proteasome Dysfunction Mediates High Glucose-Induced Apoptosis in Rodent Beta Cells and Human Islets

    PubMed Central

    Broca, Christophe; Varin, Elodie; Armanet, Mathieu; Tourrel-Cuzin, Cécile; Bosco, Domenico; Dalle, Stéphane; Wojtusciszyn, Anne

    2014-01-01

    The ubiquitin/proteasome system (UPS), a major cellular protein degradation machinery, plays key roles in the regulation of many cell functions. Glucotoxicity mediated by chronic hyperglycaemia is detrimental to the function and survival of pancreatic beta cells. The aim of our study was to determine whether proteasome dysfunction could be involved in beta cell apoptosis in glucotoxic conditions, and to evaluate whether such a dysfunction might be pharmacologically corrected. Therefore, UPS activity was measured in GK rats islets, INS-1E beta cells or human islets after high glucose and/or UPS inhibitor exposure. Immunoblotting was used to quantify polyubiquitinated proteins, endoplasmic reticulum (ER) stress through CHOP expression, and apoptosis through the cleavage of PARP and caspase-3, whereas total cell death was detected through histone-associated DNA fragments measurement. In vitro, we found that chronic exposure of INS-1E cells to high glucose concentrations significantly decreases the three proteasome activities by 20% and leads to caspase-3-dependent apoptosis. We showed that pharmacological blockade of UPS activity by 20% leads to apoptosis in a same way. Indeed, ER stress was involved in both conditions. These results were confirmed in human islets, and proteasome activities were also decreased in hyperglycemic GK rats islets. Moreover, we observed that a high glucose treatment hypersensitized beta cells to the apoptotic effect of proteasome inhibitors. Noteworthily, the decreased proteasome activity can be corrected with Exendin-4, which also protected against glucotoxicity-induced apoptosis. Taken together, our findings reveal an important role of proteasome activity in high glucose-induced beta cell apoptosis, potentially linking ER stress and glucotoxicity. These proteasome dysfunctions can be reversed by a GLP-1 analog. Thus, UPS may be a potent target to treat deleterious metabolic conditions leading to type 2 diabetes. PMID:24642635

  1. High Glucose-induced Retinal Pericyte Apoptosis Depends on Association of GAPDH and Siah1.

    PubMed

    Suarez, Sandra; McCollum, Gary W; Jayagopal, Ashwath; Penn, John S

    2015-11-20

    Diabetic retinopathy (DR) is a leading cause of blindness worldwide, and its prevalence is growing. Current therapies for DR address only the later stages of the disease, are invasive, and have limited effectiveness. Retinal pericyte death is an early pathologic feature of DR. Although it has been observed in diabetic patients and in animal models of DR, the cause of pericyte death remains unknown. A novel pro-apoptotic pathway initiated by the interaction between glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and the E3 ubiquitin ligase, seven in absentia homolog 1 (Siah1), was recently identified in ocular tissues. In this article we examined the involvement of the GAPDH/Siah1 interaction in human retinal pericyte (hRP) apoptosis. HRP were cultured in 5 mm normal glucose, 25 mm l- or d-glucose for 48 h (osmotic control and high glucose treatments, respectively). Siah1 siRNA was used to down-regulate Siah1 expression. TAT-FLAG GAPDH and/or Siah1-directed peptides were used to block GAPDH and Siah1 interaction. Co-immunoprecipitation assays were conducted to analyze the effect of high glucose on the association of GAPDH and Siah1. Apoptosis was measured by Annexin V staining and caspase-3 enzymatic activity assay. High glucose increased Siah1 total protein levels, induced the association between GAPDH and Siah1, and led to GAPDH nuclear translocation. Our findings demonstrate that dissociation of the GAPDH/Siah1 pro-apoptotic complex can block high glucose-induced pericyte apoptosis, widely considered a hallmark feature of DR. Thus, the work presented in this article can provide a foundation to identify novel targets for early treatment of DR.

  2. NFAT2 mediates high glucose-induced glomerular podocyte apoptosis through increased Bax expression

    SciTech Connect

    Li, Ruizhao; Zhang, Li; Shi, Wei; Zhang, Bin; Liang, Xinling; Liu, Shuangxin; Wang, Wenjian

    2013-04-15

    Background: Hyperglycemia promotes podocyte apoptosis and plays a key role in the pathogenesis of diabetic nephropathy. However, the mechanisms that mediate hyperglycemia-induced podocyte apoptosis is still far from being fully understood. Recent studies reported that high glucose activate nuclear factor of activated T cells (NFAT) in vascular smooth muscle or pancreatic β-cells. Here, we sought to determine if hyperglycemia activates NFAT2 in cultured podocyte and whether this leads to podocyte apoptosis. Meanwhile, we also further explore the mechanisms of NFAT2 activation and NFAT2 mediates high glucose-induced podocyte apoptosis. Methods: Immortalized mouse podocytes were cultured in media containing normal glucose (NG), or high glucose (HG) or HG plus cyclosporine A (a pharmacological inhibitor of calcinerin) or 11R-VIVIT (a special inhibitor of NFAT2). The activation of NFAT2 in podocytes was detected by western blotting and immunofluorescence assay. The role of NFAT2 in hyperglycemia-induced podocyte apoptosis was further evaluated by observing the inhibition of NFAT2 activation by 11R-VIVIT using flow cytometer. Intracellular Ca{sup 2+} was monitored in HG-treated podcocytes using Fluo-3/AM. The mRNA and protein expression of apoptosis gene Bax were measured by real time-qPCR and western blotting. Results: HG stimulation activated NFAT2 in a time- and dose-dependent manner in cultured podocytes. Pretreatment with cyclosporine A (500 nM) or 11R-VIVIT (100 nM) completely blocked NFAT2 nuclear accumulation. Meanwhile, the apoptosis effects induced by HG were also abrogated by concomitant treatment with 11R-VIVIT in cultured podocytes. We further found that HG also increased [Ca{sup 2+}]i, leading to activation of calcineurin, and subsequent increased nuclear accumulation of NFAT2 and Bax expression in cultured podocytes. Conclusion: Our results identify a new finding that HG-induced podocyte apoptosis is mediated by calcineurin/NFAT2/Bax signaling pathway

  3. Berberine enhances the AMPK activation and autophagy and mitigates high glucose-induced apoptosis of mouse podocytes.

    PubMed

    Jin, Yingli; Liu, Shuping; Ma, Qingshan; Xiao, Dong; Chen, Li

    2017-01-05

    High glucose concentration can induce injury of podocytes and berberine has a potent activity against diabetic nephropathy. However, whether and how berberine can inhibit high glucose-mediated injury of podocytes have not been clarified. This study tested the effect of berberine on high glucose-mediated apoptosis and the AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR) activation and autophagy in podocytes. The results indicated that berberine significantly mitigated high glucose-decreased cell viability, and nephrin and podocin expression as well as apoptosis in mouse podocytes. Berberine significantly increased the AMPK activation and mitigated high glucose and/or the AMPK inhibitor, compound C-mediated mTOR activation and apoptosis in podocytes. Berberine significantly enhanced the AMPK activation and protected from high glucose-induced apoptosis in the AMPK-silencing podocytes. Furthermore, berberine significantly increased the high glucose-elevated Unc-51-like autophagy-activating kinase 1 (ULK1) S317/S555 phosphorylation, Beclin-1 expression, the ratios of LC3II to LC3I expression and the numbers of autophagosomes, but reduced ULK1 S757 phosphorylation in podocytes. In addition, berberine significantly attenuated compound C-mediated inhibition of autophagy in podocytes. The protective effect of berberine on high glucose-induced podocyte apoptosis was significantly mitigated by pre-treatment with 3-methyladenine or bafilomycin A1. Collectively, berberine enhanced autophagy and protected from high glucose-induced injury in podocytes by promoting the AMPK activation. Our findings may provide new insights into the molecular mechanisms underlying the anti-diabetic nephropathy effect of berberine and may aid in design of new therapies for intervention of diabetic nephropathy.

  4. Spleen tyrosine kinase mediates high glucose-induced transforming growth factor-{beta}1 up-regulation in proximal tubular epithelial cells

    SciTech Connect

    Yang, Won Seok; Chang, Jai Won; Han, Nam Jeong; Lee, Sang Koo; Park, Su-Kil

    2012-09-10

    The role of spleen tyrosine kinase (Syk) in high glucose-induced intracellular signal transduction has yet to be elucidated. We investigated whether Syk is implicated in high glucose-induced transforming growth factor-{beta}1 (TGF-{beta}1) up-regulation in cultured human proximal tubular epithelial cells (HK-2 cell). High glucose increased TGF-{beta}1 gene expression through Syk, extracellular signal-regulated kinase (ERK), AP-1 and NF-{kappa}B. High glucose-induced AP-1 DNA binding activity was decreased by Syk inhibitors and U0126 (an ERK inhibitor). Syk inhibitors suppressed high glucose-induced ERK activation, whereas U0126 had no effect on Syk activation. High glucose-induced NF-{kappa}B DNA binding activity was also decreased by Syk inhibitors. High glucose increased nuclear translocation of p65 without serine phosphorylation of I{kappa}B{alpha} and without degradation of I{kappa}B{alpha}, but with an increase in tyrosine phosphorylation of I{kappa}B{alpha} that may account for the activation of NF-{kappa}B. Both Syk inhibitors and Syk-siRNA attenuated high glucose-induced I{kappa}B{alpha} tyrosine phosphorylation and p65 nuclear translocation. Depletion of p21-activated kinase 2 (Pak2) by transfection of Pak2-siRNA abolished high glucose-induced Syk activation. In summary, high glucose-induced TGF-{beta}1 gene transcription occurred through Pak2, Syk and subsequent ERK/AP-1 and NF-{kappa}B pathways. This suggests that Syk might be implicated in the diabetic kidney disease.

  5. Coenzyme Q10 Attenuates High Glucose-Induced Endothelial Progenitor Cell Dysfunction through AMP-Activated Protein Kinase Pathways

    PubMed Central

    Tsai, Hsiao-Ya; Lin, Chih-Pei; Huang, Po-Hsun; Li, Szu-Yuan; Chen, Jia-Shiong; Lin, Feng-Yen; Chen, Jaw-Wen; Lin, Shing-Jong

    2016-01-01

    Coenzyme Q10 (CoQ10), an antiapoptosis enzyme, is stored in the mitochondria of cells. We investigated whether CoQ10 can attenuate high glucose-induced endothelial progenitor cell (EPC) apoptosis and clarified its mechanism. EPCs were incubated with normal glucose (5 mM) or high glucose (25 mM) enviroment for 3 days, followed by treatment with CoQ10 (10 μM) for 24 hr. Cell proliferation, nitric oxide (NO) production, and JC-1 assay were examined. The specific signal pathways of AMP-activated protein kinase (AMPK), eNOS/Akt, and heme oxygenase-1 (HO-1) were also assessed. High glucose reduced EPC functional activities, including proliferation and migration. Additionally, Akt/eNOS activity and NO production were downregulated in high glucose-stimulated EPCs. Administration of CoQ10 ameliorated high glucose-induced EPC apoptosis, including downregulation of caspase 3, upregulation of Bcl-2, and increase in mitochondrial membrane potential. Furthermore, treatment with CoQ10 reduced reactive oxygen species, enhanced eNOS/Akt activity, and increased HO-1 expression in high glucose-treated EPCs. These effects were negated by administration of AMPK inhibitor. Transplantation of CoQ10-treated EPCs under high glucose conditions into ischemic hindlimbs improved blood flow recovery. CoQ10 reduced high glucose-induced EPC apoptosis and dysfunction through upregulation of eNOS, HO-1 through the AMPK pathway. Our findings provide a potential treatment strategy targeting dysfunctional EPC in diabetic patients. PMID:26682233

  6. Activation of Na+/K+-ATPase attenuates high glucose-induced H9c2 cell apoptosis via suppressing ROS accumulation and MAPKs activities by DRm217.

    PubMed

    Yan, Xiaofei; Xun, Meng; Li, Jing; Wu, Litao; Dou, Xiaojuan; Zheng, Jin

    2016-10-01

    Hyperglycemia is one of the major factors responsible for the myocardial apoptosis and dysfunction in diabetes. Many studies have proved that there is a close relationship between decreased Na(+)/K(+)-ATPase activity and diabetic cardiomyopathy. However, the effect of directly activated Na(+)/K(+)-ATPase on high glucose-induced myocardial injury is still unknown. Here we found that DRm217, a Na(+)/K(+)-ATPase's DR-region specific monoclonal antibody and direct activator, could prevent high glucose-induced H9c2 cell injury, reactive oxygen species (ROS) release, and mitochondrial dysfunction. High glucose-treatment decreased Na(+)/K(+)-ATPase activity and increased intracellular Ca(2+) level, whereas DRm217 increased Na(+)/K(+)-ATPase activity and alleviated Ca(2+) overload. Inhibition of Ca(2+) overload or closing sodium calcium exchanger (NCX channel) could reverse high glucose-induced ROS increasing and cell injury. In addition, DRm217 could significantly attenuate high glucose-induced p38, JNK and ERK1/2 phosphorylation, which were involved in high glucose-induced cell injury and ROS accumulation. Our findings suggest that DRm217 may protect against the deleterious effects of high glucose in the heart. Prevention of high glucose-induced myocardial cell injury by specific Na(+)/K(+)-ATPase activator may be an attractive therapeutic option.

  7. Pioglitazone inhibits high glucose-induced expression of receptor for advanced glycation end products in coronary artery smooth muscle cells

    PubMed Central

    DI, BEI-BING; LI, HONG-WEI; LI, WEI-PING; SHEN, XU-HUA; SUN, ZHI-JUN; WU, XING

    2015-01-01

    Receptor for advanced glycation end products (RAGE) is critical in inflammatory diseases, including diabetes and atherosclerosis. The mechanism underlying the effect of peroxisome proliferator-activated receptor γ (PPARγ) agonist pioglitazone (PIO) on RAGE expression in coronary artery smooth muscle cells (SMCs) stimulated by high glucose concentrations remains to be elucidated. In the present study, the effect and mechanism of action of PIO on RAGE expression in SMCs was investigated following treatment with high glucose concentrations. Rat coronary artery SMCs were pretreated with PIO alone, PIO and GW9662 (a PPARγ antagonist), diphenyleneiodonium (DPI; a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor) or the antioxidant pyrrolidine dithiocarbamate (PDTC; a nuclear factor-κB (NF-κB) inhibitor), followed by treatment with high glucose. RAGE mRNA and protein expression, reactive oxygen species (ROS) production and NF-κB nuclear translocation were investigated. Glucose induced RAGE expression in a dose-dependent manner, with maximal effect at a concentration of 25 mmol/l following treatment for 48 h. PIO, DPI and PDTC reduced high glucose-induced increases in RAGE protein and mRNA expression. PIO prominently downregulated RAGE expression and inhibited high glucose-induced increases in ROS production and NF-κB activation (P<0.05). Pretreatment with PIO and GW9662 did not exhibit this inhibitory effect. High glucose may stimulate RAGE expression in coronary artery SMCs through NADPH oxidase-mediated ROS generation and NF-κB activation. PIO downregulated RAGE expression and inhibited ROS production and NF-κB activation via PPARγ activation, which may prevent the inflammatory effect of AGE/RAGE system in diabetes. PMID:25523934

  8. Emodin attenuates high glucose-induced TGF-β1 and fibronectin expression in mesangial cells through inhibition of NF-κB pathway

    SciTech Connect

    Yang, Jie; Zeng, Zhi; Wu, Teng; Yang, Zhicheng; Liu, Bing; Lan, Tian

    2013-12-10

    The activation of nuclear factor-κB (NF-κB) and the subsequent overexpression of its downstream targets transforming growth factor-β1 (TGF-β1) and fibronectin (FN) are among the hallmarks for the progressive diabetic nephropathy. Our previous studies demonstrated that emodin ameliorated renal injury and inhibited extracellular matrix accumulation in kidney and mesangial cells under diabetic condition. However, the molecular mechanism has not been fully elucidated. Here, we showed that emodin significantly attenuated high glucose-induced NF-κB nuclear translocation in mesangial cells. Interestingly, emodin also inhibited the DNA-binding activity and transcriptional activity of NF-κB. Furthermore, NF-κB-mediated TGF-β1 and FN expression was significantly decreased by emodin. These results demonstrated that emodin suppressed TGF-β1 and FN overexpression through inhibition of NF-κB activation, suggesting that emodin-mediated inhibition of the NF-κB pathway could protect against diabetic nephropathy. - Highlights: • Emodin decreased high glucose-induced p65 phosphorylation in MCs. • Emodin decreased high glucose-induced IκB-α degradation in MCs. • Emodin decreased high glucose-induced p65 translocation in MCs. • Emodin blocked high glucose-induced NF-κB activity. • Emodin blocked high glucose-induced the expression of TGF-β1 and FN.

  9. Oleanolic acid ameliorates high glucose-induced endothelial dysfunction via PPARδ activation

    PubMed Central

    Zhang, Zihui; Jiang, Manli; Xie, Xinya; Yang, Haixia; Wang, Xinfeng; Xiao, Lei; Wang, Nanping

    2017-01-01

    Oleanolic acid (3β-hydroxyolean-12-en-28-oic acid, OA) is a pentacyclic triterpenes widely distributed in food, medicinal plants and nutritional supplements. OA exhibits various pharmacological properties, such as hepatoprotective and anti-tumor effects. In this study, we analyzed the effect of OA on endothelial dysfunction induced by high glucose in human vascular endothelial cells (ECs). Western blotting showed that OA attenuated high glucose-reduced nitric production oxide (NO) as well as Akt-Ser473 and eNOS-Ser1177 phosphorylation in cultured human umbilical vein ECs (HUVECs). Next, luciferase reporter assay showed that OA activated peroxisome proliferators-activated receptor δ (PPARδ) activity. Quantitative reverse transcriptase PCR (qRT-PCR) demonstrated that OA increased the expressions of PPARδ target genes (PDK4, ADRP and ANGPTL4) in ECs. Meanwhile, the induced expressions of PDK4, ADRP and ANGPTL4 by OA were inhibited by GSK0660, a specific antagonist of PPARδ. In addition, inhibition of PPARδ abolished OA-induced the Akt-Ser473 and eNOS-Ser1177 phosphorylation, and NO production. Finally, by using Multi Myograph System, we showed that OA prevented high glucose-impaired vasodilation. This protective effect on vasodilation was inhibited in aortic rings pretreated with GSK0660. Collectively, we demonstrated that OA improved high glucose-impaired endothelial function via a PPARδ-mediated mechanism and through eNOS/Akt/NO pathway. PMID:28067284

  10. Phytolacca americana inhibits the high glucose-induced mesangial proliferation via suppressing extracellular matrix accumulation and TGF-beta production.

    PubMed

    Jeong, Seung Il; Kim, Kang Ju; Choo, Yong Kug; Keum, Kyung Soo; Choi, Bong Kyu; Jung, Kyu Yong

    2004-02-01

    This study describes a potential of Phytolaccaceae (Phytolacca americana var.) as an inhibitor of high glucose-stimulated production of extracellular matrix (ECM) proteins and TGF-beta in cultured glomerular mesangial cells (GMCs). Raising the ambient glucose concentration for 24 hrs caused a dose-dependent increase in [3H]thymidine incorporation of GMCs, and the maximal response was achieved at 20 mM. Phytolaccaceae extracts (2.5-20 microg/ml) inhibited the high glucose-induced [3H]thymidine incorporation in a dose-dependent manner, and the concentrations tested here did not affect to the cell viability. Exposure of the GMCs to 20 mM glucose caused both ECM (collagen and fibronectin) accumulation and TGF-beta secretion, and these changes were significantly diminished by treatment of GMCs with Phytolaccaceae (10 microg/ml). Taken together, these results indicate that Phytolaccaceae inhibits the high glucose-induced GMCs proliferation partially through suppressing accumulation of ECM components and TGF-beta production, suggesting that Phytolaccaceae may be a promising agent for treating the development and progression of diabetic glomerulopathy.

  11. MicroRNA-34a regulates high glucose-induced apoptosis in H9c2 cardiomyocytes.

    PubMed

    Zhao, Fang; Li, Bo; Wei, Yin-zhi; Zhou, Bin; Wang, Han; Chen, Ming; Gan, Xue-dong; Wang, Zhao-hui; Xiong, Shi-xi

    2013-12-01

    Hyperglycemia is an important initiator of cardiovascular disease, contributing to the development of cardiomyocyte death and diabetic complications. The purpose of the present study was to investigate whether high glucose state could induce apoptosis of rat cardiomyocyte cell line H9c2 through microRNA-mediated Bcl-2 signaling pathway. The expression of miR-34a and Bcl-2 mRNA was detected by using real-time PCR. Western blotting was used to examine the changes in apoptosis-associated protein Bcl-2. Apoptosis of H9c2 cells was tested by using flow cytometry. The results showed that the expression of miR-34a was significantly elevated and that of Bcl-2 was strongly reduced, and apoptosis of cardiomyocytes was apparently increased in the high-glucose-treated H9c2 cells as compared with normal-glucose-treated controls. In addition, we identified Bcl-2 gene was the target of miR-34a. miR-34a mimics reduced the expression of Bcl-2 and increased glucose-induced apoptosis, but miR-34a inhibitor acted as the opposite mediator. Our data demonstrate that miR-34a contributes to high glucose-induced decreases in Bcl-2 expression and subsequent cardiomyocyte apoptosis.

  12. Tartary buckwheat flavonoids protect hepatic cells against high glucose-induced oxidative stress and insulin resistance via MAPK signaling pathways.

    PubMed

    Hu, Yuanyuan; Hou, Zuoxu; Liu, Dongyang; Yang, Xingbin

    2016-03-01

    Oxidative stress plays a crucial role in chronic complication of diabetes. In this study, the protective effect of purified tartary buckwheat flavonoids (TBF) fraction against oxidative stress induced by a high-glucose challenge, which causes insulin resistance, was investigated on hepatic HepG2 cells. Oxidative status, phosphorylated mitogen-activated protein kinases (MAPKs), nuclear factor E2 related factor 2 (Nrf2) and p-(Ser307)-IRS-1 expression, and glucose uptake were evaluated. Results suggest that treatment of HepG2 cells with TBF alone improved glucose uptake and antioxidant enzymes, and activated Nrf2, and attenuated the IRS-1 Ser307 phosphorylation, and enhanced total levels of IRS-1. Furthermore, the high glucose-induced changes in antioxidant defences, Nrf2, p-MAPKs, p-IRS1 Ser307, and IRS-1 levels, and glucose uptake were also significantly inhibited by pre-treatment with TBF. Interestingly, the selective MAPK inhibitors significantly enhanced the TBF-mediated protection by inducing changes in the redox status, glucose uptake, p-(Ser307) and total IRS-1 levels. This report firstly showed that TBF could recover the redox status of insulin-resistant HepG2 cells, suggesting that TBF significantly protected the cells against high glucose-induced oxidative stress, and these beneficial effects of TBF on redox balance and insulin resistance were mediated by targeting MAPKs.

  13. Pterostilbene attenuates high glucose-induced oxidative injury in hippocampal neuronal cells by activating nuclear factor erythroid 2-related factor 2.

    PubMed

    Yang, Yang; Fan, Chongxi; Wang, Bodong; Ma, Zhiqiang; Wang, Dongjin; Gong, Bing; Di, Shouyin; Jiang, Shuai; Li, Yue; Li, Tian; Yang, Zhi; Luo, Erping

    2017-04-01

    In the present study, neuroblastoma (SH-SY5Y) cells were used to investigate the mechanisms mediating the potential protective effects of pterostilbene (PTE) against mitochondrial metabolic impairment and oxidative stress induced by hyperglycemia for mimicking the diabetic encephalopathy. High glucose medium (100mM) decreased cellular viability after 24h incubation which was evidenced by: (i) reduced mitochondrial complex I and III activities; (ii) reduced mitochondrial cytochrome C; (iii) increased reactive oxygen species (ROS) generation; (iv) decreased mitochondrial membrane potential (ΔΨm); and (v) increased lactate dehydrogenase (LDH) levels. PTE (2.5, 5, and 10μM for 24h) was nontoxic and induced the nuclear transition of Nrf2. Pretreatment of PTE (2.5, 5, and 10μM for 2h) displayed a dose-dependently neuroprotective effect, as indicated by significantly prevented high glucose-induced loss of cellular viability, generation of ROS, reduced mitochondrial complex I and III activities, reduced mitochondrial cytochrome C, decreased ΔΨm, and increased LDH levels. Moreover, the levels of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and glutathione S-transferase (GST) were elevated after PTE treatment. In addition, the elevation of nuclear Nrf2 by PTE treatment (10μM for 2h) was abolished by Nrf2 siRNA. Importantly, Nrf2 siRNA induced the opposite changes in mitochondrial complex I and III activities, mitochondrial cytochrome C, reactive species generation, ΔΨm, and LDH. Overall, the present findings were the first to show that pterostilbene attenuated high glucose-induced central nervous system injury in vitro through the activation of Nrf2 signaling, displaying protective effects against mitochondrial dysfunction-derived oxidative stress.

  14. Sequential signaling cascade of IL-6 and PGC-1α is involved in high glucose-induced podocyte loss and growth arrest

    SciTech Connect

    Kim, Dong Il; Park, Soo Hyun

    2013-06-14

    Highlights: •The pathophysiological role of IL-6 in high glucose-induced podocyte loss. •The novel role of PGC-1α in the development of diabetic nephropathy. •Signaling of IL-6 and PGC-1α in high glucose-induced dysfunction of podocyte. -- Abstract: Podocyte loss, which is mediated by podocyte apoptosis, is implicated in the onset of diabetic nephropathy. In this study, we investigated the involvement of interleukin (IL)-6 in high glucose-induced apoptosis of rat podocytes. We also examined the pathophysiological role of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) in this system. High glucose treatment induced not only podocyte apoptosis but also podocyte growth arrest. High glucose treatment also increased IL-6 secretion and activated IL-6 signaling. The high glucose-induced podocyte apoptosis was blocked by IL-6 neutralizing antibody. IL-6 treatment or overexpression induced podocyte apoptosis and growth arrest, and IL-6 siRNA transfection blocked high glucose-induced podocyte apoptosis and growth arrest. Furthermore, high glucose or IL-6 treatment increased PGC-1α expression, and PGC-1α overexpression also induced podocyte apoptosis and growth arrest. PGC-1α siRNA transfection blocked high glucose-induced podocyte apoptosis and growth arrest. Collectively, these findings showed that high glucose promoted apoptosis and cell growth arrest in podocytes via IL-6 signaling. In addition, PGC-1α is involved in podocyte apoptosis and cell growth arrest. Therefore, blocking IL-6 and its downstream mediators such as IL6Rα, gp130 and PGC-1α may attenuate the progression of diabetic nephropathy.

  15. Triphenyltin impairs insulin secretion by decreasing glucose-induced NADP(H) and ATP production in hamster pancreatic β-cells.

    PubMed

    Miura, Yoshikazu; Hori, Yuichi; Kimura, Shinzo; Hachiya, Hiroyuki; Sakurai, Yuichirou; Inoue, Kenichi; Sawada, Tokihiko; Kubota, Keiichi

    2012-09-28

    Oral administration of triphenyltin chloride (TPT) (6 mg/100g body weight) inhibits insulin secretion by decreasing glucose-induced cytoplasmic Ca(2+) concentration ([Ca(2+)](i)) in pancreatic β-cells of the hamster. To test the possibility that the abnormal level of the [Ca(2+)](i) induced by TPT administration could be due to a defect in the metabolic signal of glucose in the β-cells, we tested the effects of TPT administration on the glucose-induced NAD(P)H and ATP production, and on the changes of membrane potential and [Ca(2+)](i) by glucose and high K(+) in the β-cells. The [Ca(2+)](i) was measured in islet cells loaded with fura-2. TPT administration significantly reduced the NAD(P)H and ATP production, the depolarization of plasma membrane, and insulin secretion by 15 mM glucose in islet cells. TPT administration also reduced the insulin secretion by 10mM dihydroxyacetone and glyceraldehyde. However, TPT administration did not affect the increase of [Ca(2+)](i) and the insulin secretion by 30 mMK(+) or 100 μM tolbutamide, and the membrane potential by 30 mMK(+), and the insulin secretion by 10mM α-ketoisocaproic acid and 0.5mM formycin A, an analog of ATP in the presence of 15 mM glucose. These results suggested that the pathogenesis of TPT-induced hyperglycemia in hamster involves the reduction of [Ca(2+)](i) and insulin secretion in response to K(ATP) channel-dependent depolarization, which is related to the decrease of NAD(P)H and ATP production in pancreatic islet cells after glucose metabolism.

  16. Protective Role of Morin, a Flavonoid, against High Glucose Induced Oxidative Stress Mediated Apoptosis in Primary Rat Hepatocytes

    PubMed Central

    Kapoor, Radhika; Kakkar, Poonam

    2012-01-01

    Apoptosis is an early event of liver damage in diabetes and oxidative stress has been linked to accelerate the apoptosis in hepatocytes. Therefore, the compounds that can scavenge ROS may confer regulatory effects on high-glucose induced apoptosis. In the present study, primary rat hepatocytes were exposed to high concentration (40 mM) of glucose. At this concentration decreased cell viability and enhanced ROS generation was observed. Depleted antioxidant status of hepatocytes under high glucose stress was also observed as evident from transcriptional level and activities of antioxidant enzymes. Further, mitochondrial depolarisation was accompanied by the loss of mitochondrial integrity and altered expression of Bax and Bcl-2. Increased translocation of apoptotic proteins like AIF (Apoptosis inducing factor) & Endo-G (endonuclease-G) from its resident place mitochondria to nucleus was also observed. Cyt-c residing in the inter-membrane space of mitochondria also translocated to cytoplasm. These apoptotic proteins initiated caspase activation, DNA fragmentation, chromatin condensation, increased apoptotic DNA content in glucose treated hepatocytes, suggesting mitochondria mediated apoptotic mode of cell death. Morin, a dietary flavonoid from Psidium guajava was effective in increasing the cell viability and decreasing the ROS level. It maintained mitochondrial integrity, inhibited release of apoptotic proteins from mitochondria, prevented DNA fragmentation, chromatin condensation and hypodiploid DNA upon exposure to high glucose. This study confirms the capacity of dietary flavonoid Morin in regulating apoptosis induced by high glucose via mitochondrial mediated pathway through intervention of oxidative stress. PMID:22899998

  17. Effects of astragalosides from Radix Astragali on high glucose-induced proliferation and extracellular matrix accumulation in glomerular mesangial cells

    PubMed Central

    CHEN, XIAO; WANG, DONG-DONG; WEI, TONG; HE, SU-MEI; ZHANG, GUAN-YING; WEI, QUN-LI

    2016-01-01

    Diabetic nephropathy (DN) exhibits a deteriorating course that may lead to end-stage renal failure. Astragalosides have been clinically tested for the treatment of DN, but the mechanism is unclear at present. In this study, the effects of astragalosides were investigated on high glucose-induced proliferation and expression of transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF), type IV collagen (colIV) and fibronectin (FN) in glomerular mesangial cells (MCs). Cell proliferation was determined by 5-bromo-2′-deoxyuridine assay, and the expression of TGF-β1, CTGF, colIV and FN mRNA and proteins in MCs was detected by reverse transcription-polymerase chain reaction and ELISA assay, respectively. The results showed that high glucose clearly induced the proliferation of MCs and increased the expression of TGF-β1, CTGF, colIV and FN. Treatment with 50, 100, 200 µg/ml astragalosides inhibited cell proliferation and the expression of TGF-β1, CTGF, colIV and FN induced by high glucose. Thus, it is concluded that astragalosides inhibit the increased cell proliferation and expression of major extracellular matrix proteins that are induced by high glucose, indicating their value for the prophylaxis and therapy of DN. PMID:27313676

  18. Protective Effects of Panax notoginseng Saponins against High Glucose-Induced Oxidative Injury in Rat Retinal Capillary Endothelial Cells

    PubMed Central

    Fan, Yue; Qiao, Yuan; Huang, Jianmei

    2016-01-01

    Diabetic retinopathy, a leading cause of visual loss and blindness, is characterized by microvascular dysfunction. Hyperglycemia is considered the major pathogenic factor for diabetic retinopathy and is associated with increased oxidative stress in the retina. In this study, we investigated the potential protective effects of Panax notoginseng Saponins (PNS) in retinal capillary endothelial cells (RCECs) exposed to high glucose conditions. We found a pronounced increase in cell viability in rat RCECs incubated with both PNS and high glucose (30 mM) for 48 h or 72 h. The increased viability was accompanied by reduced intracellular hydrogen peroxide (H2O2) and superoxide (O2−), decreased mitochondrial reactive oxygen species (ROS), and lowered malondialdehyde (MDA) levels. PNS also increased the activities of total superoxide dismutase (SOD), MnSOD, catalase (CAT), and glutathione peroxidase (GSH-PX). The glutathione (GSH) content also increased after PNS treatment. Furthermore, PNS reduced NADPH oxidase 4 (Nox4) expression. These results indicate that PNS exerts a protective effect against high glucose-induced injury in RCECs, which may be partially attributed to its antioxidative function. PMID:27019662

  19. H2 and H3 relaxin inhibit high glucose-induced apoptosis in neonatal rat ventricular myocytes.

    PubMed

    Zhang, Xiaohui; Ma, Xiao; Zhao, Meng; Zhang, Bo; Chi, Jinyu; Liu, Wenxiu; Chen, Wenjia; Fu, Yu; Liu, Yue; Yin, Xinhua

    2015-01-01

    High concentrations of glucose induce cardiomyocyte apoptosis, and contribute to diabetic cardiomyopathy. Relaxin-2 and relaxin-3 are two members of the relaxin peptide family that are cardioprotective. However, it remains unknown whether relaxin-2 or relaxin-3 can regulate apoptosis in high glucose treated-neonatal rat ventricular myocytes (NRVMs). In cultured NRVMs, 33 mmol/l high glucose (HG) increased apoptosis in a time-dependent manner. HG-increased the protein expression of cleaved caspase-8 and -9, two initiators of the extrinsic and intrinsic pathways of apoptosis, Caspase-3 was attenuated by human recombinant relaxin-2 (H2 relaxin) or relaxin-3 (H3 relaxin), indicating that H2 and H3 relaxin inhibited HG-induced apoptosis. Furthermore, endoplasmic reticulum stress (ERS) markers CHOP and caspase-12 were markedly increased in HG-treated NRVMs, leading to apoptosis; this effect was also effectively attenuated by H2 relaxin or H3 relaxin. Treatment of NRVMs with HG reduced autophagy which cannot be adjusted by H2 relaxin or H3 relaxin. In conclusion, HG-induced apoptosis in NRVMs was mediated, in part, by the activation of the extrinsic and intrinsic pathways of apoptosis and ERS, all inhibited by H2 relaxin or H3 relaxin.

  20. SIRT1 attenuates high glucose-induced insulin resistance via reducing mitochondrial dysfunction in skeletal muscle cells.

    PubMed

    Zhang, Hao-Hao; Ma, Xiao-Jun; Wu, Li-Na; Zhao, Yan-Yan; Zhang, Peng-Yu; Zhang, Ying-Hui; Shao, Ming-Wei; Liu, Fei; Li, Fei; Qin, Gui-Jun

    2015-05-01

    Insulin resistance is often characterized as the most critical factor contributing to the development of type 2 diabetes mellitus (T2DM). Sustained high glucose is an important extracellular environment that induces insulin resistance. Acquired insulin resistance is associated with reduced insulin-stimulated mitochondrial activity as a result of increased mitochondrial dysfunction. Silent information regulator 1 (SIRT1) is one member of the SIRT2 (Sir2)-like family of proteins involved in glucose homeostasis and insulin secretion in mammals. Although SIRT1 has a therapeutic effect on metabolic deterioration in insulin resistance, it is still not clear how SIRT1 is involved in the development of insulin resistance. Here, we demonstrate that pcDNA3.1 vector-mediated overexpression of SIRT1 attenuates insulin resistance in the high glucose-induced insulin-resistant skeleton muscle cells. These beneficial effects were associated with ameliorated mitochondrial dysfunction. Further studies have demonstrated that SIRT1 restores mitochondrial complex I activity leading to decreased oxidative stress and mitochondrial dysfunction. Furthermore, SIRT1 significantly elevated the level of another SIRT which is named SIRT3, and SIRT3 siRNA-suppressed SIRT1-induced mitochondria complex activity increments. Taken together, these results showed that SIRT1 improves insulin sensitivity via the amelioration of mitochondrial dysfunction, and this is achieved through the SIRT1-SIRT3-mitochondrial complex I pathway.

  1. High glucose-induced, endothelin-dependent fibronectin synthesis is mediated via NF-kappa B and AP-1.

    PubMed

    Chen, Shali; Mukherjee, Suranjana; Chakraborty, Chandan; Chakrabarti, Subrata

    2003-02-01

    Human endothelial cells cultured under high glucose (HG) conditions were shown before to upregulate several basement membrane proteins, including fibronectin (FN), thus mimicking effects of diabetes. Using human macrovascular (HUVEC) and microvascular (HMEC) endothelial cell lines, we evaluated in the present study some of the key molecular signaling events involved in HG-induced FN overexpression. This expression was shown to be dependent on endogenous endothelin (ET) receptor-mediated signaling. We also examined the roles played by protein kinase C (PKC) and the transcription factors nuclear factor kappaB (NF-kappaB) and activating protein (AP)-1 with respect to such changes. HG, PKC activators, and ETs (ET-1 and ET-3) that increased FN expression also caused activation of NF-kappaB and AP-1. Inhibitors of both NF-kappaB and AP-1 prevented HG- and ET-induced FN production. ET receptor blockade also prevented these HG- and ET-mediated changes. The results of this study indicate that glucose-induced increased FN production in diabetes may be mediated via ET-dependent NF-kappaB and AP-1 activation.

  2. High glucose induces inflammatory cytokine through protein kinase C-induced toll-like receptor 2 pathway in gingival fibroblasts

    SciTech Connect

    Jiang, Shao-Yun; Wei, Cong-Cong; Shang, Ting-Ting; Lian, Qi; Wu, Chen-Xuan; Deng, Jia-Yin

    2012-10-26

    Highlights: Black-Right-Pointing-Pointer High glucose significantly induced TLR2 expression in gingival fibroblasts. Black-Right-Pointing-Pointer High glucose increased NF-{kappa}B p65 nuclear activity, IL-1{beta} and TNF-{alpha} levels. Black-Right-Pointing-Pointer PKC-{alpha}/{delta}-TLR2 pathway is involved in periodontal inflammation under high glucose. -- Abstract: Toll-like receptors (TLRs) play a key role in innate immune response and inflammation, especially in periodontitis. Meanwhile, hyperglycemia can induce inflammation in diabetes complications. However, the activity of TLRs in periodontitis complicated with hyperglycemia is still unclear. In the present study, high glucose (25 mmol/l) significantly induced TLR2 expression in gingival fibroblasts (p < 0.05). Also, high glucose increased nuclear factor kappa B (NF-{kappa}B) p65 nuclear activity, tumor necrosis factor-{alpha} (TNF-{alpha}) and interleukin-l{beta} (IL-1{beta}) levels. Protein kinase C (PKC)-{alpha} and {delta} knockdown with siRNA significantly decreased TLR2 and NF-{kappa}B p65 expression (p < 0.05), whereas inhibition of PKC-{beta} had no effect on TLR2 and NF-{kappa}B p65 under high glucose (p < 0.05). Additional studies revealed that TLR2 knockdown significantly abrogated high-glucose-induced NF-{kappa}B expression and inflammatory cytokine secretion. Collectively, these data suggest that high glucose stimulates TNF-{alpha} and IL-1{beta} secretion via inducing TLR2 through PKC-{alpha} and PKC-{delta} in human gingival fibroblasts.

  3. Renoprotective Effects of Aldose Reductase Inhibitor Epalrestat against High Glucose-Induced Cellular Injury

    PubMed Central

    Eid, Ali Hussein

    2017-01-01

    Diabetic nephropathy (DN) is the leading cause of end stage renal disease worldwide. Increased glucose flux into the aldose reductase (AR) pathway during diabetes was reported to exert deleterious effects on the kidney. The objective of this study was to investigate the renoprotective effects of AR inhibition in high glucose milieu in vitro. Rat renal tubular (NRK-52E) cells were exposed to high glucose (30 mM) or normal glucose (5 mM) media for 24 to 48 hours with or without the AR inhibitor epalrestat (1 μM) and assessed for changes in Akt and ERK1/2 signaling, AR expression (using western blotting), and alterations in mitochondrial membrane potential (using JC-1 staining), cell viability (using MTT assay), and cell cycle. Exposure of NRK-52E cells to high glucose media caused acute activation of Akt and ERK pathways and depolarization of mitochondrial membrane at 24 hours. Prolonged high glucose exposure (for 48 hours) induced AR expression and G1 cell cycle arrest and decreased cell viability (84% compared to control) in NRK-52E cells. Coincubation of cells with epalrestat prevented the signaling changes and renal cell injury induced by high glucose. Thus, AR inhibition represents a potential therapeutic strategy to prevent DN. PMID:28386557

  4. High glucose-induced proteome alterations in hepatocytes and its possible relevance to diabetic liver disease.

    PubMed

    Chen, Jing-Yi; Chou, Hsiu-Chuan; Chen, You-Hsuan; Chan, Hong-Lin

    2013-11-01

    Hyperglycemia can cause several abnormalities in liver cells, including diabetic liver disease. Previous research has shown that high blood glucose levels can damage liver cells through glycoxidation. However, the detailed molecular mechanisms underlying the effects of high blood glucose on the development of diabetic liver disease have yet to be elucidated. In this study, we cultured a liver cell line (Chang liver cell) in mannitol-balanced 5.5 mM, 25 mM and 100 mM d-glucose media and evaluated protein expression and redox regulation. We identified 141 proteins that showed significant changes in protein expression and 29 proteins that showed significant changes in thiol reactivity, in response to high glucose concentration. Several proteins involved in transcription-control, signal transduction, redox regulation and cytoskeleton regulation showed significant changes in expression, whereas proteins involved in protein folding and gene regulation displayed changes in thiol reactivity. Further analyses of clinical plasma specimens confirmed that the proteins AKAP8L, galectin-3, PGK 1, syntenin-1, Abin 2, aldose reductase, CD63, GRP-78, GST-pi, RXR-gamma, TPI and vimentin showed type 2 diabetic liver disease-dependent alterations. In summary, in this study we used a comprehensive hepatocyte-based proteomic approach to identify changes in protein expression and to identify redox-associated diabetic liver disease markers induced by high glucose concentration. Some of the identified proteins were validated with clinical samples and are presented as potential targets for the prognosis and diagnosis of diabetic liver disease.

  5. Orientin inhibits high glucose-induced vascular inflammation in vitro and in vivo.

    PubMed

    Ku, Sae-Kwang; Kwak, Soyoung; Bae, Jong-Sup

    2014-12-01

    Vascular inflammation plays a key role in the initiation and progression of atherosclerosis, a major complication of diabetes mellitus. Orientin, a C-glycosyl flavonoid, is known to have anxiolytic and antioxidative activity. In this study, we assessed whether orientin can suppress vascular inflammation induced by high glucose (HG) in human umbilical vein endothelial cells (HUVECs) and mice. Our data indicate that HG markedly increased vascular permeability, monocyte adhesion, the expression of cell adhesion molecules (CAMs), the formation of reactive oxygen species (ROS), and the activation of nuclear factor kappa B (NF-κB). Remarkably, the vascular inflammatory effects of HG were attenuated by pretreatment with orientin. Since vascular inflammation induced by HG is critical in the development of diabetic complications, our results suggest that orientin may have significant benefits in the treatment of diabetic complications and atherosclerosis.

  6. Hyperoside inhibits high-glucose-induced vascular inflammation in vitro and in vivo.

    PubMed

    Ku, Sae-Kwang; Kwak, Soyoung; Kwon, O-Jun; Bae, Jong-Sup

    2014-10-01

    Hyperoside, an active compound from the genera of Hypericum and Crataegus, was reported to have antioxidant, antihyperglycemic, anticancer, anti-inflammatory, and anticoagulant activities. Vascular inflammatory process has been suggested to play a key role in initiation and progression of atherosclerosis, a major complication of diabetes mellitus. Thus, in this study, we attempted to determine whether hyperoside can suppress vascular inflammatory processes induced by high glucose (HG) in human umbilical vein endothelial cells (HUVECs) and mice. Data showed that HG induced markedly increased vascular permeability, monocyte adhesion, expressions of cell adhesion molecules (CAMs), formation of reactive oxygen species (ROS), and activation of nuclear factor (NF)-κB. Remarkably, all of the above-mentioned vascular inflammatory effects of HG were attenuated by pretreatment with hyperoside. Vascular inflammatory responses induced by HG are critical events underlying development of various diabetic complications; therefore, our results suggest that hyperoside may have significant therapeutic benefits against diabetic complications and atherosclerosis.

  7. Heme oxygenase-1 enhances autophagy in podocytes as a protective mechanism against high glucose-induced apoptosis

    SciTech Connect

    Dong, Chenglong; Zheng, Haining; Huang, Shanshan; You, Na; Xu, Jiarong; Ye, Xiaolong; Zhu, Qun; Feng, Yamin; You, Qiang; Miao, Heng; Ding, Dafa; Lu, Yibing

    2015-10-01

    Injury and loss of podocytes play vital roles in diabetic nephropathy progression. Emerging evidence suggests autophagy, which is induced by multiple stressors including hyperglycemia, plays a protective role. Meanwhile, heme oxygenase-1 (HO-1) possesses powerful anti-apoptotic properties. Therefore, we investigated the impact of autophagy on podocyte apoptosis under diabetic conditions and its association with HO-1. Mouse podocytes were cultured in vitro; apoptosis was detected by flow cytometry. Transmission electron microscopy and biochemical autophagic flux assays were used to measure the autophagy markers microtubule-associated protein 1 light chain 3-II (LC3-II) and beclin-1. LC3-II and beclin-1 expression peaked 12–24 h after exposing podocytes to high glucose. Inhibition of autophagy with 3-methyladenine or Beclin-1 siRNAs or Atg 5 siRNAs sensitized cells to apoptosis, suggesting autophagy is a survival mechanism. HO-1 inactivation inhibited autophagy, which aggravated podocyte injury in vitro. Hemin-induced autophagy also protected podocytes from hyperglycemia in vitro and was abrogated by HO-1 siRNA. Adenosine monophosphate-activated protein kinase phosphorylation was higher in hemin-treated and lower in HO-1 siRNA-treated podocytes. Suppression of AMPK activity reversed HO-1-mediated Beclin-1 upregulation and autophagy, indicating HO-1-mediated autophagy is AMPK dependent. These findings suggest HO-1 induction and regulation of autophagy are potential therapeutic targets for diabetic nephropathy. - Highlights: • High glucose leads to increased autophagy in podocytes at an early stage. • The early autophagic response protects against high glucose-induced apoptosis. • Heme oxygenase-1 enhances autophagy and decreases high glucose -mediated apoptosis. • Heme oxygenase-1 induces autophagy through the activation of AMPK.

  8. Poria cocos inhibits high glucose-induced proliferation of rat mesangial cells.

    PubMed

    Yoon, Jung Joo; Lee, Yun Jung; Lee, So Min; Jin, Song Nan; Kang, Dae Gill; Lee, Ho Sub

    2013-01-01

    Mesangial cell proliferation is correlated with the progression of renal failure. The purpose of this study was to determine whether a water extract of Poria cocos Wolf (WPC), a well-known medicinal plant, regulates rat mesangial cell proliferation in the presence of high glucose (HG). HG significantly accelerated [(3)H]-thymidine incorporation, which was inhibited by WPC (1-50 μg/mL) in a dose-dependent manner. Cell migration and fibronectin mRNA expression data also supported the anti-proliferative effect of WPC. Western blot analysis revealed that pretreatment with WPC decreased the expression of cyclins and cyclin-dependent kinases (CDKs) and promoted the expression of p21(waf1/cip1) and p27(kip1). WPC also suppressed HG-induced p38 mitogen-activated protein kinase (p38 MAPK) and extracellular-signal-regulated kinase 1/2 (ERK 1/2) phosphorylation. Furthermore, WPC inhibited HG-induced production of dichlorofluorescein (DCF)-sensitive intracellular reactive oxygen species (ROS). In conclusion, HG promoted mesangial cell proliferation, and WPC inhibited this activity, at least in part, via induction of cell cycle arrest and activation of anti-oxidant properties. Taken together, these results suggest that P. cocos may be a potent regulator of HG-induced proliferation.

  9. Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruption.

    PubMed

    Rajesh, Mohanraj; Mukhopadhyay, Partha; Bátkai, Sándor; Haskó, György; Liaudet, Lucas; Drel, Viktor R; Obrosova, Irina G; Pacher, Pál

    2007-07-01

    A nonpsychoactive cannabinoid cannabidiol (CBD) has been shown to exert potent anti-inflammatory and antioxidant effects and has recently been reported to lower the incidence of diabetes in nonobese diabetic mice and to preserve the blood-retinal barrier in experimental diabetes. In this study we have investigated the effects of CBD on high glucose (HG)-induced, mitochondrial superoxide generation, NF-kappaB activation, nitrotyrosine formation, inducible nitric oxide synthase (iNOS) and adhesion molecules ICAM-1 and VCAM-1 expression, monocyte-endothelial adhesion, transendothelial migration of monocytes, and disruption of endothelial barrier function in human coronary artery endothelial cells (HCAECs). HG markedly increased mitochondrial superoxide generation (measured by flow cytometry using MitoSOX), NF-kappaB activation, nitrotyrosine formation, upregulation of iNOS and adhesion molecules ICAM-1 and VCAM-1, transendothelial migration of monocytes, and monocyte-endothelial adhesion in HCAECs. HG also decreased endothelial barrier function measured by increased permeability and diminished expression of vascular endothelial cadherin in HCAECs. Remarkably, all the above mentioned effects of HG were attenuated by CBD pretreatment. Since a disruption of the endothelial function and integrity by HG is a crucial early event underlying the development of various diabetic complications, our results suggest that CBD, which has recently been approved for the treatment of inflammation, pain, and spasticity associated with multiple sclerosis in humans, may have significant therapeutic benefits against diabetic complications and atherosclerosis.

  10. High glucose induces dysfunction of airway epithelial barrier through down-regulation of connexin 43.

    PubMed

    Yu, Hongmei; Yang, Juan; Zhou, Xiangdong; Xiao, Qian; Lü, Yang; Xia, Li

    2016-03-01

    The airway epithelium is a barrier to the inhaled antigens and pathogens. Connexin 43 (Cx43) has been found to play critical role in maintaining the function of airway epithelial barrier and be involved in the pathogenesis of the diabetic retinal vasculature, diabetes nephropathy and diabetes skin. Hyperglycemia has been shown to be an independent risk factor for respiratory infections. We hypothesize that the down-regulation of Cx43 induced by HG alters the expression of tight junctions (zonula occludens-1 (ZO-1) and occludin) and contributes to dysfunction of airway epithelial barrier, and Cx43 plays a critical role in the process in human airway epithelial cells (16 HBE). We show that high glucose (HG) decreased the expression of ZO-1 and occludin, disassociated interaction between Cx43 and tight junctions, and then increased airway epithelial transepithelial electrical resistance (TER) and permeability by down-regulation of Cx43 in human airway epithelial cells. These observations demonstrate an important role for Cx43 in regulating HG-induced dysfunction of airway epithelial barrier. These findings may bring new insights into the molecular pathogenesis of pulmonary infection related to diabetes mellitus and lead to novel therapeutic intervention for the dysfunction of airway epithelial barrier in chronic inflammatory airway diseases.

  11. High glucose induces rat mesangial cells proliferation and MCP-1 expression via ROS-mediated activation of NF-κB pathway, which is inhibited by eleutheroside E.

    PubMed

    Yang, Xiuqin; Wang, Yangang; Gao, Guanqi

    2016-01-01

    Glomerular hypertrophy and extracellular matrix accumulation are early features of diabetic nephropathy (DN). High glucose-induced oxidative stress is implicated in the etiology of DN. This study aims to investigate the effect of eleutheroside E (EE) on high glucose mediated rat mesangial cells (MCs) proliferation and monocyte chemoattractant protein-1 (MCP-1) expression and the underlying mechanism. MCs proliferation was assessed by MTT assay. Reactive oxygen species (ROS) level and MCP-1 expression were evaluated by ELISA kit. The protein expression of p47, NF-κB p65, p-NF-κB p65, IκBα, p-IκBα, IKKβ and p-IKKβ were determined by Western blot. The results showed that treatment with EE markedly attenuated high glucose induced MCs proliferation and in a dose-dependent manner. Intervention with EE also significantly blocked high glucose induced intracellular ROS production by decreasing NADPH oxidase activity. Meanwhile, EE administration could effectively alleviate the high glucose-stimulated activation of NF-κB, the degradation of IκBα and the expression of MCP-1. These results demonstrate that high glucose enhances MCs proliferation and MCP-1 expression by activating the ROS/NF-κB pathway and can be inhibited by EE. Our findings provide a new perspective for the clinical treatment of DN.

  12. High glucose induces activation of NF-κB inflammatory signaling through IκBα sumoylation in rat mesangial cells

    SciTech Connect

    Huang, Wei; Xu, Ling; Zhou, Xueqin; Gao, Chenlin; Yang, Maojun; Chen, Guo; Zhu, Jianhua; Jiang, Lan; Gan, Huakui; Gou, Fang; Feng, Hong; Peng, Juan; Xu, Yong

    2013-08-30

    Highlights: •The expression of SUMO1, SUMO2/3 under high glucose was obviously enhanced. •High glucose induced degradation of IκBα and activation of NF-κB pathway. •Sumoylation of IκBα in high glucose were significantly decreased. •The proteasome inhibitor MG132 could partially revert the degradation of IκBα. -- Abstract: The posttranslational modification of proteins by small ubiquitin-like modifiers (SUMOs) has emerged as an important regulatory mechanism for the alteration of protein activity, stability, and cellular localization. The latest research demonstrates that sumoylation is extensively involved in the regulation of the nuclear factor κB (NF-κB) pathway, which plays a critical role in the regulation of inflammation and contributes to fibrosis in diabetic nephropathy (DN). However, the role of sumoylation in the regulation of NF-κB signaling in DN is still unclear. In the present study, we cultured rat glomerular mesangial cells (GMCs) stimulated by high glucose and divided GMCs into six groups: normal glucose group (5.6 mmol/L), high glucose groups (10, 20, and 30 mmol/L), mannitol group (i.e., osmotic control group), and MG132 intervention group (30 mmol/L glucose with MG132, a proteasome inhibitor). The expression of SUMO1, SUMO2/3, IκBα, NF-κBp65, and monocyte chemotactic protein 1 (MCP-1) was measured by Western blot, reverse-transcription polymerase chain reaction, and indirect immunofluorescence laser scanning confocal microscopy. The interaction between SUMO1, SUMO2/3, and IκBα was observed by co-immunoprecipitation. The results showed that the expression of SUMO1 and SUMO2/3 was dose- and time-dependently enhanced by high glucose (p < 0.05). However, the expression of IκBα sumoylation in high glucose was significantly decreased compared with the normal glucose group (p < 0.05). The expression of IκBα was dose- and time-dependently decreased, and NF-κBp65 and MCP-1 were increased under high glucose conditions, which

  13. Agmatine protects Müller cells from high-concentration glucose-induced cell damage via N-methyl-D-aspartic acid receptor inhibition.

    PubMed

    Han, Ning; Yu, Li; Song, Zhidu; Luo, Lifu; Wu, Yazhen

    2015-07-01

    Neural injury is associated with the development of diabetic retinopathy. Müller cells provide structural and metabolic support for retinal neurons. High glucose concentrations are known to induce Müller cell activity. Agmatine is an endogenous polyamine, which is enzymatically formed in the mammalian brain and has exhibited neuroprotective effects in a number of experimental models. The aims of the present study were to investigate whether agmatine protects Müller cells from glucose-induced damage and to explore the mechanisms underlying this process. Lactate dehydrogenase activity and tumor necrosis factor-α mRNA expression were significantly reduced in Müller cells exposed to a high glucose concentration, following agmatine treatment, compared with cells not treated with agmatine. In addition, agmatine treatment inhibited glucose-induced Müller cell apoptosis, which was associated with the regulation of Bax and Bcl-2 expression. Agmatine treatment suppressed glucose-induced phosphorylation of mitogen-activated protein kinase (MAPK) protein in Müller cells. The present study demonstrated that the protective effects of agmatine on Müller cells were inhibited by N-methyl-D-aspartic acid (NMDA). The results of the present study suggested that agmatine treatment protects Müller cells from high-concentration glucose-induced cell damage. The underlying mechanisms may relate to the anti-inflammatory and antiapoptotic effects of agmatine, as well as to the inhibition of the MAPK pathway, via NMDA receptor suppression. Agmatine may be of use in the development of novel therapeutic approaches for patients with diabetic retinopathy.

  14. A novel antioxidant peptide derived from wheat germ prevents high glucose-induced oxidative stress in vascular smooth muscle cells in vitro.

    PubMed

    Chen, Siyuan; Lin, Dingbo; Gao, Yulong; Cao, Xiaozhou; Shen, Xinchun

    2017-01-25

    The ingestion of whole wheat products is responsible for the prevention of a number of chronic diseases. The aim of this study is to characterize the molecular properties of a novel wheat germ-derived antioxidant peptide (AOP) in protection against high glucose-induced oxidative stress in vascular smooth muscle cells (VSMCs). AOP (amino acid sequence AREGETVVPG) was isolated from wheat germ albumin using dual-enzymatic hydrolysis/separation, followed by MS/MS. The in vitro IC50 value for Fe(2+) chelation was 0.77 mM. The stability of purified AOP was confirmed by hydrolyzation in a simulated gastrointestinal (GI) digestion system in vitro. Furthermore, AOP significantly prevented high glucose-induced cell growth by 37.4 ± 2.7%, decreased the generation of intracellular reactive oxygen species (ROS) by 22.3 ± 4.6%, suppressed the phosphorylation of PKCζ, AKT and Erk1/2, and inhibited Nox4 protein expression. Our findings suggested that AOP exerted a protective role against high glucose-induced oxidative stress through the inhibition of the PKCζ/Nox4 signaling pathway in VSMCs.

  15. Establishment of in vitro model of erectile dysfunction for the study of high-glucose-induced angiopathy and neuropathy.

    PubMed

    Yin, G N; Park, S-H; Song, K-M; Limanjaya, A; Ghatak, K; Minh, N N; Ock, J; Ryu, J-K; Suh, J-K

    2017-03-01

    Penile erection requires complex interaction between vascular endothelial cells, smooth muscle cells, pericytes, and autonomic nerves. Diabetes mellitus is one of the most common causes of erectile dysfunction (ED) and multiple pathogenic factors, such as cavernous angiopathy and autonomic neuropathy, are associated with diabetic ED. Although a variety of animal models of diabetic ED play an important role in understanding pathophysiologic mechanisms of diabetes-induced ED, these animal models have limitations for addressing the exact cellular or molecular mechanisms involved in ED. Therefore, we established an in vitro model of ED for the study of high-glucose-induced angiopathy and neuropathy. We successfully isolated and cultivated mouse cavernous endothelial cells (MCECs) and mouse cavernous pericytes (MCPs). The cells were exposed to the normal-glucose (5 mmoL) or high-glucose (30 mmoL) condition for 48 h. In vitro matrigel assay revealed impairments in tube formation in primary cultured MCECs or MCPs exposed to high-glucose condition. To study cellular interaction between MCECs and MCPs, co-culture systems including indirect contact, indirect non-contact, and direct mixed co-culture system, were established. We observed impaired tube formation and increased permeability in MCECs-MCPs co-culture exposed to high-glucose condition. To evaluate the effect of high-glucose on neurite sprouting, the mouse major pelvic ganglion (MPG) tissue was harvested and cultivated in matrigel. Neurite outgrowth and nNOS-positive nerve fibers were significantly lower in MPG tissues exposed to the high-glucose condition than in the tissues exposed to the normal-glucose condition. We believe that in vitro model of ED will aid us to understand the role of each cellular component in the pathogenesis of diabetic ED, and also be a useful tool for determining the efficacy of candidate therapeutics targeting vascular or neuronal function. This model would present a new avenue for

  16. Asiaticoside protects cochlear hair cells from high glucose-induced oxidative stress via suppressing AGEs/RAGE/NF-κB pathway.

    PubMed

    Xing, Ying; Ji, Qiuhe; Li, Xiaomiao; Ming, Jie; Zhang, Nana; Zha, Dingjun; Lin, Ying

    2017-02-01

    Asiaticoside (AC) has been known to have anti-oxidative activity, however, the effect of AC on the progression of high glucose-induced hearing loss has not been studied. This study aims to analyze the effect of AC on cochlear hair cells under the treatment of high glucose in vitro and the hearing function in vivo. The results of MTT showed that high glucose decreased the activity of HEI-OC1 cells, but AC increased the activity of HEI-OC1 cells compared with high glucose group. The results of flow cytometry showed that AC decreased the degree of apoptosis induced by high levels of glucose. The results of DCFH-DA staining showed that AC inhibited the ROS production induced by high glucose levels. The results of JC-1 staining showed that AC inhibited the mitochondrial depolarization induced by high glucose levels. Furthermore, AC decreased the threshold, and protected inner and outer hair cells from damage in rats with hearing loss induced by diabetes mellitus. Moreover, AC decreased the activity of MDA, but, increased the activity of SOD, CAT and GSH-Px in vivo. AC also decreased the expression of AGEs, RAGE and NF-κB p65. Collectively, these results suggest that AC protects cochlear hair cells from high glucose-induced injury by increasing anti-oxidative activity and suppressing the AGEs/RAGE/NF-κB pathway.

  17. Activation of the PI3K/Akt pathway by oxidative stress mediates high glucose-induced increase of adipogenic differentiation in primary rat osteoblasts.

    PubMed

    Zhang, Yu; Yang, Jian-Hong

    2013-11-01

    Diabetes mellitus is associated with increased risk of osteopenia and bone fracture that may be related to hyperglycemia. However, the mechanisms accounting for diabetic bone disorder are unclear. Here, we showed that high glucose significantly promoted the production of reactive oxygen species (ROS) in rat primary osteoblasts. Most importantly, we reported for the first time that ROS induced by high glucose increased alkaline phosphatase activity, inhibited type I collagen (collagen I) protein level and cell mineralization, as well as gene expression of osteogenic markers including runt-related transcription factor 2 (Runx2), collagen I, and osteocalcin, but promoted lipid droplet formation and gene expression of adipogenic markers including peroxisome proliferator-activated receptor gamma, adipocyte fatty acid binding protein (aP2), and adipsin, which were restored by pretreatment with N-acetyl-L-cysteine (NAC), a ROS scavenger. Moreover, high glucose-induced oxidative stress activated PI3K/Akt pathway to inhibited osteogenic differentiation but stimulated adipogenic differentiation. In contrast, NAC and a PI3K inhibitor, LY-294002, reversed the down-regulation of osteogenic markers and the up-regulation of adipogenic markers as well as the activation of Akt under high glucose. These results indicated that oxidative stress played a key role in high glucose-induced increase of adipogenic differentiation, which contributed to the inhibition of osteogenic differentiation. This process was mediated by PI3K/Akt pathway in rat primary osteoblasts. Hence, suppression of oxidative stress could be a potential therapeutic approach for diabetic osteopenia.

  18. Propolis, a Constituent of Honey, Inhibits the Development of Sugar Cataracts and High-Glucose-Induced Reactive Oxygen Species in Rat Lenses

    PubMed Central

    Shibata, Teppei; Shibata, Shinsuke; Shibata, Naoko; Kiyokawa, Etsuko; Singh, Dhirendra P.

    2016-01-01

    Purpose. This study investigated the effects of oral propolis on the progression of galactose-induced sugar cataracts in rats and the in vitro effects of propolis on high-glucose-induced reactive oxygen species (ROS) and cell death in cultured rat lens cells (RLECs). Methods. Galactose-fed rats and RLECs cultured in high glucose (55 mM) medium were treated with propolis or vehicle control. Relative lens opacity was assessed by densitometry and changes in lens morphology by histochemical analysis. Intracellular ROS levels and cell viability were measured. Results. Oral administration of propolis significantly inhibited the onset and progression of cataract in 15% and 25% of galactose-fed rats, respectively. RLECs cultured with high glucose showed a significant increase in ROS expression with reduced cell viability. Treatment of these RLECs with 5 and 50 μg/mL propolis cultured significantly reduced ROS levels and increased cell viability, indicating that the antioxidant activity of propolis protected cells against ROS-induced damage. Conclusion. Propolis significantly inhibited the onset and progression of sugar cataract in rats and mitigated high-glucose-induced ROS production and cell death. These effects may be associated with the ability of propolis to inhibit hyperglycemia-evoked oxidative or osmotic stress-induced cellular insults. PMID:27242920

  19. Protective effect of trans-δ-viniferin against high glucose-induced oxidative stress in human umbilical vein endothelial cells through the SIRT1 pathway.

    PubMed

    Zhao, Huijun; Ma, Ting; Fan, Boyi; Yang, Lei; Han, Chao; Luo, Jianguang; Kong, Lingyi

    2016-01-01

    Oxidative stress plays a critical role in the pathogenesis of diabetic vascular complications. Trans-δ-viniferin (TVN), a polyphenolic compound, has recently attracted much attention as an antioxidant exhibiting a hypoglycemic potential. In the present study, we aimed at investigating the protective effect of TVN against high glucose-induced oxidative stress in human umbilical vein endothelial cells (HUVECs) and the potential mechanism involved. We found that TVN attenuated reactive oxygen species (ROS) production, increased catalase (CAT) activity and decreased malondialdehyde (MDA) levels to ameliorate cell survival induced by 35 mM glucose. Meanwhile, it inhibited high glucose-induced apoptosis by maintaining Ca(2+) and preserving mitochondrial membrane potential (MMP) levels. The immunoblot analysis indicated that TVN efficiently regulated the cleavage of caspase family, p53, Bax and Bcl-2, all mediated by SIRT1. Furthermore, the increased level of SIRT1 induced by TVN was inhibited by nicotinamide and siRNA-medicated SIRT1 silencing (si-SIRT1), thereby confirming the significant role of SIRT1 in these events. In conclusion, our results indicated that TVN efficiently reduced oxidative stress and maintained mitochondrial function related with activating SIRT1 in high glucose-treated HUVECs. It suggested that TVN is pharmacologically promising for treating diabetic cardiovascular complications.

  20. Irisin Promotes Human Umbilical Vein Endothelial Cell Proliferation through the ERK Signaling Pathway and Partly Suppresses High Glucose-Induced Apoptosis

    PubMed Central

    Song, Haibo; Wu, Fei; Zhang, Yuan; Zhang, Yuzhu; Wang, Fang; Jiang, Miao; Wang, Zhongde; Zhang, Mingxiang; Li, Shiwu; Yang, Lijun; Wang, Xing Li; Cui, Taixing; Tang, Dongqi

    2014-01-01

    Irisin is a newly discovered myokine that links exercise with metabolic homeostasis. It is involved in modest weight loss and improves glucose intolerance. However, the direct effects and mechanisms of irisin on vascular endothelial cells (ECs) are not fully understood. In the current study, we demonstrated that irisin promoted Human Umbilical Vein Endothelial Cell (HUVEC) proliferation. It was further demonstrated that this pro-proliferation effect was mediated by irisin-induced activation of extracellular signal–related kinase (ERK) signaling pathways. Inhibition of ERK signaling with U0126 decreased the pro-proliferation effect of irisin on HUVECs. It was also demonstrated that irisin reduced high glucose-induced apoptosis by up-regulating Bcl-2 expression and down-regulating Bax, Caspase-9 and Caspase-3 expression. In summary, these results suggested that irisin plays a novel role in sustaining endothelial homeostasis by promoting HUVEC proliferation via the ERK signaling pathway and protects the cell from high glucose-induced apoptosis by regulating Bcl-2,Bax and Caspase expression. PMID:25338001

  1. The pivotal role of high glucose-induced overexpression of PKCβ in the appearance of glucagon-like peptide-1 resistance in endothelial cells.

    PubMed

    Pujadas, Gemma; De Nigris, Valeria; La Sala, Lucia; Testa, Roberto; Genovese, Stefano; Ceriello, Antonio

    2016-11-01

    Recently, it has been demonstrated that Glucagon-like peptide-1 (GLP-1) has a protective effect on endothelial cells. Our hypothesis is that this GLP-1 protective effect is partly lost when the cells are exposed to sustained high glucose concentrations. Human umbilical vein endothelial cells (HUVECs) were cultured for 21 days in normal glucose (5 mmol/L, NG) or high glucose (25 mmol/L glucose, HG). GLP-1 (7-37) and Ruboxistaurin were added at 50 and 500 nM, respectively, alone or in combination, 1 h before cell harvesting. Analysis of GLP-1 receptor protein levels, as well as of the gene expression of different ER stress-related genes, proliferation markers, antioxidant cell response-related genes, and PKA subunits, was performed. ROS production was also measured in HUVECs exposed to mentioned treatments. GLP-1 receptor expression was reduced in HUVECs exposed to chronic high glucose concentrations but was partially restored by a chemical PKCβ-specific inhibitor. GLP-1, added as an acute treatment in endothelial cells, had the capacity to induce the expression of Nrf2-detoxifying enzyme targets, to increase transcription levels of scavenger genes, to attenuate the expression of high glucose-induced PKA subunits, ER stress and also the apoptotic phenotype of HUVECs; these effects occured only when high glucose-induced PKCβ overexpression was reduced by Ruboxistaurin. In a similar manner, ROS production induced by high glucose was reduced by GLP-1 in the presence of PKCβ inhibitor. This study suggests that an increase in PKCβ, induced by high glucose, could have a role in endothelial GLP-1 resistance, reducing GLP-1 receptor levels and disrupting the GLP-1 canonical pathway.

  2. HGF alleviates high glucose-induced injury in podocytes by GSK3β inhibition and autophagy restoration.

    PubMed

    Zhang, Congying; Hou, Bo; Yu, Siying; Chen, Qi; Zhang, Nong; Li, Hui

    2016-11-01

    Podocyte injury or loss plays a major role in the pathogenesis of proteinuric kidney disease including diabetic nephropathy (DN). High basal level of autophagy is critical for podocyte health. Recent studies have revealed that hepatocyte growth factor (HGF) can ameliorate podocyte injury and proteinuria. However, little is known about the impact of HGF on podocyte autophagy. In this study, we investigated whether and how HGF affects autophagy in podocytes treated with high glucose (HG) conditions. HGF significantly diminishes apoptosis, oxidative stress and autophagy impairment inflicted by HG in podocytes. These beneficial effects of HGF disappear once HGF receptor is blocked by SU11274, a specific inhibitor of c-Met. Moreover, HGF markedly suppresses HG-stimulated glycogen synthase kinase 3beta (GSK3β) activity. Accordingly, exogenous constitutively-active GSK3β overexpression using an adenoviral vector system (Ad-GSK3β-S9A) abrogates the ability of HGF to ameliorate HG-mediated podocyte injury while neither adenoviral-mediated overexpression of wild-type GSK3β (Ad-GSK3β-WT) nor adenoviral transduction of inactive GSK3β mutant (Ad-GSK3β-K85A) can counteract the protective effects of HGF on HG-treated podocytes. Collectively, these results suggest that HGF prevents HG-induced podocyte injury via an autophagy-promoting mechanism, which involves GSK3β inhibition.

  3. Tea polyphenols alleviate high fat and high glucose-induced endothelial hyperpermeability by attenuating ROS production via NADPH oxidase pathway

    PubMed Central

    2014-01-01

    Background Hyperglycemia-induced endothelial hyperpermeability is crucial to cardiovascular disorders and macro-vascular complications in diabetes mellitus. The objective of this study is to investigate the effects of green tea polyphenols (GTPs) on endothelial hyperpermeability and the role of nicotinamide adenine dinucleotide phosphate (NADPH) pathway. Methods Male Wistar rats fed on a high fat diet (HF) were treated with GTPs (0, 0.8, 1.6, 3.2 g/L in drinking water) for 26 weeks. Bovine aortic endothelial cells (BAECs) were treated with high glucose (HG, 33 mmol/L) and GTPs (0.0, 0.4, or 4 μg/mL) for 24 hours in vitro. The endothelial permeabilities in rat aorta and monolayer BAECs were measured by Evans blue injection method and efflux of fluorescein isothiocyanate (FITC)-dextran, respectively. The reactive oxygen species (ROS) levels in rat aorta and monolayer BAECs were measured by dihydroethidium (DHE) and 2′, 7′-dichloro-fluorescein diacetate (DCFH-DA) fluorescent probe, respectively. Protein levels of NADPH oxidase subunits were determined by Western-blot. Results HF diet-fed increased the endothelial permeability and ROS levels in rat aorta while HG treatments increased the endothelial permeability and ROS levels in cultured BAECs. Co-treatment with GTPs alleviated those changes both in vivo and in vitro. In in vitro studies, GTPs treatments protected against the HG-induced over-expressions of p22phox and p67phox. Diphenylene iodonium chloride (DPI), an inhibitor of NADPH oxidase, alleviated the hyperpermeability induced by HG. Conclusions GTPs could alleviate endothelial hyperpermeabilities in HF diet-fed rat aorta and in HG treated BAECs. The decrease of ROS production resulting from down-regulation of NADPH oxidase contributed to the alleviation of endothelial hyperpermeability. PMID:24580748

  4. Berberine attenuates high glucose-induced proliferation and extracellular matrix accumulation in mesangial cells: involvement of suppression of cell cycle progression and NF-κB/AP-1 pathways.

    PubMed

    Lan, Tian; Wu, Teng; Chen, Cheng; Chen, Xiaolan; Hao, Jie; Huang, Junying; Wang, Lijing; Huang, Heqing

    2014-03-25

    Berberine has been shown to have renoprotective effects on diabetes through attenuating TGF-β1 and fibronectin (FN) expression. However, how berberine regulates TGF-β1 and FN is not fully clear. Here we investigated whether berberine inhibited TGF-β1 and FN expression in high glucose-cultured mesangial cells. Berberine significantly inhibited mesangial cell proliferation and hypertrophy by increasing the cell population in G1-phase and reducing that in S-phase. In addition, berberine reversed high glucose-induced down-regulation of cyclin-dependent kinase inhibitor p21(Waf1)/(Cip1) and p27(Kip1). Berberine inhibited p65 translocation to the nucleus and c-jun phosphorylation induced by high glucose. Furthermore, berberine attenuated high glucose-induced expression of TGF-β1 and FN. Using a luciferase reporter assay, we found that high glucose-induced transcription activity of NF-κB and AP-1 was blocked by berberine. Electrophoretic mobility shift assay showed that high glucose increased that NF-κB and AP-1 DNA binding activity. These data indicate that berberine inhibited mesangial cell proliferation and hypertrophy by modulating cell cycle progress. In addition, berberine suppressed high glucose-induced TGF-β1 and FN expression by blocking NF-κB/AP-1 pathways.

  5. High glucose induces cell death of cultured human aortic smooth muscle cells through the formation of hydrogen peroxide

    PubMed Central

    Peiró, Concepción; Lafuente, Nuria; Matesanz, Nuria; Cercas, Elena; Llergo, José L; Vallejo, Susana; Rodríguez-Mañas, Leocadio; Sánchez-Ferrer, Carlos F

    2001-01-01

    Alterations of the vessel structure, which is mainly determined by smooth muscle cells through cell growth and/or cell death mechanisms, are characteristic of diabetes complications. We analysed the influence of high glucose (22 mM) on cultured human aortic smooth muscle cell growth and death, as hyperglycaemia is considered one of the main factors involved in diabetic vasculopathy. Growth curves were performed over 96 h in medium containing 0.5% foetal calf serum. Cell number increased by 2–4 fold over the culture period in the presence of 5.5 mM (low) glucose, while a 20% reduction in final cell number was observed with high glucose. Under serum-free conditions, cell number remained constant in low glucose cultures, but a 40% decrease was observed in high glucose cultures, suggesting that high glucose may induce increased cell death rather than reduced proliferation. Reduced final cell number induced by high glucose was also observed after stimulation with 5 or 10% foetal calf serum. The possible participation of oxidative stress was investigated by co-incubating high glucose with different reactive oxygen species scavengers. Only catalase reversed the effect of high glucose. Intracellular H2O2 content, visualized with 2′,7′-dichlorofluorescein and quantified by flow cytometry, was increased after high glucose treatment. To investigate the cell death mechanism induced by high glucose, apoptosis and necrosis were quantified. No differences were observed regarding the apoptotic index between low and high glucose cultures, but lactate dehydrogenase activity was increased in high glucose cultures. In conclusion, high glucose promotes necrotic cell death through H2O2 formation, which may participate in the development of diabetic vasculopathy. PMID:11487505

  6. High glucose induces the expression of osteopontin in blood vessels in vitro and in vivo.

    PubMed

    Li, Tianjia; Ni, Leng; Liu, Xinnong; Wang, Zhanqi; Liu, Changwei

    2016-11-11

    Osteopontin (OPN) is involved in mineral metabolism and the inflammatory response while diabetes mellitus is associated with severe and extensive vascular calcification. Therefore, we speculated that OPN could be a key factor in the calcification and dysfunction of blood vessels exposed to high glucose. To identify the relationship between high glucose and OPN, we used high glucose medium to stimulate smooth muscle cells (SMCs) and vascular endothelial cells (VECs) in vitro and diabetic rats for in vivo analyses. As assessed by flow cytometry and western blots, SMC and VEC apoptosis levels increased with high glucose. Potassium and calcium uptake by cells were also increased with high glucose. These findings demonstrated the relationship between mineral metabolism and high glucose. Western blot and quantitative real time polymerase chain reaction analyses demonstrated that OPN increased in vitro with high glucose stimulation. The inflammatory factor ICAM1 and the inhibitory phosphorylation of endothelial nitric-oxide synthase (eNOS) (Thr495) were also upregulated by high glucose. In contrast, the anti-inflammatory factor Nrf2 and the activating phosphorylation of eNOS (Ser1177) were downregulated. Similar to the change of OPN, phosphorylated P38 was increased with high glucose. SB203580, an inhibitor of P38 phosphorylation, downregulated the expression of OPN and related inflammatory factors. Additionally, OPN was increased in the aortas and plasma of diabetic rats. In conclusion, our findings demonstrate that high glucose can induce the expression of OPN, which may be a key factor in the calcification and dysfunction of the vascular wall in diabetes.

  7. Experimental study on apoptosis of TNFR1 receptor pro-endothelial progenitor cells activated by high glucose induced oxidative stress

    PubMed Central

    Liu, Yong; Xei, Fei; Xu, Xiong-Fei; Zeng, Hong; He, Hu-Qiang; Zhang, Lei; Zheng, Ying-Qiang; He, Yan-Zheng

    2015-01-01

    Objective: To investigate whether high glucose in vitro activating TNFR1 and further promote rat marrow endothelial progenitor cells (EPCs) apoptosis. Methods: Rat morrow endothelial progenitor cells were cultured and identified by Confocal Microscopy; then were treated with high glucose (5.5, 15, 30, 60 mmol/L), mannitol (15, 30, 60, 90 mmol/L), high glucose + Tempol and high glucose+ MAB430. Apoptosis rate of the above cells were detected by flow cytometry. ROS and MDA level and anti-O2- were detected by colorimetric technique; the expression level of TNFR1 induced signal pathway related proteins were detected by Western blotting. Results: High glucose can induce endothelial progenitor cells apoptosis, which is mostly in the later stage (72 h-96 h) instead of the earlier stage (24 h-48 h); high glucose can also induce oxidative stress reaction and the produces ROS and MDA increase significantly in the later stage (after 72 h), but anti-O2- decrease significantly. TNF apoptosis signal pathway related protein expression level not increase in the earlier stage (before 24 h) but increase significantly in the later stage (after 72 h). Tempol and MAB430 down-regulate TNF apoptosis signal pathway related protein expression and reduce EPCs apoptosis. Conclusion: High glucose activates the TNFR1 of TPCs through oxidative stress reaction and further induces cell apoptosis. PMID:26884909

  8. Vaccarin attenuates high glucose-induced human EA•hy926 endothelial cell injury through inhibition of Notch signaling.

    PubMed

    Qiu, Yuyu; Du, Bin; Xie, Fengshan; Cai, Weiwei; Liu, Yanling; Li, Yue; Feng, Lei; Qiu, Liying

    2016-03-01

    Endothelial cell injury is a critical component of atherosclerosis and hypertension. Vaccarin is considered to be of potential benefit in the treatment of vascular diseases. The aim of the present study was to evaluate the possible effects of vaccarin in human EA·hy926 cells induced by high glucose, and to investigate its underlying mechanism in the prevention and treatment of high glucose‑induced injury. In the present study, EA·hy926 cells were exposed to 90, 180 and 270 mM high glucose for 24 h, and the induced cell injury was examined using a sulforhodamine B assay. Following treatment with high glucose, it was found that high glucose stimulated cell injury, resulting in reduced cell viability and migratory ability, increased lactate dehydrogenase (LDH) leakage and malondialdehyde (MDA) levels, and decreased superoxide dismutase (SOD) activity. High glucose further accelerated cell apoptosis via activating Notch1 and Hairy and enhancer of split 1. It was found that preincubation with vaccarin protected the EA·hy926 cells from high glucose‑induced cell injury, which promoted cell viability and migratory ability, inhibited the expression levels of LDH and MDA, and enhanced the activity of SOD. Cell migratory ability, LDH leakage, MDA levels and decreasing SOD activity were evaluated using a wound healing assay and corresponding assay kits. Cell apoptosis was detected by flow cytometry with an Annexin V‑fluorescein isothiocyanate/propidium iodide apoptosis detection kit and Hoechst staining. Furthermore, western blotting was used to detect the protein expression levels of Notch1, Hes1 and caspase‑3. In particular, in addition to inducing the downregulation of Notch signaling, vaccarin treatment downregulated the cell apoptotic pathway‑associated protein caspase 3. These findings suggested that vaccarin may be able to selectively protect the vascular endothelium from dysfunction induced by high glucose.

  9. RANTES (CCL5) reduces glucose-dependent secretion of glucagon-like peptides 1 and 2 and impairs glucose-induced insulin secretion in mice.

    PubMed

    Pais, Ramona; Zietek, Tamara; Hauner, Hans; Daniel, Hannelore; Skurk, Thomas

    2014-08-01

    Type 2 diabetes is associated with elevated circulating levels of the chemokine RANTES and with decreased plasma levels of the incretin hormone glucagon-like peptide 1 (GLP-1). GLP-1 is a peptide secreted from intestinal L-cells upon nutrient ingestion. It enhances insulin secretion from pancreatic β-cells and protects from β-cell loss but also promotes satiety and weight loss. In search of chemokines that may reduce GLP-1 secretion we identified RANTES and show that it reduces glucose-stimulated GLP-1 secretion in the human enteroendocrine cell line NCI-H716, blocked by the antagonist Met-RANTES, and in vivo in mice. RANTES exposure to mouse intestinal tissues lowers transport function of the intestinal glucose transporter SGLT1, and administration in mice reduces plasma GLP-1 and GLP-2 levels after an oral glucose load and thereby impairs insulin secretion. These data show that RANTES is involved in altered secretion of glucagon-like peptide hormones most probably acting through SGLT1, and our study identifies the RANTES-receptor CCR1 as a potential target in diabetes therapy.

  10. Epigallocatechin gallate (EGCG) attenuates high glucose-induced insulin signaling blockade in human hepG2 hepatoma cells.

    PubMed

    Lin, Chih-Li; Lin, Jen-Kun

    2008-08-01

    Insulin resistance is the primary characteristic of type 2 diabetes which as a result of insulin signaling defects. It has been suggested that the tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) displays some antidiabetic effects, but the mechanism for EGCG insulin-enhancing effects is incompletely understood. In the present study, the investigations of EGCG on insulin signaling are performed in insulin-responsive human HepG2 cells cotreated with high glucose. We found that the high glucose condition causes significant increasing Ser307 phosphorylation of insulin receptor substrate-1 (IRS-1), leading to reduce insulin-stimulated phosphorylation of Akt. As the results, the insulin metabolic effects of glycogen synthesis and glucose uptake are inhibited by high glucose. However, the treatment of EGCG improves insulin-stimulated downsignaling by reducing IRS-1 Ser307 phosphorylation. Furthermore, we also demonstrated these EGCG effects are essential depends on the 5'-AMP-activated protein kinase (AMPK) activation. Together, our data suggest a putative link between high glucose and insulin resistance in HepG2 cells, and the EGCG treatment attenuates insulin signaling blockade by reducing IRS-1 Ser307 phosphorylation through the AMPK activation pathway.

  11. High glucose-induced resistance to 5-fluorouracil in pancreatic cancer cells alleviated by 2-deoxy-D-glucose.

    PubMed

    Cheng, Yao; Diao, Dongmei; Zhang, Hao; Guo, Qi; Wu, Xuandi; Song, Yongchun; Dang, Chengxue

    2014-03-01

    Abnormal glucose metabolism from hyperglycemia or diabetes aggravates the progression of pancreatic cancer. It is unknown whether high glucose has an impact on the antitumor effect of 5-fluorouracil (5-Fu) and whether targeting aberrant glucose metabolism using 2-deoxy-D-glucose (2-DG) may reverse this effect in high-glucose microenvironments. The cell viability of AsPC-1 and Panc-1 was analyzed by MTT assay following 5-Fu treatment at different glucose concentrations. Altered sensitivity to 5-Fu by 2-DG was also analyzed. LY294002 was used to inhibit PI3K-Akt signaling to determine the mechanism involved. In response to glucose, 5-Fu-induced cell growth inhibition was attenuated in a dose-dependent manner, accompanied with activated p-Akt, while 2-DG enhanced 5-Fu-induced cell growth inhibition. Moreover, blocking the PI3K/Akt pathway by LY294002 effectively eliminated 2-DG-induced apoptosis. In conclusion, high glucose weakens the antitumor effect of 5-Fu via PI3K/Akt signaling. Using 2-DG in combination with 5-Fu significantly increased their therapeutic effectiveness in high-glucose microenvironments.

  12. High glucose-induced oxidative stress represses sirtuin deacetylase expression and increases histone acetylation leading to neural tube defects.

    PubMed

    Yu, Jingwen; Wu, Yanqing; Yang, Peixin

    2016-05-01

    Aberrant epigenetic modifications are implicated in maternal diabetes-induced neural tube defects (NTDs). Because cellular stress plays a causal role in diabetic embryopathy, we investigated the possible role of the stress-resistant sirtuin (SIRT) family histone deacetylases. Among the seven sirtuins (SIRT1-7), pre-gestational maternal diabetes in vivo or high glucose in vitro significantly reduced the expression of SIRT 2 and SIRT6 in the embryo or neural stem cells, respectively. The down-regulation of SIRT2 and SIRT6 was reversed by superoxide dismutase 1 (SOD1) over-expression in the in vivo mouse model of diabetic embryopathy and the SOD mimetic, tempol and cell permeable SOD, PEGSOD in neural stem cell cultures. 2,3-dimethoxy-1,4-naphthoquinone (DMNQ), a superoxide generating agent, mimicked high glucose-suppressed SIRT2 and SIRT6 expression. The acetylation of histone 3 at lysine residues 56 (H3K56), H3K14, H3K9, and H3K27, putative substrates of SIRT2 and SIRT6, was increased by maternal diabetes in vivo or high glucose in vitro, and these increases were blocked by SOD1 over-expression or tempol treatment. SIRT2 or SIRT6 over-expression abrogated high glucose-suppressed SIRT2 or SIRT6 expression, and prevented the increase in acetylation of their histone substrates. The potent sirtuin activator (SRT1720) blocked high glucose-increased histone acetylation and NTD formation, whereas the combination of a pharmacological SIRT2 inhibitor and a pan SIRT inhibitor mimicked the effect of high glucose on increased histone acetylation and NTD induction. Thus, diabetes in vivo or high glucose in vitro suppresses SIRT2 and SIRT6 expression through oxidative stress, and sirtuin down-regulation-induced histone acetylation may be involved in diabetes-induced NTDs. The mechanism underlying pre-gestational diabetes-induced neural tube defects (NTDs) is still elusive. Our study unravels a new epigenetic mechanism in which maternal diabetes-induced oxidative stress represses

  13. Maresin 1 Mitigates High Glucose-Induced Mouse Glomerular Mesangial Cell Injury by Inhibiting Inflammation and Fibrosis

    PubMed Central

    Tang, Shi; Long, Yang; Huang, Wei; Chen, Jiao; Fan, Fang; Jiang, Chunxia

    2017-01-01

    Background. Inflammation and fibrosis are the important pathophysiologic processes in diabetic nephropathy (DN). Maresin 1 is a potential anti-inflammatory lipid mediator, which has displayed powerful proresolving activities. Aim. We determine whether maresin 1 has protective effect on mouse glomerular mesangial cells (GMCs) induced by high glucose. Methods. We cultured GMCs stimulated by high glucose and categorized as follows: normal glucose group (5.6 mmol/L), high glucose group (30 mmol/L), mannitol group, maresin 1 intervention group (1, 10, and 100 nmol/L), maresin 1 and normal glucose group, and the N-acetylcysteine (NAC) intervention group (10 μmol/L NAC). After 24 h, the expression of ROS, NLRP3, caspase-1, procaspase-1, IL-1β, and pro-IL-1β was detected by western-blot, RT-PCR, and immunofluorescence. After 48 h, the expression of TGF-β1 and FN was detected by RT-PCR and ELISA. Results. Compared with normal glucose group, the expression of ROS, NLRP3, caspase-1, IL-1β, TGF-β1, and FN increased in high glucose group (P < 0.05), but it decreased after the treatment of maresin 1 in different concentrations. On the contrary, the expression of procaspase-1 and pro-IL-1β protein was restrained by high glucose and enhanced by maresin 1 in a dose-dependent manner (P < 0.05). Conclusion. Maresin 1 can inhibit NLRP3 inflammasome, TGF-β1, and FN in GMCs; it may have protective effect on DN by mitigating the inflammation and early fibrosis. PMID:28182085

  14. Mechanical strain- and high glucose-induced alterations in mesangial cell collagen metabolism: role of TGF-beta.

    PubMed

    Riser, B L; Cortes, P; Yee, J; Sharba, A K; Asano, K; Rodriguez-Barbero, A; Narins, R G

    1998-05-01

    Cultured mesangial cells (MC) exposed to cyclic mechanical strain or high glucose levels increase their secretion of transforming growth factor-beta1 (TGF-beta1) and collagen, suggesting possible mechanisms for the development of diabetic renal sclerosis resulting from intraglomerular hypertension and/or hyperglycemia. This study examines whether glucose interacts with mechanical strain to influence collagen metabolism and whether this change is mediated by TGF-beta. Accordingly, rat MC were grown on flexible-bottom plates in 8 or 35 mM glucose media, subjected to 2 to 5 d of cyclic stretching, and assayed for TGF-beta1 mRNA, TGF-beta1 secretion, and the incorporation of 14C-proline into free or protein-associated hydroxyproline to assess the dynamics of collagen metabolism. Stretching or high glucose exposure increased TGF-beta1 secretion twofold and TGF-beta1 mRNA levels by 30 and 45%, respectively. However, the combination of these stimuli increased secretion greater than fivefold without further elevating mRNA. In 8 mM glucose medium, stretching significantly increased MC collagen synthesis and breakdown, but did not alter accumulation, whereas those stretched in 35 mM glucose markedly increased collagen accumulation. TGF-beta neutralization significantly reduced baseline collagen synthesis, breakdown, and accumulation in low glucose, but had no significant effect on the changes induced by stretch. In contrast, the same treatment of MC in high glucose medium greatly reduced stretch-induced synthesis and breakdown of collagen and totally abolished the increase in collagen accumulation. These results indicate that TGF-beta plays a positive regulatory role in MC collagen synthesis, breakdown, and accumulation. However, in low glucose there is no stretch-induced collagen accumulation, and the effect of TGF-beta is limited to basal collagen turnover. In high glucose media, TGF-beta is a critical mediator of stretch-induced collagen synthesis and catabolism, and

  15. Hydrophobic motif site-phosphorylated protein kinase CβII between mTORC2 and Akt regulates high glucose-induced mesangial cell hypertrophy.

    PubMed

    Das, Falguni; Ghosh-Choudhury, Nandini; Mariappan, Meenalakshmi M; Kasinath, Balakuntalam S; Choudhury, Goutam Ghosh

    2016-04-01

    PKCβII controls the pathologic features of diabetic nephropathy, including glomerular mesangial cell hypertrophy. PKCβII contains the COOH-terminal hydrophobic motif site Ser-660. Whether this hydrophobic motif phosphorylation contributes to high glucose-induced mesangial cell hypertrophy has not been determined. Here we show that, in mesangial cells, high glucose increased phosphorylation of PKCβII at Ser-660 in a phosphatidylinositol 3-kinase (PI3-kinase)-dependent manner. Using siRNAs to downregulate PKCβII, dominant negative PKCβII, and PKCβII hydrophobic motif phosphorylation-deficient mutant, we found that PKCβII regulates activation of mechanistic target of rapamycin complex 1 (mTORC1) and mesangial cell hypertrophy by high glucose. PKCβII via its phosphorylation at Ser-660 regulated phosphorylation of Akt at both catalytic loop and hydrophobic motif sites, resulting in phosphorylation and inactivation of its substrate PRAS40. Specific inhibition of mTORC2 increased mTORC1 activity and induced mesangial cell hypertrophy. In contrast, inhibition of mTORC2 decreased the phosphorylation of PKCβII and Akt, leading to inhibition of PRAS40 phosphorylation and mTORC1 activity and prevented mesangial cell hypertrophy in response to high glucose; expression of constitutively active Akt or mTORC1 restored mesangial cell hypertrophy. Moreover, constitutively active PKCβII reversed the inhibition of high glucose-stimulated Akt phosphorylation and mesangial cell hypertrophy induced by suppression of mTORC2. Finally, using renal cortexes from type 1 diabetic mice, we found that increased phosphorylation of PKCβII at Ser-660 was associated with enhanced Akt phosphorylation and mTORC1 activation. Collectively, our findings identify a signaling route connecting PI3-kinase to mTORC2 to phosphorylate PKCβII at the hydrophobic motif site necessary for Akt phosphorylation and mTORC1 activation, leading to mesangial cell hypertrophy.

  16. MicroRNA-29 regulates high-glucose-induced apoptosis in human retinal pigment epithelial cells through PTEN.

    PubMed

    Lin, Xiaohui; Zhou, Xiyuan; Liu, Danning; Yun, Lixia; Zhang, Lina; Chen, Xiaohai; Chai, Qinghe; Li, Langen

    2016-04-01

    Hyperglycemia or high-glucose (HG)-induced apoptosis in human retinal pigment epithelial (RPE) cells is a characteristic process in diabetic retinopathy. In our study, we examined whether microRNA-29 (miR-29) may regulate HG-induced RPE cell apoptosis. Human RPE cell line, ARPE-19 cells, was treated with various high concentration of glucose in vitro. HG-induced RPE cell apoptosis was examined by terminal deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL) assay and miR-29 gene expression by quantitative RT-PCR (qRT-PCR). miR-29 was then downregulated in RPE cells, and its effect on HG-induced apoptosis was examined by TUNEL assay and western blot assay on caspase-7 protein. Association of miR-29 on its downstream target, PTEN, in HG-induced RPE cell apoptosis was evaluated by dual-luciferase assay and qRT-PCR. PTEN was silenced in RPE cells. The effects of PTEN downregulation on miR-29-mediated HG-induced RPE cell apoptosis were also examined by TUNEL and western blot assays. HG induced significant apoptosis in RPE cells in a dose-dependent manner. miR-29 was upregulated by HG in RPE cells. miR-29 downregulation protected HG-induced apoptosis and reduced the production of caspase-7 protein in RPE cells. PTEN was shown to be directly downregulated by HG and then upregulated by miR-29 downregulation in RPE cells. Small interfering RNA (siRNA)-mediated PTEN downregulation reversed the protective effect of miR-29 downregulation on HG-induced RPE cell apoptosis. This study demonstrates that miR-29, through inverse association of PTEN, plays an important role in the process of HG-induced apoptosis in RPE cells.

  17. Quercetin and sesamin protect neuronal PC12 cells from high-glucose-induced oxidation, nitrosative stress, and apoptosis.

    PubMed

    Bournival, Julie; Francoeur, Marc-André; Renaud, Justine; Martinoli, Maria-Grazia

    2012-06-01

    Complications of diabetes are now well-known to affect sensory, motor, and autonomic nerves. Diabetes is also thought to be involved in neurodegenerative processes characteristic of several neurodegenerative diseases. Indeed, it has been acknowledged recently that hyperglycemia-induced oxidative stress contributes to numerous cellular reactions typical of central nervous system deterioration. The goal of the present study was to evaluate the effects of the polyphenol quercetin and the lignan sesamin on high-glucose (HG)-induced oxidative damage in an in vitro model of dopaminergic neurons, neuronal PC12 cells. When incubated with HG (13.5 mg/mL), neuronal PC12 cells showed a significant increase of cellular death. Our results revealed that quercetin and sesamin defend neuronal PC12 cells from HG-induced cellular demise. An elevated level of reactive oxygen and nitrogen species is a consequence of improved oxidative stress after HG administration, and we demonstrated that this production diminishes with quercetin and sesamin treatment. We also found that quercetin and sesamin elicited an increment of superoxide dismutase activity. DNA fragmentation, Bax/Bcl-2 ratio, nuclear translocation of apoptosis-inducing factor, as well as poly(adenosine diphosphate [ADP]-ribose) polymerase cleavage were significantly reduced by quercetin and sesamin administration, affirming their antiapoptotic features. Also, HG treatment impacted caspase-3 cleavage, supporting caspase-3-dependent pathways as mechanisms of apoptotic death. Our results indicate a powerful role for these natural dietary compounds and emphasize preventive or complementary nutritional strategies for diabetes control.

  18. Aspalathin and Nothofagin from Rooibos (Aspalathus linearis) inhibits high glucose-induced inflammation in vitro and in vivo.

    PubMed

    Ku, Sae-Kwang; Kwak, Soyoung; Kim, Yaesol; Bae, Jong-Sup

    2015-02-01

    Vascular inflammation plays a key role in the initiation and progression of atherosclerosis, a major complication of diabetes mellitus. Aspalathin (Asp) and nothofagin (Not) are two major active dihydrochalcones found in green rooibos, which have been reported for their antioxidant activity. In this study, we assessed whether Asp or Not can suppress vascular inflammation induced by high glucose (HG) in human umbilical vein endothelial cells (HUVECs) and mice. We monitored the effects of Asp or Not on HG-induced vascular hyperpermeability, expression of cell adhesion molecules (CAMs), formation of reactive oxygen species (ROS), and activation of nuclear factor (NF)-κB in vitro and in vivo. Our data indicate that HG markedly increased vascular permeability, monocyte adhesion, expression of CAMs, formation of ROS, and activation of NF-κB. Remarkably, treatment of Asp or Not inhibited HG-mediated vascular hyperpermeability, adhesion of monocytes toward HUVECs, and expression of CAMs. In addition, Asp or Not suppressed the formation of ROS and the activation of NF-κB. Since vascular inflammation induced by HG is critical in the development of diabetic complications, our results suggest that Asp or Not may have significant benefits in the treatment of diabetic complications.

  19. Suppression of ROS Production by Exendin-4 in PSC Attenuates the High Glucose-Induced Islet Fibrosis

    PubMed Central

    Kim, Ji-Won; Park, Shin-Young; You, Young-Hye; Ham, Dong-Sik; Lee, Seung-Hwan; Yang, Hae Kyung; Jeong, In-Kyung; Ko, Seung-Hyun

    2016-01-01

    Pancreatic stellate cells (PSCs) play a major role to fibrotic islet destruction observed in diabetic patients and animal model of diabetes. Exendin-4 (Ex-4) is a potent insulinotropic agent and has been approved for the treatment of type 2 diabetes. However, there have been no reports demonstrating the effects of Ex-4 on pancreatic islet fibrosis. In this study, Ex-4 treatment clearly attenuated fibrotic islet destruction and improved glucose tolerance and islet survival. GLP-1 receptor expression was upregulated during activation and proliferation of PSCs by hyperglycemia. The activation of PKA pathway by Ex-4 plays a role in ROS production and angiotensin II (Ang II) production. Exposure to high glucose stimulated ERK activation and Ang II-TGF- β1 production in PSCs. Interestingly, Ex-4 significantly reduced Ang II and TGF-β1 production by inhibition of ROS production but not ERK phosphorylation. Ex-4 may be useful not only as an anti-diabetic agent but also as an anti-fibrotic agent in type 2 diabetes due to its ability to inhibit PSC activation and proliferation and improve islet fibrosis in OLETF rats. PMID:27977690

  20. The antioxidant silybin prevents high glucose-induced oxidative stress and podocyte injury in vitro and in vivo

    PubMed Central

    Khazim, Khaled; Gorin, Yves; Cavaglieri, Rita Cassia; Abboud, Hanna E.

    2013-01-01

    Podocyte injury, a major contributor to the pathogenesis of diabetic nephropathy, is caused at least in part by the excessive generation of reactive oxygen species (ROS). Overproduction of superoxide by the NADPH oxidase isoform Nox4 plays an important role in podocyte injury. The plant extract silymarin is attributed antioxidant and antiproteinuric effects in humans and in animal models of diabetic nephropathy. We investigated the effect of silybin, the active constituent of silymarin, in cultures of mouse podocytes and in the OVE26 mouse, a model of type 1 diabetes mellitus and diabetic nephropathy. Exposure of podocytes to high glucose (HG) increased 60% the intracellular superoxide production, 90% the NADPH oxidase activity, 100% the Nox4 expression, and 150% the number of apoptotic cells, effects that were completely blocked by 10 μM silybin. These in vitro observations were confirmed by similar in vivo findings. The kidney cortex of vehicle-treated control OVE26 mice displayed greater Nox4 expression and twice as much superoxide production than cortex of silybin-treated mice. The glomeruli of control OVE26 mice displayed 35% podocyte drop out that was not present in the silybin-treated mice. Finally, the OVE26 mice experienced 54% more pronounced albuminuria than the silybin-treated animals. In conclusion, this study demonstrates a protective effect of silybin against HG-induced podocyte injury and extends this finding to an animal model of diabetic nephropathy. PMID:23804455

  1. Anthocyanins inhibit high-glucose-induced cholesterol accumulation and inflammation by activating LXRα pathway in HK-2 cells.

    PubMed

    Du, Chunyang; Shi, Yonghong; Ren, Yunzhuo; Wu, Haijiang; Yao, Fang; Wei, Jinying; Wu, Ming; Hou, Yanjuan; Duan, Huijun

    2015-01-01

    The dysregulation of cholesterol metabolism and inflammation plays a significant role in the progression of diabetic nephropathy (DN). Anthocyanins are polyphenols widely distributed in food and exert various biological effects including antioxidative, anti-inflammatory, and antihyperlipidemic effects. However, it remains unclear whether anthocyanins are associated with DN, and the mechanisms involved in the reciprocal regulation of inflammation and cholesterol efflux are yet to be elucidated. In this study, we evaluated the regulation of cholesterol metabolism and the anti-inflammatory effects exerted by anthocyanins (cyanidin-3-O-β-glucoside chloride [C3G] or cyanidin chloride [Cy]) and investigated the underlying molecular mechanism of action using high-glucose (HG)-stimulated HK-2 cells. We found that anthocyanins enhanced cholesterol efflux and ABCA1 expression markedly in HK-2 cells. In addition, they increased peroxisome proliferator-activated receptor alpha (PPARα) and liver X receptor alpha (LXRα) expression and decreased the HG-induced expression of the proinflammatory cytokines intercellular adhesion molecule-1 (ICAM1), monocyte chemoattractant protein-1 (MCP1), and transforming growth factor-β1 (TGFβ1), as well as NFκB activation. Incubation with the PPARα-specific inhibitor GW6471 and LXRα shRNA attenuated the anthocyanin-mediated promotion of ABCA1 expression and cholesterol efflux, suggesting that anthocyanins activated PPARα-LXRα-ABCA1-dependent cholesterol efflux in HK-2 cells. Moreover, the knockout of LXRα abrogated the anti-inflammatory effect of anthocyanins, whereas the PPARα antagonist GW6471 does not have this effect. Further investigations revealed that LXRα might interfere with anthocyanin-induced decreased ICAM1, MCP1, and TGFβ1 expression by reducing the nuclear translocation of NFκB. Collectively, these findings suggest that blocking cholesterol deposition and inhibiting the LXRα pathway-induced inflammatory response

  2. Resveratrol inhibits high glucose induced collagen upregulation in cardiac fibroblasts through regulating TGF-β1-Smad3 signaling pathway.

    PubMed

    Liu, Junhui; Zhuo, Xiaozhen; Liu, Weimin; Wan, Zhaofei; Liang, Xiao; Gao, Shanshan; Yuan, Zuyi; Wu, Yue

    2015-02-05

    Cardiac fibrosis is a common pathological process presented in a variety of diseases, including hypertension and diabetes. Cardiac fibroblasts (CFs) have been identified as the most important participants in the development of cardiac fibrosis. Exposure of cultured CFs to high glucose (HG) or angiotensin II (Ang II) resulted in increased collagen synthesis. Resveratrol (Res) is a natural polyphenol exhibiting anti-fibrosis effects in a number of different organs fibrosis process, whether Res can prevent HG and Ang II induced fibrosis response in CFs remains unclear. The aim of this work was to evaluate the effects of Res in HG and Ang II induced fibrosis response in CFs. We cultured rat CFs in either normal glucose (5.6 mM) or HG (25 mM) media in the presence of Res or not and the changes in collagens synthesis and TGF-β1 production were assessed by Real-time PCR, Western blotting, and enzyme linked immunosorbent assay (ELISA). Furthermore, normal and diabetic mice (induced by single dose of streptozotocin (100 mg/kg) via tail vein) receiving Res (10 mg/kg) were used to explore the effects of Res on cardiac fibrosis in vivo. Masson staining and immunohistochemistry were performed to visualize cardiac collagen deposition. Results indicate that CFs exposed to HG condition shows enhanced proliferation rate. Furthermore, in the presence of HG or Ang II, CFs exhibited increased collagens synthesis and TGF-β1 production. And these effects were abolished by Res intervention. In vivo results show that diabetic mice exhibit increased collagen deposition in the cardiac compared with the normal mice. And this change was prevented by the treatment of Res. These results suggest that Res possesses a potential antifibrogenic effect in hypertension and diabetes-related cardiac fibrosis. Moreover, the action mechanism is probably associated with its ability to reduce TGF-β1 content in CFs.

  3. Overexpression of miR-34c inhibits high glucose-induced apoptosis in podocytes by targeting Notch signaling pathways.

    PubMed

    Liu, Xiang-Dong; Zhang, Lian-Yun; Zhu, Tie-Chui; Zhang, Rui-Fang; Wang, Shu-Long; Bao, Yan

    2015-01-01

    Recent findings have shown that microRNAs play critical roles in the pathogenesis of diabetic nephropathy. miR-34c has been found to inhibit fibrosis and the epithelial-mesenchymal transition of kidney cells. However, the role of miR-34c in diabetic nephropathy has not been well studied. The current study was designed to investigate the role and potential underlying mechanism of miR-34c in regulating diabetic nephropathy. After treating podocytes with high glucose (HG) in vitro, we found that miR-34c was downregulated and that overexpression of miR-34c inhibited HG-induced podocyte apoptosis. The direct interaction between miR-34c and the 3'-untranslated region (UTR) of Notch1 and Jagged1 was validated by dual-luciferase reporter assay. Moreover, Notch1 and Jagged1 as putative targets of miR-34c were downregulated by miR-34c overexpression in HG-treated podocytes. Overexpression of miR-34c inhibited HG-induced Notch signaling pathway activation, as indicated by decreased expression of the Notch intracellular domain (NICD) and downstream genes including Hes1 and Hey1. Furthermore, miR-34c overexpression increased the expression of the anti-apoptotic gene Bcl-2, and decreased the expression of the pro-apoptotic protein Bax and cleaved Caspase-3. Additionally, the phosphorylation of p53 was also downregulated by miR-34c overexpression. Taken together, our findings suggest that miR-34c overexpression inhibits the Notch signaling pathway by targeting Notch1 and Jaggged1 in HG-treated podocytes, representing a novel and potential therapeutic target for the treatment of diabetic nephropathy.

  4. Protective effect of hydrogen-rich medium against high glucose-induced apoptosis of Schwann cells in vitro.

    PubMed

    Yu, Yang; Ma, Xiaoye; Yang, Tao; Li, Bo; Xie, Keliang; Liu, Daquan; Wang, Guolin; Yu, Yonghao

    2015-09-01

    Diabetic peripheral neuropathy (DPN) is considered to be one of the most prevalent and life threatening microvascular diabetic complications. DPN affects up to 50% of patients with diabetes mellitus and there are currently no efficacious therapeutic strategies available for its treatment. Previous studies have reported that oxidative stress and poly(ADP‑ribose) polymerase‑1 (PARP‑1) may be unifying factors for hyperglycemic injury. The aim of the present study was to investigate the protective effects of hydrogen‑rich medium (HM) on high glucose (HG)‑mediated oxidative stress, PARP‑1 activation and the apoptosis of Schwann cells (SCs) in vitro. The cells were divided into different groups, and were treated for 48 h. Cell viability and apoptosis were evaluated using Cell Counting kit‑8 and annexin V/propidium iodide assays, respectively. The concentrations of 8‑hydroxy‑2‑deoxyguanosine (8‑OHdG) and peroxynitrite (ONOO‑) were detected using an enzyme‑linked immunosorbent assay. The presence of intracellular oxygen free radicals was confirmed using flow cytometric analysis. Colorimetric assays were performed to determine the activity of caspase‑3, and western blotting was performed to detect the protein expression levels of PARP‑1, cleaved PARP‑1, PAR, apoptosis‑inducing factor (AIF), B‑cell lymphoma 2 (Bcl‑2) and Bcl‑2‑associated X protein. HG was found to induce severe oxidative stress and promote the caspase‑dependent and caspase‑independent apoptosis of SCs. Treatment with HM inhibited HG‑induced oxidative stress by suppressing hydroxyl and ONOO‑ production, levels of 8‑OHdG, caspase‑3 activity and apoptosis in the SCs. Furthermore, treatment with HM downregulated the HG‑induced release of PAR, the activation of PARP‑1 and nuclear translocation of AIF, and upregulated the expression of Bcl‑2 in the SCs. These results indicated that HM inhibited the HG‑induced‑oxidative stress‑associated caspase

  5. Effects of the New Aldose Reductase Inhibitor Benzofuroxane Derivative BF-5m on High Glucose Induced Prolongation of Cardiac QT Interval and Increase of Coronary Perfusion Pressure

    PubMed Central

    Di Filippo, C.; Ferraro, B.; Maisto, R.; Trotta, M. C.; Di Carluccio, N.; Sartini, S.; La Motta, C.; Ferraraccio, F.; Rossi, F.; D'Amico, M.

    2016-01-01

    This study investigated the effects of the new aldose reductase inhibitor benzofuroxane derivative 5(6)-(benzo[d]thiazol-2-ylmethoxy)benzofuroxane (BF-5m) on the prolongation of cardiac QT interval and increase of coronary perfusion pressure (CPP) in isolated, high glucose (33.3 mM D-glucose) perfused rat hearts. BF-5m was dissolved in the Krebs solution at a final concentration of 0.01 μM, 0.05 μM, and 0.1 μM. 33.3 mM D-glucose caused a prolongation of the QT interval and increase of CPP up to values of 190 ± 12 ms and 110 ± 8 mmHg with respect to the values of hearts perfused with standard Krebs solution (11.1 mM D-glucose). The QT prolongation was reduced by 10%, 32%, and 41%, respectively, for the concentration of BF-5m 0.01 μM, 0.05 μM, and 0.1 μM. Similarly, the CPP was reduced by 20% for BF-5m 0.05 μM and by 32% for BF-5m 0.1 μM. BF-5m also increased the expression levels of sirtuin 1, MnSOD, eNOS, and FOXO-1, into the heart. The beneficial actions of BF-5m were partly abolished by the pretreatment of the rats with the inhibitor of the sirtuin 1 activity EX527 (10 mg/kg/day/7 days i.p.) prior to perfusion of the hearts with high glucose + BF-5m (0.1 μM). Therefore, BF-5m supplies cardioprotection from the high glucose induced QT prolongation and increase of CPP. PMID:26839893

  6. MiR-18b suppresses high-glucose-induced proliferation in HRECs by targeting IGF-1/IGF1R signaling pathways.

    PubMed

    Wu, Jin-hui; Wang, Yi-han; Wang, Wei; Shen, Wei; Sang, Yan-zhi; Liu, Lin; Chen, Cui-min

    2016-04-01

    MicroRNAs (miRNAs) are important for the proliferation of endothelial cells and have been shown to be involved in diabetic retinopathy (DR). In previous study, we found that miRNAs might play a critical role in hyperglycemia-induced endothelial cell proliferation based on miRNA expression profiling. Here, the roles of microRNA-18b (miR-18b) in the proliferation of human retinal endothelial cells (HRECs) were investigated in an in vitro model of HRECs grown in high glucose. We identified that levels of miR-18b were decreased in high-glucose-induced HRECs, compared with those in cells incubated in normal glucose. However, the reduction of miR-18b up-regulated vascular endothelial growth factor (VEGF) secretion and promoted effects on in vitro proliferation of HRECs. Mechanistically, insulin growth factor-1 (IGF-1) was identified as a target of miR-18b. IGF-1 simulation could antagonize the effect induced by miR-18b up-regulation, promoting cell proliferation and increasing VEGF production. In contrast, the opposite results were observed with silencing IGF-1, which was consistent with the effects of miR-18b overexpression. MiR-18b exerted its function on VEGF synthesis and cell proliferation by suppressing the IGF-1/insulin growth factor-1 receptor (IGF1R) pathway, consequently inhibiting the downstream phosphorylation of Akt, MEK, and ERK. Hence, this may provide a new insight into understanding the mechanism of DR pathogenesis, as well as a potential therapeutic target for proliferative DR.

  7. Metformin and Resveratrol Inhibited High Glucose-Induced Metabolic Memory of Endothelial Senescence through SIRT1/p300/p53/p21 Pathway

    PubMed Central

    Gao, Haiyang; Xu, Ruixia; Teng, Siyong; Wu, Yongjian

    2015-01-01

    Endothelial senescence plays crucial roles in diabetic vascular complication. Recent evidence indicated that transient hyperglycaemia could potentiate persistent diabetic vascular complications, a phenomenon known as “metabolic memory.” Although SIRT1 has been demonstrated to mediate high glucose-induced endothelial senescence, whether and how “metabolic memory” would affect endothelial senescence through SIRT1 signaling remains largely unknown. In this study, we investigated the involvement of SIRT1 axis as well as the protective effects of resveratrol (RSV) and metformin (MET), two potent SIRT1 activators, during the occurrence of “metabolic memory” of cellular senescence (senescent “memory”). Human umbilical vascular endothelial cells (HUVECs) were cultured in either normal glucose (NG)/high glucose (HG) media for 6 days, or 3 days of HG followed by 3 days of NG (HN), with or without RSV or MET treatment. It was shown that HN incubation triggered persistent downregulation of deacetylase SIRT1 and upregulation of acetyltransferase p300, leading to sustained hyperacetylation (at K382) and activation of p53, and subsequent p53/p21-mediated senescent “memory.” In contrast, senescent “memory” was abrogated by overexpression of SIRT1 or knockdown of p300. Interestingly, we found that SIRT1 and p300 could regulate each other in response to HN stimulation, suggesting that a delicate balance between acetyltransferases and deacetylases may be particularly important for sustained acetylation and activation of non-histone proteins (such as p53), and eventually the occurrence of “metabolic memory.” Furthermore, we found that RSV or MET treatment prevented senescent “memory” by modulating SIRT1/p300/p53/p21 pathway. Notably, early and continuous treatment of MET, but not RSV, was particularly important for preventing senescent “memory.” In conclusion, short-term high glucose stimulation could induce sustained endothelial senescence via SIRT

  8. The dual targeting of EGFR and ErbB2 with the inhibitor Lapatinib corrects high glucose-induced apoptosis and vascular dysfunction by opposing multiple diabetes-induced signaling changes.

    PubMed

    Benter, Ibrahim F; Sarkhou, Fatima; Al-Khaldi, Abeer T; Chandrasekhar, Bindu; Attur, Sreeja; Dhaunsi, Gursev S; Yousif, Mariam H M; Akhtar, Saghir

    2015-01-01

    The epidermal growth factor receptors, EGFR and EGFR2 (ErbB2), appear important mediators of diabetes-induced vascular dysfunction. We investigated whether targeted dual inhibition of EGFR and ErbB2 with Lapatinib would be effective in treating diabetes-induced vascular dysfunction in a rat model of type 1 diabetes. In streptozotocin-induced diabetes, chronic 4-week oral or acute, ex vivo, administration of Lapatinib prevented the development of vascular dysfunction as indicated by the attenuation of the hyper-reactivity of the diabetic mesenteric vascular bed (MVB) to norephinephrine without correcting hyperglycemia. Chronic in vivo or acute ex vivo Lapatinib treatment also significantly attenuated diabetes-induced increases in phosphorylation of EGFR, ErbB2, ERK1/2, AKT, ROCK2 and IkB-alpha as well as normalized the reduced levels of phosphorylated FOXO3A, and eNOS (Ser1177) in the diabetic MVB. Similar results were observed in vascular smooth muscle cells (VSMCs) cultured in high glucose (25 mM) treated with Lapatinib or small interfering RNA (siRNA) targeting the ErbB2 receptor. Lapatinib also prevented high glucose-induced apoptosis in VSMC. Thus, Lapatinib corrects hyperglycemia-induced apoptosis and vascular dysfunction with concomitant reversal of diabetes or high glucose-induced signaling changes in EGFR/ErbB2 and downstream signaling pathways implying that targeted dual inhibition of EGFR/ErbB2 might be an effective vasculoprotective treatment strategy in diabetic patients.

  9. Synthesis and Characterization of Sygyzium cumini Nanoparticles for Its Protective Potential in High Glucose-Induced Cardiac Stress: a Green Approach.

    PubMed

    Atale, Neha; Saxena, Sharad; Nirmala, J Grace; Narendhirakannan, R T; Mohanty, Sujata; Rani, Vibha

    2017-03-01

    There exists a complex and multifactorial relationship between diabetes and cardiovascular disease. Hyperglycemia is an important factor imposing damage (glucose toxicity) on cardiac cell leading to diabetic cardiomyopathy. There are substantial clinical evidences on the adverse effects of conventional therapies in the prevention/treatment of diabetic cardiovascular complications. Currently, green-synthesized nanoparticles have emerged as a safe, efficient, and inexpensive alternative for therapeutic uses. The present study discloses the silver nanoparticle biosynthesizing capability and cardioprotective potential of Syzygium cumini seeds already reported to have antidiabetic properties. Newly generated silver nanoparticles S. cumini MSE silver nanoparticles (SmSNPs) were characterized by UV-visible spectroscopy, scanning electron microscopy (SEM), zeta sizer, X-ray diffraction (XRD), and Fourier transform infrared (FTIR) spectroscopy. Using methanolic extract of S. cumini seeds, an average size of 40-100-nm nanoparticles with 43.02 nm and -19.6 mV zeta potential were synthesized. The crystalline nature of SmSNPs was identified by using XRD. 2,2-Diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid (ABTS) assays revealed the antioxidative potential to be 66.87 (±0.7) % and 86.07 (±0.92) % compared to 60.29 (±0.02) % and 85.67 (±1.27) % for S. cumini MSE. In vitro study on glucose-stressed H9C2 cardiac cells showed restoration in cell size, nuclear morphology, and lipid peroxide formation upon treatment of SmSNPs. Our findings concluded that S. cumini MSE SmSNPs significantly suppress the glucose-induced cardiac stress in vitro by maintaining the cellular integrity and reducing the oxidative damages therefore establishing its therapeutic potential in diabetic cardiomyopathy.

  10. High glucose-induced mitochondrial respiration and reactive oxygen species in mouse cerebral pericytes is reversed by pharmacological inhibition of mitochondrial carbonic anhydrases: Implications for cerebral microvascular disease in diabetes.

    PubMed

    Shah, Gul N; Morofuji, Yoichi; Banks, William A; Price, Tulin O

    2013-10-18

    Hyperglycemia-induced oxidative stress leads to diabetes-associated damage to the microvasculature of the brain. Pericytes in close proximity to endothelial cells in the brain microvessels are vital to the integrity of the blood-brain barrier and are especially susceptible to oxidative stress. According to our recently published results, streptozotocin-diabetic mouse brain exhibits oxidative stress and loose pericytes by twelve weeks of diabetes, and cerebral pericytes cultured in high glucose media suffer intracellular oxidative stress and apoptosis. Oxidative stress in diabetes is hypothesized to be caused by reactive oxygen species (ROS) produced during hyperglycemia-induced enhanced oxidative metabolism of glucose (respiration). To test this hypothesis, we investigated the effect of high glucose on respiration rate and ROS production in mouse cerebral pericytes. Previously, we showed that pharmacological inhibition of mitochondrial carbonic anhydrases protects the brain from oxidative stress and pericyte loss. The high glucose-induced intracellular oxidative stress and apoptosis of pericytes in culture were also reversed by inhibition of mitochondrial carbonic anhydrases. Therefore, we extended our current study to determine the effect of these inhibitors on high glucose-induced increases in pericyte respiration and ROS. We now report that both the respiration and ROS are significantly increased in pericytes challenged with high glucose. Furthermore, inhibition of mitochondrial carbonic anhydrases significantly slowed down both the rate of respiration and ROS production. These data provide new evidence that pharmacological inhibitors of mitochondrial carbonic anhydrases, already in clinical use, may prove beneficial in protecting the brain from oxidative stress caused by ROS produced as a consequence of hyperglycemia-induced enhanced respiration.

  11. Glucose-Induced Acidification in Yeast Cultures

    ERIC Educational Resources Information Center

    Myers, Alan; Bourn, Julia; Pool, Brynne

    2005-01-01

    We present an investigation (for A-level biology students and equivalent) into the mechanism of glucose-induced extracellular acidification in unbuffered yeast suspensions. The investigation is designed to enhance understanding of aspects of the A-level curriculum that relate to the phenomenon (notably glucose catabolism) and to develop key skills…

  12. Cocoa flavonoids attenuate high glucose-induced insulin signalling blockade and modulate glucose uptake and production in human HepG2 cells.

    PubMed

    Cordero-Herrera, Isabel; Martín, María Ángeles; Goya, Luis; Ramos, Sonia

    2014-02-01

    Insulin resistance is the primary characteristic of type 2 diabetes. Cocoa and its main flavanol, (-)-epicatechin (EC), display some antidiabetic effects, but the mechanisms for their preventive activities related to glucose metabolism and insulin signalling in the liver remain largely unknown. In the present work, the preventive effect of EC and a cocoa polyphenolic extract (CPE) on insulin signalling and on both glucose production and uptake are studied in insulin-responsive human HepG2 cells treated with high glucose. Pre-treatment of cells with EC or CPE reverted decreased tyrosine-phosphorylated and total levels of IR, IRS-1 and -2 triggered by high glucose. EC and CPE pre-treatment also prevented the inactivation of the PI3K/AKT pathway and AMPK, as well as the diminution of GLUT-2 levels induced by high glucose. Furthermore, pre-treatment of cells with EC and CPE avoided the increase in PEPCK levels and the diminished glucose uptake provoked by high glucose, returning enhanced levels of glucose production and decreased glycogen content to control values. These findings suggest that EC and CPE improved insulin sensitivity of HepG2 treated with high glucose, preventing or delaying a potential hepatic dysfunction through the attenuation of the insulin signalling blockade and the modulation of glucose uptake and production.

  13. Hydrogen sulfide inhibits high glucose-induced matrix protein synthesis by activating AMP-activated protein kinase in renal epithelial cells.

    PubMed

    Lee, Hak Joo; Mariappan, Meenalakshmi M; Feliers, Denis; Cavaglieri, Rita C; Sataranatarajan, Kavithalakshmi; Abboud, Hanna E; Choudhury, Goutam Ghosh; Kasinath, Balakuntalam S

    2012-02-10

    Hydrogen sulfide, a signaling gas, affects several cell functions. We hypothesized that hydrogen sulfide modulates high glucose (30 mm) stimulation of matrix protein synthesis in glomerular epithelial cells. High glucose stimulation of global protein synthesis, cellular hypertrophy, and matrix laminin and type IV collagen content was inhibited by sodium hydrosulfide (NaHS), an H(2)S donor. High glucose activation of mammalian target of rapamycin (mTOR) complex 1 (mTORC1), shown by phosphorylation of p70S6 kinase and 4E-BP1, was inhibited by NaHS. High glucose stimulated mTORC1 to promote key events in the initiation and elongation phases of mRNA translation: binding of eIF4A to eIF4G, reduction in PDCD4 expression and inhibition of its binding to eIF4A, eEF2 kinase phosphorylation, and dephosphorylation of eEF2; these events were inhibited by NaHS. The role of AMP-activated protein kinase (AMPK), an inhibitor of protein synthesis, was examined. NaHS dose-dependently stimulated AMPK phosphorylation and restored AMPK phosphorylation reduced by high glucose. Compound C, an AMPK inhibitor, abolished NaHS modulation of high glucose effect on events in mRNA translation as well as global and matrix protein synthesis. NaHS induction of AMPK phosphorylation was inhibited by siRNA for calmodulin kinase kinase β, but not LKB1, upstream kinases for AMPK; STO-609, a calmodulin kinase kinase β inhibitor, had the same effect. Renal cortical content of cystathionine β-synthase and cystathionine γ-lyase, hydrogen sulfide-generating enzymes, was significantly reduced in mice with type 1 diabetes or type 2 diabetes, coinciding with renal hypertrophy and matrix accumulation. Hydrogen sulfide is a newly identified modulator of protein synthesis in the kidney, and reduction in its generation may contribute to kidney injury in diabetes.

  14. Connexin43 regulates high glucose-induced expression of fibronectin, ICAM-1 and TGF-β1 via Nrf2/ARE pathway in glomerular mesangial cells.

    PubMed

    Chen, Zhiquan; Xie, Xi; Huang, Junying; Gong, Wenyan; Zhu, Xiaoyu; Chen, Qiuhong; Huang, Jiani; Huang, Heqing

    2017-01-01

    Nrf2/ARE signaling pathway is a crucial cellular defense system to cope with oxidative stress, which is adaptively activated, in diabetic condition that is not efficient enough to resist the oxidative stress provoked by hyperglycemia. We have previously demonstrated that Connexin43 (Cx43) attenuates renal fibrosis through c-Src. However, the underlying mechanisms need to be further clarified. It has been reported that Cx43 possesses the ability of anti-oxidative. The current study aimed to determine if Cx43 exerts protective effects on renal fibrosis in diabetes via activation of Nrf2/ARE pathway and explore the underlying molecular mechanisms. The following findings were observed: (1) Cx43 expression decreased and c-Src activity increased in kidneys of diabetic animals; (2) Over-expressed Cx43 in high glucose treated GMCs inhibited protein levels of FN, ICAM-1 and TGF-β1; (3) Nrf2/ARE signaling adaptively responded to high glucose treatment in GMCs; (4) Cx43 reduced ROS generation by boost Nrf2/ARE signaling under high glucose condition; (5) Inhibition of c-Src activity promoted nucleus accumulation of Nrf2; (6) Over-expressed Cx43 inhibited c-Src activity and the interaction between c-Src and Nrf2 in GMCs cultured in high glucose. Thus we propose that Cx43 might enhance the activation of Nrf2/ARE pathway by means of inhibiting c-Src activity to hinder the nuclear export of Nrf2, and then reduce expression of FN, ICAM-1 and TGF-β1, ultimately attenuating renal fibrosis in diabetes.

  15. High glucose induces platelet-derived growth factor-C via carbohydrate response element-binding protein in glomerular mesangial cells.

    PubMed

    Kitsunai, Hiroya; Makino, Yuichi; Sakagami, Hidemitsu; Mizumoto, Katsutoshi; Yanagimachi, Tsuyoshi; Atageldiyeva, Kuralay; Takeda, Yasutaka; Fujita, Yukihiro; Abiko, Atsuko; Takiyama, Yumi; Haneda, Masakazu

    2016-03-01

    Persistent high concentration of glucose causes cellular stress and damage in diabetes via derangement of gene expressions. We previously reported high glucose activates hypoxia-inducible factor-1αand downstream gene expression in mesangial cells, leading to an extracellular matrix expansion in the glomeruli. A glucose-responsive transcription factor carbohydrate response element-binding protein (ChREBP) is a key mediator for such perturbation of gene regulation. To provide insight into glucose-mediated gene regulation in mesangial cells, we performed chromatin immunoprecipitation followed byDNAmicroarray analysis and identified platelet-derived growth factor-C (PDGF-C) as a novel target gene of ChREBP In streptozotocin-induced diabetic mice, glomerular cells showed a significant increase inPDGF-C expression; the ratio ofPDGF-C-positive cells to the total number glomerular cells demonstrated more than threefold increase when compared with control animals. In cultured human mesangial cells, high glucose enhanced expression ofPDGF-C protein by 1.9-fold. Knock-down of ChREBPabrogated this induction response. UpregulatedPDGF-C contributed to the production of typeIVand typeVIcollagen, possibly via an autocrine mechanism. Interestingly, urinaryPDGF-C levels in diabetic model mice were significantly elevated in a fashion similar to urinary albumin. Taken together, we hypothesize that a high glucose-mediated induction ofPDGF-C via ChREBPin mesangial cells contributes to the development of glomerular mesangial expansion in diabetes, which may provide a platform for novel predictive and therapeutic strategies for diabetic nephropathy.

  16. Hydrogen sulfide releasing aspirin, ACS14, attenuates high glucose-induced increased methylglyoxal and oxidative stress in cultured vascular smooth muscle cells.

    PubMed

    Huang, Qian; Sparatore, Anna; Del Soldato, Piero; Wu, Lingyun; Desai, Kaushik

    2014-01-01

    Hydrogen sulfide is a gasotransmitter with vasodilatory and anti-inflammatory properties. Aspirin is an irreversible cyclooxygenase inhibitor anti-inflammatory drug. ACS14 is a novel synthetic hydrogen sulfide releasing aspirin which inhibits cyclooxygenase and has antioxidant effects. Methylglyoxal is a chemically active metabolite of glucose and fructose, and a major precursor of advanced glycation end products formation. Methylglyoxal is harmful when produced in excess. Plasma methylglyoxal levels are significantly elevated in diabetic patients. Our aim was to investigate the effects of ACS14 on methylglyoxal levels in cultured rat aortic vascular smooth muscle cells. We used cultured rat aortic vascular smooth muscle cells for the study. Methylglyoxal was measured by HPLC after derivatization, and nitrite+nitrate with an assay kit. Western blotting was used to determine NADPH oxidase 4 (NOX4) and inducible nitric oxide synthase (iNOS) protein expression. Dicholorofluorescein assay was used to measure oxidative stress. ACS14 significantly attenuated elevation of intracellular methylglyoxal levels caused by incubating cultured vascular smooth muscle cells with methylglyoxal (30 µM) and high glucose (25 mM). ACS14, but not aspirin, caused a significant attenuation of increase in nitrite+nitrate levels caused by methylglyoxal or high glucose. ACS14, aspirin, and sodium hydrogen sulfide (NaHS, a hydrogen sulfide donor), all attenuated the increase in oxidative stress caused by methylglyoxal and high glucose in cultured cells. ACS14 prevented the increase in NOX4 expression caused by incubating the cultured VSMCs with MG (30 µM). ACS14, aspirin and NaHS attenuated the increase in iNOS expression caused by high glucose (25 mM). In conclusion, ACS14 has the novel ability to attenuate an increase in methylglyoxal levels which in turn can reduce oxidative stress, decrease the formation of advanced glycation end products and prevent many of the known deleterious effects

  17. Fagopyrum tataricum (buckwheat) improved high-glucose-induced insulin resistance in mouse hepatocytes and diabetes in fructose-rich diet-induced mice.

    PubMed

    Lee, Chia-Chen; Hsu, Wei-Hsuan; Shen, Siou-Ru; Cheng, Yu-Hsiang; Wu, She-Ching

    2012-01-01

    Fagopyrum tataricum (buckwheat) is used for the treatment of type 2 diabetes mellitus in Taiwan. This study was to evaluate the antihyperglycemic and anti-insulin resistance effects of 75% ethanol extracts of buckwheat (EEB) in FL83B hepatocytes by high-glucose (33 mM) induction and in C57BL/6 mice by fructose-rich diet (FRD; 60%) induction. The active compounds of EEB (100 μg/mL; 50 mg/kg bw), quercetin (6 μg/mL; 3 mg/kg bw), and rutin (23 μg/mL; 11.5 mg/kg bw) were also employed to treat FL83B hepatocytes and animal. Results indicated that EEB, rutin, and quercetin + rutin significantly improved 2-NBDG uptake via promoting Akt phosphorylation and preventing PPARγ degradation caused by high-glucose induction for 48 h in FL83B hepatocytes. We also found that EEB could elevate hepatic antioxidant enzymes activities to attenuate insulin resistance as well as its antioxidation caused by rutin and quercetin. Finally, EEB also inhibited increases in blood glucose and insulin levels of C57BL/6 mice induced by FRD.

  18. Nrf2 and NF-κB modulation by sulforaphane counteracts multiple manifestations of diabetic neuropathy in rats and high glucose-induced changes.

    PubMed

    Negi, Geeta; Kumar, Ashutosh; Sharma, Shyam S

    2011-11-01

    High glucose driven reactive oxygen intermediates production and inflammatory damage are recognized contributors of nerve dysfunction and subsequent damage in diabetic neuropathy. Sulforaphane, a known chemotherapeutic agent holds a promise for diabetic neuropathy because of its dual antioxidant and anti-inflammatory activities. The present study investigated the effect of sulforaphane in streptozotocin (STZ) induced diabetic neuropathy in rats. For in vitro experiments neuro2a cells were incubated with sulforaphane in the presence of normal (5.5 mM) and high glucose (30 mM). For in vivo studies, sulforaphane (0.5 and 1 mg/kg) was administered six weeks post diabetes induction for two weeks. Motor nerve conduction velocity (MNCV), nerve blood flow (NBF) and pain behavior were improved and malondialdehyde (MDA) level was reduced by sulforaphane. Antioxidant effect of sulforaphane is derived from nuclear erythroid 2-related factor 2 (Nrf2) activation as demonstrated by increased expression of Nrf2 and downstream targets hemeoxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO-1) in neuro2a cells and sciatic nerve of diabetic animals. Nuclear factor-kappa B (NF-κB) inhibition seemed to be responsible for antiinflammatory activity of sulforaphane as there was reduction in NF-κB expression and IκB kinase (IKK) phosphorylation along with abrogation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression and tumor necrosis factor-α (TNF-α) and interleukine-6 (IL-6) levels. Here in this study we provide an evidence that sulforaphane is effective in reversing the various deficits in experimental diabetic neuropathy. This study supports the defensive role of Nrf2 in neurons under conditions of oxidative stress and also suggests that the NF-κB pathway is an important modulator of inflammatory damage in diabetic neuropathy.

  19. DANGER is involved in high glucose-induced radioresistance through inhibiting DAPK-mediated anoikis in non-small cell lung cancer.

    PubMed

    Kwon, TaeWoo; Youn, HyeSook; Son, Beomseok; Kim, Daehoon; Seong, Ki Moon; Park, Sungkyun; Kim, Wanyeon; Youn, BuHyun

    2016-02-09

    18F-labeled fluorodeoxyglucose (FDG) uptake during FDG positron emission tomography seems to reflect increased radioresistance. However, the exact molecular mechanism underlying high glucose (HG)-induced radioresistance is unclear. In the current study, we showed that ionizing radiation-induced activation of the MEK-ERK-DAPK-p53 signaling axis is required for anoikis (anchorage-dependent apoptosis) of non-small cell lung cancer (NSCLC) cells in normal glucose media. Phosphorylation of DAPK at Ser734 by ERK was essential for p53 transcriptional activity and radiosensitization. In HG media, overexpressed DANGER directly bound to the death domain of DAPK, thus inhibiting the catalytic activity of DAPK. In addition, inhibition of the DAPK-p53 signaling axis by DANGER promoted anoikis-resistance and epithelial-mesenchymal transition (EMT), resulting in radioresistance of HG-treated NSCLC cells. Notably, knockdown of DANGER enhanced anoikis, EMT inhibition, and radiosensitization in a mouse xenograft model of lung cancer. Taken together, our findings offered evidence that overexpression of DANGER and the subsequent inhibitory effect on DAPK kinase activity are critical responses that account for HG-induced radioresistance of NSCLC.

  20. MicroRNA-9 inhibits high glucose-induced proliferation, differentiation and collagen accumulation of cardiac fibroblasts by down-regulation of TGFBR2

    PubMed Central

    Li, Jiaxin; Dai, Yingnan; Su, Zhendong; Wei, Guoqian

    2016-01-01

    To investigate the effects of miR-9 on high glucose (HG)-induced cardiac fibrosis in human cardiac fibroblasts (HCFs), and to establish the mechanism underlying these effects. HCFs were transfected with miR-9 inhibitor or mimic, and then treated with normal or HG. Cell viability and proliferation were detected by using the Cell Counting Kit-8 (CCK-8) assay and Brdu-ELISA assay. Cell differentiation and collagen accumulation of HCFs were detected by qRT-PCR and Western blot assays respectively. The mRNA and protein expressions of transforming growth factor-β receptor type II (TGFBR2) were determined by qRT-PCR and Western blotting. Up-regulation of miR-9 dramatically improved HG-induced increases in cell proliferation, differentiation and collagen accumulation of HCFs. Moreover, bioinformatics analysis predicted that the TGFBR2 was a potential target gene of miR-9. Luciferase reporter assay demonstrated that miR-9 could directly target TGFBR2. Inhibition of TGFBR2 had the similar effect as miR-9 overexpression. Down-regulation of TGFBR2 in HCFs transfected with miR-9 inhibitor partially reversed the protective effect of miR-9 overexpression on HG-induced cardiac fibrosis in HCFs. Up-regulation of miR-9 ameliorates HG-induced proliferation, differentiation and collagen accumulation of HCFs by down-regulation of TGFBR2. These results provide further evidence for protective effect of miR-9 overexpression on HG-induced cardiac fibrosis. PMID:27756824

  1. Erianin inhibits high glucose-induced retinal angiogenesis via blocking ERK1/2-regulated HIF-1α-VEGF/VEGFR2 signaling pathway

    PubMed Central

    Yu, Zengyang; Zhang, Tianyu; Gong, Chenyuan; Sheng, Yuchen; Lu, Bin; Zhou, Lingyu; Ji, Lili; Wang, Zhengtao

    2016-01-01

    Erianin is a natural compound found in Dendrobium chrysotoxum Lindl. Diabetic retinopathy (DR) is a serious and common microvascular complication of diabetes. This study aims to investigate the inhibitory mechanism of erianin on retinal neoangiogenesis and its contribution to the amelioration of DR. Erianin blocked high glucose (HG)-induced tube formation and migration in choroid-retinal endothelial RF/6A cells. Erianin inhibited HG-induced vascular endothelial growth factor (VEGF) expression, hypoxia-inducible factor 1-alpha (HIF-1α) translocation into nucleus and ERK1/2 activation in RF/6A and microglia BV-2 cells. MEK1/2 inhibitor U0126 blocked HG-induced HIF-1α and ERK1/2 activation in both above two cells. In addition, erianin abrogated VEGF-induced angiogenesis in vitro and in vivo, and also inhibited VEGF-induced activation of VEGF receptor 2 (VEGFR2) and its downstream cRaf-MEK1/2-ERK1/2 and PI3K-AKT signaling pathways in RF/6A cells. Furthermore, erianin reduced the increased retinal vessels, VEGF expression and microglia activation in streptozotocin (STZ)-induced hyperglycemic and oxygen-induced retinopathy (OIR) mice. In conclusion, our results demonstrate that erianin inhibits retinal neoangiogenesis by abrogating HG-induced VEGF expression by blocking ERK1/2-mediated HIF-1α activation in retinal endothelial and microglial cells, and further suppressing VEGF-induced activation of VEGFR2 and its downstream signals in retinal endothelial cells. PMID:27678303

  2. Glucose induces apoptosis of cardiomyocytes via microRNA-1 and IGF-1.

    PubMed

    Yu, Xi-Yong; Song, Yao-Hua; Geng, Yong-Jian; Lin, Qiu-Xiong; Shan, Zhi-Xin; Lin, Shu-Guang; Li, Yangxin

    2008-11-21

    Glucose toxicity is an important initiator of cardiovascular disease, contributing to the development of cardiomyocyte death and diabetic complications. The present study investigated whether high glucose state could induce apoptosis of rat cardiomyocyte cell line H9C2 through microRNA regulated insulin-like growth factor (IGF-1) signaling pathway. Our data showed that H9C2 cells exposed to high glucose have increased miR-1 expression level, decreased mitochondrial membrane potential, increased cytochrome-c release, and increased apoptosis. Glucose induced mitochondrial dysfunction, cytochrome-c release and apoptosis was blocked by IGF-1. Using prediction algorithms, we identified 3'-untranslated regions of IGF-1 gene are the target of miR-1. miR-1 mimics, but not mutant miR-1, blocked the capacity of IGF-1 to prevent glucose-induced mitochondrial dysfunction, cytochrome-c release and apoptosis. In conclusion, our data demonstrate that IGF-1 inhibits glucose-induced mitochondrial dysfunction, cytochrome-c release and apoptosis and IGF-1's effect is regulated by miR-1.

  3. Glucose-induced β cell production of IL-1β contributes to glucotoxicity in human pancreatic islets

    PubMed Central

    Maedler, Kathrin; Sergeev, Pavel; Ris, Frédéric; Oberholzer, José; Joller-Jemelka, Helen I.; Spinas, Giatgen A.; Kaiser, Nurit; Halban, Philippe A.; Donath, Marc Y.

    2002-01-01

    In type 2 diabetes, chronic hyperglycemia is suggested to be detrimental to pancreatic β cells, causing impaired insulin secretion. IL-1β is a proinflammatory cytokine acting during the autoimmune process of type 1 diabetes. IL-1β inhibits β cell function and promotes Fas-triggered apoptosis in part by activating the transcription factor NF-κB. Recently, we have shown that increased glucose concentrations also induce Fas expression and β cell apoptosis in human islets. The aim of the present study was to test the hypothesis that IL-1β may mediate the deleterious effects of high glucose on human β cells. In vitro exposure of islets from nondiabetic organ donors to high glucose levels resulted in increased production and release of IL-1β, followed by NF-κB activation, Fas upregulation, DNA fragmentation, and impaired β cell function. The IL-1 receptor antagonist protected cultured human islets from these deleterious effects. β cells themselves were identified as the islet cellular source of glucose-induced IL-1β. In vivo, IL-1β–producing β cells were observed in pancreatic sections of type 2 diabetic patients but not in nondiabetic control subjects. Similarly, IL-1β was induced in β cells of the gerbil Psammomys obesus during development of diabetes. Treatment of the animals with phlorizin normalized plasma glucose and prevented β cell expression of IL-1β. These findings implicate an inflammatory process in the pathogenesis of glucotoxicity in type 2 diabetes and identify the IL-1β/NF-κB pathway as a target to preserve β cell mass and function in this condition. PMID:12235117

  4. Cardioprotective role of Syzygium cumini against glucose-induced oxidative stress in H9C2 cardiac myocytes.

    PubMed

    Atale, Neha; Chakraborty, Mainak; Mohanty, Sujata; Bhattacharya, Susinjan; Nigam, Darshika; Sharma, Manish; Rani, Vibha

    2013-09-01

    Diabetic patients are known to have an independent risk of cardiomyopathy. Hyperglycemia leads to upregulation of reactive oxygen species (ROS) that may contribute to diabetic cardiomyopathy. Thus, agents that suppress glucose-induced intracellular ROS levels can have therapeutic potential against diabetic cardiomyopathy. Syzygium cumini is well known for its anti-diabetic potential, but its cardioprotective properties have not been evaluated yet. The aim of the present study is to analyze cardioprotective properties of methanolic seed extract (MSE) of S. cumini in diabetic in vitro conditions. ROS scavenging activity of MSE was studied in glucose-stressed H9C2 cardiac myoblasts after optimizing the safe dose of glucose and MSE by 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide. 2',7'-dichlorfluorescein diacetate staining and Fluorescence-activated cell sorting analysis confirmed the suppression of ROS production by MSE in glucose-induced cells. The intracellular NO and H2O2 radical-scavenging activity of MSE was found to be significantly high in glucose-induced cells. Exposure of glucose-stressed H9C2 cells to MSE showed decline in the activity of catalase and superoxide dismutase enzymes and collagen content. 4',6-diamidino-2-phenylindole, propidium iodide and 10-N-nonyl-3,6-bis (dimethylamino) acridine staining revealed that MSE protects myocardial cells from glucose-induced stress. Taken together, our findings revealed that the well-known anti-diabetic S. cumini can also protect the cardiac cells from glucose-induced stress.

  5. Icariin attenuates high glucose-induced type IV collagen and fibronectin accumulation in glomerular mesangial cells by inhibiting transforming growth factor-β production and signalling through G protein-coupled oestrogen receptor 1.

    PubMed

    Li, Yi-Chen; Ding, Xuan-Sheng; Li, Hui-Mei; Zhang, Cheng

    2013-09-01

    Icariin has been shown to attenuate diabetic nephropathy in rats by decreasing transforming growth factor-β (TGF-β) and type IV collagen expression, but its mode of action in glomerular mesangial cells is uncertain. The present study aimed to investigate the effect of icariin on excess mesangial type IV collagen and fibronectin accumulation induced by high glucose, and to determine the mechanism underlying its protective effects. Under high-glucose conditions, icariin diminished type IV collagen and fibronectin accumulation, as well as TGF-β production in human and rat mesangial cells. Mesangial cells treated with icariin after TGF-β1 exposure expressed less type IV collagen and fibronectin than those without icariin treatment, suggesting inhibition by icariin of TGF-β1 downstream pathways. On TGF-β1 stimulation, icariin inhibited TGF-β canonical Smad signalling and extracellular signal-regulated kinase (ERK)1/2 signalling by decreasing Smad2/3 and ERK1/2 phosphorylation in a dose-dependent manner. U0126, which blocked the ERK1/2 pathway, exerted an additive effect on the icariin suppression of type IV collagen and fibronectin expression, enhancing the beneficial effects of icariin. The G protein-coupled oestrogen receptor 1 (GPER) antagonist, G-15, abolished the icariin-induced inhibition of type IV collagen, and fibronectin overproduction and TGF-β signalling. Treatment of cells with fulvestrant, a downregulator of the oestrogen receptor, enhanced the action of icariin. In conclusion, icariin decreased type IV collagen and fibronectin accumulation induced by high glucose in mesangial cells by inhibiting TGF-β production, as well as Smad and ERK signalling in a GPER-dependent manner.

  6. TGR5 suppresses high glucose-induced upregulation of fibronectin and transforming growth factor-β1 in rat glomerular mesangial cells by inhibiting RhoA/ROCK signaling.

    PubMed

    Xiong, Fengxiao; Li, Xuejuan; Yang, Zhiying; Wang, Yu; Gong, Wenyan; Huang, Junying; Chen, Cheng; Liu, Peiqing; Huang, Heqing

    2016-12-01

    RhoA/ROCK can cause renal inflammation and fibrosis in the context of diabetes by activating nuclear factor-κB (NF-κB). TGR5 is known for its role in maintaining metabolic homeostasis and anti-inflammation, which is closely related to NF-κB inhibition. Given that TGR5 is highly enriched in kidney, we aim to investigate the regulatory role of TGR5 on fibronectin (FN) and transforming growth factor-β1 (TGF-β1) in high glucose (HG)-treated rat glomerular mesangial cells (GMCs). Both the factors are closely related to renal inflammations and mediated by NF-κB. Moreover, our study determines whether such regulation is achieved by the inhibition of RhoA/ROCK and the subsequent NF-κB suppression. Polymerase chain reaction was taken to test the mRNA level of TGR5. Western blot was used to measure the protein expressions of TGR5, FN, TGF-β1, p65, IκBα, phospho-MYPT1 (Thr853), and MYPT1. Glutathione S-transferase-pull down and immunofluorescence were conducted to test the activation of RhoA, the distribution of TGR5, and p65, respectively. Electrophoretic mobility shift assay was adopted to measure the DNA binding activity of NF-κB. In GMCs, TGR5 activation or overexpression significantly suppressed FN and TGF-β1 protein expressions, NF-κB, and RhoA/ROCK activation induced by HG or transfection of constitutively active RhoA. By contrast, TGR5 RNA interference caused enhancement of FN, TGF-β1 protein expressions, increase of RhoA/ROCK activation. However, TGR5 cannot suppress RhoA/ROCK activation when a selective Protein kinase A (PKA) inhibitor was used. This study suggests that in HG-treated GMCs, TGR5 significantly suppresses the NF-κB-mediated upregulation of FN and TGF-β1, which are hallmarks of diabetic nephropathy. These functions are closely related to the suppression of RhoA/ROCK via PKA.

  7. The Social Experiences of High School Students with Visual Impairments

    ERIC Educational Resources Information Center

    Jessup, Glenda; Bundy, Anita C.; Broom, Alex; Hancock, Nicola

    2017-01-01

    Introduction: This study explores the social experiences in high school of students with visual impairments. Methods: Experience sampling methodology was used to examine (a) how socially included students with visual impairments feel, (b) the internal qualities of their activities, and (c) the factors that influence a sense of inclusion. Twelve…

  8. L-cysteine reversibly inhibits glucose-induced biphasic insulin secretion and ATP production by inactivating PKM2.

    PubMed

    Nakatsu, Daiki; Horiuchi, Yuta; Kano, Fumi; Noguchi, Yoshiyuki; Sugawara, Taichi; Takamoto, Iseki; Kubota, Naoto; Kadowaki, Takashi; Murata, Masayuki

    2015-03-10

    Increase in the concentration of plasma L-cysteine is closely associated with defective insulin secretion from pancreatic β-cells, which results in type 2 diabetes (T2D). In this study, we investigated the effects of prolonged L-cysteine treatment on glucose-stimulated insulin secretion (GSIS) from mouse insulinoma 6 (MIN6) cells and from mouse pancreatic islets, and found that the treatment reversibly inhibited glucose-induced ATP production and resulting GSIS without affecting proinsulin and insulin synthesis. Comprehensive metabolic analyses using capillary electrophoresis time-of-flight mass spectrometry showed that prolonged L-cysteine treatment decreased the levels of pyruvate and its downstream metabolites. In addition, methyl pyruvate, a membrane-permeable form of pyruvate, rescued L-cysteine-induced inhibition of GSIS. Based on these results, we found that both in vitro and in MIN6 cells, L-cysteine specifically inhibited the activity of pyruvate kinase muscle isoform 2 (PKM2), an isoform of pyruvate kinases that catalyze the conversion of phosphoenolpyruvate to pyruvate. L-cysteine also induced PKM2 subunit dissociation (tetramers to dimers/monomers) in cells, which resulted in impaired glucose-induced ATP production for GSIS. DASA-10 (NCGC00181061, a substituted N,N'-diarylsulfonamide), a specific activator for PKM2, restored the tetramer formation and the activity of PKM2, glucose-induced ATP production, and biphasic insulin secretion in L-cysteine-treated cells. Collectively, our results demonstrate that impaired insulin secretion due to exposure to L-cysteine resulted from its direct binding and inactivation of PKM2 and suggest that PKM2 is a potential therapeutic target for T2D.

  9. High skin temperature and hypohydration impair aerobic performance.

    PubMed

    Sawka, Michael N; Cheuvront, Samuel N; Kenefick, Robert W

    2012-03-01

    This paper reviews the roles of hot skin (>35°C) and body water deficits (>2% body mass; hypohydration) in impairing submaximal aerobic performance. Hot skin is associated with high skin blood flow requirements and hypohydration is associated with reduced cardiac filling, both of which act to reduce aerobic reserve. In euhydrated subjects, hot skin alone (with a modest core temperature elevation) impairs submaximal aerobic performance. Conversely, aerobic performance is sustained with core temperatures >40°C if skin temperatures are cool-warm when euhydrated. No study has demonstrated that high core temperature (∼40°C) alone, without coexisting hot skin, will impair aerobic performance. In hypohydrated subjects, aerobic performance begins to be impaired when skin temperatures exceed 27°C, and even warmer skin exacerbates the aerobic performance impairment (-1.5% for each 1°C skin temperature). We conclude that hot skin (high skin blood flow requirements from narrow skin temperature to core temperature gradients), not high core temperature, is the 'primary' factor impairing aerobic exercise performance when euhydrated and that hypohydration exacerbates this effect.

  10. Paradoxical glucose-induced hyperkalemia. Combined aldosterone-insulin deficiency.

    PubMed

    Goldfarb, S; Strunk, B; Singer, I; Goldberg, M

    1975-11-01

    Severe hyperkalemia associated with spontaneous hyperglycemia as well as with the intravenous infusions of glucose occurred in an insulin-requiring diabetic patient in the absence of potassium administration, the use of diuretics which inhibit urinary potassium excretion or acidemia. Metabolic balance studies revealed, in addition to diabets, the presence of isolated aldosterone deficiency of the hyporeninemic type. Intravenous glucose infusions (0.5 g/kg body weight) produced significant hyperkalemia but desoxycortisone acetate (DOCA) therapy (10 mg/day) prevented the glucose-induced hyperkalemia. In this patient, the serum potassium concentration increases after the intravenous infusions of glucose because there is insufficient aldosterone and insulin to reverse the transfer of potassium to the extracellular fluid which normally occurs after hypertonic infusions of glucose. Although DOCA replacement modifies the distribution of potassium in the extracellular fluid and blunts the hyperkalemic effect of intravenous infusions of glucose, a rise in the insulin level is required for the usual hypokalemic response to intravenously administered glucose. These studies illustrate the risk of raising blood glucose levels in patients with combined aldosterone and insulin deficiency and the tendency towards hyperkalemia in diabetic patients under certain clinical conditions.

  11. Cysteine analogues potentiate glucose-induced insulin release in vitro

    SciTech Connect

    Ammon, H.P.; Hehl, K.H.; Enz, G.; Setiadi-Ranti, A.; Verspohl, E.J.

    1986-12-01

    In rat pancreatic islets, cysteine analogues, including glutathione, acetylcysteine, cysteamine, D-penicillamine, L-cysteine ethyl ester, and cysteine-potentiated glucose (11.1 mM) induced insulin secretion in a concentration-dependent manner. Their maximal effects were similar and occurred at approximately 0.05, 0.05, 0.1, 0.5, 1.0, 1.0 mM, respectively. At substimulatory glucose levels (2.8 mM), insulin release was not affected by these compounds. In contrast, thiol compounds, structurally different from cysteine and its analogues, such as mesna, tiopronin, meso-2,3-dimercaptosuccinic acid (DMSA), dimercaprol (BAL), beta-thio-D-glucose, as well as those cysteine analogues that lack a free-thiol group, including L-cystine, cystamine, D-penicillamine disulfide, S-carbocysteine, and S-carbamoyl-L-cysteine, did not enhance insulin release at stimulatory glucose levels (11.1 mM); cystine (5 mM) was inhibitory. These in vitro data indicate that among the thiols tested here, only cysteine and its analogues potentiate glucose-induced insulin secretion, whereas thiols that are structurally not related to cysteine do not. This suggests that a cysteine moiety in the molecule is necessary for the insulinotropic effect. For their synergistic action to glucose, the availability of a sulfhydryl group is also a prerequisite. The maximal synergistic action is similar for all cysteine analogues tested, whereas the potency of action is different, suggesting similarity in the mechanism of action but differences in the affinity to the secretory system.

  12. Fenofibrate Attenuated Glucose-Induced Mesangial Cells Proliferation and Extracellular Matrix Synthesis via PI3K/AKT and ERK1/2

    PubMed Central

    Zhu, Fengming; Ma, Zufu; Liao, Wenhui; He, Yong; He, JinSeng; Li, Wei; Yang, Juan; Lu, Qian; Xu, Gang; Yao, Ying

    2013-01-01

    Excess mesangial extracellular matrix (ECM) and mesangial cell proliferation is the major pathologic feature of diabetic nephropathy (DN). Fenofibrate, a PPARα agonist, has been shown to attenuate extracellular matrix formation in diabetic nephropathy. However, the mechanisms underlying this effect remain to be elucidated. In this study, the effect of fenofibrate on high-glucose induced cell proliferation and extracellular matrix exertion and its mechanisms were investigated in cultured rat mesangial cells by the methylthiazoletetrazolium (MTT) assay, flow cytometry and western blot. The results showed that treatment of mesangial cells (MCs) with fenofibrate repressed high-glucose induced up-regulation of extracellular matrix Collagen-IV, and inhibited entry of cell cycle into the S phase. This G1 arrest and ECM inhibition was caused by the reduction of phosphorylation and activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT. On the contrary, PPARα siRNA accelerated high glucose-induced cell cycle progression by ERK1/2 and AKT activation. Taken together, fenofibrate ameliorated glucose-induced mesangial cell proliferation and matrix production via its inhibition of PI3K/AKT and ERK1/2 signaling pathways. Such mechanisms may contribute to the favorable effects of treatment using fenofibrate in diabetic nephropathy. PMID:24130796

  13. High blood pressure in older subjects with cognitive impairment.

    PubMed

    Mossello, Enrico; Simoni, David

    2016-06-22

    High blood pressure and cognitive impairment often coexist in old age, but their pathophysiological association is complex. Several longitudinal studies have shown that high blood pressure at midlife is a risk factor for cognitive impairment and dementia, although this association is much less clear in old age. The effect of blood pressure lowering in reducing the risk of dementia is only borderline significant in clinical trials of older subjects, partly due to the insufficient follow-up time. Conversely, dementia onset is associated with a decrease of blood pressure values, probably secondary to neurodegeneration. Prognostic effect of blood pressure values in cognitively impaired older subjects is still unclear, with aggressive blood pressure lowering being potentially harmful in this patients category. Brief cognitive screening, coupled with simple motor assessment, are warranted to identify frail older subjects who need a more cautious approach to antihypertensive treatment. Values obtained with ambulatory blood pressure monitoring seem more useful than clinical ones to predict the outcome of cognitively impaired older subjects. Future studies should identify the most appropriate blood pressure targets in older subjects with cognitive impairment.

  14. Executive Function Impairments in High IQ Adults with ADHD

    ERIC Educational Resources Information Center

    Brown, Thomas E.; Reichel, Philipp C.; Quinlan, Donald M.

    2009-01-01

    Objectives: To demonstrate that high IQ adults diagnosed with ADHD suffer from executive function (EF) impairments that: a) can be identified with a combination of standardized measures and self-report data; and b) occur more commonly in this group than in the general population. Method: 157 ADHD adults with IQ greater than or equal to 120 were…

  15. The protective effect of magnesium lithospermate B against glucose-induced intracellular oxidative damage

    SciTech Connect

    Qu, Jian; Ren, Xian; Hou, Rui-ying; Dai, Xing-ping; Zhao, Ying-chun; Xu, Xiao-jing; Zhang, Wei; Zhou, Gan; Zhou, Hong-hao; Liu, Zhao-qian

    2011-07-22

    Highlights: {yields} LAB reduced the ROS production in HEK293T cells cultured under oxidative stress. High dose of glucose enhanced the expression of HO-1 mRNA and HO-1 protein in a time-dependent manner. {yields} LAB enhanced the expression of HO-1 mRNA and HO-1 protein in a dose-dependent manner treated with high dose of glucose. {yields} LAB plays an important role against glucose-induced intracellular oxidative damage. {yields} The enhanced expression of HO-1 mRNA and HO-1 protein caused by LAB is regulated via Nrf2 signal pathway. -- Abstract: Objectives: To investigate the effects of magnesium lithospermate B (LAB) on intracellular reactive oxygen species (ROS) production induced by high dose of glucose or H{sub 2}O{sub 2}, we explored the influences of LAB on the expression of heme oxygenase-1 (HO-1) and nuclear factor E2-related factor-2 (Nrf2) in HEK293T cells after treatment with high dose of glucose. Materials and methods: The total nuclear proteins in HEK293T cells were extracted with Cytoplasmic Protein Extraction Kit. The ROS level was determined by flow cytometry. The mRNA and protein expression of HO-1 and Nrf2 were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot. Results: LAB reduced the ROS production in HEK293T cells cultured under oxidative stress. High dose of glucose enhanced the expression of HO-1 mRNA and HO-1 protein in a time-dependent manner. LAB enhanced the expression of HO-1 mRNA and HO-1 protein in a dose-dependent manner treated with high dose of glucose. The amount of Nrf2 translocation was enhanced after cells were pretreated with 50 {mu}mol/L or 100 {mu}mol/L LAB. Silencing of Nrf2 gene eliminated the enhanced expression of HO-1 protein induced by high dose of glucose plus LAB. Conclusions: LAB plays an important role against glucose-induced intracellular oxidative damage. The enhanced expression of HO-1 mRNA and HO-1 protein caused by LAB is regulated via Nrf2 signal pathway.

  16. PED/PEA-15 regulates glucose-induced insulin secretion by restraining potassium channel expression in pancreatic beta-cells.

    PubMed

    Miele, Claudia; Raciti, Gregory Alexander; Cassese, Angela; Romano, Chiara; Giacco, Ferdinando; Oriente, Francesco; Paturzo, Flora; Andreozzi, Francesco; Zabatta, Assunta; Troncone, Giancarlo; Bosch, Fatima; Pujol, Anna; Chneiweiss, Hervé; Formisano, Pietro; Beguinot, Francesco

    2007-03-01

    The phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes (ped/pea-15) gene is overexpressed in human diabetes and causes this abnormality in mice. Transgenic mice with beta-cell-specific overexpression of ped/pea-15 (beta-tg) exhibited decreased glucose tolerance but were not insulin resistant. However, they showed impaired insulin response to hyperglycemia. Islets from the beta-tg also exhibited little response to glucose. mRNAs encoding the Sur1 and Kir6.2 potassium channel subunits and their upstream regulator Foxa2 were specifically reduced in these islets. Overexpression of PED/PEA-15 inhibited the induction of the atypical protein kinase C (PKC)-zeta by glucose in mouse islets and in beta-cells of the MIN-6 and INS-1 lines. Rescue of PKC-zeta activity elicited recovery of the expression of the Sur1, Kir6.2, and Foxa2 genes and of glucose-induced insulin secretion in PED/PEA-15-overexpressing beta-cells. Islets from ped/pea-15-null mice exhibited a twofold increased activation of PKC-zeta by glucose; increased abundance of the Sur1, Kir6.2, and Foxa2 mRNAs; and enhanced glucose effect on insulin secretion. In conclusion, PED/PEA-15 is an endogenous regulator of glucose-induced insulin secretion, which restrains potassium channel expression in pancreatic beta-cells. Overexpression of PED/PEA-15 dysregulates beta-cell function and is sufficient to impair glucose tolerance in mice.

  17. A high fructose diet impairs spatial memory in male rats.

    PubMed

    Ross, A P; Bartness, T J; Mielke, J G; Parent, M B

    2009-10-01

    Over the past three decades there has been a substantial increase in the amount of fructose consumed by North Americans. Recent evidence from rodents indicates that hippocampal insulin signaling facilitates memory and excessive fructose consumption produces hippocampal insulin resistance. Based on this evidence, the present study tested the hypothesis that a high fructose diet would impair hippocampal-dependent memory. Adult male Sprague-Dawley rats (postnatal day 61) were fed either a control (0% fructose) or high fructose diet (60% of calories). Food intake and body mass were measured regularly. After 19 weeks, the rats were given 3 days of training (8 trials/day) in a spatial version of the water maze task, and retention performance was probed 48 h later. The high fructose diet did not affect acquisition of the task, but did impair performance on the retention test. Specifically, rats fed a high fructose diet displayed significantly longer latencies to reach the area where the platform had been located, made significantly fewer approaches to that area, and spent significantly less time in the target quadrant than did control diet rats. There was no difference in swim speed between the two groups. The retention deficits correlated significantly with fructose-induced elevations of plasma triglyceride concentrations. Consequently, the impaired spatial water maze retention performance seen with the high fructose diet may have been attributable, at least in part, to fructose-induced increases in plasma triglycerides.

  18. Ethanol extract of Moringa oliefera prevents in vitro glucose induced cataract on isolated goat eye lens

    PubMed Central

    Kurmi, Raghvendra; Ganeshpurkar, Aditya; Bansal, Divya; Agnihotri, Abhishek; Dubey, Nazneen

    2014-01-01

    Aim of Study: The aim of current work was to evaluate in vitro anticataract potential of Moringa oliefera extract. Materials and Methods: Goat eye lenses were divided into 4 groups; Group served as control, Group II as toxic control, Group III and Group IV were incubated in extract (250 μg/ml and 500 μg/ml of extract of M. oliefera) Group II, III and IV were incubated in 55 mM glucose in artificial aqueous humor to induce lens opacification. Estimation of total, water soluble protein, catalase, glutathione and malondialdehyde along with photographic evaluation of lens was done. Results: Group II (toxic control) lenses showed high amount of MDA (Malondialdehyde), soluble, insoluble protein, decreased catalase and glutathione levels, while lenses treated with Moringa oliefera extract (Group III and Group IV) showed significant (* P < 0.05) reduction in MDA and increased level of catalase, glutathione, total and soluble protein. Conclusion: Results of present findings suggest protective effect of Moringa oliefera in prevention of in vitro glucose induced cataract. PMID:24008789

  19. High body mass index is associated with impaired cognitive control.

    PubMed

    Sellaro, Roberta; Colzato, Lorenza S

    2017-06-01

    The prevalence of weight problems is increasing worldwide. There is growing evidence that high body mass index (BMI) is associated with frontal lobe dysfunction and cognitive deficits concerning mental flexibility and inhibitory control efficiency. The present study aims at replicating and extending these observations. We compared cognitive control performance of normal weight (BMI < 25) and overweight (BMI ≥ 25) university students on a task tapping either inhibitory control (Experiment 1) or interference control (Experiment 2). Experiment 1 replicated previous findings that found less efficient inhibitory control in overweight individuals. Experiment 2 complemented these findings by showing that cognitive control impairments associated with high BMI also extend to the ability to resolve stimulus-induced response conflict and to engage in conflict-driven control adaptation. The present results are consistent with and extend previous literature showing that high BMI in young, otherwise healthy individuals is associated with less efficient cognitive control functioning.

  20. Snf1-Dependent Transcription Confers Glucose-Induced Decay upon the mRNA Product

    PubMed Central

    Braun, Katherine A.; Dombek, Kenneth M.

    2015-01-01

    In the yeast Saccharomyces cerevisiae, the switch from respiratory metabolism to fermentation causes rapid decay of transcripts encoding proteins uniquely required for aerobic metabolism. Snf1, the yeast ortholog of AMP-activated protein kinase, has been implicated in this process because inhibiting Snf1 mimics the addition of glucose. In this study, we show that the SNF1-dependent ADH2 promoter, or just the major transcription factor binding site, is sufficient to confer glucose-induced mRNA decay upon heterologous transcripts. SNF1-independent expression from the ADH2 promoter prevented glucose-induced mRNA decay without altering the start site of transcription. SNF1-dependent transcripts are enriched for the binding motif of the RNA binding protein Vts1, an important mediator of mRNA decay and mRNA repression whose expression is correlated with decreased abundance of SNF1-dependent transcripts during the yeast metabolic cycle. However, deletion of VTS1 did not slow the rate of glucose-induced mRNA decay. ADH2 mRNA rapidly dissociated from polysomes after glucose repletion, and sequences bound by RNA binding proteins were enriched in the transcripts from repressed cells. Inhibiting the protein kinase A pathway did not affect glucose-induced decay of ADH2 mRNA. Our results suggest that Snf1 may influence mRNA stability by altering the recruitment activity of the transcription factor Adr1. PMID:26667037

  1. Succinate is a preferential metabolic stimulus-coupling signal for glucose-induced proinsulin biosynthesis translation.

    PubMed

    Alarcon, Cristina; Wicksteed, Barton; Prentki, Marc; Corkey, Barbara E; Rhodes, Christopher J

    2002-08-01

    The secondary signals emanating from increased glucose metabolism, which lead to specific increases in proinsulin biosynthesis translation, remain elusive. It is known that signals for glucose-stimulated insulin secretion and proinsulin biosynthesis diverge downstream of glycolysis. Consequently, the mitochondrial products ATP, Krebs cycle intermediates, glutamate, and acetoacetate were investigated as candidate stimulus-coupling signals specific for glucose-induced proinsulin biosynthesis in rat islets. Decreasing ATP levels by oxidative phosphorylation inhibitors showed comparable effects on proinsulin biosynthesis and total protein synthesis. Although it is a cofactor, ATP is unlikely to be a metabolic stimulus-coupling signal specific for glucose-induced proinsulin biosynthesis. Neither glutamic acid methyl ester nor acetoacetic acid methyl ester showed a specific effect on glucose-stimulated proinsulin biosynthesis. Interestingly, among Krebs cycle intermediates, only succinic acid monomethyl ester specifically stimulated proinsulin biosynthesis. Malonic acid methyl ester, an inhibitor of succinate dehydrogenase, also specifically increased glucose-induced proinsulin biosynthesis without affecting islet ATP levels or insulin secretion. Glucose caused a 40% increase in islet intracellular succinate levels, but malonic acid methyl ester showed no further effect, probably due to efficient conversion of succinate to succinyl-CoA. In this regard, a GTP-dependent succinyl-CoA synthetase activity was found in cytosolic fractions of pancreatic islets. Thus, succinate and/or succinyl-CoA appear to be preferential metabolic stimulus-coupling factors for glucose-induced proinsulin biosynthesis translation.

  2. Acrolein impairs the cholesterol transport functions of high density lipoproteins.

    PubMed

    Chadwick, Alexandra C; Holme, Rebecca L; Chen, Yiliang; Thomas, Michael J; Sorci-Thomas, Mary G; Silverstein, Roy L; Pritchard, Kirkwood A; Sahoo, Daisy

    2015-01-01

    High density lipoproteins (HDL) are considered athero-protective, primarily due to their role in reverse cholesterol transport, where they transport cholesterol from peripheral tissues to the liver for excretion. The current study was designed to determine the impact of HDL modification by acrolein, a highly reactive aldehyde found in high abundance in cigarette smoke, on the cholesterol transport functions of HDL. HDL was chemically-modified with acrolein and immunoblot and mass spectrometry analyses confirmed apolipoprotein crosslinking, as well as acrolein adducts on apolipoproteins A-I and A-II. The ability of acrolein-modified HDL (acro-HDL) to serve as an acceptor of free cholesterol (FC) from COS-7 cells transiently expressing SR-BI was significantly decreased. Further, in contrast to native HDL, acro-HDL promotes higher neutral lipid accumulation in murine macrophages as judged by Oil Red O staining. The ability of acro-HDL to mediate efficient selective uptake of HDL-cholesteryl esters (CE) into SR-BI-expressing cells was reduced compared to native HDL. Together, the findings from our studies suggest that acrolein modification of HDL produces a dysfunctional particle that may ultimately promote atherogenesis by impairing functions that are critical in the reverse cholesterol transport pathway.

  3. [High frequency of dyslipidemia and impaired fasting glycemia in a high altitude Peruvian population].

    PubMed

    Málaga, Germán; Zevallos-Palacios, Claudia; Lazo, María de los Ángeles; Huayanay, Carlos

    2010-01-01

    We performed a cross sectional study in Lari (3600 m), a highland rural community from Arequipa, Peru. We evaluated a body mass index (BMI), glycemia and lipid profile in 74 over 18 year persons. The mean age was 51.7 ± 18.0 years, 62.2% were women, mean of BMI was 25.6 ± 3.7. Prevalence of hypercholesterolemia was 40.6%, "low HDL" in 77% of the population (93.5% in women vs 50% in men, p <0.001) and elevated level of LDL was 71.7%. The prevalence of impaired fasting glycemia was 27%. In conclusion, we found high prevalence of impaired fasting glycemia, hypercholesterolemia and especially "low HDL" in high altitude rural natives. These findings must be considered to realize interventions in high altitude populations to avoid future cardiovascular complications.

  4. Consumption of a glucose diet enhances the sensitivity of pancreatic islets from adrenalectomized genetically obese (ob/ob) mice to glucose-induced insulin secretion.

    PubMed

    Mistry, A M; Chen, N G; Lee, Y S; Romsos, D R

    1995-03-01

    Consumption of a glucose diet for 4 d markedly elevates plasma insulin concentrations in adrenalectomized ob/ob mice. The present study examined regulation of insulin secretion from perifused pancreatic islets of female adrenalectomized genetically obese (ob/ob) and lean mice fed a glucose diet for 4 d. These mice were fed a high carbohydrate commercial diet for 21 d, or the high carbohydrate commercial diet for 17 d and a purified high glucose diet for the last 4 d of the 21-d feeding period. Adrenalectomy equalized plasma insulin concentrations, pancreatic islet size, rates of insulin secretion in response to 20 mmol/L glucose and insulin mRNA relative abundance in ob/ob and lean mice fed the commercial diet, but the threshold for glucose-induced insulin secretion determined by a linear glucose gradient remained lower in islets from adrenalectomized ob/ob mice than in those from lean mice (3.8 +/- 0.1 vs. 4.9 +/- 0.2 mmol/L glucose), and addition of acetylcholine to the perifusate lowered the threshold to only 2.0 +/- 0.1 mmol/L glucose in islets from ob/ob mice vs. 3.3 +/- 0.1 mmol/L glucose in lean mice. Switching from the commercial diet to the glucose diet for 4 d increased plasma insulin concentrations -10-fold in islets from adrenalectomized ob/ob mice without affecting islet size, 20 mmol/L glucose-induced insulin secretion or insulin mRNA abundance. Consumption of the glucose diet did, however, markedly lower the threshold for glucose-induced insulin secretion in islets from adrenalectomized ob/ob mice to approximate the abnormally low glucose thresholds in intact ob/ob mice.(ABSTRACT TRUNCATED AT 250 WORDS)

  5. Statins suppress glucose-induced plasminogen activator inhibitor-1 expression by regulating RhoA and nuclear factor-κB activities in cardiac microvascular endothelial cells.

    PubMed

    Ni, Xiao-Qing; Zhu, Jian-Hua; Yao, Ning-Hua; Qian, Juan; Yang, Xiang-Jun

    2013-01-01

    The aim of this study was to investigate the possible proinflammatory signaling pathways involved in statin inhibition of glucose-induced plasminogen activator inhibitor-1 (PAI-1) expression in cardiac microvascular endothelial cells (CMECs). Primary rat CMECs were grown in the presence of 5.7 or 23 mmol/L glucose. PAI-1 mRNA and protein expression levels were measured by realtime polymerase chain reaction, Western blotting and enzyme-linked immunosorbent assay, respectively. A pull-down assay was performed to determine RhoA activity. IκBα protein expression was measured by Western blotting, nuclear factor (NF)-κB activation was detected by electrophoretic mobility shift assay and its transcription activity was determined by a dual luciferase reporter gene assay. PAI-1 mRNA and protein expression levels were both increased with high glucose concentrations, but they were significantly suppressed by simvastatin and atorvastatin treatment (P < 0.01) and the effects were reversed by mevalonate (100 μmol/L) and geranylgeranyl pyrophosphate (10 μmol/L) but not farnesyl pyrophosphate (10 μmol/L). Such effects were similar to those of a RhoA inhibitor, C3 exoenzyme (5 μg/mL), inhibitors of RhoA kinase (ROCK), Y-27632 (10 μmol/L) and hydroxyfasudil (10 μmol/L) and an NF-κB inhibitor, BAY 11-7082 (5 μmol/L). High glucose-induced RhoA and NF-κB activations in CMECs were both significantly inhibited by statins (P < 0.01). Simvastatin and atorvastatin equally suppress high glucose-induced PAI-1 expression. These effects of statins may occur partly by regulating the RhoA/ROCK-NF-κB pathway. The multifunctional roles of statins may be particularly beneficial for patients with metabolic syndrome.

  6. Adiponectin increases glucose-induced insulin secretion through the activation of lipid oxidation.

    PubMed

    Patané, G; Caporarello, N; Marchetti, P; Parrino, C; Sudano, D; Marselli, L; Vigneri, R; Frittitta, L

    2013-12-01

    The expression of adiponectin receptors has been demonstrated in human and rat pancreatic beta cells, where globular (g) adiponectin rescues rat beta cells from cytokine and fatty acid-induced apoptosis. The aim of our study was to evaluate whether adiponectin has a direct effect on insulin secretion and the metabolic pathways involved. Purified human pancreatic islets and rat beta cells (INS-1E) were exposed (1 h) to g-adiponectin, and glucose-induced insulin secretion was measured. A significant increase in glucose-induced insulin secretion was observed in the presence of g-adiponectin (1 nmol/l) with respect to control cells in both human pancreatic islets (n = 5, p < 0.05) and INS-1E cells (n = 5, p < 0.001). The effect of globular adiponectin on insulin secretion was independent of AMP-dependent protein kinase (AMPK) activation or glucose oxidation. In contrast, g-adiponectin significantly increased oleate oxidation (n = 5, p < 0.05), and the effect of g-adiponectin (p < 0.001) on insulin secretion by INS-1E was significantly reduced in the presence of etomoxir (1 μmol/l), an inhibitor of fatty acid beta oxidation. g-Adiponectin potentiates glucose-induced insulin secretion in both human pancreatic islets and rat beta cells via an AMPK independent pathway. Increased fatty acid oxidation rather than augmented glucose oxidation is the mechanism responsible. Overall, our data indicate that, in addition to its anti-apoptotic action, g-adiponectin has another direct effect on beta cells by potentiating insulin secretion. Adiponectin, therefore, in addition to its well-known effect on insulin sensitivity, has important effects at the pancreatic level.

  7. Uncoupling protein 2 negatively regulates glucose-induced glucagon-like peptide 1 secretion.

    PubMed

    Zhang, Hongjie; Li, Jing; Liang, Xiangying; Luo, Yun; Zen, Ke; Zhang, Chen-Yu

    2012-04-01

    It is known that endogenous levels of the incretin hormone glucagon-like peptide 1 (GLP1) can be enhanced by various secretagogues, but the mechanism underlying GLP1 secretion is still not fully understood. We assessed the possible effect of uncoupling protein 2 (UCP2) on GLP1 secretion in mouse intestinal tract and NCI-H716 cells, a well-characterized human enteroendocrine L cell model. Localization of UCP2 and GLP1 in the gastrointestinal tract was assessed by immunofluorescence staining. Ucp2 mRNA levels in gut were analyzed by quantitative RT-PCR. Human NCI-H716 cells were transiently transfected with siRNAs targeting UCP2. The plasma and ileum tissue levels of GLP1 (7-36) amide were measured using an ELISA kit. UCP2 was primarily expressed in the mucosal layer and colocalized with GLP1 in gastrointestinal mucosa. L cells secreting GLP1 also expressed UCP2. After glucose administration, UCP2-deficient mice showed increased glucose-induced GLP1 secretion compared with wild-type littermates. GLP1 secretion increased after NCI-H716 cells were transfected with siRNAs targeting UCP2. UCP2 was markedly upregulated in ileum tissue from ob/ob mice, and GLP1 secretion decreased compared with normal mice. Furthermore, GLP1 secretion increased after administration of genipin by oral gavage. Taken together, these results reveal an inhibitory role of UCP2 in glucose-induced GLP1 secretion.

  8. Personal-Space Preference among Male Elementary and High School Students with and without Visual Impairments.

    ERIC Educational Resources Information Center

    Eaton, Susan B.; Fuchs, Lynn S.; Snook-Hill, Mary-Maureen

    1998-01-01

    Compared elementary and high school boys who were either severely visually impaired, sighted but blindfolded, and sighted with no visual restrictions. Investigated personal-space preference (PSP) and found the visually impaired and blindfolded boys chose a smaller initial PSP, but all three groups were similar on approach PSP and stop-distance…

  9. High-calorie food-cues impair working memory performance in high and low food cravers.

    PubMed

    Meule, Adrian; Skirde, Ann Kathrin; Freund, Rebecca; Vögele, Claus; Kübler, Andrea

    2012-10-01

    The experience of food craving can lead to cognitive impairments. Experimentally induced chocolate craving exhausts cognitive resources and, therefore, impacts working memory, particularly in trait chocolate cravers. In the current study, we investigated the effects of exposure to food-cues on working memory task performance in a group with frequent and intense (high cravers, n=28) and less pronounced food cravings (low cravers, n=28). Participants performed an n-back task that contained either pictures of high-calorie sweets, high-calorie savory foods, or neutral objects. Current subjective food craving was assessed before and after the task. All participants showed slower reaction times and made more omission errors in response to food-cues, particularly savory foods. There were no differences in task performance between groups. State cravings did not differ between groups before the task, but increased more in high cravers compared to low cravers during the task. Results support findings about food cravings impairing visuo-spatial working memory performance independent of trait cravings. They further show that this influence is not restricted to chocolate, but also applies to high-calorie savory foods. Limiting working memory capacity may be especially crucial in persons who are more prone to high-calorie food-cues and experience such cravings habitually.

  10. Theophylline prevents the inhibitory effect of prostaglandin E2 on glucose-induced insulin secretion in man.

    PubMed

    Giugliano, D; Cozzolino, D; Salvatore, T; Giunta, R; Torella, R

    1988-06-01

    This study was undertaken to assess the mechanism by which prostaglandins of the E series inhibit glucose-induced insulin secretion in man. Acute insulin response (mean change 3-10 min) to iv glucose (0.33 g/kg) was decreased by 40% during the infusion of prostaglandin E2 (10 micrograms/min) and glucose disappearance rates were reduced (P less than 0.05). Insulin response to arginine (5 g iv) and tolbutamide (1 g iv) were not affected by the same rate of prostaglandin E2 infusion. The inhibitory effect of prostaglandin E2 on glucose-induced insulin secretion was prevented by theophylline (100 mg as a loading dose followed by a 5 mg/min infusion), a drug that increases the intracellular cAMP concentrations by inhibiting phosphodiesterase activity. Our data suggest the involvement of the adenylate cyclase system in the inhibitory action of prostaglandin E2 on glucose-induced insulin secretion in man.

  11. Augmented glucose-induced insulin release in mice lacking G(o2), but not G(o1) or G(i) proteins.

    PubMed

    Wang, Ying; Park, Sangeun; Bajpayee, Neil S; Nagaoka, Yoshiko; Boulay, Guylain; Birnbaumer, Lutz; Jiang, Meisheng

    2011-01-25

    Insulin secretion by pancreatic β cells is a complex and highly regulated process. Disruption of this process can lead to diabetes mellitus. One of the various pathways involved in the regulation of insulin secretion is the activation of heterotrimeric G proteins. Bordetella pertussis toxin (PTX) promotes insulin secretion, suggesting the involvement of one or more of three G(i) and/or two G(o) proteins as suppressors of insulin secretion from β cells. However, neither the mechanism of this inhibitory modulation of insulin secretion nor the identity of the G(i/o) proteins involved has been elucidated. Here we show that one of the two splice variants of G(o), G(o2), is a key player in the control of glucose-induced insulin secretion by β cells. Mice lacking G(o2)α, but not those lacking α subunits of either G(o1) or any G(i) proteins, handle glucose loads more efficiently than wild-type (WT) mice, and do so by increased glucose-induced insulin secretion. We thus provide unique genetic evidence that the G(o2) protein is a transducer in an inhibitory pathway that prevents damaging oversecretion of insulin.

  12. Cognitive Impairment Following High Fat Diet Consumption is Associated with Brain Inflammation

    PubMed Central

    Pistell, Paul J.; Morrison, Christopher D.; Gupta, Sunita; Knight, Alecia G.; Keller, Jeffrey N.; Ingram, Donald K.; Bruce-Keller, Annadora J.

    2009-01-01

    C57Bl/6 mice were administered a high fat, Western diet (WD, 41% fat) or a very high fat lard diet (HFL, 60% fat), and evaluated for cognitive ability using the Stone T-maze and for biochemical markers of brain inflammation. WD consumption resulted in significantly increased body weight and astrocyte reactivity, but not impaired cognition, microglial reactivity, or heightened cytokine levels. HFL increased body weight, and impaired cognition, increased brain inflammation, and decreased BDNF. Collectively, these data suggest that while different diet formulations can increase body weight, the ability of high fat diets to disrupt cognition is linked to brain inflammation. PMID:20004026

  13. Measuring ADHD and ODD Symptoms and Impairment Using High School Teachers' Ratings

    ERIC Educational Resources Information Center

    Evans, Steven W.; Brady, Christine E.; Harrison, Judith R.; Bunford, Nora; Kern, Lee; State, Talida; Andrews, Christiana

    2013-01-01

    We analyzed the results of high school teachers' ratings of symptoms of attention deficit hyperactivity disorder (ADHD) and oppositional defiant disorder, as well as school-related impairment of 875 adolescents. One hundred forty-three teachers at 19 high schools across 4 states each rated 6 students from their first-period classes according to…

  14. Overexpression of SIRT1 in Rat Skeletal Muscle Does Not Alter Glucose Induced Insulin Resistance

    PubMed Central

    Brandon, Amanda E.; Tid-Ang, Jennifer; Wright, Lauren E.; Stuart, Ella; Suryana, Eurwin; Bentley, Nicholas; Turner, Nigel; Cooney, Gregory J.; Ruderman, Neil B.; Kraegen, Edward W.

    2015-01-01

    SIRT1 is a NAD+-dependent deacetylase thought to regulate cellular metabolic pathways in response to alterations in nutrient flux. In the current study we investigated whether acute changes in SIRT1 expression affect markers of muscle mitochondrial content and also determined whether SIRT1 influenced muscle insulin resistance induced by acute glucose oversupply. In male Wistar rats either SIRT1 or a deacetylase inactive mutant form (H363Y) was electroprated into the tibialis cranialis (TC) muscle. The other leg was electroporated with an empty control vector. One week later, glucose was infused and hyperglycaemia was maintained at ~11mM. After 5 hours, 11mM glucose induced significant insulin resistance in skeletal muscle. Interestingly, overexpression of either SIRT1 or SIRT1 (H363Y) for 1 week did not change markers of mitochondrial content or function. SIRT1 or SIRT1 (H363Y) overexpression had no effect on the reduction in glucose uptake and glycogen synthesis in muscle in response to hyperglycemia. Therefore we conclude that acute increases in SIRT1 protein have little impact on mitochondrial content and that overexpressing SIRT1 does not prevent the development of insulin resistance during hyperglycaemia. PMID:25798922

  15. Nigella sativa seed extracts enhance glucose-induced insulin release from rat-isolated Langerhans islets.

    PubMed

    Rchid, Halima; Chevassus, Hugues; Nmila, Rachid; Guiral, Carine; Petit, Pierre; Chokaïri, Mustapha; Sauvaire, Yves

    2004-10-01

    Nigella sativa L. 'Black cumin' (Ranunculaceae) is one of the plants commonly used in Moroccan folk medicine for treatment of various ailments including diabetes mellitus. The present study was undertaken to investigate the effect of different N. sativa seed extracts on insulin secretion. Different fractions of the seed were prepared: the defatted fraction (HR II), which was divided into two subfractions: the first (HR III) containing acidic and neutral compounds and the second (HR IV) containing basic compounds. The insulin secretory effects of these extracts were evaluated individually at different concentrations (0.01, 0.1, 1 and 5 mg/mL), in vitro in isolated rat pancreatic islets in the presence of 8.3 mmol/L glucose. The results show that addition of the defatted whole extract or of the basic subfraction of the seed in the incubation medium significantly increased glucose-induced insulin release from the islets. In the case of the acidic and neutral subfraction, the stimulatory effect was observed only for the higher concentration (5 mg/mL). However, a clear concentration-dependent increase in insulin release from isolated pancreatic islets was observed for the basic subfraction. Our data show that the antidiabetic properties of N. sativa seeds may be, at least partly, mediated by stimulated insulin release, and that the basic subfraction largely contributes to this stimulatory effect. Further phytochemical studies are underway in order to isolate the pharmacological compound(s) responsible for the insulinotropic effect of N. sativa seeds.

  16. Caffeine prevents cognitive impairment induced by chronic psychosocial stress and/or high fat-high carbohydrate diet.

    PubMed

    Alzoubi, K H; Abdul-Razzak, K K; Khabour, O F; Al-Tuweiq, G M; Alzubi, M A; Alkadhi, K A

    2013-01-15

    Caffeine alleviates cognitive impairment associated with a variety of health conditions. In this study, we examined the effect of caffeine treatment on chronic stress- and/or high fat-high carbohydrate Western diet (WD)-induced impairment of learning and memory in rats. Chronic psychosocial stress, WD and caffeine (0.3 g/L in drinking water) were simultaneously administered for 3 months to adult male Wistar rats. At the conclusion of the 3 months, and while the previous treatments continued, rats were tested in the radial arm water maze (RAWM) for learning, short-term and long-term memory. This procedure was applied on a daily basis to all animals for 5 consecutive days or until the animal reaches days to criterion (DTC) in the 12th learning trial and memory tests. DTC is the number of days that the animal takes to make zero error in two consecutive days. Chronic stress and/or WD groups caused impaired learning, which was prevented by chronic caffeine administration. In the memory tests, chronic caffeine administration also prevented memory impairment during chronic stress conditions and/or WD. Furthermore, DTC value for caffeine treated stress, WD, and stress/WD groups indicated that caffeine normalizes memory impairment in these groups. These results showed that chronic caffeine administration prevented stress and/or WD-induced impairment of spatial learning and memory.

  17. A catechin-enriched green tea extract prevents glucose-induced survival reduction in Caenorhabditis elegans through sir-2.1 and uba-1 dependent hormesis.

    PubMed

    Deusing, Dorothé Jenni; Winter, Sarah; Kler, Adolf; Kriesl, Erwin; Bonnländer, Bernd; Wenzel, Uwe; Fitzenberger, Elena

    2015-04-01

    Hyperglycemia is a hallmark of diabetes mellitus which leads to the onset of complications in the long term. Green tea through its high content of polyphenolic catechins, on the other hand, is suggested to prevent or at least delay such detrimental complications. In the present study we fed the nematode Caenorhabditis elegans on a liquid medium supplemented with 10mM glucose in the absence or presence of a catechin-enriched green tea extract (CEGTE). After exposure of young adults for 48h survival was subsequently measured under heat stress at 37°C. Whereas CEGTE at 0.01% did not affect the survival of wild type nematodes, it completely reversed the glucose-induced survival reduction. Those effects were not achieved through the monomeric catechins included in CEGTE. RNA interference (RNAi) for sir-2.1 not only prevented the survival extension by CEGTE under simultaneous glucose exposure but also caused a further reduction of survival. Likewise, the knockdown of uba-1, encoding the only E1-ubiquitin-activating enzyme in C. elegans, proved that UBA-1 is essential for the survival extension by CEGTE and that its loss of function changes CEGTE from a survival extending into a survival reducing extract. Stimulation of the proteasome by CEGTE was finally proven through measurements of the proteolytic cleavage of a fluorogenic peptide substrate. To conclude, our studies provide evidence that CEGTE reverses glucose-induced damage in C. elegans through activation of adaptive responses mediated by SIR-2.1 and proteasomal degradation. The hormetic mode of action is revealed by a reduction of survival once the adaptive processes were blocked.

  18. An inhibitor of thrombin activated fibrinolysis inhibitor (TAFI) can reduce extracellular matrix accumulation in an in vitro model of glucose induced ECM expansion.

    PubMed

    Atkinson, J M; Pullen, N; Johnson, T S

    2013-06-24

    Chronic kidney disease (CKD) is characterised by the pathological accumulation of extracellular matrix (ECM) proteins leading to progressive kidney scarring via glomerular and tubular basement membrane expansion. Increased ECM synthesis and deposition, coupled with reduced ECM breakdown contribute to the elevated ECM level in CKD. Previous pre-clinical studies have demonstrated that increased plasmin activity has a beneficial effect in the protein overload model of CKD. As plasmin activation is downregulated by the action of the thrombin activated fibrinolytic inhibitor (TAFI), we tested the hypothesis that inhibition of TAFI might increase plasmin activity and reduce ECM accumulation in an in vitro model of glucose induced ECM expansion. Treatment of NRK52E tubular epithelial cells with increasing concentrations of glucose resulted in a 40% increase in TAFI activity, a 38% reduction in plasmin activity and a subsequent increase in ECM accumulation. In this model system, application of the previously reported TAFI inhibitor UK-396082 [(2S)-5-amino-2-[(1-n-propyl-1H-imidazol-4-yl)methyl]pentanoic acid] caused a reduction in TAFI activity, increased plasmin activity and induced a parallel decrease in ECM levels. In contrast, RNAi knockdown of plasmin resulted in an increase in ECM levels. The data presented here indicate that high glucose induces TAFI activity, inhibiting plasmin activation which results in elevated ECM levels in tubular epithelial cells. The results support the hypothesis that UK-396082 is able to reduce TAFI activity, normalising plasmin activity and preventing excess ECM accumulation suggesting that TAFI inhibition may have potential as an anti-scarring strategy in CKD.

  19. Brief Report: Biochemical Correlates of Clinical Impairment in High Functioning Autism and Asperger's Disorder

    ERIC Educational Resources Information Center

    Kleinhans, Natalia M.; Richards, Todd; Weaver, Kurt E.; Liang, Olivia; Dawson, Geraldine; Aylward, Elizabeth

    2009-01-01

    Amygdala dysfunction has been proposed as a critical contributor to social impairment in autism spectrum disorders (ASD). The current study investigated biochemical abnormalities in the amygdala in 20 high functioning adults with autistic disorder or Asperger's disorder and 19 typically developing adults matched on age and IQ. Magnetic resonance…

  20. Social Studies: A Resource Guide for Hearing-Impaired High School Students.

    ERIC Educational Resources Information Center

    Jaggers, Robert A.; Jaggers, Barbara A.

    The guide was written to give secondary level hearing impaired students exposure to real life problems from a social studies perspective. Units are outlined for the three levels of the high school years and provide an overview, information on vocabulary, target competencies, suggested activities, sources, and a list of objectives. The units are…

  1. Phenylethanoid glycosides of Pedicularis muscicola Maxim ameliorate high altitude-induced memory impairment.

    PubMed

    Zhou, Baozhu; Li, Maoxing; Cao, Xinyuan; Zhang, Quanlong; Liu, Yantong; Ma, Qiang; Qiu, Yan; Luan, Fei; Wang, Xianmin

    2016-04-01

    Exposure to hypobaric hypoxia causes oxidative stress, neuronal degeneration and apoptosis that leads to memory impairment. Though oxidative stress contributes to neuronal degeneration and apoptosis in hypobaric hypoxia, the ability for phenylethanoid glycosides of Pedicularis muscicola Maxim (PhGs) to reverse high altitude memory impairment has not been studied. Rats were supplemented with PhGs orally for a week. After the fourth day of drug administration, rats were exposed to a 7500 m altitude simulation in a specially designed animal decompression chamber for 3 days. Spatial memory was assessed by the 8-arm radial maze test before and after exposure to hypobaric hypoxia. Histological assessment of neuronal degeneration was performed by hematoxylin-eosin (HE) staining. Changes in oxidative stress markers and changes in the expression of the apoptotic marker, caspase-3, were assessed in the hippocampus. Our results demonstrated that after exposure to hypobaric hypoxia, PhGs ameliorated high altitude memory impairment, as shown by the decreased values obtained for reference memory error (RME), working memory error (WME), and total error (TE). Meanwhile, administration of PhGs decreased hippocampal reactive oxygen species levels and consequent lipid peroxidation by elevating reduced glutathione levels and enhancing the free radical scavenging enzyme system. There was also a decrease in the number of pyknotic neurons and a reduction in caspase-3 expression in the hippocampus. These findings suggest that PhGs may be used therapeutically to ameliorate high altitude memory impairment.

  2. Vitamin E prevents high-fat high-carbohydrates diet-induced memory impairment: the role of oxidative stress.

    PubMed

    Alzoubi, Karem H; Khabour, Omar F; Salah, Heba A; Hasan, Zuheir

    2013-07-02

    Memory and learning are impaired by imbalanced diet consumption. High-fat high-carbohydrate diet (HFCD) induces oxidative stress, which results in neuronal damage and interference with synaptic transmission; hence, a decline in cognitive function. Vitamin E is a fat soluble antioxidant that is believed to have positive effects on learning and memory. In this study, we tested the hypothesis that chronic administration of vitamin E prevents learning and memory impairment induced by HFCD. In addition, possible molecular targets for HFCD, and vitamin E that lead to cognitive effects were examined. Vitamin E and/or HFCD were concurrently administered to animals for 6 weeks. Thereafter, behavioral studies were conducted to test the spatial learning and memory using radial arm water maze (RAWM). Additionally, brain derived neurotrophic factor (BDNF) level and antioxidant markers were assessed in the hippocampus. The results of this project revealed that HFCD impairs both short-term and long-term memories (p<0.05). The administration of vitamin E prevented the memory impairment induced by HFCD consumption (p<0.05). The consumption of HFCD reduced activities of hippocampal superoxide dismutase (SOD) and catalase (p<0.05); whereas the levels of thiobarbituric acid reactive substances (TBARS) and oxidized glutathione (GSSG) were elevated (p<0.05). The administration of vitamin E normalized the effect of HFCD on the oxidative stress markers. None of the treatments induced changes in the levels of BDNF or glutathione peroxidase (GPx). In conclusion, HFCD induces memory impairment, and the administration of vitamin E prevented this impairment probably through normalizing antioxidant mechanisms in the hippocampus.

  3. Interpreting the Meaning of the Terms "Certified" and "Highly Qualified" for Teachers of Students with Visual Impairments

    ERIC Educational Resources Information Center

    Pogrund, Rona L.; Wibbenmeyer, Kristina A.

    2008-01-01

    This article investigates the value of the term "highly qualified" as it relates to teachers of students with visual impairments. Routes to certification of teachers of students with visual impairments in the United States are not uniform and may not always reflect high-quality teacher preparation. A rationale for more stringent national…

  4. Mathematical impairment associated with high-contrast abnormalities in change detection and magnocellular visual evoked response.

    PubMed

    Jastrzebski, Nicola R; Crewther, Sheila G; Crewther, David P

    2015-10-01

    The cause of developmental dyscalculia, a specific deficit in acquisition of arithmetic skills, particularly of enumeration, has never been investigated with respect to the patency of the visual magnocellular system. Here, the question of dysfunction of the afferent magnocellular cortical input and its dorsal stream projections was tested directly using nonlinear analysis of the visual evoked potential (VEP) and through the psychophysical ability to rapidly detect visual change. A group of young adults with self-reported deficiencies of arithmetical ability, showed marked impairment in magnitude estimation and enumeration performance-though not in lexical decision reaction times when compared with an arithmetically capable group controlled for age and handedness. Multifocal nonlinear VEPs were recorded at low (24 %) and high (96 %) contrast. First- and second-order VEP kernels were comparable between groups at low contrast, but not at high contrast. The mathematically impaired group showed an abnormal lack of contrast saturation in the shortest latency first-order peak (N60) and a delayed P100 positivity in the first slice of the second-order kernel. Both features have previously been argued to be physiological markers of magnocellular function. Mathematically impaired participants also performed worse on a gap paradigm change detection for digit task showing increased reaction times for high-contrast stimuli but not for low-contrast stimuli compared with controls. The VEP results give direct evidence of abnormality in the occipital processing of magnocellular information in those with mathematical impairment. The anomalous high visual contrast physiological and psychophysical performance suggests an abnormality in the inhibitory processes that normally result in saturation of contrast gain in the magnocellular system.

  5. Self-awareness of functional impairment in individuals at clinical high-risk for psychosis

    PubMed Central

    Olvet, Doreen M.; Carrión, Ricardo E.; Auther, Andrea M.; Cornblatt, Barbara A.

    2013-01-01

    Aims A major public health concern associated with schizophrenia is the long-term disability that involves an inability to function independently in the community. An individual’s self-awareness of functional impairment may be a significant factor contributing to long-term disability. In fact, subjective interpretation of one’s illness impacts treatment participation and adherence, and is linked to poor outcomes. However, it remains unclear how illness-related functional impairment is perceived by individuals prior to the onset of psychosis. This study aims to examine the relationship between clinician-based and self-report assessments of functioning, as well as the contribution of clinical symptoms to this relationship in individuals at clinical high-risk for psychosis. Methods The Sheehan Disability Scale, a self-rated instrument, was used to measure disruption in daily functioning in social and role functioning due to symptoms in a sample of 73 treatment-seeking patients at clinical high-risk for psychosis and 50 healthy controls. Results Relative to healthy controls, clinical high-risk patients self-reported significant disruptions in social and role functioning. In addition, a specific relationship emerged in that clinician-rated measures of functioning and depression were related to disability scores. Conclusions These findings suggest that clinical high-risk patients are significantly disturbed by their illness. Self-reported disruption of daily functioning was associated with clinician-rated functioning and depressive symptoms, further highlighting the impact of functional impairments on the level of distress experienced by patients in the early phases of the illness. Intervention strategies that repair functional impairment before the onset of psychosis may prevent long-term disability. PMID:23968457

  6. Effect of blueberries and insulin on glucose induced neurotoxicity in brain cells in vitro

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Introduction Literature had shown that disruption in glucose metabolism seen in metabolic syndrome maybe responsible for neuronal cell-death. Oxidative stress (OS) and inflammation (INF) triggered by the impaired metabolic process are considered to be the primary factors for the toxic neuronal atmos...

  7. Cognitive Impairment of School Children at High Altitude: The Case for Oxygen Conditioning in Schools.

    PubMed

    West, John B

    2016-09-01

    West, John B. Cognitive impairment of school children at high altitude: the case for oxygen conditioning in schools. High Alt Med Biol. 17:203-207, 2016.-The hypoxia of high altitude frequently affects cognitive function. Recent work has shown that high altitude impairs the neuropsychological function of children of school age when compared with a similar control group of children at low altitude. This implies that the learning process is compromised at high altitude. One option is to bus children down to a lower altitude for schooling, but this is generally impracticable. Recently the new technique of oxygen conditioning has been introduced. The procedure is similar to air conditioning except that instead of altering the temperature of the air, the oxygen concentration is increased, thus raising the PO2 in the inspired air of classrooms. The result is that the children are physiologically at a lower altitude. Just as in very hot or cold climates, it is now unacceptable to have schools that are not air conditioned; in the future the same may apply to schools at high altitude that are not oxygen conditioned.

  8. Contributions of low and high spatial frequency processing to impaired object recognition circuitry in schizophrenia.

    PubMed

    Calderone, Daniel J; Hoptman, Matthew J; Martínez, Antígona; Nair-Collins, Sangeeta; Mauro, Cristina J; Bar, Moshe; Javitt, Daniel C; Butler, Pamela D

    2013-08-01

    Patients with schizophrenia exhibit cognitive and sensory impairment, and object recognition deficits have been linked to sensory deficits. The "frame and fill" model of object recognition posits that low spatial frequency (LSF) information rapidly reaches the prefrontal cortex (PFC) and creates a general shape of an object that feeds back to the ventral temporal cortex to assist object recognition. Visual dysfunction findings in schizophrenia suggest a preferential loss of LSF information. This study used functional magnetic resonance imaging (fMRI) and resting state functional connectivity (RSFC) to investigate the contribution of visual deficits to impaired object "framing" circuitry in schizophrenia. Participants were shown object stimuli that were intact or contained only LSF or high spatial frequency (HSF) information. For controls, fMRI revealed preferential activation to LSF information in precuneus, superior temporal, and medial and dorsolateral PFC areas, whereas patients showed a preference for HSF information or no preference. RSFC revealed a lack of connectivity between early visual areas and PFC for patients. These results demonstrate impaired processing of LSF information during object recognition in schizophrenia, with patients instead displaying increased processing of HSF information. This is consistent with findings of a preference for local over global visual information in schizophrenia.

  9. A specific impairment in cognitive control in individuals with high-functioning autism.

    PubMed

    Barbalat, Guillaume; Leboyer, Marion; Zalla, Tiziana

    2014-11-01

    Although it is largely demonstrated that Autism Spectrum Disorders (ASDs) are characterized by executive dysfunctions, little is known about the fine-grained levels of this impairment. Here, we investigated the hierarchical architecture of control modules in autism using an experimental paradigm based upon a multistage model of executive functions. This model postulates that executive functions are hierarchically organized as a cascade of three different control processes, which are implemented according to information conveyed by sensory signals (sensory control), the immediate perceptual context (contextual control), and the temporal episode in which stimuli occur (episodic control). Sixteen high-functioning adults with autism or Asperger Syndrome (HFA/AS) and sixteen matched comparison participants took part in two distinct visuo-motor association experiments designed to separately vary the demands of sensory and episodic controls (first experiment) and contextual and episodic controls (second experiment). Participants with HFA/AS demonstrated no significant differences in performances with comparison participants when they had to control sensory or contextual information. However, they showed decreased accuracy when having to control information related to episodic signals. Remarkably, performances in episodic control were associated to the autism spectrum quotient in both groups, suggesting that this episodic control impairment might be at the core of ASDs. Those results plead for a specific, rather than generalised, deficit in executive functions in autism. Our study contributes to a better understanding of the impaired cognitive processes that are unique to autism and warrants confirmation using other models of executive functions.

  10. High dose zinc supplementation induces hippocampal zinc deficiency and memory impairment with inhibition of BDNF signaling.

    PubMed

    Yang, Yang; Jing, Xiao-Peng; Zhang, Shou-Peng; Gu, Run-Xia; Tang, Fang-Xu; Wang, Xiu-Lian; Xiong, Yan; Qiu, Mei; Sun, Xu-Ying; Ke, Dan; Wang, Jian-Zhi; Liu, Rong

    2013-01-01

    Zinc ions highly concentrate in hippocampus and play a key role in modulating spatial learning and memory. At a time when dietary fortification and supplementation of zinc have increased the zinc consuming level especially in the youth, the toxicity of zinc overdose on brain function was underestimated. In the present study, weaning ICR mice were given water supplemented with 15 ppm Zn (low dose), 60 ppm Zn (high dose) or normal lab water for 3 months, the behavior and brain zinc homeostasis were tested. Mice fed high dose of zinc showed hippocampus-dependent memory impairment. Unexpectedly, zinc deficiency, but not zinc overload was observed in hippocampus, especially in the mossy fiber-CA3 pyramid synapse. The expression levels of learning and memory related receptors and synaptic proteins such as NMDA-NR2A, NR2B, AMPA-GluR1, PSD-93 and PSD-95 were significantly decreased in hippocampus, with significant loss of dendritic spines. In keeping with these findings, high dose intake of zinc resulted in decreased hippocampal BDNF level and TrkB neurotrophic signaling. At last, increasing the brain zinc level directly by brain zinc injection induced BDNF expression, which was reversed by zinc chelating in vivo. These results indicate that zinc plays an important role in hippocampus-dependent learning and memory and BDNF expression, high dose supplementation of zinc induces specific zinc deficiency in hippocampus, which further impair learning and memory due to decreased availability of synaptic zinc and BDNF deficit.

  11. Pressor recovery after acute stress is impaired in high fructose-fed Lean Zucker rats.

    PubMed

    Thompson, Jennifer A; D'Angelo, Gerard; Mintz, James D; Fulton, David J; Stepp, David W

    2016-06-01

    Insulin resistance is a powerful predictor of cardiovascular disease; however, the mechanistic link remains unclear. This study aims to determine if early cardiovascular changes associated with short-term fructose feeding in the absence of obesity manifest as abnormal blood pressure control. Metabolic dysfunction was induced in Lean Zucker rats by short-term high-fructose feeding. Rats were implanted with telemetry devices for the measurement of mean arterial blood pressure (MAP) and subjected to air jet stress at 5 and 8 weeks after feeding. Additional animals were catheterized under anesthesia for the determination of MAP and blood flow responses in the hind limb and mesenteric vascular beds to intravenous injection of isoproterenol (0.001-0.5 μm), a β-adrenergic agonist. Metabolic dysfunction in high-fructose rats was not accompanied by changes in 24-h MAP Yet, animals fed a high-fructose diet for 8 weeks exhibited a marked impairment in blood pressure recovery after air-jet stress. Dose-dependent decreases in MAP and peripheral blood flow in response to isoproterenol treatment were significantly attenuated in high-fructose rats. These data suggest that impaired blood pressure recovery to acute mental stress precedes the onset of hypertension in the early stages of insulin resistance. Further, blunted responses to isoproterenol implicate β2-adrenergic sensitivity as a possible mechanism responsible for altered blood pressure control after short-term high-fructose feeding.

  12. Methylphenidate prevents high-fat diet (HFD)-induced learning/memory impairment in juvenile mice.

    PubMed

    Kaczmarczyk, Melissa M; Machaj, Agnieszka S; Chiu, Gabriel S; Lawson, Marcus A; Gainey, Stephen J; York, Jason M; Meling, Daryl D; Martin, Stephen A; Kwakwa, Kristin A; Newman, Andrew F; Woods, Jeffrey A; Kelley, Keith W; Wang, Yanyan; Miller, Michael J; Freund, Gregory G

    2013-09-01

    The prevalence of childhood obesity has risen dramatically and coincident with this upsurge is a growth in adverse childhood psychological conditions including impulsivity, depression, anxiety and attention deficit/hyperactive disorder (ADHD). Due to confounds that exist when determining causality of childhood behavioral perturbations, controversy remains as to whether overnutrition and/or childhood obesity is important. Therefore, we examined juvenile mice to determine if biobehaviors were impacted by a short-term feeding (1-3wks) of a high-fat diet (HFD). After 1wk of a HFD feeding, mouse burrowing and spontaneous wheel running were increased while mouse exploration of the open quadrants of a zero maze, perfect alternations in a Y-maze and recognition of a novel object were impaired. Examination of mouse cortex, hippocampus and hypothalamus for dopamine and its metabolites demonstrated increased homovanillic acid (HVA) concentrations in the hippocampus and cortex that were associated with decreased cortical BDNF gene expression. In contrast, pro-inflammatory cytokine gene transcripts and serum IL-1α, IL-1β, TNF-α and IL-6 were unaffected by the short-term HFD feeding. Administration to mice of the psychostimulant methylphenidate prevented HFD-dependent impairment of learning/memory. HFD learning/memory impairment was not inhibited by the anti-depressants desipramine or reboxetine nor was it blocked in IDO or IL-1R1 knockout mice. In sum, a HFD rapidly impacts dopamine metabolism in the brain appearing to trigger anxiety-like behaviors and learning/memory impairments prior to the onset of weight gain and/or pre-diabetes. Thus, overnutrition due to fats may be central to childhood psychological perturbations such as anxiety and ADHD.

  13. Protective Effects of Liraglutide and Linagliptin in C. elegans as a New Model for Glucose-Induced Neurodegeneration.

    PubMed

    Wongchai, K; Schlotterer, A; Lin, J; Humpert, P M; Klein, T; Hammes, H-P; Morcos, M

    2016-01-01

    Liraglutide and linagliptin are novel drugs for the treatment of diabetes. Antioxidative and neuroprotective effects have been described for both compounds. However, it is not yet known, whether these mechanisms are also protective against diabetic retinal neurodegeneration. We assessed the antioxidative and neuroprotective capabilities of liraglutide and linagliptin as well as the signaling pathways involved, by using C. elegans as a model for glucose-induced neurodegeneration. C. elegans were cultivated under conditions, which mimic clinical hyperglycemia, and treated with 160 μmol/l liraglutide or 13 μmol/l linagliptin. Oxidative stress was reduced by 29 or 78% and methylglyoxal-derived advanced glycation endproducts (AGEs) by 33 or 22%, respectively. This resulted in an improved neuronal function by 42 or 60% and an extended mean lifespan by 9 or 11%, respectively. Antioxidative and AGE reducing effects of liraglutide and linagliptin were not dependent on v-akt murine thymoma viral oncogene homologue 1/forkhead box O1 (AKT1/FOXO). Neuroprotection by liraglutide was AKT1/FOXO dependent, yet AKT1/FOXO independent upon linagliptin treatment. Both liraglutide and linagliptin exert neuroprotective effects in an experimental model for glucose-induced neurodegeneration, however, the signaling pathways differ in the present study. Further pharmacological intervention with these pathways may help to delay the clinical onset of diabetic retinopathy by preserving neuronal integrity.

  14. Memantine rescues transient cognitive impairment caused by high-molecular-weight aβ oligomers but not the persistent impairment induced by low-molecular-weight oligomers.

    PubMed

    Figueiredo, Cláudia P; Clarke, Julia R; Ledo, José Henrique; Ribeiro, Felipe C; Costa, Carine V; Melo, Helen M; Mota-Sales, Axa P; Saraiva, Leonardo M; Klein, William L; Sebollela, Adriano; De Felice, Fernanda G; Ferreira, Sergio T

    2013-06-05

    Brain accumulation of soluble amyloid-β oligomers (AβOs) has been implicated in synapse failure and cognitive impairment in Alzheimer's disease (AD). However, whether and how oligomers of different sizes induce synapse dysfunction is a matter of controversy. Here, we report that low-molecular-weight (LMW) and high-molecular-weight (HMW) Aβ oligomers differentially impact synapses and memory. A single intracerebroventricular injection of LMW AβOs (10 pmol) induced rapid and persistent cognitive impairment in mice. On the other hand, memory deficit induced by HMW AβOs (10 pmol) was found to be reversible. While memory impairment in LMW oligomer-injected mice was associated with decreased hippocampal synaptophysin and GluN2B immunoreactivities, synaptic pathology was not detected in the hippocampi of HMW oligomer-injected mice. On the other hand, HMW oligomers, but not LMW oligomers, induced oxidative stress in hippocampal neurons. Memantine rescued both neuronal oxidative stress and the transient memory impairment caused by HMW oligomers, but did not prevent the persistent cognitive deficit induced by LMW oligomers. Results establish that different Aβ oligomer assemblies act in an orchestrated manner, inducing different pathologies and leading to synapse dysfunction. Furthermore, results suggest a mechanistic explanation for the limited efficacy of memantine in preventing memory loss in AD.

  15. Impaired glucose tolerance in rats fed low-carbohydrate, high-fat diets.

    PubMed

    Bielohuby, Maximilian; Sisley, Stephanie; Sandoval, Darleen; Herbach, Nadja; Zengin, Ayse; Fischereder, Michael; Menhofer, Dominik; Stoehr, Barbara J M; Stemmer, Kerstin; Wanke, Rüdiger; Tschöp, Matthias H; Seeley, Randy J; Bidlingmaier, Martin

    2013-11-01

    Moderate low-carbohydrate/high-fat (LC-HF) diets are widely used to induce weight loss in overweight subjects, whereas extreme ketogenic LC-HF diets are used to treat neurological disorders like pediatric epilepsy. Usage of LC-HF diets for improvement of glucose metabolism is highly controversial; some studies suggest that LC-HF diets ameliorate glucose tolerance, whereas other investigations could not identify positive effects of these diets or reported impaired insulin sensitivity. Here, we investigate the effects of LC-HF diets on glucose and insulin metabolism in a well-characterized animal model. Male rats were fed isoenergetic or hypocaloric amounts of standard control diet, a high-protein "Atkins-style" LC-HF diet, or a low-protein, ketogenic, LC-HF diet. Both LC-HF diets induced lower fasting glucose and insulin levels associated with lower pancreatic β-cell volumes. However, dynamic challenge tests (oral and intraperitoneal glucose tolerance tests, insulin-tolerance tests, and hyperinsulinemic euglycemic clamps) revealed that LC-HF pair-fed rats exhibited impaired glucose tolerance and impaired hepatic and peripheral tissue insulin sensitivity, the latter potentially being mediated by elevated intramyocellular lipids. Adjusting visceral fat mass in LC-HF groups to that of controls by reducing the intake of LC-HF diets to 80% of the pair-fed groups did not prevent glucose intolerance. Taken together, these data show that lack of dietary carbohydrates leads to glucose intolerance and insulin resistance in rats despite causing a reduction in fasting glucose and insulin concentrations. Our results argue against a beneficial effect of LC-HF diets on glucose and insulin metabolism, at least under physiological conditions. Therefore, use of LC-HF diets for weight loss or other therapeutic purposes should be balanced against potentially harmful metabolic side effects.

  16. Partial genetic deficiency in tissue kallikrein impairs adaptation to high potassium intake in humans.

    PubMed

    Monteiro, Joana S; Blanchard, Anne; Curis, Emmanuel; Chambrey, Régine; Jeunemaitre, Xavier; Azizi, Michel

    2013-12-01

    Inactivation of the tissue kallikrein gene in mice impairs renal handling of potassium due to enhanced H, K-ATPase activity, and induces hyperkalemia. We investigated whether the R53H loss-of-function polymorphism of the human tissue kallikrein gene affects renal potassium handling. In a crossover study, 30 R53R homozygous and 10 R53H heterozygous healthy males were randomly assigned to a low-sodium/high-potassium or a high-sodium/low-potassium diet to modulate tissue kallikrein synthesis. On the seventh day of each diet, participants were studied before and during a 2-h infusion of furosemide to stimulate distal potassium secretion. Urinary kallikrein activity was significantly lower in R53H than in R53R subjects on the low-sodium/high-potassium diet and was similarly reduced in both genotypes on high-sodium/low-potassium. Plasma potassium and renal potassium reabsorption were similar in both genotypes on an ad libitum sodium/potassium diet or after 7 days of a high-sodium/low-potassium diet. However, the median plasma potassium was significantly higher after 7 days of low-sodium/high-potassium diet in R53H than in R53R individuals. Urine potassium excretion and plasma aldosterone concentrations were similar. On the low-sodium/high-potassium diet, furosemide-induced decrease in plasma potassium was significantly larger in R53H than in R53R subjects. Thus, impaired tissue kallikrein stimulation by a low-sodium/high-potassium diet in R53H subjects with partial tissue kallikrein deficiency highlights an inappropriate renal adaptation to potassium load, consistent with experimental data in mice.

  17. Dietary trimethylamine N-oxide exacerbates impaired glucose tolerance in mice fed a high fat diet.

    PubMed

    Gao, Xiang; Liu, Xiaofang; Xu, Jie; Xue, Changhu; Xue, Yong; Wang, Yuming

    2014-10-01

    Trimethylamine N-oxide (TMAO) is an oxidation product of trimethylamine (TMA) and is present in many aquatic foods. Here, we investigated the effects of TMAO on glucose tolerance in high fat diet (HFD)-fed mice. Male C57BL/6 mice were randomly assigned to the control, high fat (HF), and TMAO groups. The HF group was fed a diet containing 25% fat, and the TMAO group was fed the HFD plus 0.2% TMAO for 4 weeks. After 3 weeks of feeding, oral glucose tolerance tests were performed. Dietary TMAO increased fasting insulin levels and homeostasis model assessment-estimated insulin resistance (HOMA-IR) and exacerbated the impaired glucose tolerance in HFD-fed mice. These effects were associated with the expression of genes related to the insulin signal pathway, glycogen synthesis, gluconeogenesis and glucose transport in liver. mRNA levels of the pro-inflammatory cytokine MCP-1 increased significantly and of the anti-inflammatory cytokine IL-10 greatly decreased in adipose tissue. Our results suggest that dietary TMAO exacerbates impaired glucose tolerance, obstructs the hepatic insulin signaling pathway, and causes adipose tissue inflammation in mice fed a high fat diet.

  18. Impaired jump landing after exercise in recreational and in high-performance athletes.

    PubMed

    Kuni, Benita; Cárdenas-Montemayor, Eloy; Bangert, Yannic; Rupp, Rüdiger; Ales, Janez; Friedmann-Bette, Birgit; Schmitt, Holger

    2014-08-01

    The risk of sustaining injuries increases with fatigue. The aim of this study was to analyze the influence of fatigue on dynamic postural control in jump landing and stabilization (ST) in athletes of different levels. In all, 18 high-performance ball sports athletes and 24 recreationally active subjects performed a jump test (JT) before and at 1, 5, 10, 15, and 20 minutes after a 30-minute treadmill run at the individual anaerobic threshold. An overhead ball switch hit during a forward jump triggered indicator lamps on either side of a force plate. After landing on the plate, ST on 1 leg (no light cue) or a second jump sideways (toward a light cue) was required. The ST force integral index was calculated for the ST trials. Dynamic postural control was significantly impaired in jump landing and ST in the first minute after the run: mean difference ± SD: 0.25 ± 0.48 m·s-1 (95% confidence interval: 0.10-0.40 m·s-1, p = 0.043; analysis of variance). No significant group differences were found. Under fatigued conditions, dynamic postural control in jump landing was impaired in an unexpected ST task. Not only recreational but also high-performance athletes were affected. Ball sports athletes could add a training exercise to their workout, which alternates between periods of high effort and neuromuscular training. Resistance to fatigue effects should be checked on a regular basis using JTs.

  19. High concentrations of stavudine impair fatty acid oxidation without depleting mitochondrial DNA in cultured rat hepatocytes.

    PubMed

    Igoudjil, Anissa; Massart, Julie; Begriche, Karima; Descatoire, Véronique; Robin, Marie-Anne; Fromenty, Bernard

    2008-06-01

    The antiretroviral nucleoside reverse-transcriptase inhibitor (NRTI) stavudine (d4T) can induce mild to severe liver injuries such as steatosis (i.e. triglyceride accumulation), steatohepatitis and liver failure. NRTI-induced toxicity has been ascribed to the inhibition of mitochondrial DNA (mtDNA) replication causing mtDNA depletion and respiratory chain dysfunction. This can secondarily impair the tricarboxylic acid cycle and fatty acid oxidation (FAO), thus leading to lactic acidosis and hepatic steatosis. However, NRTIs could also impair mitochondrial function and induce hepatic steatosis through other mechanisms. In this study, we sought to determine whether d4T could inhibit mitochondrial FAO and induce triglyceride accumulation through a mtDNA-independent mechanism. Since human tumoral and non-tumoral hepatic cell lines were unable to efficiently oxidize palmitic acid, the effects of d4T on mitochondrial FAO were assessed on cultured rat hepatocytes. Our results showed that 750 microM of d4T significantly inhibited palmitic acid oxidation after 48 or 72 h of culture, without inducing cell death. Importantly, high concentrations of zidovudine and zalcitabine (two other NRTIs that can induce hepatic steatosis), or beta-aminoisobutyric acid (a d4T metabolite), did not impair FAO in rat hepatocytes. D4T-induced FAO inhibition was observed without mtDNA depletion and lactate production, and was fully prevented with l-carnitine or clofibrate coincubation. l-carnitine also prevented the accretion of neutral lipids within rat hepatocytes. High concentrations of d4T were unable to inhibit FAO on freshly isolated liver mitochondria. Moreover, a microarray analysis was performed to clarify the mechanism whereby d4T can inhibit mitochondrial FAO and induce triglyceride accumulation in rat hepatocytes. The microarray data, confirmed by quantitative real-time PCR analysis, showed that d4T increased the expression of sterol regulatory element-binding protein-1c (SREBP1c

  20. Impaired dynamic cerebral autoregulation at extreme high altitude even after acclimatization.

    PubMed

    Iwasaki, Ken-ichi; Zhang, Rong; Zuckerman, Julie H; Ogawa, Yojiro; Hansen, Lærke H; Levine, Benjamin David

    2011-01-01

    Cerebral blood flow (CBF) increases and dynamic cerebral autoregulation is impaired by acute hypoxia. We hypothesized that progressive hypocapnia with restoration of arterial oxygen content after altitude acclimatization would normalize CBF and dynamic cerebral autoregulation. To test this hypothesis, dynamic cerebral autoregulation was examined by spectral and transfer function analyses between arterial pressure and CBF velocity variabilities in 11 healthy members of the Danish High-Altitude Research Expedition during normoxia and acute hypoxia (10.5% O(2)) at sea level, and after acclimatization (for over 1 month at 5,260 m at Chacaltaya, Bolivia). Arterial pressure and CBF velocity in the middle cerebral artery (transcranial Doppler), were recorded on a beat-by-beat basis. Steady-state CBF velocity increased during acute hypoxia, but normalized after acclimatization with partial restoration of SaO(2) (acute, 78% ± 2%; chronic, 89% ± 1%) and progression of hypocapnia (end-tidal carbon dioxide: acute, 34 ± 2 mm Hg; chronic, 21 ± 1 mm Hg). Coherence (0.40 ± 0.05 Units at normoxia) and transfer function gain (0.77 ± 0.13 cm/s per mm Hg at normoxia) increased, and phase (0.86 ± 0.15 radians at normoxia) decreased significantly in the very-low-frequency range during acute hypoxia (gain, 141% ± 24%; coherence, 136% ± 29%; phase, -25% ± 22%), which persisted after acclimatization (gain, 136% ± 36%; coherence, 131% ± 50%; phase, -42% ± 13%), together indicating impaired dynamic cerebral autoregulation in this frequency range. The similarity between both acute and chronic conditions suggests that dynamic cerebral autoregulation is impaired by hypoxia even after successful acclimatization to an extreme high altitude.

  1. Experimental studies of high-accuracy RFID localization with channel impairments

    NASA Astrophysics Data System (ADS)

    Pauls, Eric; Zhang, Yimin D.

    2015-05-01

    Radio frequency identification (RFID) systems present an incredibly cost-effective and easy-to-implement solution to close-range localization. One of the important applications of a passive RFID system is to determine the reader position through multilateration based on the estimated distances between the reader and multiple distributed reference tags obtained from, e.g., the received signal strength indicator (RSSI) readings. In practice, the achievable accuracy of passive RFID reader localization suffers from many factors, such as the distorted RSSI reading due to channel impairments in terms of the susceptibility to reader antenna patterns and multipath propagation. Previous studies have shown that the accuracy of passive RFID localization can be significantly improved by properly modeling and compensating for such channel impairments. The objective of this paper is to report experimental study results that validate the effectiveness of such approaches for high-accuracy RFID localization. We also examine a number of practical issues arising in the underlying problem that limit the accuracy of reader-tag distance measurements and, therefore, the estimated reader localization. These issues include the variations in tag radiation characteristics for similar tags, effects of tag orientations, and reader RSS quantization and measurement errors. As such, this paper reveals valuable insights of the issues and solutions toward achieving high-accuracy passive RFID localization.

  2. Monomethylated-adenines potentiate glucose-induced insulin production and secretion via inhibition of phosphodiesterase activity in rat pancreatic islets.

    PubMed

    Boland, Brandon B; Alarcón, Cristina; Ali, Almas; Rhodes, Christopher J

    2015-01-01

    Monomethyladenines have effects on DNA repair, G-protein-coupled receptor antagonism and autophagy. In islet ß-cells, 3-methyladenine (3-MA) has been implicated in DNA-repair and autophagy, but its mechanism of action is unclear. Here, the effect of monomethylated adenines was examined in rat islets. 3-MA, N6-methyladenine (N6-MA) and 9-methyladenine (9-MA), but not 1- or 7-monomethylated adenines, specifically potentiated glucose-induced insulin secretion (3-4 fold; p ≤ 0.05) and proinsulin biosynthesis (∼2-fold; p ≤ 0.05). Using 3-MA as a 'model' monomethyladenine, it was found that 3-MA augmented [cAMP]i accumulation (2-3 fold; p ≤ 0.05) in islets within 5 minutes. The 3-, N6- and 9-MA also enhanced glucose-induced phosphorylation of the cAMP/protein kinase-A (PKA) substrate cAMP-response element binding protein (CREB). Treatment of islets with pertussis or cholera toxin indicated 3-MA mediated elevation of [cAMP]i was not mediated via G-protein-coupled receptors. Also, 3-MA did not compete with 9-cyclopentyladenine (9-CPA) for adenylate cyclase inhibition, but did for the pan-inhibitor of phosphodiesterase (PDE), 3-isobutyl-1-methylxanthine (IBMX). Competitive inhibition experiments with PDE-isoform specific inhibitors suggested 3-MA to have a preference for PDE4 in islet ß-cells, but this was likely reflective of PDE4 being the most abundant PDE isoform in ß-cells. In vitro enzyme assays indicated that 3-, N6- and 9-MA were capable of inhibiting most PDE isoforms found in ß-cells. Thus, in addition to known inhibition of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3'K)/m Target of Rapamycin (mTOR) signaling, 3-MA also acts as a pan-phosphodiesterase inhibitor in pancreatic ß-cells to elevate [cAMP]i and then potentiate glucose-induced insulin secretion and production in parallel.

  3. An investigation of the career development of high school adolescents with hearing impairments in New Zealand.

    PubMed

    Furlonger, B

    1998-07-01

    Although the need for better-skilled workers has been signaled by the marketplace, people with hearing impairments generally are employed in unskilled or semiskilled jobs. They are, therefore, at heightened risk of unemployment and underemployment. Compounding this risk are the levels of vocational preparation and job awareness of adolescents with hearing impairments, which are generally considered inadequate. With a view to improving prevocational programs for hearing impaired adolescents, the researcher collected information on career awareness and vocational maturity. Significant differences were identified between hearing impaired and hearing adolescents on a range of career measures. In particular, adolescents with hearing impairments were identified as having less career awareness.

  4. High glucose impairs insulin signaling via activation of PKR pathway in L6 muscle cells.

    PubMed

    Udumula, Mary Priyanka; Babu, Mangali Suresh; Bhat, Audesh; Dhar, Indu; Sriram, Dharmarajan; Dhar, Arti

    2017-05-06

    Double stranded RNA (dsRNA) activated protein kinase R (PKR), a ubiquitously expressed serine/threonine kinase is a key inducer of inflammation, insulin resistance and glucose homeostasis in obesity. Recent studies have demonstrated that PKR can respond to metabolic stress in mice as well as in humans. However the underlying molecular mechanism is not fully understood. The aim of the present study was to examine the effect of high glucose on cultured rat L6 muscle cells and to investigate whether inhibition of PKR could prevent any deleterious effects of high glucose in these cells. PKR expression was determined by immunofluorescence and immunoblotting. The expression of different insulin signaling gene markers were measured by RT-PCR. Oxidative stress and apoptosis were determined by flow cytometry. High glucose treated L6 muscle cells developed a significant increase in PKR expression. Impaired insulin signaling as well as reduced insulin stimulated glucose uptake was observed in high glucose treated L6 muscle cells. A significant increase in reactive oxygen species generation and apoptosis formation was also observed in high glucose treated cultured L6 muscle cells. All these effects of high glucose were attenuated by a selective PKR inhibitor imoxin. Our study demonstrates PKR may have an additive role against the deleterious effects of high glucose in diabetes. Prevention of PKR activation, by safer and specific inhibitors is a therapeutic option in metabolic disorders that needs to be explored further.

  5. Genome-wide association analysis demonstrates the highly polygenic character of age-related hearing impairment

    PubMed Central

    Fransen, Erik; Bonneux, Sarah; Corneveaux, Jason J; Schrauwen, Isabelle; Di Berardino, Federica; White, Cory H; Ohmen, Jeffrey D; Van de Heyning, Paul; Ambrosetti, Umberto; Huentelman, Matthew J; Van Camp, Guy; Friedman, Rick A

    2015-01-01

    We performed a genome-wide association study (GWAS) to identify the genes responsible for age-related hearing impairment (ARHI), the most common form of hearing impairment in the elderly. Analysis of common variants, with and without adjustment for stratification and environmental covariates, rare variants and interactions, as well as gene-set enrichment analysis, showed no variants with genome-wide significance. No evidence for replication of any previously reported genes was found. A study of the genetic architecture indicates for the first time that ARHI is highly polygenic in nature, with probably no major genes involved. The phenotype depends on the aggregated effect of a large number of SNPs, of which the individual effects are undetectable in a modestly powered GWAS. We estimated that 22% of the variance in our data set can be explained by the collective effect of all genotyped SNPs. A score analysis showed a modest enrichment in causative SNPs among the SNPs with a P-value below 0.01. PMID:24939585

  6. Dynamin-related protein 1 mediates low glucose-induced endothelial dysfunction in human arterioles.

    PubMed

    Tanner, Michael J; Wang, Jingli; Ying, Rong; Suboc, Tisha B; Malik, Mobin; Couillard, Allison; Branum, Amberly; Puppala, Venkata; Widlansky, Michael E

    2017-03-01

    Intensive glycemic regulation has resulted in an increased incidence of hypoglycemia. Hypoglycemic burden correlates with adverse cardiovascular complications and contributes acutely and chronically to endothelial dysfunction. Prior data indicate that mitochondrial dysfunction contributes to hypoglycemia-induced endothelial dysfunction, but the mechanisms behind this linkage remain unknown. We attempt to determine whether clinically relevant low-glucose (LG) exposures acutely induce endothelial dysfunction through activation of the mitochondrial fission process. Characterization of mitochondrial morphology was carried out in cultured endothelial cells by using confocal microscopy. Isolated human arterioles were used to explore the effect LG-induced mitochondrial fission has on the formation of detrimental reactive oxygen species (ROS), bioavailability of nitric oxide (NO), and endothelial-dependent vascular relaxation. Fluorescence microscopy was employed to visualize changes in mitochondrial ROS and NO levels and videomicroscopy applied to measure vasodilation response. Pharmacological disruption of the profission protein Drp1 with Mdivi-1 during LG exposure reduced mitochondrial fragmentation among vascular endothelial cells (LG: 0.469; LG+Mdivi-1: 0.276; P = 0.003), prevented formation of vascular ROS (LG: 2.036; LG+Mdivi-1: 1.774; P = 0.005), increased the presence of NO (LG: 1.352; LG+Mdivi-1: 1.502; P = 0.048), and improved vascular dilation response to acetylcholine (LG: 31.6%; LG+Mdivi-1; 78.5% at maximum dose; P < 0.001). Additionally, decreased expression of Drp1 via siRNA knockdown during LG conditions also improved vascular relaxation. Exposure to LG imparts endothelial dysfunction coupled with altered mitochondrial phenotypes among isolated human arterioles. Disruption of Drp1 and subsequent mitochondrial fragmentation events prevents impaired vascular dilation, restores mitochondrial phenotype, and implicates mitochondrial fission as a primary

  7. Psilocybin impairs high-level but not low-level motion perception.

    PubMed

    Carter, Olivia L; Pettigrew, John D; Burr, David C; Alais, David; Hasler, Felix; Vollenweider, Franz X

    2004-08-26

    The hallucinogenic serotonin(1A&2A) agonist psilocybin is known for its ability to induce illusions of motion in otherwise stationary objects or textured surfaces. This study investigated the effect of psilocybin on local and global motion processing in nine human volunteers. Using a forced choice direction of motion discrimination task we show that psilocybin selectively impairs coherence sensitivity for random dot patterns, likely mediated by high-level global motion detectors, but not contrast sensitivity for drifting gratings, believed to be mediated by low-level detectors. These results are in line with those observed within schizophrenic populations and are discussed in respect to the proposition that psilocybin may provide a model to investigate clinical psychosis and the pharmacological underpinnings of visual perception in normal populations.

  8. Brief report: biochemical correlates of clinical impairment in high functioning autism and Asperger's disorder.

    PubMed

    Kleinhans, Natalia M; Richards, Todd; Weaver, Kurt E; Liang, Olivia; Dawson, Geraldine; Aylward, Elizabeth

    2009-07-01

    Amygdala dysfunction has been proposed as a critical contributor to social impairment in autism spectrum disorders (ASD). The current study investigated biochemical abnormalities in the amygdala in 20 high functioning adults with autistic disorder or Asperger's disorder and 19 typically developing adults matched on age and IQ. Magnetic resonance spectroscopy was used to measure N-acetyl aspartate (NAA), creatine/phosphocreatine (Cre), choline/choline containing compounds (Cho), and Myoinositol (mI) in the right and left amygdala. There were no significant between-group differences in any of the metabolites. However, NAA and Cre levels were significantly correlated to clinical ratings on the Autism Diagnostic Interview-Revised. This suggests that altered metabolite levels in the amygdala may be associated with a more severe early developmental course in ASD.

  9. High Current Anxiety Symptoms, But Not a Past Anxiety Disorder Diagnosis, are Associated with Impaired Fear Extinction.

    PubMed

    Duits, Puck; Cath, Danielle C; Heitland, Ivo; Baas, Johanna M P

    2016-01-01

    Although impaired fear extinction has repeatedly been demonstrated in patients with anxiety disorders, little is known about whether these impairments persist after treatment. The current comparative exploratory study investigated fear extinction in 26 patients treated for their anxiety disorder in the years preceding the study as compared to 17 healthy control subjects. Fear-potentiated startle and subjective fear were measured in a cue and context fear conditioning paradigm within a virtual reality environment. Results indicated no differences in fear extinction between treated anxiety patients and control subjects. However, scores on the Beck Anxiety Inventory across all participants revealed impaired extinction of fear potentiated startle in subjects with high compared to low anxiety symptoms over the past week. Taken together, this exploratory study found no support for impaired fear extinction in treated anxiety patients, and implies that current anxiety symptoms rather than previous patient status determine the success of extinction.

  10. High Current Anxiety Symptoms, But Not a Past Anxiety Disorder Diagnosis, are Associated with Impaired Fear Extinction

    PubMed Central

    Duits, Puck; Cath, Danielle C.; Heitland, Ivo; Baas, Johanna M. P.

    2016-01-01

    Although impaired fear extinction has repeatedly been demonstrated in patients with anxiety disorders, little is known about whether these impairments persist after treatment. The current comparative exploratory study investigated fear extinction in 26 patients treated for their anxiety disorder in the years preceding the study as compared to 17 healthy control subjects. Fear-potentiated startle and subjective fear were measured in a cue and context fear conditioning paradigm within a virtual reality environment. Results indicated no differences in fear extinction between treated anxiety patients and control subjects. However, scores on the Beck Anxiety Inventory across all participants revealed impaired extinction of fear potentiated startle in subjects with high compared to low anxiety symptoms over the past week. Taken together, this exploratory study found no support for impaired fear extinction in treated anxiety patients, and implies that current anxiety symptoms rather than previous patient status determine the success of extinction. PMID:26955364

  11. High-fat diet induces hepatic insulin resistance and impairment of synaptic plasticity.

    PubMed

    Liu, Zhigang; Patil, Ishan Y; Jiang, Tianyi; Sancheti, Harsh; Walsh, John P; Stiles, Bangyan L; Yin, Fei; Cadenas, Enrique

    2015-01-01

    High-fat diet (HFD)-induced obesity is associated with insulin resistance, which may affect brain synaptic plasticity through impairment of insulin-sensitive processes underlying neuronal survival, learning, and memory. The experimental model consisted of 3 month-old C57BL/6J mice fed either a normal chow diet (control group) or a HFD (60% of calorie from fat; HFD group) for 12 weeks. This model was characterized as a function of time in terms of body weight, fasting blood glucose and insulin levels, HOMA-IR values, and plasma triglycerides. IRS-1/Akt pathway was assessed in primary hepatocytes and brain homogenates. The effect of HFD in brain was assessed by electrophysiology, input/output responses and long-term potentiation. HFD-fed mice exhibited a significant increase in body weight, higher fasting glucose- and insulin levels in plasma, lower glucose tolerance, and higher HOMA-IR values. In liver, HFD elicited (a) a significant decrease of insulin receptor substrate (IRS-1) phosphorylation on Tyr608 and increase of Ser307 phosphorylation, indicative of IRS-1 inactivation; (b) these changes were accompanied by inflammatory responses in terms of increases in the expression of NFκB and iNOS and activation of the MAP kinases p38 and JNK; (c) primary hepatocytes from mice fed a HFD showed decreased cellular oxygen consumption rates (indicative of mitochondrial functional impairment); this can be ascribed partly to a decreased expression of PGC1α and mitochondrial biogenesis. In brain, HFD feeding elicited (a) an inactivation of the IRS-1 and, consequentially, (b) a decreased expression and plasma membrane localization of the insulin-sensitive neuronal glucose transporters GLUT3/GLUT4; (c) a suppression of the ERK/CREB pathway, and (d) a substantial decrease in long-term potentiation in the CA1 region of hippocampus (indicative of impaired synaptic plasticity). It may be surmised that 12 weeks fed with HFD induce a systemic insulin resistance that impacts

  12. Could a high-fat diet rich in unsaturated fatty acids impair the cardiovascular system?

    PubMed Central

    Medei, Emiliano; Lima-Leopoldo, Ana Paula; Pereira-Junior, Pedro Paulo; Leopoldo, André Soares; Campos, Dijon Henrique Salomé; Raimundo, Juliana Montani; Sudo, Roberto Takashi; Zapata-Sudo, Gisele; Bruder-Nascimento, Thiago; Cordellini, Sandra; Nascimento, José Hamilton Matheus; Cicogna, Antonio Carlos

    2010-01-01

    BACKGROUND: Dyslipidemia results from consumption of a diet rich in saturated fatty acids and is usually associated with cardiovascular disease. A diet rich in unsaturated fatty acids is usually associated with improved cardiovascular condition. OBJECTIVE: To investigate whether a high-fat diet rich in unsaturated fatty acids (U-HFD) – in which fatty acid represents approximately 45% of the total calories – impairs the cardiovascular system. METHODS: Male, 30-day-old Wistar rats were fed a standard (control) diet or a U-HFD containing 83% unsaturated fatty acid for 19 weeks. The in vivo electrocardiogram, the spectral analysis of heart rate variability, and the vascular reactivity responses to phenylephrine, acetylcholine, noradrenaline and prazosin in aortic ring preparations were analyzed to assess the cardiovascular parameters. RESULTS: After 19 weeks, the U-HFD rats had increased total body fat, baseline glucose levels and feed efficiency compared with control rats. However, the final body weight, systolic blood pressure, area under the curve for glucose, calorie intake and heart weight/final body weight ratio were similar between the groups. In addition, both groups demonstrated no alteration in the electrocardiogram or cardiac sympathetic parameters. There was no difference in the responses to acetylcholine or the maximal contractile response of the thoracic aorta to phenylephrine between groups, but the concentration necessary to produce 50% of maximal response showed a decrease in the sensitivity to phenylephrine in U-HFD rats. The cumulative concentration-effect curve for noradrenaline in the presence of prazosin was shifted similarly in both groups. CONCLUSIONS: The present work shows that U-HFD did not impair the cardiovascular parameters analyzed. PMID:21165364

  13. Carnitine protects the nematode Caenorhabditis elegans from glucose-induced reduction of survival depending on the nuclear hormone receptor DAF-12

    SciTech Connect

    Deusing, Dorothé Jenni Beyrer, Melanie Fitzenberger, Elena Wenzel, Uwe

    2015-05-08

    Besides its function in transport of fatty acids into mitochondria in order to provide substrates for β-oxidation, carnitine has been shown to affect also glucose metabolism and to inhibit several mechanisms associated with diabetic complications. In the present study we used the mev-1 mutant of the nematode Caenorhabditis elegans fed on a high glucose concentration in liquid media as a diabetes model and tested the effects of carnitine supplementation on their survival under heat-stress. Carnitine at 100 μM completely prevented the survival reduction that was caused by the application of 10 mM glucose. RNA-interference for sir-2.1, a candidate genes mediating the effects of carnitine revealed no contribution of the sirtuin for the rescue of survival. Under daf-12 RNAi rescue of survival by carnitine was abolished. RNA-interference for γ-butyrobetaine hydroxylase 2, encoding the key enzyme for carnitine biosynthesis did neither increase glucose toxicity nor prevent the rescue of survival by carnitine, suggesting that the effects of carnitine supplementation on carnitine levels were significant. Finally, it was demonstrated that neither the amount of lysosomes nor the proteasomal activity were increased by carnitine, excluding that protein degradation pathways, such as autophagy or proteasomal degradation, are involved in the protective carnitine effects. In conclusion, carnitine supplementation prevents the reduction of survival caused by glucose in C. elegans in dependence on a nuclear hormone receptor which displays high homologies to the vertebrate peroxisomal proliferator activated receptors. - Highlights: • Carnitine protects from glucose-induced reduction of stress-resistance. • Carnitine acts via the PPAR homolog DAF-12 on glucose toxicity. • Carnitine protects from glucose toxicity independent of protein degradation.

  14. Telomere stability is frequently impaired in high-risk groups of patients with myelodysplastic syndromes.

    PubMed

    Ohyashiki, J H; Iwama, H; Yahata, N; Ando, K; Hayashi, S; Shay, J W; Ohyashiki, K

    1999-05-01

    Genomic instability induces an accumulation of genetic changes and may play a role in the pathogenesis of myelodysplastic syndromes (MDS). To clarify the possible association between genomic instability and clinical outcome in MDS patients, we compared telomere dynamics to the recently established International Prognostic Scoring System (IPSS) risk groups for MDS. We measured the terminal restriction fragments (TRFs) of 93 patients with MDS at the time of diagnosis, and telomerase activity was analyzed in 62 patients with MDS using the PCR-based telomeric repeat amplification protocol (TRAP) assay. A total of 53 of 93 MDS patients had TRFs within the age-matched normal range, and the remaining patients showed shortened TRFs (35 patients) or elongated TRFs (5 patients). MDS patients with shortened TRFs had a significantly low hemoglobin concentration (P = 0.04), a high percentage of marrow blasts (P = 0.02), and a high incidence of cytogenetic abnormalities (P < 0.05). The incidence of leukemic transformation was significantly high in patients with shortened TRF length (P < 0.05). In addition, patients with shortened TRF length were frequently seen in the IPSS high-risk group (P < 0.01). Most of the MDS patients had normal-to-low levels of telomerase activity, suggesting that changes in TRF length rather than telomerase activity may more accurately reflect the pathophysiology of MDS. MDS patients with shortened TRF length had a very poor prognosis (P < 0.01), suggesting that telomere dynamics may be linked to clinical outcome in MDS patients. Thus, an abnormal mechanism of telomere maintenance in subgroups of MDS patients may be an early indication of genomic instability. This study demonstrates that telomere stability is frequently impaired in a high-risk group of MDS patients and suggests that, in combination with the IPSS classification system, measurement of TRFs may be useful in the future to stratify MDS patients according to risk and manage the care of MDS

  15. Neuropsychological presentation and adaptive skills in high-functioning adolescents with visual impairment: A preliminary investigation.

    PubMed

    Greenaway, R; Pring, L; Schepers, A; Isaacs, D P; Dale, N J

    2017-01-01

    Studies in infants and young children with congenital visual impairment (VI) have indicated early developmental vulnerabilities, conversely research with older children and adults have highlighted areas of cognitive strength. A minimal amount is known, however, about the possible combination of strengths and weaknesses in adolescence, and this present study therefore aims to explore the neuropsychological presentation and adaptive behavior profile in high-functioning adolescents with congenital VI. Participants completed a battery of commonly used neuropsychological measures assessing memory, executive function, and attention. The measures utilized focused on auditory neuropsychological function, because only subtests that could be completed with auditory administration were suitable for this sample. Parents completed standardized measures of adaptive behavior, executive function, and social communication. Compared to aged-based norms for normal sight, adolescents with VI demonstrated strengths in aspects of working memory and verbal memory. Furthermore, performance across the neuropsychological battery was within or above the average range for the majority of the sample. In contrast, parent-report measures indicated areas of weakness in adaptive functioning, social communication, and behavioral executive functioning. Overall, this study provides preliminary evidence that relative to fully sighted peers, high-functioning adolescents with VI present with an uneven profile of cognitive and adaptive skills, which has important implications for assessment and intervention.

  16. Selective impairment of cognitive empathy for moral judgment in adults with high functioning autism.

    PubMed

    Gleichgerrcht, Ezequiel; Torralva, Teresa; Rattazzi, Alexia; Marenco, Victoria; Roca, María; Manes, Facundo

    2013-10-01

    Faced with a moral dilemma, conflict arises between a cognitive controlled response aimed at maximizing welfare, i.e. the utilitarian judgment, and an emotional aversion to harm, i.e. the deontological judgment. In the present study, we investigated moral judgment in adult individuals with high functioning autism/Asperger syndrome (HFA/AS), a clinical population characterized by impairments in prosocial emotions and social cognition. In Experiment 1, we compared the response patterns of HFA/AS participants and neurotypical controls to moral dilemmas with low and high emotional saliency. We found that HFA/AS participants more frequently delivered the utilitarian judgment. Their perception of appropriateness of moral transgression was similar to that of controls, but HFA/AS participants reported decreased levels of emotional reaction to the dilemma. In Experiment 2, we explored the way in which demographic, clinical and social cognition variables including emotional and cognitive aspects of empathy and theory of mind influenced moral judgment. We found that utilitarian HFA/AS participants showed a decreased ability to infer other people's thoughts and to understand their intentions, as measured both by performance on neuropsychological tests and through dispositional measures. We conclude that greater prevalence of utilitarianism in HFA/AS is associated with difficulties in specific aspects of social cognition.

  17. Selective impairment of cognitive empathy for moral judgment in adults with high functioning autism

    PubMed Central

    Torralva, Teresa; Rattazzi, Alexia; Marenco, Victoria; Roca, María; Manes, Facundo

    2013-01-01

    Faced with a moral dilemma, conflict arises between a cognitive controlled response aimed at maximizing welfare, i.e. the utilitarian judgment, and an emotional aversion to harm, i.e. the deontological judgment. In the present study, we investigated moral judgment in adult individuals with high functioning autism/Asperger syndrome (HFA/AS), a clinical population characterized by impairments in prosocial emotions and social cognition. In Experiment 1, we compared the response patterns of HFA/AS participants and neurotypical controls to moral dilemmas with low and high emotional saliency. We found that HFA/AS participants more frequently delivered the utilitarian judgment. Their perception of appropriateness of moral transgression was similar to that of controls, but HFA/AS participants reported decreased levels of emotional reaction to the dilemma. In Experiment 2, we explored the way in which demographic, clinical and social cognition variables including emotional and cognitive aspects of empathy and theory of mind influenced moral judgment. We found that utilitarian HFA/AS participants showed a decreased ability to infer other people’s thoughts and to understand their intentions, as measured both by performance on neuropsychological tests and through dispositional measures. We conclude that greater prevalence of utilitarianism in HFA/AS is associated with difficulties in specific aspects of social cognition. PMID:22689217

  18. Impaired Global, and Compensatory Local, Biological Motion Processing in People with High Levels of Autistic Traits

    PubMed Central

    van Boxtel, Jeroen J. A.; Lu, Hongjing

    2013-01-01

    People with Autism Spectrum Disorder (ASD) are hypothesized to have poor high-level processing but superior low-level processing, causing impaired social recognition, and a focus on non-social stimulus contingencies. Biological motion perception provides an ideal domain to investigate exactly how ASD modulates the interaction between low and high-level processing, because it involves multiple processing stages, and carries many important social cues. We investigated individual differences among typically developing observers in biological motion processing, and whether such individual differences associate with the number of autistic traits. In Experiment 1, we found that individuals with fewer autistic traits were automatically and involuntarily attracted to global biological motion information, whereas individuals with more autistic traits did not show this pre-attentional distraction. We employed an action adaptation paradigm in the second study to show that individuals with more autistic traits were able to compensate for deficits in global processing with an increased involvement in local processing. Our findings can be interpreted within a predictive coding framework, which characterizes the functional relationship between local and global processing stages, and explains how these stages contribute to the perceptual difficulties associated with ASD. PMID:23630514

  19. High cortisol awakening response is associated with impaired error monitoring and decreased post-error adjustment.

    PubMed

    Zhang, Liang; Duan, Hongxia; Qin, Shaozheng; Yuan, Yiran; Buchanan, Tony W; Zhang, Kan; Wu, Jianhui

    2015-01-01

    The cortisol awakening response (CAR), a rapid increase in cortisol levels following morning awakening, is an important aspect of hypothalamic-pituitary-adrenocortical axis activity. Alterations in the CAR have been linked to a variety of mental disorders and cognitive function. However, little is known regarding the relationship between the CAR and error processing, a phenomenon that is vital for cognitive control and behavioral adaptation. Using high-temporal resolution measures of event-related potentials (ERPs) combined with behavioral assessment of error processing, we investigated whether and how the CAR is associated with two key components of error processing: error detection and subsequent behavioral adjustment. Sixty university students performed a Go/No-go task while their ERPs were recorded. Saliva samples were collected at 0, 15, 30 and 60 min after awakening on the two consecutive days following ERP data collection. The results showed that a higher CAR was associated with slowed latency of the error-related negativity (ERN) and a higher post-error miss rate. The CAR was not associated with other behavioral measures such as the false alarm rate and the post-correct miss rate. These findings suggest that high CAR is a biological factor linked to impairments of multiple steps of error processing in healthy populations, specifically, the automatic detection of error and post-error behavioral adjustment. A common underlying neural mechanism of physiological and cognitive control may be crucial for engaging in both CAR and error processing.

  20. High-Content Imaging Assays for Identifying Compounds that Generate Superoxide and Impair Mitochondrial Membrane Potential in Adherent Eukaryotic Cells.

    PubMed

    Billis, Puja; Will, Yvonne; Nadanaciva, Sashi

    2014-02-19

    Reactive oxygen species (ROS) are constantly produced in cells as a result of aerobic metabolism. When there is an excessive production of ROS and the cell's antioxidant defenses are overwhelmed, oxidative stress occurs. The superoxide anion is a type of ROS that is produced primarily in mitochondria but is also generated in other regions of the cell including peroxisomes, endoplasmic reticulum, plasma membrane, and cytosol. Here, a high-content imaging assay using the dye dihydroethidium is described for identifying compounds that generate superoxide in eukaryotic cells. A high-content imaging assay using the fluorescent dye tetramethylrhodamine methyl ester is also described to identify compounds that impair mitochondrial membrane potential in eukaryotic cells. The purpose of performing both assays is to identify compounds that (1) generate superoxide at lower concentrations than they impair mitochondrial membrane potential, (2) impair mitochondrial membrane potential at lower concentrations than they generate superoxide, (3) generate superoxide and impair mitochondrial function at similar concentrations, and (4) do not generate superoxide or impair mitochondrial membrane potential during the duration of the assays.

  1. Comparison of seven water quality assessment methods for the characterization and management of highly impaired river systems.

    PubMed

    Ji, Xiaoliang; Dahlgren, Randy A; Zhang, Minghua

    2016-01-01

    In the context of water resource management and pollution control, the characterization of water quality impairments and identification of dominant pollutants are of critical importance. In this study, water quality impairment was assessed on the basis of 7 hydrochemical variables that were monitored bimonthly at 17 sites in 2010 along the rural-suburban-urban portion of the Wen-Rui Tang River in eastern China. Seven methods were used to assess water quality in the river system. These methods included single-factor assessment, water quality grading, comprehensive pollution index, the Nemerow pollution index, principle component analysis, fuzzy comprehensive evaluation, and comprehensive water quality identification index. Our analysis showed that the comprehensive water quality identification index was the best method for assessing water quality in the Wen-Rui Tang River due to its ability to effectively characterize highly polluted waters with multiple impairments. Furthermore, a guideline for the applications of these methods was presented based on their characteristics and efficacy. Results indicated that the dominant pollutant impairing water quality was total nitrogen comprised mainly of ammonium. The temporal variation of water quality was closely related to precipitation as a result of dilution. The spatial variation of water quality was associated with anthropogenic influences (urban, industrial, and agriculture activities) and water flow direction (downstream segments experiencing cumulative effects of upstream inputs). These findings provide valuable information and guidance for water pollution control and water resource management in highly polluted surface waters with multiple water quality impairments in areas with rapid industrial growth and urbanization.

  2. Effect of Betula pendula Leaf Extract on α-Glucosidase and Glutathione Level in Glucose-Induced Oxidative Stress

    PubMed Central

    Bljajić, Kristina; Šoštarić, Nina; Petlevski, Roberta; Vujić, Lovorka; Brajković, Andrea; Fumić, Barbara; de Carvalho, Isabel Saraiva

    2016-01-01

    B. pendula leaf is a common ingredient in traditional herbal combinations for treatment of diabetes in southeastern Europe. Present study investigated B. pendula ethanolic and aqueous extract as inhibitors of carbohydrate hydrolyzing enzymes, as well as their ability to restore glutathione concentration in Hep G2 cells subjected to glucose-induced oxidative stress. Phytochemical analysis revealed presence of rutin and other quercetin derivatives, as well as chlorogenic acid. In general, ethanolic extract was richer in phenolic substances than the aqueous extract. Furthermore, a comprehensive analysis of antioxidant activity of two extracts (determined by DPPH and ABTS radical scavenging activity, total antioxidant activity, and chelating activity as well as ferric-reducing antioxidant power) has shown that ethanolic extract was better radical scavenger and metal ion reductant. In addition, ethanolic extract effectively increased cellular glutathione levels caused by hyperglycemia and inhibited α-glucosidase with the activity comparable to that of acarbose. Therefore, in vitro research using B. pendula plant extracts has confirmed their antidiabetic properties. PMID:27668005

  3. Role of Nodal-PITX2C signaling pathway in glucose-induced cardiomyocyte hypertrophy.

    PubMed

    Su, Dongmei; Jing, Sun; Guan, Lina; Li, Qian; Zhang, Huiling; Gao, Xiaobo; Ma, Xu

    2014-06-01

    Pathological cardiac hypertrophy is a major cause of morbidity and mortality in cardiovascular disease. Recent studies have shown that cardiomyocytes, in response to high glucose (HG) stimuli, undergo hypertrophic growth. While much work still needs to be done to elucidate this important mechanism of hypertrophy, previous works have showed that some pathways or genes play important roles in hypertrophy. In this study, we showed that sublethal concentrations of glucose (25 mmol/L) could induce cardiomyocyte hypertrophy with an increase in the cellular surface area and the upregulation of the atrial natriuretic peptide (ANP) gene, a hypertrophic marker. High glucose (HG) treatments resulted in the upregulation of the Nodal gene, which is under-expressed in cardiomyocytes. We also determined that the knockdown of the Nodal gene resisted HG-induced cardiomyocyte hypertrophy. The overexpression of Nodal was able to induce hypertrophy in cardiomyocytes, which was associated with the upregulation of the PITX2C gene. We also showed that increases in the PITX2C expression, in response to Nodal, were mediated by the Smad4 signaling pathway. This study is highly relevant to the understanding of the effects of the Nodal-PITX2C pathway on HG-induced cardiomyocyte hypertrophy, as well as the related molecular mechanisms.

  4. Bovine retinal pericytes are resistant to glucose-induced oxidative stress in vitro.

    PubMed

    Agardh, Carl-David; Hultberg, Björn; Nayak, Ramesh C; Farthing-Nayak, Pamela; Agardh, Elisabet

    2005-01-01

    Diabetic retinopathy is a sight-threatening complication of diabetes, and loss of pericytes represents early signs of its development. We tested the hypothesis that high glucose levels may induce signs of oxidative stress in cultured bovine retinal pericytes. Pericytes were exposed to either normal (5.5 mM) or high (22 mM) glucose levels for 1, 3, and 5 days. Signs of oxidative stress were measured by expression of copper/zinc superoxide dismutase, manganese superoxide dismutase, catalase, and glutathione peroxidase using real-time RTPCR. To elucidate the role of oxidative stress, we also measured glutathione (GSH) concentration in the cells and investigated the impact of thiol-reactive metal ions and hydrogen peroxide (H(2)O(2)) on intracellular GSH. Despite the stimulation with high glucose, thiol-reactive metal ions, or H(2)O(2), there was no clear increased expression of antioxidant enzymes or influence of GSH levels. Lipid peroxidation (malondialdehyde level) was increased in bovine aortic smooth muscle cells, but not in bovine retinal pericytes. The data indicate that pericytes do not develop oxidative stress in response to hyperglycemia. However, it is not definitively excluded that oxidative stress may occur after longer time periods of glucose stimulation.

  5. Acute Thermotherapy Prevents Impairments in Cutaneous Microvascular Function Induced by a High Fat Meal

    PubMed Central

    Harvey, Jennifer C.; Roseguini, Bruno T.; Goerger, Benjamin M.; Fallon, Elizabeth A.

    2016-01-01

    We tested the hypothesis that a high fat meal (HFM) would impair cutaneous vasodilation, while thermotherapy (TT) would reverse the detrimental effects. Eight participants were instrumented with skin heaters and laser-Doppler (LD) probes and tested in three trials: control, HFM, and HFM + TT. Participants wore a water-perfused suit perfused with 33°C (control and HFM) or 50°C (HFM + TT) water. Participants consumed 1 g fat/kg body weight. Blood samples were taken at baseline and two hours post-HFM. Blood pressure was measured every 5–10 minutes. Microvascular function was assessed via skin local heating from 33°C to 39°C two hours after HFM. Cutaneous vascular conductance (CVC) was calculated and normalized to maximal vasodilation (%CVCmax). HFM had no effect on initial peak (48 ± 4 %CVCmax) compared to control (49 ± 4 %CVCmax) but attenuated the plateau (51 ± 4 %CVCmax) compared to control (63 ± 4 %CVCmax, P < 0.001). Initial peak was augmented in HFM + TT (66 ± 4 %CVCmax) compared to control and HFM (P < 0.05), while plateau (73 ± 3 % CVCmax) was augmented only compared to the HFM trial (P < 0.001). These data suggest that HFM negatively affects cutaneous vasodilation but can be minimized by TT. PMID:27595112

  6. High School Teachers' Perspectives on Supporting Students with Visual Impairments toward Higher Education: Access, Barriers, and Success

    ERIC Educational Resources Information Center

    Reed, Maureen; Curtis, Kathryn

    2011-01-01

    The objective of the study presented here was to understand the experiences of teachers in assisting students with visual impairments in making the transition to higher education. The teachers reported barriers in high school that affect students' access to and success in higher education. Furthermore, institutions of higher education provided…

  7. The Use of Assistive Technology by High School Students with Visual Impairments: A Second Look at the Current Problem

    ERIC Educational Resources Information Center

    Kelly, Stacy M.

    2011-01-01

    Even though a wide variety of assistive technology tools and devices are available in the marketplace, many students with visual impairments (that is, those who are blind or have low vision) have not yet benefitted from using this specialized technology. This article presents a study that assessed the use of assistive technology by high school…

  8. Self-reported sleep disturbances associated with procedural learning impairment in adolescents at ultra-high risk for psychosis.

    PubMed

    Lunsford-Avery, Jessica R; Dean, Derek J; Mittal, Vijay A

    2017-03-16

    Sleep disturbance contributes to impaired procedural learning in schizophrenia, yet little is known about this relationship prior to psychosis onset. Adolescents at ultra high-risk (UHR; N=62) for psychosis completed the Pittsburgh Sleep Quality Index (PSQI) and a procedural learning task (Pursuit Rotor). Increased self-reported problems with sleep latency, efficiency, and quality were associated with impaired procedural learning rate. Further, within-sample comparisons revealed that UHR youth reporting better sleep displayed a steeper learning curve than those with poorer sleep. Sleep disturbances appear to contribute to cognitive/motor deficits in the UHR period and may play a role in psychosis etiology.

  9. Ethylene acts as a negative regulator of glucose induced lateral root emergence in Arabidopsis.

    PubMed

    Singh, Manjul; Gupta, Aditi; Laxmi, Ashverya

    2015-01-01

    Plants, being sessile organisms, are more exposed to the hazards of constantly changing environmental conditions globally. During the lifetime of a plant, the root system encounters various challenges such as obstacles, pathogens, high salinity, water logging, nutrient scarcity etc. The developmental plasticity of the root system provides brilliant adaptability to plants to counter the changes exerted by both external as well as internal cues and achieve an optimized growth status. Phytohormones are one of the major intrinsic factors regulating all aspects of plant growth and development both independently as well as through complex signal integrations at multiple levels. We have previously shown that glucose (Glc) and brassinosteroid (BR) signalings interact extensively to regulate lateral root (LR) development in Arabidopsis. (1) Auxin efflux as well as influx and downstream signaling components are also involved in Glc-BR regulation of LR emergence. Here, we provide evidence for involvement of ethylene signaling machinery downstream to Glc and BR in regulation of LR emergence.

  10. Ethylene acts as a negative regulator of glucose induced lateral root emergence in Arabidopsis

    PubMed Central

    Singh, Manjul; Gupta, Aditi; Laxmi, Ashverya

    2015-01-01

    Plants, being sessile organisms, are more exposed to the hazards of constantly changing environmental conditions globally. During the lifetime of a plant, the root system encounters various challenges such as obstacles, pathogens, high salinity, water logging, nutrient scarcity etc. The developmental plasticity of the root system provides brilliant adaptability to plants to counter the changes exerted by both external as well as internal cues and achieve an optimized growth status. Phytohormones are one of the major intrinsic factors regulating all aspects of plant growth and development both independently as well as through complex signal integrations at multiple levels. We have previously shown that glucose (Glc) and brassinosteroid (BR) signalings interact extensively to regulate lateral root (LR) development in Arabidopsis.1 Auxin efflux as well as influx and downstream signaling components are also involved in Glc-BR regulation of LR emergence. Here, we provide evidence for involvement of ethylene signaling machinery downstream to Glc and BR in regulation of LR emergence. PMID:26236960

  11. Functionally-detected cognitive impairment in high school football players without clinically-diagnosed concussion.

    PubMed

    Talavage, Thomas M; Nauman, Eric A; Breedlove, Evan L; Yoruk, Umit; Dye, Anne E; Morigaki, Katherine E; Feuer, Henry; Leverenz, Larry J

    2014-02-15

    Head trauma and concussion in football players have recently received considerable media attention. Postmortem evidence suggests that accrual of damage to the brain may occur with repeated blows to the head, even when the individual blows fail to produce clinical symptoms. There is an urgent need for improved detection and characterization of head trauma to reduce future injury risk and promote development of new therapies. In this study we examined neurological performance and health in the presence of head collision events in high school football players, using longitudinal measures of collision events (the HIT(™) System), neurocognitive testing (ImPACT(™)), and functional magnetic resonance imaging MRI (fMRI). Longitudinal assessment (including baseline) was conducted in 11 young men (ages 15-19 years) participating on the varsity and junior varsity football teams at a single high school. We expected and observed subjects in two previously described categories: (1) no clinically-diagnosed concussion and no changes in neurological behavior, and (2) clinically-diagnosed concussion with changes in neurological behavior. Additionally, we observed players in a previously undiscovered third category, who exhibited no clinically-observed symptoms associated with concussion, but who demonstrated measurable neurocognitive (primarily visual working memory) and neurophysiological (altered activation in the dorsolateral prefrontal cortex [DLPFC]) impairments. This new category was associated with significantly higher numbers of head collision events to the top-front of the head, directly above the DLPFC. The discovery of this new category suggests that more players are suffering neurological injury than are currently being detected using traditional concussion-assessment tools. These individuals are unlikely to undergo clinical evaluation, and thus may continue to participate in football-related activities, even when changes in brain physiology (and potential brain

  12. Chronic ingestion of 2-deoxy-D-glucose induces cardiac vacuolization and increases mortality in rats

    SciTech Connect

    Minor, Robin K.; Smith, Daniel L.; Sossong, Alex M.; Kaushik, Susmita; Poosala, Suresh; Spangler, Edward L.; Roth, George S.; Lane, Mark; Allison, David B.; Cabo, Rafael de; Ingram, Donald K.; Mattison, Julie A.

    2010-03-15

    Calorie restriction (CR), the purposeful reduction of energy intake with maintenance of adequate micronutrient intake, is well known to extend the lifespan of laboratory animals. Compounds like 2-deoxy-D-glucose (2DG) that can recapitulate the metabolic effects of CR are of great interest for their potential to extend lifespan. 2DG treatment has been shown to have potential therapeutic benefits for treating cancer and seizures. 2DG has also recapitulated some hallmarks of the CR phenotype including reduced body temperature and circulating insulin in short-term rodent trials, but one chronic feeding study in rats found toxic effects. The present studies were performed to further explore the long-term effects of 2DG in vivo. First we demonstrate that 2DG increases mortality of male Fischer-344 rats. Increased incidence of pheochromocytoma in the adrenal medulla was also noted in the 2DG treated rats. We reconfirm the cardiotoxicity of 2DG in a 6-week follow-up study evaluating male Brown Norway rats and a natural form of 2DG in addition to again examining effects in Fischer-344 rats and the original synthetic 2DG. High levels of both 2DG sources reduced weight gain secondary to reduced food intake in both strains. Histopathological analysis of the hearts revealed increasing vacuolarization of cardiac myocytes with dose, and tissue staining revealed the vacuoles were free of both glycogen and lipid. We did, however, observe higher expression of both cathepsin D and LC3 in the hearts of 2DG-treated rats which indicates an increase in autophagic flux. Although a remarkable CR-like phenotype can be reproduced with 2DG treatment, the ultimate toxicity of 2DG seriously challenges 2DG as a potential CR mimetic in mammals and also raises concerns about other therapeutic applications of the compound.

  13. Caffeine prevents weight gain and cognitive impairment caused by a high-fat diet while elevating hippocampal BDNF.

    PubMed

    Moy, Gregory A; McNay, Ewan C

    2013-01-17

    Obesity, high-fat diets, and subsequent type 2 diabetes (T2DM) are associated with cognitive impairment. Moreover, T2DM increases the risk of Alzheimer's disease (AD) and leads to abnormal elevation of brain beta-amyloid levels, one of the hallmarks of AD. The psychoactive alkaloid caffeine has been shown to have therapeutic potential in AD but the central impact of caffeine has not been well-studied in the context of a high-fat diet. Here we investigated the impact of caffeine administration on metabolism and cognitive performance, both in control rats and in rats placed on a high-fat diet. The effects of caffeine were significant: caffeine both (i) prevented the weight-gain associated with the high-fat diet and (ii) prevented cognitive impairment. Caffeine did not alter hippocampal metabolism or insulin signaling, likely because the high-fat-fed animals did not develop full-blown diabetes; however, caffeine did prevent or reverse a decrease in hippocampal brain-derived neurotrophic factor (BDNF) seen in high-fat-fed animals. These data confirm that caffeine may serve as a neuroprotective agent against cognitive impairment caused by obesity and/or a high-fat diet. Increased hippocampal BDNF following caffeine administration could explain, at least in part, the effects of caffeine on cognition and metabolism.

  14. Impaired Lipid and Glucose Homeostasis in Hexabromocyclododecane-Exposed Mice Fed a High-Fat Diet

    PubMed Central

    Koike, Eiko; Win-Shwe, Tin-Tin; Yamamoto, Megumi; Takano, Hirohisa

    2014-01-01

    Background: Hexabromocyclododecane (HBCD) is an additive flame retardant used in the textile industry and in polystyrene foam manufacturing. Because of its lipophilicity and persistency, HBCD accumulates in adipose tissue and thus has the potential of causing metabolic disorders through disruption of lipid and glucose homeostasis. However, the association between HBCD and obesity remains unclear. Objectives: We investigated whether exposure to HBCD contributes to initiation and progression of obesity and related metabolic dysfunction in mice fed a normal diet (ND) or a high-fat diet (HFD). Methods: Male C57BL/6J mice were fed a HFD (62.2 kcal% fat) or a ND and treated orally with HBCD (0, 1.75, 35, or 700 μg/kg body weight) weekly from 6 to 20 weeks of age. We examined body weight, liver weight, blood biochemistry, histopathological changes, and gene expression profiles in the liver and adipose tissue. Results: In HFD-fed mice, body and liver weight were markedly increased in mice treated with the high (700 μg/kg) and medium (35 μg/kg) doses of HBCD compared with vehicle. This effect was more prominent in the high-dose group. These increases were paralleled by increases in random blood glucose and insulin levels and enhancement of microvesicular steatosis and macrophage accumulation in adipose tissue. HBCD-treated HFD-fed mice also had increased mRNA levels of Pparg (peroxisome proliferator-activated receptor-γ) in the liver and decreased mRNA levels of Glut4 (glucose transporter 4) in adipose tissue compared with vehicle-treated HFD-fed mice. Conclusions: Our findings suggest that HBCD may contribute to enhancement of diet-induced body weight gain and metabolic dysfunction through disruption of lipid and glucose homeostasis, resulting in accelerated progression of obesity. Citation: Yanagisawa R, Koike E, Win-Shwe TT, Yamamoto M, Takano H. 2014. Impaired lipid and glucose homeostasis in hexabromocyclododecane-exposed mice fed a high-fat diet. Environ Health

  15. A High-Fat Diet Causes Impairment in Hippocampal Memory and Sex-Dependent Alterations in Peripheral Metabolism

    PubMed Central

    Underwood, Erica L.; Thompson, Lucien T.

    2016-01-01

    While high-fat diets are associated with rising incidence of obesity/type-2 diabetes and can induce metabolic and cognitive deficits, sex-dependent comparisons are rarely systematically made. Effects of exclusive consumption of a high-fat diet (HFD) on systemic metabolism and on behavioral measures of hippocampal-dependent memory were compared in young male and female LE rats. Littermates were fed from weaning either a HFD or a control diet (CD) for 12 wk prior to testing. Sex-different effects of the HFD were observed in classic metabolic signs associated with type-2 diabetes. Males fed the HFD became obese, and had elevated fasted blood glucose levels, elevated corticosterone, and impaired glucose-tolerance, while females on the HFD exhibited only elevated corticosterone. Regardless of peripheral metabolism alteration, rats of both sexes fed the HFD were equally impaired in a spatial object recognition memory task associated with impaired hippocampal function. While the metabolic changes reported here have been characterized previously in males, the set of diet-induced effects observed here in females are novel. Impaired memory can have significant cognitive consequences, over the short-term and over the lifespan. A significant need exists for comparative research into sex-dependent differences underlying obesity and metabolic syndromes relating systemic, cognitive, and neural plasticity mechanisms. PMID:26819773

  16. High Glucose Impairs Insulin Signaling in the Glomerulus: An In Vitro and Ex Vivo Approach

    PubMed Central

    Katsoulieris, Elias N.; Drossopoulou, Garyfalia I.; Kotsopoulou, Eleni S.; Vlahakos, Dimitrios V.; Lianos, Elias A.; Tsilibary, Effie C.

    2016-01-01

    Objective Chronic hyperglycaemia, as seen in type II diabetes, results in both morphological and functional impairments of podocytes in the kidney. We investigated the effects of high glucose (HG) on the insulin signaling pathway, focusing on cell survival and apoptotic markers, in immortalized human glomerular cells (HGEC; podocytes) and isolated glomeruli from healthy rats. Methods and Findings HGEC and isolated glomeruli were cultured for various time intervals under HG concentrations in the presence or absence of insulin. Our findings indicated that exposure of HGEC to HG led to downregulation of all insulin signaling markers tested (IR, p-IR, IRS-1, p-Akt, p-Fox01,03), as well as to increased sensitivity to apoptosis (as seen by increased PARP cleavage, Casp3 activation and DNA fragmentation). Short insulin pulse caused upregulation of insulin signaling markers (IR, p-IR, p-Akt, p-Fox01,03) in a greater extent in normoglycaemic cells compared to hyperglycaemic cells and for the case of p-Akt, in a PI3K-dependent manner. IRS-1 phosphorylation of HG-treated podocytes was negatively regulated, favoring serine versus tyrosine residues. Prolonged insulin treatment caused a significant decrease of IR levels, while alterations in glucose concentrations for various time intervals demonstrated changes of IR, p-IR and p-Akt levels, suggesting that the IR signaling pathway is regulated by glucose levels. Finally, HG exerted similar effects in isolated glomeruli. Conclusions These results suggest that HG compromises the insulin signaling pathway in the glomerulus, promoting a proapoptotic environment, with a possible critical step for this malfunction lying at the level of IRS-1 phosphorylation; thus we herein demonstrate glomerular insulin signaling as another target for investigation for the prevention and/ or treatment of diabetic nephropathy. PMID:27434075

  17. Transcriptional Consequence and Impaired Gametogenesis with High-Grade Aneuploidy in Arabidopsis thaliana

    PubMed Central

    Chen, I-Ju; Liu, Yu-Chen; Chung, Mei-Chu; Lo, Wan-Sheng

    2014-01-01

    Aneuploidy features a numerical chromosome variant that the number of chromosomes in the nucleus of a cell is not an exact multiple of the haploid number, which may have an impact on morphology and gene expression. Here we report a tertiary trisomy uncovered by characterizing a T-DNA insertion mutant (aur2-1/+) in the Arabidopsis (Arabidopsis thaliana) AURORA2 locus. Whole-genome analysis with DNA tiling arrays revealed a chromosomal translocation linked to the aur2-1 allele, which collectively accounted for a tertiary trisomy 2. Morphologic, cytogenetic and genetic analyses of aur2-1 progeny showed impaired male and female gametogenesis to various degrees and a tight association of the aur2-1 allele with the tertiary trisomy that was preferentially inherited. Transcriptome analysis showed overlapping and distinct gene expression profiles between primary and tertiary trisomy 2 plants, particularly genes involved in response to stress and various types of external and internal stimuli. Additionally, transcriptome and gene ontology analyses revealed an overrepresentation of nuclear-encoded organelle-related genes functionally involved in plastids, mitochondria and peroxisomes that were differentially expressed in at least three if not all Arabidopsis trisomics. These observations support a previous hypothesis that aneuploid cells have higher energy requirement to overcome the detrimental effects of an unbalanced genome. Moreover, our findings extend the knowledge of the complex nature of the T-DNA insertion event influencing plant genomic integrity by creating high-grade trisomy. Finally, gene expression profiling results provide useful information for future research to compare primary and tertiary trisomics for the effects of aneuploidy on plant cell physiology. PMID:25514186

  18. Mitochondrial function in human skeletal muscle is not impaired by high intensity exercise.

    PubMed

    Tonkonogi, M; Walsh, B; Tiivel, T; Saks, V; Sahlin, K

    1999-03-01

    The hypothesis that high-intensity (HI) intermittent exercise impairs mitochondrial function was investigated with different microtechniques in human muscle samples. Ten male students performed three bouts of cycling at 130% of peak O2 consumption (V.O2,peak). Muscle biopsies were taken from the vastus lateralis muscle at rest, at fatigue and after 110 min recovery. Mitochondrial function was measured both in isolated mitochondria and in muscle fibre bundles made permeable with saponin (skinned fibres). In isolated mitochondria there was no change in maximal respiration, rate of adenosine 5'-triphosphate (ATP) production (measured with bioluminescence) and respiratory control index after exercise or after recovery. The ATP production per consumed oxygen (P/O ratio) also remained unchanged at fatigue but decreased by 4% (P<0.05) after recovery. In skinned fibres, maximal adenosine 5'-diphosphate (ADP)-stimulated respiration increased by 23% from rest to exhaustion (P<0.05) and remained elevated after recovery, whereas the respiratory rates in the absence of ADP and at 0.1 mM ADP (submaximal respiration) were unchanged. The ratio between respiration at 0.1 and 1 mM ADP (ADP sensitivity index) decreased at fatigue (P<0.05) but after the recovery period was not significantly different from that at rest. It is concluded that mitochondrial oxidative potential is maintained or improved during exhaustive HI exercise. The finding that the sensitivity of mitochondrial respiration to ADP is reversibly decreased after strenuous exercise may indicate that the control of mitochondrial respiration is altered.

  19. High prevalence of abnormal circadian blood pressure regulation and impaired glucose tolerance in adults with hypopituitarism.

    PubMed

    Krzyzanowska, K; Schnack, C; Mittermayer, F; Kopp, H P; Hofer, M; Kann, T; Schernthaner, G

    2005-09-01

    Patients with hypopituitarism have an increased mortality from cardiovascular events. Reduced nocturnal blood pressure decline (non-dipping) and impaired glucose tolerance are considered as cardiovascular risk factors. To evaluate the role of these risk factors in patients with hypopituitarism we determined the 24-hour blood pressure regulation and glucose tolerance status in hypopituitary patients with and without growth hormone (GH) deficiency. Sixty-one hypopituitary subjects 5 +/- 3 years after brain surgery because of macroadenoma, 61 patients with type 2 diabetes mellitus (T2DM), and 20 healthy controls were included. Forty-four hypopituitary patients were GH deficient and 28 of these on GH treatment. Non-dipping was observed in 41 % (n = 7) of hypopituitary subjects with normal GH release, in 46 % (n = 13) of patients on GH therapy, and in 69 % (n = 11) of untreated GH deficient patients. Untreated GH deficient patients had a higher systolic night/day ratio (1.00 +/- 0.03) compared to non GH deficient (0.92 +/- 0.02; p < 0.02) and GH treated hypopituitary patients (0.93 +/- 0.01; p < 0.02). The rate of non-dipping in hypopituitarism was comparable to that in T2DM. Pathologic glucose tolerance was diagnosed in 30 % of the hypopituitary patients. The prevalence of non-dipping was independent of glucose metabolism in hypopituitary patients. All controls had normal night time blood pressure fall and glucose metabolism. The high prevalence of nocturnal non-dipping and glucose intolerance detected in this cohort might contribute to the increased cardiovascular risk of hypopituitary patients.

  20. High fat diet impairs the function of glucagon-like peptide-1 producing L-cells

    PubMed Central

    Richards, Paul; Pais, Ramona; Habib, Abdella M.; Brighton, Cheryl A.; Yeo, Giles S.H.; Reimann, Frank; Gribble, Fiona M.

    2016-01-01

    Glucagon-like peptide-1 (GLP-1) acts as a satiety signal and enhances insulin release. This study examined how GLP-1 production from intestinal L-cells is modified by dietary changes. Methods Transgenic mouse models were utilized in which L-cells could be purified by cell specific expression of a yellow fluorescent protein, Venus. Mice were fed on chow or 60% high fat diet (HFD) for 2 or 16 weeks. L-cells were purified by flow cytometry and analysed by microarray and quantitative RT-PCR. Enteroendocrine cell populations were examined by FACS analysis, and GLP-1 secretion was assessed in primary intestinal cultures. Results Two weeks HFD reduced the numbers of GLP-1 positive cells in the colon, and of GIP positive cells in the small intestine. Purified small intestinal L-cells showed major shifts in their gene expression profiles. In mice on HFD for 16 weeks, significant reductions were observed in the expression of L-cell specific genes, including those encoding gut hormones (Gip, Cck, Sct, Nts), prohormone processing enzymes (Pcsk1, Cpe), granins (Chgb, Scg2), nutrient sensing machinery (Slc5a1, Slc15a1, Abcc8, Gpr120) and enteroendocrine-specific transcription factors (Etv1, Isl1, Mlxipl, Nkx2.2 and Rfx6). A corresponding reduction in the GLP-1 secretory responsiveness to nutrient stimuli was observed in primary small intestinal cultures. Conclusion Mice fed on HFD exhibited reduced expression in L-cells of many L-cell specific genes, suggesting an impairment of enteroendocrine cell function. Our results suggest that a western style diet may detrimentally affect the secretion of gut hormones and normal post-prandial signaling, which could impact on insulin secretion and satiety. PMID:26145551

  1. Serum metabolic variables associated with impaired glucose tolerance induced by high-fat-high-cholesterol diet in Macaca mulatta.

    PubMed

    Li, Xinli; Chen, Younan; Liu, Jingping; Yang, Guang; Zhao, Jiuming; Liao, Guangneng; Shi, Meimei; Yuan, Yujia; He, Sirong; Lu, Yanrong; Cheng, Jingqiu

    2012-11-01

    Dyslipidemia caused by 'Western-diet pattern' is a strong risk factor for the onset of diabetes. This study aimed to disclose the relationship between the serum metabolite changes induced by habitual intake of high-fat and high-cholesterol (HFHC) diet and the development of impaired glucose tolerance (IGT) and insulin resistance through animal models of Macaca mulatta. Sixteen M. mulatta (six months old) were fed a control diet or a HFHC diet for 18 months. The diet effect on serum metabolic profiles was investigated by longitudinal research. Islet function was assessed by intravenous glucose tolerance and hyperinsulinemic-euglycemic clamp test. Metabonomics were determined by (1)H proton nuclear magnetic resonance spectroscopy. Prolonged diet-dependent hyperlipidemia facilitated visceral fat accumulation in liver and skeletal muscle and disorder of glucose homeostasis in juvenile monkeys. Glucose disappearance rate (K(Glu)) and insulin response to the glucose challenge effects in HFHC monkeys were significantly lower than in control monkeys. Otherwise, serum trimethylamine-N-oxide (TMAO), lactate and leucine/isoleucine were significantly higher in HFHC monkeys. Sphingomyelin and choline were the most positively correlated with K(Glu) (R(2) = 0.778), as well as negative correlation (R(2) = 0.64) with total cholesterol. The HFHC diet induced visceral fat, abnormal lipid metabolism and IGT prior to weight gain and body fat content increase in juvenile monkeys. We suggest that increased serum metabolites, such as TMAO, lactate, branched-chain amino acids and decreased sphingomyelin and choline, may serve as possible predictors for the evaluation of IGT and insulin resistance risks in the prediabetic state.

  2. High-affinity α4β2 nicotinic receptors mediate the impairing effects of acute nicotine on contextual fear extinction.

    PubMed

    Kutlu, Munir Gunes; Holliday, Erica; Gould, Thomas J

    2016-02-01

    Previously, studies from our lab have shown that while acute nicotine administered prior to training and testing enhances contextual fear conditioning, acute nicotine injections prior to extinction sessions impair extinction of contextual fear. Although there is also strong evidence showing that the acute nicotine's enhancing effects on contextual fear conditioning require high-affinity α4β2 nicotinic acetylcholine receptors (nAChRs), it is unknown which nAChR subtypes are involved in the acute nicotine-induced impairment of contextual fear extinction. In this study, we investigated the effects of acute nicotine administration on contextual fear extinction in knock-out (KO) mice lacking α4, β2 or α7 subtypes of nAChRs and their wild-type (WT) littermates. Both KO and WT mice were first trained and tested for contextual fear conditioning and received a daily contextual extinction session for 4 days. Subjects received intraperitoneal injections of nicotine (0.18 mg/kg) or saline 2-4 min prior to each extinction session. Our results showed that the mice that lack α4 and β2 subtypes of nAChRs showed normal contextual fear extinction but not the acute nicotine-induced impairment while the mice that lack the α7 subtype showed both normal contextual extinction and nicotine-induced impairment of contextual extinction. In addition, control experiments showed that acute nicotine-induced impairment of contextual fear extinction persisted when nicotine administration was ceased and repeated acute nicotine administrations alone did not induce freezing behavior in the absence of context-shock learning. These results clearly demonstrate that high-affinity α4β2 nAChRs are necessary for the effects of acute nicotine on contextual fear extinction.

  3. Inhibition of SGLT2 alleviates diabetic nephropathy by suppressing high glucose-induced oxidative stress in type 1 diabetic mice.

    PubMed

    Hatanaka, Takashi; Ogawa, Daisuke; Tachibana, Hiromi; Eguchi, Jun; Inoue, Tatsuyuki; Yamada, Hiroshi; Takei, Kohji; Makino, Hirofumi; Wada, Jun

    2016-08-01

    It is unclear whether the improvement in diabetic nephropathy by sodium glucose cotransporter 2 (SGLT2) inhibitors is caused by a direct effect on SGLT2 or by the improvement in hyperglycemia. Here, we investigated the effect of dapagliflozin on early-stage diabetic nephropathy using a mouse model of type 1 diabetes and murine proximal tubular epithelial cells. Eight-week-old Akita mice were treated with dapagliflozin or insulin for 12 weeks. Body weight, urinary albumin excretion, blood pressure, as well as levels of blood glucose and hemoglobin A1c were measured. Expansion of the mesangial matrix, interstitial fibrosis, and macrophage infiltration in kidneys were evaluated by histology. Oxidative stress and apoptosis were evaluated in kidneys and cultured proximal tubular epithelial cells. Compared with nontreated mice, dapagliflozin and insulin decreased blood glucose and hemoglobin A1c levels equally. Urine volume and water intake increased significantly in the dapagliflozin-treated group compared with those in the insulin-treated group, but there were no differences in body weight or blood pressure between the two groups. Macrophage infiltration and fibrosis in renal interstitium improved significantly in the dapagliflozin group compared with the insulin group. Oxidative stress was attenuated by dapagliflozin, and suppression occurred in a dose-dependent manner. RNAi knockdown of SGLT2 resulted in reduced oxidative stress. Dapagliflozin ameliorates diabetic nephropathy by suppressing hyperglycemia-induced oxidative stress in a manner independent of hyperglycemia improvement in Akita mice. Our findings suggest that dapagliflozin may be a novel therapeutic approach for the treatment of diabetic nephropathy.

  4. Factors Predicting Post-High School Employment for Young Adults with Visual Impairments

    ERIC Educational Resources Information Center

    McDonnall, Michele Capella

    2010-01-01

    Although low levels of employment among transition-age youth with visual impairments (VI) have long been a concern, empirical research in this area is very limited. The purpose of this study was to identify factors that predict future employment for this population and to compare these factors to the factors that predict employment for the general…

  5. An Investigation of the Career Development of High School Adolescents with Hearing Impairments in New Zealand.

    ERIC Educational Resources Information Center

    Furlonger, Brett

    1998-01-01

    A survey compared the career development and vocational maturity of 26 New Zealand adolescents with deafness and their hearing peers. Significant differences were identified between the two groups on career measures. In particular, adolescents with hearing impairments were identified as having less career awareness. Gender differences were also…

  6. Impaired Timing and Frequency Discrimination in High-Functioning Autism Spectrum Disorders

    ERIC Educational Resources Information Center

    Bhatara, Anjali; Babikian, Talin; Laugeson, Elizabeth; Tachdjian, Raffi; Sininger, Yvonne S.

    2013-01-01

    Individuals with autism spectrum disorders (ASD) frequently demonstrate preserved or enhanced frequency perception but impaired timing perception. The present study investigated the processing of spectral and temporal information in 12 adolescents with ASD and 15 age-matched controls. Participants completed two psychoacoustic tasks: one determined…

  7. A high fat diet-induced impaired glucose metabolism in mice with targeted deletion of calpain in osteoblasts.

    PubMed

    Kashiwagi, Aki; Fein, Mikaela J; Shimada, Masako

    2011-06-03

    The ubiquitously expressed Calpains 1 and 2 belong to a family of calcium-dependent intracellular cysteine proteases. Both calpains are heterodimers consisting of a large subunit and a small regulatory subunit encoded by the gene Capns1. To investigate a role for the calpain small subunit in cells of the osteoblast lineage in vivo, we previously generated osteoblast-specific Capns1 knockout mice and characterized their bone phenotype. In this study, we further examined effects of low calcium and high fat diets on their bone, fat, and glucose homeostasis. Osteoblast-specific Capns1 knockout mice showed significantly reduced serum levels of total and uncarboxylated osteocalcin, and this was presumably due to their impaired bone formation and bone resorption. The reduced bone resorptive function of the mutant mice was also significant under a low calcium diet. Thus, these results suggest that reduced uncarboxylated osteocalcin levels of mutant mice were, at least in part, due to their osteoporotic bone with impaired bone resorptive function. Interestingly, unlike osteocalcin knockout mice, mutant mice on a normal chow diet were leaner than control littermates; this was likely due to their reduced food intake and overall lower energy homeostasis. To test this hypothesis, we next provided mutant mice with a high fat diet and further examined an effect of their reduced uncarboxylated osteocalcin levels on body composition and glucose metabolism. The average mean body weight of mutant mice became indistinguishable with that of controls after 2 weeks on a high fat diet, and continued to show an upward trend, at least, up to 6weeks. Moreover, mutant mice on a high fat diet exhibited a significant increase in serum levels of leptin and resistin, adipocyte-specific adipokines, and developed impaired glucose tolerance. Collectively, mice with osteoporosis and reduced bone resorptive function showed reduced serum uncarboxylated osteocalcin levels and were susceptible to

  8. Progression of impairment in adolescents with attention-deficit/hyperactivity disorder through the transition out of high school: Contributions of parent involvement and college attendance.

    PubMed

    Howard, Andrea L; Strickland, Noelle J; Murray, Desiree W; Tamm, Leanne; Swanson, James M; Hinshaw, Stephen P; Arnold, L Eugene; Molina, Brooke S G

    2016-02-01

    Long-term, prospective follow-up studies of children diagnosed with attention-deficit/hyperactivity disorder (ADHD) show that symptoms tend to decline with age, but impairments in daily life functioning often persist into adulthood. We examined the developmental progression of impairments before and after the transition out of high school in relation to parent involvement during adolescence, parent support during adulthood, and college attendance, using 8 waves of data from the prospective 16-year follow-up of the Multimodal Treatment of ADHD (MTA) study. Participants were 548 proband children diagnosed with Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV; American Psychiatric Association, 2000) ADHD Combined Type and 258 age- and sex-matched comparison children (Local Normative Comparison Group; LNCG) randomly sampled from probands' schools. Impairment was assessed consistently by parent report from childhood through adulthood. Results showed that impairment worsens over time both before and after the transition to adulthood for those with ADHD histories, in contrast to non-ADHD peers, whose impairments remained stably low over time. However, impairment stabilized after leaving high school for young adults with ADHD histories who attended college. Involved parenting in adolescence was associated with less impairment overall. Attending college was associated with a stable post-high school trajectory of impairment regardless of parents' involvement during adolescence, but young adults with histories of involved parenting and who attended college were the least impaired overall.

  9. Progression of impairment in adolescents with ADHD through the transition out of high school: Contributions of parent involvement and college attendance

    PubMed Central

    Howard, Andrea L.; Strickland, Noelle; Murray, Desiree W.; Tamm, Leanne; Swanson, James M.; Hinshaw, Stephen P.; Arnold, L. Eugene; Molina, Brooke S. G.

    2016-01-01

    Long-term, prospective follow-up studies of children diagnosed with Attention-Deficit/Hyperactivity Disorder (ADHD) show that symptoms tend to decline with age, but impairments in daily life functioning often persist into adulthood. We examined the developmental progression of impairments before and after the transition out of high school in relation to parent involvement during adolescence, parent support during adulthood, and college attendance, using 8 waves of data from the prospective 16-year follow-up of the Multimodal Treatment of ADHD (MTA) Study. Participants were 548 proband children diagnosed with DSM-IV ADHD Combined Type and 258 age- and sex-matched comparison children (Local Normative Comparison Group; LNCG) randomly sampled from probands' schools. Impairment was assessed consistently by parent report from childhood through adulthood. Results showed that impairment worsens over time both before and after the transition to adulthood for those with ADHD histories, in contrast to non-ADHD peers, whose impairments remained stably low over time. However, impairment stabilized after leaving high school for young adults with ADHD histories who attended college. Involved parenting in adolescence was associated with less impairment overall. Attending college was associated with a stable post-high school trajectory of impairment regardless of parents' involvement during adolescence, but young adults with histories of involved parenting and who attended college were the least impaired overall. PMID:26854508

  10. Excess glucose induces hypoxia-inducible factor-1α in pancreatic cancer cells and stimulates glucose metabolism and cell migration

    PubMed Central

    Liu, Zhiwen; Jia, Xiaohui; Duan, Yijie; Xiao, Huijie; Sundqvist, Karl-Gösta; Permert, Johan; Wang, Feng

    2013-01-01

    Pancreatic cancer patients frequently show hyperglycemia, but it is uncertain whether hyperglycemia stimulates pancreatic cancer cells. We have investigated whether excess glucose induces hypoxia-inducible factor-1α (HIF-1α) and stimulates glucose metabolism and cell migration in pancreatic cancer cells. We studied wild-type (wt) MiaPaCa2 pancreatic cancer cells and a MiaPaCa2 subline (namely si-MiaPaCa2) that had HIF-1α-specific small interfering RNA. Wt-MiaPaCa2 cells are known to be HIF-1α-positive in hypoxia and HIF-1α-negative in normoxia, whereas si-MiaPaCa2 cells are devoid of HIF-1α in both normoxia and hypoxia. We incubated these cells with different amounts of glucose and determined HIF-1α mRNA and protein by real-time polymerase chain reaction and western blotting. We determined glucose consumption, lactate production and intracellular hexokinase-II and ATP to assess glucose metabolisms and determined pyruvate dehydrogenase kinase-1, reactive oxygen species and fumarate to assess mitochondrial activities. Further, we studied cell migration using a Boyden chamber. Excess glucose (16.7−22.2mM) increased HIF-1α in hypoxic wt-MiaPaCa2 cells. HIF-1α expression increased ATP contents and inhibited mitochondrial activities. Extracellular glucose and hypoxia stimulated glucose metabolisms independent of HIF-1α. Excess glucose stimulated the migration of wt- and si-MiaPaCa2 cells in both normoxia and hypoxia. Thus, glucose stimulated cell migration independent of HIF-1α. Nevertheless, hypoxic wt-MiaPaCa2 cells showed greater migrating ability than their si-MiaPaCa2 counterparts. We conclude that (1) excess glucose increases HIF-1α and ATP in hypoxic wt-MiaPaCa2 cells, (2) extracellular glucose and hypoxia regulate glucose metabolisms independent of HIF-1α and (3) glucose stimulates cell migration by mechanisms that are both dependent on HIF-1α and independent of it. PMID:23377827

  11. Estimates of compression at low and high frequencies using masking additivity in normal and impaired ears

    PubMed Central

    Plack, Christopher J.; Oxenham, Andrew J.; Simonson, Andrea M.; O’Hanlon, Catherine G.; Drga, Vit; Arifianto, Dhany

    2008-01-01

    Auditory compression was estimated at 250 and 4000 Hz by using the additivity of forward masking technique, which measures the effects on signal threshold of combining two temporally nonoverlapping forward maskers. The increase in threshold in the combined-masker condition compared to the individual-masker conditions can be used to estimate compression. The signal was a 250 or 4000 Hz tone burst and the maskers (M1 and M2) were bands of noise. Signal thresholds were measured in the presence of M1 and M2 alone and combined for a range of masker levels. The results were used to derive response functions at each frequency. The procedure was conducted with normal-hearing and hearing-impaired listeners. The results suggest that the response function in normal ears is similar at 250 and 4000 Hz with a mid level compression exponent of about 0.2. However, compression extends over a smaller range of levels at 250 Hz. The results confirm previous estimates of compression using temporal masking curves (TMCs) without assuming a linear off-frequency reference as in the TMC procedure. The impaired ears generally showed less compression. Importantly, some impaired ears showed a linear response at 250 Hz, providing a further indication that low-frequency compression originates in the cochlea. PMID:18537383

  12. Visual Impairment

    MedlinePlus

    ... Loss Surgery? A Week of Healthy Breakfasts Shyness Visual Impairment KidsHealth > For Teens > Visual Impairment Print A ... with the brain, making vision impossible. What Is Visual Impairment? Many people have some type of visual ...

  13. Lipid mixtures containing a very high proportion of saturated fatty acids only modestly impair insulin signaling in cultured muscle cells.

    PubMed

    Newsom, Sean A; Everett, Allison C; Park, Sanghee; Van Pelt, Douglas W; Hinko, Alexander; Horowitz, Jeffrey F

    2015-01-01

    In vitro examinations of the effect of saturated fatty acids on skeletal muscle insulin action often use only one or two different fatty acid species, which does not resemble the human plasma fatty acid profile. We compared graded concentrations (0.1-0.8 mM) of 3 different lipid mixtures: 1) a physiologic fatty acid mixture (NORM; 40% saturated fatty acids), 2) a physiologic mixture high in saturated fatty acids (HSFA; 60% saturated fatty acids), and 3) 100% palmitate (PALM) on insulin signaling and fatty acid partitioning into triacylglycerol (TAG) and diacylglycerol (DAG) in cultured muscle cells. As expected, PALM readily impaired insulin-stimulated pAktThr308/Akt and markedly increased intracellular DAG content. In contrast, the fatty acid mixtures only modestly impaired insulin-stimulated pAktThr308M/Akt, and we found no differences between NORM and HSFA. Importantly, NORM and HSFA did not increase DAG content, but instead dose-dependently increased TAG accumulation. Therefore, the robust impairment in insulin signaling found with palmitate exposure was attenuated with physiologic mixtures of fatty acids, even with a very high proportion of saturated fatty acids. This may be explained in part by selective partitioning of fatty acids into neutral lipid (i.e., TAG) when muscle cells were exposed to physiologic lipid mixtures.

  14. Highly Conserved Testicular Localization of Claudin-11 in Normal and Impaired Spermatogenesis

    PubMed Central

    Stammler, Angelika; Lüftner, Benjamin Udo; Kliesch, Sabine; Weidner, Wolfgang; Bergmann, Martin; Middendorff, Ralf; Konrad, Lutz

    2016-01-01

    In this study we tested expression of tight junction proteins in human, mouse and rat and analyzed the localization of claudin-11 in testis of patients with normal and impaired spermatogenesis. Recent concepts generated in mice suggest that the stage-specifically expressed claudin-3 acts as a basal barrier, sealing the seminiferous epithelium during migration of spermatocytes. Corresponding mechanisms have never been demonstrated in humans. Testicular biopsies (n = 103) from five distinct groups were analyzed: normal spermatogenesis (NSP, n = 28), hypospermatogenesis (Hyp, n = 24), maturation arrest at the level of primary spermatocytes (MA, n = 24), Sertoli cell only syndrome (SCO, n = 19), and spermatogonial arrest (SGA, n = 8). Protein expression of claudin-3, -11 and occludin was analyzed. Human, mice and rat testis robustly express claudin-11 protein. Occludin was detected in mouse and rat and claudin-3 was found only in mice. Thus, we selected claudin-11 for further analysis of localization. In NSP, claudin-11 is located at Sertoli-Sertoli junctions and in Sertoli cell contacts towards spermatogonia. Typically, claudin-11 patches do not reach the basal membrane, unless flanked by the Sertoli cell body or patches between two Sertoli cell bodies. The amount of basal claudin-11 patches was found to be increased in impaired spermatogenesis. Only claudin-11 is expressed in all three species examined. The claudin-11 pattern is robust in man with impaired spermatogenesis, but the proportion of localization is altered in SCO and MA. We conclude that claudin-11 might represent the essential component of the BTB in human. PMID:27486954

  15. Maternal high-fat diet impairs cardiac function in offspring of diabetic pregnancy through metabolic stress and mitochondrial dysfunction

    PubMed Central

    Mdaki, Kennedy S.; Larsen, Tricia D.; Wachal, Angela L.; Schimelpfenig, Michelle D.; Weaver, Lucinda J.; Dooyema, Samuel D. R.; Louwagie, Eli J.

    2016-01-01

    Offspring of diabetic pregnancies are at risk of cardiovascular disease at birth and throughout life, purportedly through fuel-mediated influences on the developing heart. Preventative measures focus on glycemic control, but the contribution of additional offenders, including lipids, is not understood. Cellular bioenergetics can be influenced by both diabetes and hyperlipidemia and play a pivotal role in the pathophysiology of adult cardiovascular disease. This study investigated whether a maternal high-fat diet, independently or additively with diabetes, could impair fuel metabolism, mitochondrial function, and cardiac physiology in the developing offspring's heart. Sprague-Dawley rats fed a control or high-fat diet were administered placebo or streptozotocin to induce diabetes during pregnancy and then delivered offspring from four groups: control, diabetes exposed, diet exposed, and combination exposed. Cardiac function, cellular bioenergetics (mitochondrial stress test, glycolytic stress test, and palmitate oxidation assay), lipid peroxidation, mitochondrial histology, and copy number were determined. Diabetes-exposed offspring had impaired glycolytic and respiratory capacity and a reduced proton leak. High-fat diet-exposed offspring had increased mitochondrial copy number, increased lipid peroxidation, and evidence of mitochondrial dysfunction. Combination-exposed pups were most severely affected and demonstrated cardiac lipid droplet accumulation and diastolic/systolic cardiac dysfunction that mimics that of adult diabetic cardiomyopathy. This study is the first to demonstrate that a maternal high-fat diet impairs cardiac function in offspring of diabetic pregnancies through metabolic stress and serves as a critical step in understanding the role of cellular bioenergetics in developmentally programmed cardiac disease. PMID:26801311

  16. Social Communication Disorder outside Autism? A Diagnostic Classification Approach to Delineating Pragmatic Language Impairment, High Functioning Autism and Specific Language Impairment

    ERIC Educational Resources Information Center

    Gibson, Jenny; Adams, Catherine; Lockton, Elaine; Green, Jonathan

    2013-01-01

    Background: Developmental disorders of language and communication present considerable diagnostic challenges due to overlapping of symptomatology and uncertain aetiology. We aimed to further elucidate the behavioural and linguistic profile associated with impairments of social communication occurring outside of an autism diagnosis. Methods: Six to…

  17. High Tech Aids Low Vision: A Review of Image Processing for the Visually Impaired

    PubMed Central

    Moshtael, Howard; Aslam, Tariq; Underwood, Ian; Dhillon, Baljean

    2015-01-01

    Recent advances in digital image processing provide promising methods for maximizing the residual vision of the visually impaired. This paper seeks to introduce this field to the readership and describe its current state as found in the literature. A systematic search revealed 37 studies that measure the value of image processing techniques for subjects with low vision. The techniques used are categorized according to their effect and the principal findings are summarized. The majority of participants preferred enhanced images over the original for a wide range of enhancement types. Adapting the contrast and spatial frequency content often improved performance at object recognition and reading speed, as did techniques that attenuate the image background and a technique that induced jitter. A lack of consistency in preference and performance measures was found, as well as a lack of independent studies. Nevertheless, the promising results should encourage further research in order to allow their widespread use in low-vision aids. PMID:26290777

  18. High education may offer protection against tauopathy in patients with mild cognitive impairment.

    PubMed

    Rolstad, Sindre; Nordlund, Arto; Eckerström, Carl; Gustavsson, Marie H; Blennow, Kaj; Olesen, Pernille J; Zetterberg, Henrik; Wallin, Anders

    2010-01-01

    The concepts of brain and cognitive reserve stem from the observation that premorbid factors (e.g., education) result in variation in the response to brain pathology. Potential early influence of reserve on pathology, as assessed using the cerebrospinal fluid biomarkers total tau (t-tau) and amyloid-beta42, and cognition was explored in mild cognitive impairment (MCI) patients who remained stable over a two-year period. A total of 102 patients with stable MCI grouped on the basis of educational level were compared with regard to biomarker concentrations and cognitive performance. Stable MCI patients with higher education had lower concentrations of t-tau as compared to those with lower education. Also, educational level predicted a significant proportion of the total variance in t-tau concentrations. Our results suggest that higher education may offer protection against tauopathy.

  19. High Tech Aids Low Vision: A Review of Image Processing for the Visually Impaired.

    PubMed

    Moshtael, Howard; Aslam, Tariq; Underwood, Ian; Dhillon, Baljean

    2015-08-01

    Recent advances in digital image processing provide promising methods for maximizing the residual vision of the visually impaired. This paper seeks to introduce this field to the readership and describe its current state as found in the literature. A systematic search revealed 37 studies that measure the value of image processing techniques for subjects with low vision. The techniques used are categorized according to their effect and the principal findings are summarized. The majority of participants preferred enhanced images over the original for a wide range of enhancement types. Adapting the contrast and spatial frequency content often improved performance at object recognition and reading speed, as did techniques that attenuate the image background and a technique that induced jitter. A lack of consistency in preference and performance measures was found, as well as a lack of independent studies. Nevertheless, the promising results should encourage further research in order to allow their widespread use in low-vision aids.

  20. Impaired inactivation of digestive proteases: The possible key factor for the high susceptibility of germ-free and antibiotic-treated animals to gut epithelial injury

    PubMed Central

    Qin, Xiaofa

    2017-01-01

    Recent study shows that germ-free and antibiotic-treated animals are highly susceptible to gut epithelial injury. This paper addresses that impaired inactivation of digestive proteases may be the key factor for the increased susceptibility. PMID:28251033

  1. Impaired inactivation of digestive proteases: The possible key factor for the high susceptibility of germ-free and antibiotic-treated animals to gut epithelial injury.

    PubMed

    Qin, Xiaofa

    2017-02-15

    Recent study shows that germ-free and antibiotic-treated animals are highly susceptible to gut epithelial injury. This paper addresses that impaired inactivation of digestive proteases may be the key factor for the increased susceptibility.

  2. Are the High Hip Fracture Rates Among Norwegian Women Explained by Impaired Bone Material Properties?

    PubMed

    Duarte Sosa, Daysi; Vilaplana, Laila; Güerri, Roberto; Nogués, Xavier; Wang-Fagerland, Morten; Diez-Perez, Adolfo; F Eriksen, Erik

    2015-10-01

    Hip fracture rates in Norway rank among the highest in the world, more than double that of Spanish women. Previous studies were unable to demonstrate significant differences between the two populations with respect to bone mass or calcium metabolism. In order to test whether the difference in fracture propensity between both populations could be explained by differences in bone material quality we assessed bone material strength using microindentation in 42 Norwegian and 46 Spanish women with normal BMD values, without clinical or morphometric vertebral fractures, no clinical or laboratory signs of secondary osteoporosis, and without use of drugs with known influence on bone metabolism. Bone material properties were assessed by microindentation of the thick cortex of the mid tibia following local anesthesia of the area using the Osteoprobe device (Active Life Scientific, Santa Barbara, CA, USA). Indentation distance was standardized against a calibration phantom of methylmethacrylate and results, as percentage of this reference value, expressed as bone material strength index units (BMSi). We found that the bone material properties reflected in the BMSi value of Norwegian women was significantly inferior when compared to Spanish women (77 ± 7.1 versus 80.7 ± 7.8, p < 0.001). Total hip BMD was significantly higher in Norwegian women (1.218 g/cm(2) versus 0.938 g/cm(2) , p < 0.001) but regression analysis revealed that indentation values did not vary with BMD r(2)  = 0.03 or age r(2)  = 0.04. In conclusion Norwegian women show impaired bone material properties, higher bone mass, and were taller than Spanish women. The increased height will increase the impact on bone after falls, and impaired bone material properties may further enhance the risk fracture after such falls. These ethnic differences in bone material properties may partly explain the higher propensity for fracture in Norwegian women.

  3. Auditory working memory impairments in individuals at familial high risk for schizophrenia

    PubMed Central

    Seidman, Larry J.; Meyer, Eric C.; Giuliano, Anthony J.; Breiter, Hans C.; Goldstein, Jill M.; Kremen, William S.; Thermenos, Heidi W.; Toomey, Rosemary; Stone, William S.; Tsuang, Ming T.; Faraone, Stephen V.

    2012-01-01

    Objectives The search for predictors of schizophrenia has accelerated with a growing focus on early intervention and prevention of psychotic illness. Studying nonpsychotic relatives of individuals with schizophrenia enables identification of markers of vulnerability for the illness independent of confounds associated with psychosis. The goal of these studies was to develop new auditory continuous performance tests (ACPTs) and evaluate their effects in individuals with schizophrenia and their relatives. Methods We carried out two studies of auditory vigilance with tasks involving working memory (WM) and interference control with increasing levels of cognitive load to discern the information processing vulnerabilities in a sample of schizophrenia patients, and two samples of nonpsychotic relatives of individuals with schizophrenia and controls. Study 1 assessed adults (mean age = 41), and Study 2 assessed teenagers and young adults age 13-25 (mean =19). Results Patients with schizophrenia were impaired on all five versions of the ACPTs, while relatives were impaired only on WM tasks, particularly the two interference tasks that maximize cognitive load. Across all groups, the interference tasks were more difficult to perform than the other tasks. Schizophrenia patients performed worse than relatives who performed worse than controls. For patients, the effect sizes were large (Cohen’s d =1.5), whereas for relatives, they were moderate (d = ~0.40-0.50). There was no age by group interaction in the relatives –control comparison except for participants <31 years of age. Conclusions Novel WM tasks that manipulate cognitive load and interference control index an important component of the vulnerability to schizophrenia. PMID:22563872

  4. Thermosensing mechanisms and their impairment by high-fat diet in orexin neurons.

    PubMed

    Belanger-Willoughby, N; Linehan, V; Hirasawa, M

    2016-06-02

    In homeotherms, the hypothalamus controls thermoregulatory and adaptive mechanisms in energy balance, sleep-wake and locomotor activity to maintain optimal body temperature. Orexin neurons may be involved in these functions as they promote thermogenesis, food intake and behavioral arousal, and are sensitive to temperature and metabolic status. How thermal and energy balance signals are integrated in these neurons is unknown. Thus, we investigated the cellular mechanisms of thermosensing in orexin neurons and their response to a change in energy status using whole-cell patch clamp on rat brain slices. We found that warming induced an increase in miniature excitatory postsynaptic current (EPSC) frequency, which was blocked by the transient receptor potential vanilloid-1 (TRPV1) receptor antagonist AMG9810 and mimicked by its agonist capsaicin, suggesting that the synaptic effect is mediated by heat-sensitive TRPV1 channels. Furthermore, warming inhibits orexin neurons by activating ATP-sensitive potassium (KATP) channels, an effect regulated by uncoupling protein 2 (UCP2), as the UCP2 inhibitor genipin abolished this response. These properties are unique to orexin neurons in the lateral hypothalamus, as neighboring melanin-concentrating hormone neurons showed no response to warming within the physiological temperature range. Interestingly, in rats fed with western diet for 1 or 11weeks, orexin neurons had impaired synaptic and KATP response to warming. In summary, this study reveals several mechanisms underlying thermosensing in orexin neurons and their attenuation by western diet. Overeating induced by western diet may in part be due to impaired orexin thermosensing, as post-prandial thermogenesis may promote satiety and lethargy by inhibiting orexin neurons.

  5. Impaired-Driving Prevalence Among US High School Students: Associations With Substance Use and Risky Driving Behaviors

    PubMed Central

    Li, Kaigang; Simons-Morton, Bruce G.; Hingson, Ralph

    2013-01-01

    Objectives. We examined the prevalence of impaired driving among US high school students and associations with substance use and risky driving behavior. Methods. We assessed driving while alcohol or drug impaired (DWI) and riding with alcohol- or drug-impaired drivers (RWI) in a nationally representative sample of 11th-grade US high school students (n = 2431). We examined associations with drinking and binge drinking, illicit drug use, risky driving, and demographic factors using multivariate sequential logistic regression analysis. Results. Thirteen percent of 11th-grade students reported DWI at least 1 of the past 30 days, and 24% reported RWI at least once in the past year. Risky driving was positively associated with DWI (odds ratio [OR] = 1.25; P < .001) and RWI (OR = 1.09; P < .05), controlling for binge drinking (DWI: OR = 3.17; P < .01; RWI: OR = 6.12; P < .001) and illicit drug use (DWI: OR = 5.91; P < .001; RWI: OR = 2.29; P = .05). DWI was higher for adolescents who drove after midnight (OR = 15.7), drove while sleepy or drowsy (OR = 8.6), read text messages (OR = 11.8), sent text messages (OR = 5.0), and made cell phone calls (OR = 3.2) while driving. Conclusions. Our findings suggest the need for comprehensive approaches to the prevention of DWI, RWI, and other risky driving behavior. PMID:24028236

  6. Shell-Less Chick Embryo Culture as an Alternative in vitro Model to Investigate Glucose-Induced Malformations in Mammalian Embryos

    PubMed Central

    Datar, Savita; Bhonde, Ramesh R.

    2005-01-01

    We have developed a simple shell-less chick embryo culture system to study glucose-induced malformations. This system involves the culturing of chick embryos from the second day to the fifth day of incubation, with associated yolk and thick and thin albumen outside the egg shell. The system allows the observation of embryonic development of chicks in a glass bowl. Developing embryos at 24 h, 48 h and 72 h incubation, corresponding to the Hamberger Hamilton (HH) stages from 7 to 21, were treated with two concentrations of glucose (50 mM and 100 mM) for 24 h. Glucose treatment resulted in a mortality rate of over 70% in younger embryos. Furthermore, a variety of malformations such as retarded growth, abnormal heart development, macrosomia, exencephaly, etc. were observed in older embryos, which were similar to those reported in mammalian embryos as a consequence of diabetic pregnancy. The glucose-induced malformations were found to be concentration- and stage-dependent, thus emphasizing the roles of the degree of hyperglycemia and the stage of embryonic development in diabetic growth anomalies. Here we demonstrate for the first time that the present system can be used (i) for experiments at early stages of chick embryo development and (ii) for assessing the effects of acute glucose toxicity similar to those reported for mammalian embryos in a hyperglycemic environment. PMID:17491698

  7. Increased Glucose-induced Secretion of Glucagon-like Peptide-1 in Mice Lacking the Carcinoembryonic Antigen-related Cell Adhesion Molecule 2 (CEACAM2)*

    PubMed Central

    Ghanem, Simona S.; Heinrich, Garrett; Lester, Sumona G.; Pfeiffer, Verena; Bhattacharya, Sumit; Patel, Payal R.; DeAngelis, Anthony M.; Dai, Tong; Ramakrishnan, Sadeesh K.; Smiley, Zachary N.; Jung, Dae Y.; Lee, Yongjin; Kitamura, Tadahiro; Ergun, Suleyman; Kulkarni, Rohit N.; Kim, Jason K.; Giovannucci, David R.; Najjar, Sonia M.

    2016-01-01

    Carcinoembryonic antigen-related cell adhesion molecule 2 (CEACAM2) regulates food intake as demonstrated by hyperphagia in mice with the Ceacam2 null mutation (Cc2−/−). This study investigated whether CEACAM2 also regulates insulin secretion. Ceacam2 deletion caused an increase in β-cell secretory function, as assessed by hyperglycemic clamp analysis, without affecting insulin response. Although CEACAM2 is expressed in pancreatic islets predominantly in non-β-cells, basal plasma levels of insulin, glucagon and somatostatin, islet areas, and glucose-induced insulin secretion in pooled Cc2−/− islets were all normal. Consistent with immunofluorescence analysis showing CEACAM2 expression in distal intestinal villi, Cc2−/− mice exhibited a higher release of oral glucose-mediated GLP-1, an incretin that potentiates insulin secretion in response to glucose. Compared with wild type, Cc2−/− mice also showed a higher insulin excursion during the oral glucose tolerance test. Pretreating with exendin(9–39), a GLP-1 receptor antagonist, suppressed the effect of Ceacam2 deletion on glucose-induced insulin secretion. Moreover, GLP-1 release into the medium of GLUTag enteroendocrine cells was increased with siRNA-mediated Ceacam2 down-regulation in parallel to an increase in Ca2+ entry through L-type voltage-dependent Ca2+ channels. Thus, CEACAM2 regulates insulin secretion, at least in part, by a GLP-1-mediated mechanism, independent of confounding metabolic factors. PMID:26586918

  8. The Development of Multisensory Integration in High-Functioning Autism: High-Density Electrical Mapping and Psychophysical Measures Reveal Impairments in the Processing of Audiovisual Inputs

    PubMed Central

    Brandwein, Alice B.; Foxe, John J.; Butler, John S.; Russo, Natalie N.; Altschuler, Ted S.; Gomes, Hilary; Molholm, Sophie

    2013-01-01

    Successful integration of auditory and visual inputs is crucial for both basic perceptual functions and for higher-order processes related to social cognition. Autism spectrum disorders (ASD) are characterized by impairments in social cognition and are associated with abnormalities in sensory and perceptual processes. Several groups have reported that individuals with ASD are impaired in their ability to integrate socially relevant audiovisual (AV) information, and it has been suggested that this contributes to the higher-order social and cognitive deficits observed in ASD. However, successful integration of auditory and visual inputs also influences detection and perception of nonsocial stimuli, and integration deficits may impair earlier stages of information processing, with cascading downstream effects. To assess the integrity of basic AV integration, we recorded high-density electrophysiology from a cohort of high-functioning children with ASD (7–16 years) while they performed a simple AV reaction time task. Children with ASD showed considerably less behavioral facilitation to multisensory inputs, deficits that were paralleled by less effective neural integration. Evidence for processing differences relative to typically developing children was seen as early as 100 ms poststimulation, and topographic analysis suggested that children with ASD relied on different cortical networks during this early multisensory processing stage. PMID:22628458

  9. Visual short-term memory for high resolution associations is impaired in patients with medial temporal lobe damage.

    PubMed

    Koen, Joshua D; Borders, Alyssa A; Petzold, Michael T; Yonelinas, Andrew P

    2017-02-01

    The medial temporal lobe (MTL) plays a critical role in episodic long-term memory, but whether the MTL is necessary for visual short-term memory is controversial. Some studies have indicated that MTL damage disrupts visual short-term memory performance whereas other studies have failed to find such evidence. To account for these mixed results, it has been proposed that the hippocampus is critical in supporting short-term memory for high resolution complex bindings, while the cortex is sufficient to support simple, low resolution bindings. This hypothesis was tested in the current study by assessing visual short-term memory in patients with damage to the MTL and controls for high resolution and low resolution object-location and object-color associations. In the location tests, participants encoded sets of two or four objects in different locations on the screen. After each set, participants performed a two-alternative forced-choice task in which they were required to discriminate the object in the target location from the object in a high or low resolution lure location (i.e., the object locations were very close or far away from the target location, respectively). Similarly, in the color tests, participants were presented with sets of two or four objects in a different color and, after each set, were required to discriminate the object in the target color from the object in a high or low resolution lure color (i.e., the lure color was very similar or very different, respectively, to the studied color). The patients were significantly impaired in visual short-term memory, but importantly, they were more impaired for high resolution object-location and object-color bindings. The results are consistent with the proposal that the hippocampus plays a critical role in forming and maintaining complex, high resolution bindings. © 2016 Wiley Periodicals, Inc.

  10. Self-rated social skills predict visual perception: impairments in object discrimination requiring transient attention associated with high autistic tendency.

    PubMed

    Laycock, Robin; Cross, Alana Jade; Dalle Nogare, Felicity; Crewther, Sheila Gillard

    2014-02-01

    Autism is usually defined by impairments in the social domain but has also been linked to deficient dorsal visual stream processing. However, inconsistent findings make the nature of this relationship unclear and thus, we examined the role of stimulus-driven transient attention, presumably activated by the dorsal stream in autistic tendency. Contrast thresholds for object discrimination were compared between groups with high and low self-rated autistic tendency utilizing the socially based Autism Spectrum Quotient (AQ). Visual stimuli were presented with either abrupt or with ramped contrast onsets/offsets in order to manipulate the demands of transient attention. Larger impairments in performance of abrupt compared with ramped object presentation were established in the high AQ group. Furthermore, self-reported social skills predicted abrupt task performance, suggesting an important visual perception deficiency in autism-related traits. Autism spectrum disorder may be associated with reduced utilization of the dorsal stream to rapidly activate attention prior to ventral stream processing when stimuli are transient.

  11. Restoration of autophagy alleviates hepatic ER stress and impaired insulin signalling transduction in high fructose-fed male mice.

    PubMed

    Wang, Hao; Sun, Ruo-Qiong; Zeng, Xiao-Yi; Zhou, Xiu; Li, Songpei; Jo, Eunjung; Molero, Juan C; Ye, Ji-Ming

    2015-01-01

    High-carbohydrate (mainly fructose) consumption is a major dietary factor for hepatic insulin resistance, involving endoplasmic reticulum (ER) stress and lipid accumulation. Because autophagy has been implicated in ER stress, the present study investigated the role of autophagy in high-fructose (HFru) diet-induced hepatic ER stress and insulin resistance in male C57BL/6J mice. The results show that chronic HFru feeding induced glucose intolerance and impaired insulin signaling transduction in the liver, associated with ER stress and the accumulation of lipids. Intriguingly, hepatic autophagy was suppressed as a result of activation of mammalian target of rapamycin. The suppressed autophagy was detected within 6 hours after HFru feeding along with activation of both inositol-requiring enzyme 1 and protein kinase RNA-like endoplasmic reticulum kinase pathways. These events occurred prior to lipid accumulation or lipogenesis and were sufficient to blunt insulin signaling transduction with activation of c-Jun N-terminal kinase/inhibitory-κB kinase and serine phosphorylation of insulin receptor substrate 1. The stimulation of autophagy attenuated ER stress- and c-Jun N-terminal kinase/inhibitory-κB kinase-associated impairment in insulin signaling transduction in a mammalian target of rapamycin -independent manner. Taken together, our data suggest that restoration of autophagy functions disrupted by fructose is able to alleviate ER stress and improve insulin signaling transduction.

  12. A high-fat high-sugar diet-induced impairment in place-recognition memory is reversible and training-dependent.

    PubMed

    Tran, Dominic M D; Westbrook, R Frederick

    2017-03-01

    A high-fat high-sugar (HFHS) diet is associated with cognitive deficits in people and produces spatial learning and memory deficits in rodents. Notable, such diets rapidly impair place-, but not object-recognition memory in rats within one week of exposure. Three experiments examined whether this impairment was reversed by removal of the diet, or prevented by pre-diet training. Experiment 1 showed that rats switched from HFHS to chow recovered from the place-recognition impairment that they displayed while on HFHS. Experiment 2 showed that control rats ("Untrained") who were exposed to an empty testing arena while on chow, were impaired in place-recognition when switched to HFHS and tested for the first time. However, rats tested ("Trained") on the place and object task while on chow, were protected from the diet-induce deficit and maintained good place-recognition when switched to HFHS. Experiment 3 examined the conditions of this protection effect by training rats in a square arena while on chow, and testing them in a rectangular arena while on HFHS. We have previously demonstrated that chow rats, but not HFHS rats, show geometry-based reorientation on a rectangular arena place-recognition task (Tran & Westbrook, 2015). Experiment 3 assessed whether rats switched to the HFHS diet after training on the place and object tasks in a square area, would show geometry-based reorientation in a rectangular arena. The protective benefit of training was replicated in the square arena, but both Untrained and Trained HFHS failed to show geometry-based reorientation in the rectangular arena. These findings are discussed in relation to the specificity of the training effect, the role of the hippocampus in diet-induced deficits, and their implications for dietary effects on cognition in people.

  13. High prevalence of vaterite in sagittal otoliths causes hearing impairment in farmed fish

    PubMed Central

    Reimer, T.; Dempster, T.; Warren-Myers, F.; Jensen, A. J.; Swearer, S. E.

    2016-01-01

    The rapid growth of aquaculture raises questions about the welfare status of mass-produced species. Sagittal otoliths are primary hearing structures in the inner ear of all teleost (bony) fishes and are normally composed of aragonite, though abnormal vaterite replacement is sometimes seen in the wild. We provide the first widespread evaluation of the prevalence of vaterite in otoliths, showing that farmed fish have levels of vaterite replacement over 10 times higher than wild fish, regardless of species. We confirm this observation with extensive sampling of wild and farmed Atlantic salmon in Norway, the world’s largest producer, and verify that vateritic otoliths are common in farmed salmon worldwide. Using a mechanistic model of otolith oscillation in response to sound, we demonstrate that average levels of vaterite replacement result in a 28–50% loss of otolith functionality across most of a salmonid’s known hearing range and throughout its life cycle. The underlying cause(s) of vaterite formation remain unknown, but the prevalence of hearing impairment in farmed fish has important implications for animal welfare, the survival of escapees and their effects on wild populations, and the efficacy of restocking programs based on captive-bred fish. PMID:27121086

  14. Using artificial neural networks in clinical neuropsychology: high performance in mild cognitive impairment and Alzheimer's disease.

    PubMed

    Quintana, María; Guàrdia, Joan; Sánchez-Benavides, Gonzalo; Aguilar, Miguel; Molinuevo, José Luis; Robles, Alfredo; Barquero, María Sagrario; Antúnez, Carmen; Martínez-Parra, Carlos; Frank-García, Anna; Fernández, Manuel; Blesa, Rafael; Peña-Casanova, Jordi

    2012-01-01

    Mild cognitive impairment (MCI) is a transitional state between normal aging and Alzheimer disease (AD). Artificial neural networks (ANNs) are computational tools that can provide valuable support to clinical decision making, classification, and prediction of cognitive functioning. The aims of this study were to develop, train, and explore and develop the ability of ANNs to differentiate MCI and AD, and to study the relevant variables in MCI and AD diagnosis. The sample consisted of 346 controls and 79 MCI and 97 AD patients. A linear discriminant analysis (LDA) and ANNs with 12 input neurons (10 subtests of a neuropsychological test, the abbreviated Barcelona Test; age; and education), 4 hidden neurons, and output neuron (diagnosis) were used to classify the patients. The ANNs were superior to LDA in its ability to classify correctly patients (100-98.33% vs. 96.4-80%, respectively) and showed better predictive performance. Semantic fluency, working and episodic memory and education showed up as the most significant and sensitive variables for classification. Our results indicate that ANNs have an excellent capacity to discriminate MCI and AD patients from healthy controls. These findings provide evidence that ANNs can be a useful tool for the analysis of neuropsychological profiles related to clinical syndromes.

  15. High fidelity simian immunodeficiency virus reverse transcriptase mutants have impaired replication in vitro and in vivo.

    PubMed

    Lloyd, Sarah B; Lichtfuss, Marit; Amarasena, Thakshila H; Alcantara, Sheilajen; De Rose, Robert; Tachedjian, Gilda; Alinejad-Rokny, Hamid; Venturi, Vanessa; Davenport, Miles P; Winnall, Wendy R; Kent, Stephen J

    2016-05-01

    The low fidelity of HIV replication facilitates immune and drug escape. Some reverse transcriptase (RT) inhibitor drug-resistance mutations increase RT fidelity in biochemical assays but their effect during viral replication is unclear. We investigated the effect of RT mutations K65R, Q151N and V148I on SIV replication and fidelity in vitro, along with SIV replication in pigtailed macaques. SIVmac239-K65R and SIVmac239-V148I viruses had reduced replication capacity compared to wild-type SIVmac239. Direct virus competition assays demonstrated a rank order of wild-type>K65R>V148I mutants in terms of viral fitness. In single round in vitro-replication assays, SIVmac239-K65R demonstrated significantly higher fidelity than wild-type, and rapidly reverted to wild-type following infection of macaques. In contrast, SIVmac239-Q151N was replication incompetent in vitro and in pigtailed macaques. Thus, we showed that RT mutants, and specifically the common K65R drug-resistance mutation, had impaired replication capacity and higher fidelity. These results have implications for the pathogenesis of drug-resistant HIV.

  16. Perfectionism, emotion dysregulation, and affective disturbance in relation to clinical impairment in college-age women at high risk for or with eating disorders.

    PubMed

    Byrne, Meghan E; Eichen, Dawn M; Fitzsimmons-Craft, Ellen E; Taylor, C Barr; Wilfley, Denise E

    2016-12-01

    Individuals with eating disorders (EDs) demonstrate impaired quality of life; however, less than one-third report severe clinical impairment. Thus, it is important to determine factors that may identify those who are most likely to report marked impairment. Perfectionism, emotion dysregulation, and aspects of affective disturbance, such as anxiety and depression, are independently associated with eating pathology and clinical impairment in eating and other disorders. However, little research has explored these three factors concurrently in relation to eating pathology. It is possible that the combined interaction effect of these constructs could be especially harmful. The current study examined the influence of these constructs and their interactions on clinical impairment in college-aged women at high risk for or with a DSM-5 clinical or subclinical ED. Although the three-way interaction of perfectionism, emotion dysregulation, and affective disturbance (i.e., anxiety or depression) was not significant, the two-way interaction between perfectionism and emotion dysregulation was significant such that those who were high in both perfectionism and emotion dysregulation reported the highest levels of clinical impairment. This suggests that the combination of perfectionism and emotion dysregulation may be especially problematic for those with or at high risk for EDs. Interestingly, perfectionism alone was not a predictor of clinical impairment when accounting for the other constructs, implying that perfectionism may have a greater impact when in conjunction with emotion dysregulation. Understanding the impact of combined perfectionistic tendencies and emotion dysregulation on clinical impairment may better inform treatment and more directly target contributors to impaired quality of life.

  17. Notoginsenoside R1 attenuates glucose-induced podocyte injury via the inhibition of apoptosis and the activation of autophagy through the PI3K/Akt/mTOR signaling pathway

    PubMed Central

    Huang, Guodong; Zou, Bingyu; Lv, Jianzhen; Li, Tongyu; Huai, Guoli; Xiang, Shaowei; Lu, Shilong; Luo, Huan; Zhang, Yaping; Jin, Yi; Wang, Yi

    2017-01-01

    Injury to terminally differentiated podocytes contributes ignificantly to proteinuria and glomerulosclerosis. The aim of this study was to examine the protective effects of notoginsenoside R1 (NR1) on the maintenance of podocyte number and foot process architecture via the inhibition of apoptosis, the induction of autophagy and the maintenance pf podocyte biology in target cells. The effects of NR1 on conditionally immortalized human podocytes under high glucose conditions were evaluated by determining the percentage apoptosis, the percentage autophagy and the expression levels of slit diaphragm proteins. Our results revealed that NR1 protected the podocytes against high glucose-induced injury by decreasing apoptosis, increasing autophagy and by promoting cytoskeletal recovery. The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway was further investigated in order to elucidate the mechanisms responsible for the protective effects of NR1 on podocytes. Our data indicated that treatment with NR increased the phosphorylation levels of PI3K, Akt and mTOR, leading to the activation of the PI3K/Akt/mTOR signaling pathway in podocytes. To the best of our knowledge, this is the first in vitro study to demonstrate that NR1 protects podocytes by activating the PI3K/Akt/mTOR pathway. PMID:28112381

  18. Cognitive impairment and structural brain changes in patients with clinically isolated syndrome at high risk for multiple sclerosis.

    PubMed

    Hynčicová, Eva; Vyhnálek, Martin; Kalina, Adam; Martinkovič, Lukáš; Nikolai, Tomáš; Lisý, Jiří; Hort, Jakub; Meluzínová, Eva; Laczó, Jan

    2017-03-01

    Patients with clinically isolated syndrome (CIS), unlike those with multiple sclerosis (MS), have a selective cognitive impairment which is not consistently related to structural brain changes. Our objective was to characterize a profile of cognitive impairment and its association with structural brain changes in patients with CIS who are at high risk of developing MS. Patients with CIS at high risk for MS on interferon-beta (n = 51) and age-, gender-, and education-matched controls (n = 44) underwent comprehensive neuropsychological testing and MRI brain scan with voxel-based morphometry. The CIS group had lower cognitive performance in verbal and nonverbal memory, information processing speed/attention/working memory, and executive and visuo-spatial functions compared to controls (p ≤ 0.040). Lower cognitive performance was present in 18-37 and 14-26% of patients with CIS at high risk for MS depending on the criteria used. Brain volume was reduced predominantly in fronto-temporal regions and the thalamus in the CIS group (p ≤ 0.019). Cognitive performance was not associated with structural brain changes except for the association between worse visuo-spatial performance and lower white matter volume in the CIS group (β = 0.29; p = 0.042). Our results indicated that patients with CIS at high risk for MS may have a pattern of lower cognitive performance and regional brain atrophy similar to that found in patients with MS. Lower cognitive performance may be present in up to one-third of patients with CIS at high risk for MS, but, unlike patients with MS, variability in their cognitive performance may lead to a lack of consistent associations with structural brain changes.

  19. Silymarin released from sterile wafers restores glucose impaired endothelial cell migration.

    PubMed

    Gadad, Pramod C; Matthews, Kerr H; Knott, Rachel M

    2013-11-30

    Reduced oxygen tension combined with high glucose concentration leads to chronic wounds in diabetic patients. Delayed wound healing is due in part to impaired angiogenesis as a result of reduced endothelial cell migration. Topical applications, in the form of sterile lyophilised wafers hold promise for the treatment of chronic diabetic wounds. In this study wafers containing silymarin were prepared using xanthan gum and sterilised with 25 and 40 kGy gamma radiation. The rheological properties of xanthan gels, before and after lyophilisation, were measured and it was concluded that an increased dose of gamma rays (40 kGy) increased the viscosity coefficient and yield stress of silymarin wafers. HPLC analysis indicated that 89-90% of silymarin was retained in the wafers after irradiation. Dermal microvascular cell migration studies in the presence of high glucose and reduced oxygen tension levels, using novel radial migration and wound healing assays developed 'in house', were also undertaken. Silymarin, when formulated as a lyophilised wafer, successfully retained its ability to overcome the high glucose induced reduction in endothelial cell migration.

  20. Musical Sound Quality Impairments in Cochlear Implant (CI) Users as a Function of Limited High-Frequency Perception

    PubMed Central

    Roy, Alexis T.; Jiradejvong, Patpong; Carver, Courtney

    2012-01-01

    The purpose of this study was to (a) apply the musical sound quality assessment method, Cochlear Implant-MUltiple Stimulus with Hidden Reference and Anchor (CI-MUSHRA), to quantify musical sound quality deficits in CI (cochlear implant) users with respect to high-frequency loss, and (b) assess possible correlations between CI-MUSHRA performance and self-reported musical sound quality, as assessed by more traditional rating scales. Five versions of real-world musical stimuli were created: 8-,4-, and 2-kHz low-pass-filtered (LPF) versions with increasing high-frequency removal, a composite stimulus containing a 1-kHz LPF-filtered version and white noise (“anchor”), and an unaltered version (“hidden reference”). Using the CI-MUSHRA methodology, these versions were simultaneously presented to participants in addition to a labeled reference. Participants listened to all versions and provided ratings based on a 100-point scale that reflected perceived sound quality difference among the versions. A total of 25 musical stimuli were tested. As comparison measures, participants completed four Visual Analogue Scales (VAS) to assess musical sound quality. Overall, compared to normal hearing (NH) listeners, CI users demonstrated an impaired ability to discriminate between unaltered and altered musical stimuli with variable amounts of high-frequency information removed. Performance using CI-MUSHRA to evaluate this parameter did not correlate to measurements of musical sound quality, as assessed by VAS. This study identified high-frequency loss as one acoustic parameter contributing to overall CI-mediated musical sound quality limitations. CI-MUSHRA provided a quantitative assessment of musical sound quality. This method offers the potential to quantify CI impairments of many different acoustic parameters related to musical sound quality in the future. PMID:23172009

  1. Pairing high-frequency data with a link-node model to manage dissolved oxygen impairment in a dredged estuary.

    PubMed

    Camarillo, Mary Kay; Weissmann, Gregory A; Gulati, Shelly; Herr, Joel; Sheeder, Scott; Stringfellow, William T

    2016-08-01

    High-frequency data and a link-node model were used to investigate the relative importance of mass loads of oxygen-demanding substances and channel geometry on recurrent low dissolved oxygen (DO) in the San Joaquin River Estuary in California. The model was calibrated using 6 years of data. The calibrated model was then used to determine the significance of the following factors on low DO: excavation of the river to allow navigation of large vessels, non-point source pollution from the agricultural watershed, effluent from a wastewater treatment plant, and non-point source pollution from an urban area. An alternative metric for low DO, excess net oxygen demand (ENOD), was applied to better characterize DO impairment. Model results indicate that the dredged ship channel had the most significant effect on DO (62 % fewer predicted hourly DO violations), followed by mass load inputs from the watershed (52 % fewer predicted hourly DO violations). Model results suggest that elimination of any one factor will not completely resolve DO impairment and that continued use of supplemental aeration is warranted. Calculation of ENOD proved more informative than the sole use of DO. Application of the simple model allowed for interpretation of the extensive data collected. The current monitoring program could be enhanced by additional monitoring stations that would provide better volumetric estimates of low DO.

  2. Maternal high-fat diet during lactation impairs thermogenic function of brown adipose tissue in offspring mice

    PubMed Central

    Liang, Xingwei; Yang, Qiyuan; Zhang, Lupei; Maricelli, Joseph W; Rodgers, Buel D.; Zhu, Mei-Jun; Du, Min

    2016-01-01

    Maternal obesity and high-fat diet (HFD) predisposes offspring to obesity and metabolic diseases. Due to uncoupling, brown adipose tissue (BAT) dissipates energy via heat generation, mitigating obesity and diabetes. The lactation stage is a manageable period for improving the health of offspring of obese mothers, but the impact of maternal HFD during lactation on offspring BAT function is unknown. To determine, female mice were fed either a control or HFD during lactation. At weaning, HFD offspring gained more body weight and had greater body fat mass compared to the control, and these differences maintained into adulthood, which correlated with glucose intolerance and insulin resistance in HFD offspring. Adaptive thermogenesis of BAT was impaired in HFD offspring at weaning. In adulthood, HFD offspring BAT had lower Ucp1 expression and thermogenic activity. Mechanistically, maternal HFD feeding during lactation elevated peripheral serotonin, which decreased the sensitivity of BAT to sympathetic β3-adrenergic signaling. Importantly, early postnatal metformin administration decreased serotonin concentration and ameliorated the impairment of offspring BAT due to maternal HFD. Our data suggest that attenuation of BAT thermogenic function may be a key mechanism linking maternal HFD during lactation to persisted metabolic disorder in the offspring. PMID:27686741

  3. Anemia and Red Blood Cell Indices Predict HIV-Associated Neurocognitive Impairment in the Highly Active Antiretroviral Therapy Era

    PubMed Central

    Kallianpur, Asha R.; Wang, Quan; Jia, Peilin; Hulgan, Todd; Zhao, Zhongming; Letendre, Scott L.; Ellis, Ronald J.; Heaton, Robert K.; Franklin, Donald R.; Barnholtz-Sloan, Jill; Collier, Ann C.; Marra, Christina M.; Clifford, David B.; Gelman, Benjamin B.; McArthur, Justin C.; Morgello, Susan; Simpson, David M.; McCutchan, J. A.; Grant, Igor

    2016-01-01

    Background. Anemia has been linked to adverse human immunodeficiency virus (HIV) outcomes, including dementia, in the era before highly active antiretroviral therapy (HAART). Milder forms of HIV-associated neurocognitive disorder (HAND) remain common in HIV-infected persons, despite HAART, but whether anemia predicts HAND in the HAART era is unknown. Methods. We evaluated time-dependent associations of anemia and cross-sectional associations of red blood cell indices with neurocognitive impairment in a multicenter, HAART-era HIV cohort study (N = 1261), adjusting for potential confounders, including age, nadir CD4+ T-cell count, zidovudine use, and comorbid conditions. Subjects underwent comprehensive neuropsychiatric and neuromedical assessments. Results. HAND, defined according to standardized criteria, occurred in 595 subjects (47%) at entry. Mean corpuscular volume and mean corpuscular hemoglobin were positively associated with the global deficit score, a continuous measure of neurocognitive impairment (both P < .01), as well as with all HAND, milder forms of HAND, and HIV-associated dementia in multivariable analyses (all P < .05). Anemia independently predicted development of HAND during a median follow-up of 72 months (adjusted hazard ratio, 1.55; P < .01). Conclusions. Anemia and red blood cell indices predict HAND in the HAART era and may contribute to risk assessment. Future studies should address whether treating anemia may help to prevent HAND or improve cognitive function in HIV-infected persons. PMID:26690344

  4. High Fat Diet Inhibits Dendritic Cell and T Cell Response to Allergens but Does Not Impair Inhalational Respiratory Tolerance

    PubMed Central

    Pizzolla, Angela; Oh, Ding Yuan; Luong, Suzanne; Prickett, Sara R.; Henstridge, Darren C.; Febbraio, Mark A.; O’Hehir, Robyn E.; Rolland, Jennifer M.; Hardy, Charles L.

    2016-01-01

    The incidence of obesity has risen to epidemic proportions in recent decades, most commonly attributed to an increasingly sedentary lifestyle, and a ‘western’ diet high in fat and low in fibre. Although non-allergic asthma is a well-established co-morbidity of obesity, the influence of obesity on allergic asthma is still under debate. Allergic asthma is thought to result from impaired tolerance to airborne antigens, so-called respiratory tolerance. We sought to investigate whether a diet high in fats affects the development of respiratory tolerance. Mice fed a high fat diet (HFD) for 8 weeks showed weight gain, metabolic disease, and alteration in gut microbiota, metabolites and glucose metabolism compared to age-matched mice fed normal chow diet (ND). Respiratory tolerance was induced by repeated intranasal (i.n.) administration of ovalbumin (OVA), prior to induction of allergic airway inflammation (AAI) by sensitization with OVA in alum i.p. and subsequent i.n. OVA challenge. Surprisingly, respiratory tolerance was induced equally well in HFD and ND mice, as evidenced by decreased lung eosinophilia and serum OVA-specific IgE production. However, in a pilot study, HFD mice showed a tendency for impaired activation of airway dendritic cells and regulatory T cells compared with ND mice after induction of respiratory tolerance. Moreover, the capacity of lymph node cells to produce IL-5 and IL-13 after AAI was drastically diminished in HFD mice compared to ND mice. These results indicate that HFD does not affect the inflammatory or B cell response to an allergen, but inhibits priming of Th2 cells and possibly dendritic cell and regulatory T cell activation. PMID:27483441

  5. Impaired fitness of human immunodeficiency virus type 1 variants with high-level resistance to protease inhibitors.

    PubMed Central

    Croteau, G; Doyon, L; Thibeault, D; McKercher, G; Pilote, L; Lamarre, D

    1997-01-01

    One hope to maintain the benefits of antiviral therapy against the human immunodeficiency virus type 1 (HIV-1), despite the development of resistance, is the possibility that resistant variants will show decreased viral fitness. To study this possibility, HIV-1 variants showing high-level resistance (up to 1,500-fold) to the substrate analog protease inhibitors BILA 1906 BS and BILA 2185 BS have been characterized. Active-site mutations V32I and I84V/A were consistently observed in the protease of highly resistant viruses, along with up to six other mutations. In vitro studies with recombinant mutant proteases demonstrated that these mutations resulted in up to 10(4)-fold increases in the Ki values toward BILA 1906 BS and BILA 2185 BS and a concomitant 2,200-fold decrease in catalytic efficiency of the enzymes toward a synthetic substrate. When introduced into viral molecular clones, the protease mutations impaired polyprotein processing, consistent with a decrease in enzyme activity in virions. Despite these observations, however, most mutations had little effect on viral replication except when the active-site mutations V32I and I84V/A were coexpressed in the protease. The latter combinations not only conferred a significant growth reduction of viral clones on peripheral blood mononuclear cells but also caused the complete disappearance of mutated clones when cocultured with wild-type virus on T-cell lines. Furthermore, the double nucleotide mutation I84A rapidly reverted to I84V upon drug removal, confirming its impact on viral fitness. Therefore, high-level resistance to protease inhibitors can be associated with impaired viral fitness, suggesting that antiviral therapies with such inhibitors may maintain some clinical benefits. PMID:8995629

  6. Impaired clearance of accumulated lysosomal glycogen in advanced Pompe disease despite high-level vector-mediated transgene expression

    PubMed Central

    Sun, Baodong; Zhang, Haoyue; Bird, Andrew; Li, Songtao; Young, Sarah P.; Koeberl, Dwight D.

    2013-01-01

    Background Infantile-onset glycogen storage disease type II (GSD-II; Pompe disease; MIM 232300) causes death early in childhood from cardiorespiratory failure in absence of effective treatment, whereas late-onset Pompe disease causes a progressive skeletal myopathy. The limitations of enzyme replacement therapy could potentially be addressed with adeno-associated virus (AAV) vector-mediated gene therapy. Methods AAV vectors containing tissue-specific regulatory cassettes, either liver-specific or muscle-specific, were administered to 12 and 17 month old Pompe disease mice to evaluate the efficacy of gene therapy in advanced Pompe disease. Biochemical correction was evaluated through GAA activity and glycogen content analyses of the heart and skeletal muscle. Western blotting, urinary biomarker, and Rotarod performance were evaluated following vector administration. Results The AAV vector containing the liver-specific regulatory cassette secreted high-level hGAA into the blood and corrected glycogen storage in the heart and diaphragm. The biochemical correction of the heart and diaphragm was associated with efficacy, as reflected by increased Rotarod performance; however, the clearance of glycogen from skeletal muscles was relatively impaired, in comparison with younger Pompe disease mice. An alternative vector containing a muscle-specific regulatory cassette transduced skeletal muscle with high efficiency, but also failed to achieve complete clearance of accumulated glycogen. Decreased transduction of the heart and liver in older mice, especially in females, was implicated as a cause for reduced efficacy in advanced Pompe disease. Conclusion The impaired efficacy of AAV vector-mediated gene therapy in old Pompe disease mice emphasized the need for early treatment to achieve full efficacy. PMID:19621331

  7. Treadmill exercise alleviates impairment of cognitive function by enhancing hippocampal neuroplasticity in the high-fat diet-induced obese mice

    PubMed Central

    Kim, Tae-Woon; Choi, Hyun-Hee; Chung, Yong-Rak

    2016-01-01

    Physical exercise is one of the most effective methods for managing obesity, and exercise exerts positive effects on various brain functions. Excessive weight gain is known to be related to the impairment of cognitive function. High-fat diet-induced obesity impairs hippocampal neuroplasticity, which impedes cognitive function, such as learning ability and memory function. In this study, we investigated the effect of treadmill exercise on impairment of cognitive function in relation with hippocampal neuroplasticity using high-fat diet-induced obese mice. After obesity was induced by a 20-week high-fat (60%) diet, treadmill exercise was performed for 12 weeks. In the present results, cognitive function was impaired in the high-fat diet-induced obese mice. Brain-derived neurotrophic factor (BDNF) and tyrosin kinase B (TrkB) expression and cell proliferation were decreased in the high-fat diet-induced obese mice. Treadmill exercise improved cognitive function through enhancing neuroplasticity, including increased expression of BDNF and TrkB and enhanced cell proliferation. The present results suggest that treadmill exercise enhances hippocampal neuroplasticity, and then potentially plays a protective role against obesity-induced cognitive impairment. PMID:27419109

  8. Treadmill exercise alleviates impairment of cognitive function by enhancing hippocampal neuroplasticity in the high-fat diet-induced obese mice.

    PubMed

    Kim, Tae-Woon; Choi, Hyun-Hee; Chung, Yong-Rak

    2016-06-01

    Physical exercise is one of the most effective methods for managing obesity, and exercise exerts positive effects on various brain functions. Excessive weight gain is known to be related to the impairment of cognitive function. High-fat diet-induced obesity impairs hippocampal neuroplasticity, which impedes cognitive function, such as learning ability and memory function. In this study, we investigated the effect of treadmill exercise on impairment of cognitive function in relation with hippocampal neuroplasticity using high-fat diet-induced obese mice. After obesity was induced by a 20-week high-fat (60%) diet, treadmill exercise was performed for 12 weeks. In the present results, cognitive function was impaired in the high-fat diet-induced obese mice. Brain-derived neurotrophic factor (BDNF) and tyrosin kinase B (TrkB) expression and cell proliferation were decreased in the high-fat diet-induced obese mice. Treadmill exercise improved cognitive function through enhancing neuroplasticity, including increased expression of BDNF and TrkB and enhanced cell proliferation. The present results suggest that treadmill exercise enhances hippocampal neuroplasticity, and then potentially plays a protective role against obesity-induced cognitive impairment.

  9. Field trial on glucose-induced insulin and metabolite responses in Estonian Holstein and Estonian Red dairy cows in two herds

    PubMed Central

    2010-01-01

    Background Insulin secretion and tissue sensitivity to insulin is considered to be one of the factors controlling lipid metabolism post partum. The objective of this study was to compare glucose-induced blood insulin and metabolite responses in Estonian Holstein (EH, n = 14) and Estonian Red (ER, n = 14) cows. Methods The study was carried out using the glucose tolerance test (GTT) performed at 31 ± 1.9 days post partum during negative energy balance. Blood samples were obtained at -15, -5, 5, 10, 20, 30, 40, 50 and 60 min relative to infusion of 0.15 g/kg BW glucose and analysed for glucose, insulin, triglycerides (TG), non-esterified fatty acids (NEFA), cholesterol and β-hydroxybutyrate (BHB). Applying the MIXED Procedure with the SAS System the basal concentration of cholesterol, and basal concentration and concentrations at post-infusion time points for other metabolites, area under the curve (AUC) for glucose and insulin, clearance rate (CR) for glucose, and maximum increase from basal concentration for glucose and insulin were compared between breeds. Results There was a breed effect on blood NEFA (P < 0.05) and a time effect on all metabolites concentration (P < 0.01). The following differences were observed in EH compared to ER: lower blood insulin concentration 5 min after glucose infusion (P < 0.05), higher glucose concentration 20 (P < 0.01) and 30 min (P < 0.05) after infusion, and higher NEFA concentration before (P < 0.01) and 5 min after infusion (P < 0.05). Blood TG concentration in ER remained stable, while in EH there was a decrease from the basal level to the 40th min nadir (P < 0.01), followed by an increase to the 60th min postinfusion (P < 0.01). Conclusion Our results imply that glucose-induced changes in insulin concentration and metabolite responses to insulin differ between EH and ER dairy cows. PMID:20089161

  10. Impairment of GLP1-induced insulin secretion: role of genetic background, insulin resistance and hyperglycaemia.

    PubMed

    Herzberg-Schäfer, S; Heni, M; Stefan, N; Häring, H-U; Fritsche, A

    2012-10-01

    One major risk factor of type 2 diabetes is the impairment of glucose-induced insulin secretion which is mediated by the individual genetic background and environmental factors. In addition to impairment of glucose-induced insulin secretion, impaired glucagon-like peptide (GLP)1-induced insulin secretion has been identified to be present in subjects with diabetes and impaired glucose tolerance, but little is known about its fundamental mechanisms. The state of GLP1 resistance is probably an important mechanism explaining the reduced incretin effect observed in type 2 diabetes. In this review, we address methods that can be used for the measurement of insulin secretion in response to GLP1 in humans, and studies showing that specific diabetes risk genes are associated with resistance of the secretory function of the β-cell in response to GLP1 administration. Furthermore, we discuss other factors that are associated with impaired GLP1-induced insulin secretion, for example, insulin resistance. Finally, we provide evidence that hyperglycaemia per se, the genetic background and their interaction result in the development of GLP1 resistance of the β-cell. We speculate that the response or the non-response to therapy with GLP1 analogues and/or dipeptidyl peptidase-4 (DPP-IV) inhibitors is critically dependent on GLP1 resistance.

  11. Interpersonal sensitivity and functioning impairment in youth at ultra-high risk for psychosis.

    PubMed

    Masillo, A; Valmaggia, L R; Saba, R; Brandizzi, M; Lindau, J F; Solfanelli, A; Curto, M; Narilli, F; Telesforo, L; Kotzalidis, G D; Di Pietro, D; D'Alema, M; Girardi, P; Fiori Nastro, P

    2016-01-01

    A personality trait that often elicits poor and uneasy interpersonal relationships is interpersonal sensitivity. The aim of the present study was to explore the relationship between interpersonal sensitivity and psychosocial functioning in individuals at ultra-high risk for psychosis as compared to help-seeking individuals who screened negative for an ultra-high risk of psychosis. A total sample of 147 adolescents and young adult who were help seeking for emerging mental health problems participated in the study. The sample was divided into two groups: 39 individuals who met criteria for an ultra-high-risk mental state (UHR), and 108 (NS). The whole sample completed the Interpersonal Sensitivity Measure (IPSM) and the Global Functioning: Social and Role Scale (GF:SS; GF:RS). Mediation analysis was used to explore whether attenuated negative symptoms mediated the relationship between interpersonal sensitivity and social functioning. Individuals with UHR state showed higher IPSM scores and lower GF:SS and GF:RS scores than NS participants. A statistically negative significant correlation between two IPSM subscales (Interpersonal Awareness and Timidity) and GF:SS was found in both groups. Our results also suggest that the relationship between the aforementioned aspects of interpersonal sensitivity and social functioning was not mediated by negative prodromal symptoms. This study suggests that some aspects of interpersonal sensitivity were associated with low level of social functioning. Assessing and treating interpersonal sensitivity may be a promising therapeutic target to improve social functioning in young help-seeking individuals.

  12. A high-fat diet impairs learning that is dependent on the dorsal hippocampus but spares other forms of learning.

    PubMed

    Stouffer, Eric M; Warninger, Elizabeth E; Michener, Paige N

    2015-12-01

    Two experiments were conducted to evaluate the effects of a high-fat diet (HFD) on two tasks that were either dependent on the dorsal hippocampus (DH) or independent of the DH. A total of 80 adult male Sprague Dawley rats were administered either a lard-based HFD (60% of calories from fat) or a control diet (10% of calories from fat) for 8 weeks, and then were trained and tested on either the latent cue preference (LCP) task or the conditioned cue preference (CCP) task in a 3-compartment box apparatus (2 end-compartments and 1 middle-compartment). The end compartments of the box apparatus contained either a single environmental cue (DH-independent) or multiple environmental cues (DH-dependent). During training trials for the LCP and CCP tasks, on alternating days, rats were given access to water in 1 of the 2 end compartments and no water in the opposite end compartment. Rats were water-replete during LCP training and were water-deprived during CCP training. During testing for both tasks, all rats were water-deprived and given free access to all compartments while the amounts of time spent in each compartment were recorded. Results showed that rats given the HFD demonstrated no compartment preferences during both LCP and CCP testing when the compartments contained multiple cues, while rats fed the control diet demonstrated normal compartment preference behavior. However, when the compartments contained a single environmental cue, rats given either the HFD and control diet demonstrated normal LCP and CCP learning. These results demonstrate that consumption of a HFD disrupted both LCP and CCP learning in a multiple-cue (DH-dependent) environment, but did not impair either type of learning in a single-cue (DH-independent) environment. This may be due to selective impairment of the DH caused by increased oxidative stress, inflammation, and/or disrupted neurotransmission produced by consumption of the HFD.

  13. High daytime and nighttime ambulatory pulse pressure predict poor cognitive function and mild cognitive impairment in hypertensive individuals

    PubMed Central

    Riba-Llena, Iolanda; Nafría, Cristina; Filomena, Josefina; Tovar, José L; Vinyoles, Ernest; Mundet, Xavier; Jarca, Carmen I; Vilar-Bergua, Andrea; Montaner, Joan

    2016-01-01

    High blood pressure accelerates normal aging stiffness process. Arterial stiffness (AS) has been previously associated with impaired cognitive function and dementia. Our aims are to study how cognitive function and status (mild cognitive impairment, MCI and normal cognitive aging, NCA) relate to AS in a community-based population of hypertensive participants assessed with office and 24-hour ambulatory blood pressure measurements. Six hundred ninety-nine participants were studied, 71 had MCI and the rest had NCA. Office pulse pressure (PP), carotid–femoral pulse wave velocity, and 24-hour ambulatory PP monitoring were collected. Also, participants underwent a brain magnetic resonance to study cerebral small–vessel disease (cSVD) lesions. Multivariate analysis–related cognitive function and cognitive status to AS measurements after adjusting for demographic, vascular risk factors, and cSVD. Carotid–femoral pulse wave velocity and PP at different periods were inversely correlated with several cognitive domains, but only awake PP measurements were associated with attention after correcting for confounders (beta = −0.22, 95% confidence interval (CI) −0.41, −0.03). All ambulatory PP measurements were related to MCI, which was independently associated with nocturnal PP (odds ratio (OR) = 2.552, 95% CI 1.137, 5.728) and also related to the presence of deep white matter hyperintensities (OR = 1.903, 1.096, 3.306). Therefore, higher day and night ambulatory PP measurements are associated with poor cognitive outcomes. PMID:25966945

  14. High-dose dexamethasone corrects impaired myeloid-derived suppressor cell function via Ets1 in immune thrombocytopenia.

    PubMed

    Hou, Yu; Feng, Qi; Xu, Miao; Li, Guo-Sheng; Liu, Xue-Na; Sheng, Zi; Zhou, Hai; Ma, Ji; Wei, Yu; Sun, Yuan-Xin; Yu, Ying-Yi; Qiu, Ji-Hua; Shao, Lin-Lin; Liu, Xin-Guang; Hou, Ming; Peng, Jun

    2016-03-24

    Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature cells and natural inhibitors of adaptive immunity. In this study, the MDSC population was evaluated in adult patients with primary immune thrombocytopenia (ITP), where cell-mediated immune mechanisms are involved in platelet destruction. Our data demonstrated that both the numbers and suppressive functions of MDSCs were impaired in the peripheral blood and spleens of patients with ITP compared with healthy control patients. High-dose dexamethasone (HD-DXM) treatment rescued MDSC numbers in patients with ITP. And DXM modulation promoted the suppressive function of MDSCs induced in vitro. Moreover, the expression of interleukin 10 and transforming growth factor β was significantly upregulated in DXM-modulated MDSCs compared with the unmodulated cultures. DXM-modulated MDSCs inhibited autologous CD4(+)T-cell proliferation and significantly attenuated cytotoxic T lymphocyte-mediated platelet lysis, further indicating enhanced control over T-cell responses. Elevated expression of the transcription factor Ets1 was identified in DXM-modulated MDSCs. Transfection of Ets-1 small interfering RNA efficiently blocked regulatory effects of MDSCs, which almost offset the augmentation of MDSC function by DXM. Meanwhile, splenocytes from CD61 knockout mice immunized with CD61(+)platelets were transferred into severe combined immunodeficient (SCID) mouse recipients (C57/B6 background) to induce a murine model of severe ITP. We passively transferred the DXM-modulated MDSCs induced from bone marrow of wild-type C57/B6 mice into the SCID mouse recipients, which significantly increased platelet counts in vivo compared with those receiving splenocyte engraftment alone. These findings suggested that impaired MDSCs are involved in the pathogenesis of ITP, and that HD-DXM corrected MDSC functions via a mechanism underlying glucocorticoid action and Ets1.

  15. Limitations on High Data Rate Optical Fiber Transmission Systems Due to Transmission Impairment

    SciTech Connect

    Menyuk, Curtis R.

    2002-03-15

    This project supplemented our regular DOE grant from the Basic Energy Sciences organization with the goal of fostering industrial partnerships and student internships. During the project period, we have interacted with between 15 and 20 companies in the optical fiber telecommunications equipment industry, and our students have participated in a number of highly visible projects with companies such as Ciena, Science Applications International Corporation, KDD, ATT, Virtual Photonics, Inc., Phaethon Telecommunications, PhotonEx, and others. The project led to many successful interactions and numerous job offers for our students.

  16. UV-B impairs growth and gas exchange in grapevines grown in high altitude.

    PubMed

    Berli, Federico J; Alonso, Rodrigo; Bressan-Smith, Ricardo; Bottini, Rubén

    2013-09-01

    We previously demonstrated that solar ultraviolet-B (UV-B) radiation levels in high altitude vineyards improve berry quality in Vitis vinifera cv. Malbec, but also reduce berry size and yield, possibly as a consequence of increased oxidative damage and growth reductions (lower photosynthesis). The defense mechanisms toward UV-B signal and/or evoked damage promote production of antioxidant secondary metabolites instead of primary metabolites. Purportedly, the UV-B effects will depend on tissues developmental stage and interplay with other environmental conditions, especially stressful situations. In this work, grapevines were exposed to high solar UV-B (+UV-B) and reduced (by filtering) UV-B (-UV-B) treatments during three consecutive seasons, and the effects of UV-B, developmental stages and seasons on the physiology were studied, i.e. growth, tissues morphology, photosynthesis, photoprotective pigments, proline content and antioxidant capacity of leaves. The +UV-B reduced photosynthesis and stomatal conductance, mainly through limitation in gas exchange, reducing plant's leaf area, net carbon fixation and growth. The +UV-B augmented leaf thickness, and also the amounts of photoprotective pigments and proline, thereby increasing the antioxidant capacity of leaves. The defense mechanisms triggered by + UV-B reduced lipid peroxidation, but they were insufficient to protect the photosynthetic pigments per leaf dry weight basis. The +UV-B effects depend on tissues developmental stage and interplay with other environmental conditions such as total radiation and air temperatures.

  17. Cognitive control processes underlying time-based prospective memory impairment in individuals with high depressive symptomatology.

    PubMed

    Li, Yanqi Ryan; Weinborn, Michael; Loft, Shayne; Maybery, Murray

    2014-06-01

    The current study compared time-based prospective memory (PM) for individuals with high depressive symptomatology (HDS) and low depressive symptomatology (LDS). We examined PM accuracy rate, clock-checking frequency, and decrements in ongoing task performance (i.e., costs to ongoing tasks) associated with an embedded time-based PM task. HDS participants demonstrated numerically lower but statistically comparable clock-checking frequency to LDS participants. However, their PM performance was significantly poorer than that of LDS participants. The pattern of observed costs to ongoing tasks and correlational analyses between ongoing task performance and PM accuracy showed that, relative to LDS participants, HDS participants were restricted in their allocation of attentional resources to support PM. We concluded that although HDS and LDS participants externally controlled their time-based PM task performance (i.e., clock-checking) similarly, the HDS participants lacked the cognitive initiative to allocate attentional resources to internally control PM task performance. Such internal control might reflect time-estimation processes, the resources required to maintain the PM task response intention, and/or the ability to coordinate the PM task response with ongoing task demands. To our knowledge, this is the first paper to have examined time-based PM strategies used by HDS individuals beyond clock-checking. The data suggest that interventions that encourage intermittent strategic reviews of PM goals may be beneficial for individuals with high depressive symptomatology.

  18. Maternal high-fat diet is associated with impaired fetal lung development.

    PubMed

    Mayor, Reina S; Finch, Katelyn E; Zehr, Jordan; Morselli, Eugenia; Neinast, Michael D; Frank, Aaron P; Hahner, Lisa D; Wang, Jason; Rakheja, Dinesh; Palmer, Biff F; Rosenfeld, Charles R; Savani, Rashmin C; Clegg, Deborah J

    2015-08-15

    Maternal nutrition has a profound long-term impact on infant health. Poor maternal nutrition influences placental development and fetal growth, resulting in low birth weight, which is strongly associated with the risk of developing chronic diseases, including heart disease, hypertension, asthma, and type 2 diabetes, later in life. Few studies have delineated the mechanisms by which maternal nutrition affects fetal lung development. Here, we report that maternal exposure to a diet high in fat (HFD) causes placental inflammation, resulting in placental insufficiency, fetal growth restriction (FGR), and inhibition of fetal lung development. Notably, pre- and postnatal exposure to maternal HFD also results in persistent alveolar simplification in the postnatal period. Our novel findings provide a strong association between maternal diet and fetal lung development.

  19. Chronic High Fat Diet Consumption Impairs Metabolic Health of Male Mice.

    PubMed

    Morselli, Eugenia; Criollo, Alfredo; Rodriguez-Navas, Carlos; Clegg, Deborah J

    We show that chronic high fat diet (HFD) feeding affects the hypothalamus of male but not female mice. In our study we demonstrate that palmitic acid and sphingolipids accumulate in the central nervous system of HFD-fed males. Additionally, we show that HFD-feeding reduces proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) thus reducing estrogen receptor α (ERα) and driving hypothalamic inflammation in male but not female mice. Hypothalamic inflammation correlates with markers of metabolic dysregulation as indicated by dysregulation in glucose intolerance and myocardial function. Lastly, we demonstrate that there are blockages in mitophagy and lipophagy in hypothalamic tissues in males. Our data suggest there is a sexually dimorphic response to chronic HDF exposure, females; despite gaining the same amount of body weight following HFD-feeding, appear to be protected from the adverse metabolic effects of the HFD.

  20. Chronic High Fat Diet Consumption Impairs Metabolic Health of Male Mice

    PubMed Central

    Morselli, Eugenia; Criollo, Alfredo; Rodriguez-Navas, Carlos; Clegg, Deborah J.

    2015-01-01

    We show that chronic high fat diet (HFD) feeding affects the hypothalamus of male but not female mice. In our study we demonstrate that palmitic acid and sphingolipids accumulate in the central nervous system of HFD-fed males. Additionally, we show that HFD-feeding reduces proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) thus reducing estrogen receptor α (ERα) and driving hypothalamic inflammation in male but not female mice. Hypothalamic inflammation correlates with markers of metabolic dysregulation as indicated by dysregulation in glucose intolerance and myocardial function. Lastly, we demonstrate that there are blockages in mitophagy and lipophagy in hypothalamic tissues in males. Our data suggest there is a sexually dimorphic response to chronic HDF exposure, females; despite gaining the same amount of body weight following HFD-feeding, appear to be protected from the adverse metabolic effects of the HFD. PMID:26046098

  1. High Capacity Phase/Amplitude Modulated Optical Communication Systems and Nonlinear Inter-Channel Impairments

    NASA Astrophysics Data System (ADS)

    Tavassoli, Vahid

    This thesis studies and mathematically models nonlinear interactions among channels of modern high bit rate (amplitude/) phase modulated optical systems. First, phase modulated analogue systems are studied and a differential receiving method is suggested with experimental validation. The main focus of the rest of the thesis is on digital advanced modulation format systems. Cross-talk due to fiber Kerr nonlinearity in two-format hybrid systems as well as 16-QAM systems is mathematically modelled and verified by simulation for different system parameters. A comparative study of differential receivers and coherent receivers is also given for hybrid systems. The model is based on mathematically proven assumptions and provides an intuitive analytical understanding of nonlinear cross-talk in such systems.

  2. Gallic Acid Ameliorated Impaired Glucose and Lipid Homeostasis in High Fat Diet-Induced NAFLD Mice

    PubMed Central

    Chao, Jung; Huo, Teh-Ia; Cheng, Hao-Yuan; Tsai, Jen-Chieh; Liao, Jiunn-Wang; Lee, Meng-Shiou; Qin, Xue-Mei; Hsieh, Ming-Tsuen; Pao, Li-Heng; Peng, Wen-Huang

    2014-01-01

    Gallic acid (GA), a naturally abundant plant phenolic compound in vegetables and fruits, has been shown to have potent anti-oxidative and anti-obesity activity. However, the effects of GA on nonalcoholic fatty liver disease (NAFLD) are poorly understood. In this study, we investigated the beneficial effects of GA administration on nutritional hepatosteatosis model by a more “holistic view” approach, namely 1H NMR-based metabolomics, in order to prove efficacy and to obtain information that might lead to a better understanding of the mode of action of GA. Male C57BL/6 mice were placed for 16 weeks on either a normal chow diet, a high fat diet (HFD, 60%), or a high fat diet supplemented with GA (50 and 100 mg/kg/day, orally). Liver histopathology and serum biochemical examinations indicated that the daily administration of GA protects against hepatic steatosis, obesity, hypercholesterolemia, and insulin resistance among the HFD-induced NAFLD mice. In addition, partial least squares discriminant analysis scores plots demonstrated that the cluster of HFD fed mice is clearly separated from the normal group mice plots, indicating that the metabolic characteristics of these two groups are distinctively different. Specifically, the GA-treated mice are located closer to the normal group of mice, indicating that the HFD-induced disturbances to the metabolic profile were partially reversed by GA treatment. Our results show that the hepatoprotective effect of GA occurs in part through a reversing of the HFD caused disturbances to a range of metabolic pathways, including lipid metabolism, glucose metabolism (glycolysis and gluconeogenesis), amino acids metabolism, choline metabolism and gut-microbiota-associated metabolism. Taken together, this study suggested that a 1H NMR-based metabolomics approach is a useful platform for natural product functional evaluation. The selected metabolites are potentially useful as preventive action biomarkers and could also be used to help

  3. Impaired high-intensity cycling performance time at low levels of dehydration.

    PubMed

    Walsh, R M; Noakes, T D; Hawley, J A; Dennis, S C

    1994-10-01

    On two separate occasions six trained subjects (peak oxygen consumption [VO2peak] 4.41/min) rode for 60 min at 70% of VO2peak and then to exhaustion at 90% of VO2peak to determine the effects of mild dehydration on high-intensity cycling performance time in the heat (32 degrees C, 60% relative humidity, wind speed 3 km/h). In one trial (F) subjects ingested a 400 ml bolus of 20 mmol/l NaCl immediately before, and then as repetitive 120 ml feedings every 10 min during the first 50 min of exercise. In the other trial they did not ingest fluid (NF) either before or during exercise. The order of testing was in a counter-balanced random sequence. For the first 60 min of exercise mean (+/- SD) VO2 (2.90 +/- 0.39 vs 2.93 +/- 0.38 l/min) and respiratory exchange ratio (RER; 0.95 +/- 0.03 vs 0.94 +/- 0.04) values were similar between F and NF trials. However, weight loss was significantly reduced during F compared to NF (0.16 +/- 0.39 vs 1.30 +/- 0.22 kg; p < 0.005) and high-intensity cycling time to exhaustion was significantly increased (9.8 +/- 3.9 vs 6.8 +/- 3.0 min; p < 0.005). Increased cycling times to exhaustion in the F trial were not associated with any measurable differences in heart rate (HR), body temperature, respiratory gas exchange, leg muscle power over 5 sec, or the degree to which fluid ingestion reduced the level of dehydration within the group. Only the ratings of perceived exertion (RPE) and plasma anti diuretic hormone (ADH) concentrations were significantly increased in the NF trial compared to the F trial.(ABSTRACT TRUNCATED AT 250 WORDS)

  4. High-level amikacin resistance in Escherichia coli due to phosphorylation and impaired aminoglycoside uptake.

    PubMed Central

    Perlin, M H; Lerner, S A

    1986-01-01

    Plasmid pMP1-1 in Escherichia coli L-0 encodes aminoglycoside (AG) 3'-phosphotransferase II [APH(3')-II]. This enzyme modifies and confers high-level resistance to kanamycin. Although amikacin is a substrate for APH(3')-II, strain L-0(pMP1-1) is susceptible to amikacin. Plasmid pMP1-2 is a spontaneous mutant of pMP1-1 which determines increased APH(3')-II activity for amikacin, apparently as a result of an increase in the copy number of the plasmid. From amikacin-susceptible, gentamicin-susceptible transformants and transconjugants that bear the APH(3')-II gene on plasmid pMP1-1 or pMP1-2 or cloned into multicopy plasmid pBR322, we selected spontaneous mutants at concentrations of amikacin or gentamicin that were two to four times higher than the MICs of these antibiotics. In each case, whether they were selected by using amikacin or gentamicin, the mutants exhibited modest (two- to eightfold) increases in the MIC of gentamicin and major (64- to 128-fold) increases in the MIC of amikacin. Using these laboratory strains of E. coli, we examined the effects on AG susceptibility of the interaction of AG-modifying enzyme activity and generalized AG uptake. Increasing the level of activity of an AG phosphotransferase in these strains lowered their susceptibility to AGs which were substrates for which the enzyme had low Kms. However, an increase in AG-modifying activity alone did not result in large increases in the MICs for poor substrates of the enzyme. In strains which lacked AG-modifying enzymes, a decrease in the rate of AG uptake increased the MICs modestly for a broad spectrum of AGs. When a strain bore the phosphotransferase, a decrease in generalized AG uptake could raise the MIC further, not only for low-Km substrates, but even for AG substrates for which the enzyme had high Kms. Thus, increased modifying activity, together with a diminished rate of uptake, could produce even higher MICs for poor AG substrates. PMID:2424366

  5. Biomechanical correlates of symptomatic and asymptomatic neurophysiological impairment in high school football.

    PubMed

    Breedlove, Evan L; Robinson, Meghan; Talavage, Thomas M; Morigaki, Katherine E; Yoruk, Umit; O'Keefe, Kyle; King, Jeff; Leverenz, Larry J; Gilger, Jeffrey W; Nauman, Eric A

    2012-04-30

    Concussion is a growing public health issue in the United States, and chronic traumatic encephalopathy (CTE) is the chief long-term concern linked to repeated concussions. Recently, attention has shifted toward subconcussive blows and the role they may play in the development of CTE. We recruited a cohort of high school football players for two seasons of observation. Acceleration sensors were placed in the helmets, and all contact activity was monitored. Pre-season computer-based neuropsychological tests and functional magnetic resonance imaging (fMRI) tests were also obtained in order to assess cognitive and neurophysiological health. In-season follow-up scans were then obtained both from individuals who had sustained a clinically-diagnosed concussion and those who had not. These changes were then related through stepwise regression to history of blows recorded throughout the football season up to the date of the scan. In addition to those subjects who had sustained a concussion, a substantial portion of our cohort who did not sustain concussions showed significant neurophysiological changes. Stepwise regression indicated significant relationships between the number of blows sustained by a subject and the ensuing neurophysiological change. Our findings reinforce the hypothesis that the effects of repetitive blows to the head are cumulative and that repeated exposure to subconcussive blows is connected to pathologically altered neurophysiology.

  6. Evidence of impairment of normal inflammatory reaction by a high-fat diet.

    PubMed

    Laflamme, C; Bertheau-Mailhot, G; Giambelluca, M S; Cloutier, N; Boilard, E; Pouliot, M

    2014-04-01

    The murine dorsal air pouch model is a valuable tool for studying acute peripheral inflammatory reactions. We used this model to study the effect of diet on the onset of acute inflammation. Mice were fed a normal or a high-fat diet (HFD) for 5 weeks. Air pouches were raised and injected with non-stimulating (saline) or stimulating solution (saline containing lipopolysaccharides). After 4 h, leukocytes in the pouch fluid were enumerated, sorted and their viability measured. Cytokine/chemokine levels in the cell-free fluid were measured using a cytometric bead assay. Gene expression level was measured in leukocytes and in lining tissues using comparative real-time PCR. Leukocyte migration and cytokine/chemokine secretion were decreased substantially in mice fed the HFD. In contrast, leptin levels were elevated. Gene expression profiles in leukocytes recovered from the pouch and in the pouch-lining tissue (believed to have an important role in the initiation of granulocyte recruitment) were depressed. Genes encoding CC and CXC family chemokines were among the most negatively affected. These results suggest that a HFD can alter peripheral tissue activation as well as leukocyte recruitment and response, thereby affecting the development of an effective local immune response, which could have deleterious consequences.

  7. High-NaCl diet impairs dynamic renal blood flow autoregulation in rats with adenine-induced chronic renal failure.

    PubMed

    Saeed, Aso; DiBona, Gerald F; Grimberg, Elisabeth; Nguy, Lisa; Mikkelsen, Minne Line Nedergaard; Marcussen, Niels; Guron, Gregor

    2014-03-15

    This study examined the effects of 2 wk of high-NaCl diet on kidney function and dynamic renal blood flow autoregulation (RBFA) in rats with adenine-induced chronic renal failure (ACRF). Male Sprague-Dawley rats received either chow containing adenine or were pair-fed an identical diet without adenine (controls). After 10 wk, rats were randomized to either remain on the same diet (0.6% NaCl) or to be switched to high 4% NaCl chow. Two weeks after randomization, renal clearance experiments were performed under isoflurane anesthesia and dynamic RBFA, baroreflex sensitivity (BRS), systolic arterial pressure variability (SAPV), and heart rate variability were assessed by spectral analytical techniques. Rats with ACRF showed marked reductions in glomerular filtration rate and renal blood flow (RBF), whereas mean arterial pressure and SAPV were significantly elevated. In addition, spontaneous BRS was reduced by ∼50% in ACRF animals. High-NaCl diet significantly increased transfer function fractional gain values between arterial pressure and RBF in the frequency range of the myogenic response (0.06-0.09 Hz) only in ACRF animals (0.3 ± 4.0 vs. -4.4 ± 3.8 dB; P < 0.05). Similarly, a high-NaCl diet significantly increased SAPV in the low-frequency range only in ACRF animals. To conclude, a 2-wk period of a high-NaCl diet in ACRF rats significantly impaired dynamic RBFA in the frequency range of the myogenic response and increased SAPV in the low-frequency range. These abnormalities may increase the susceptibility to hypertensive end-organ injury and progressive renal failure by facilitating pressure transmission to the microvasculature.

  8. High insulin levels in KK-Ay diabetic mice cause increased cortical bone mass and impaired trabecular micro-structure.

    PubMed

    Fu, Cen; Zhang, Xiaolin; Ye, Fei; Yang, Jianhong

    2015-04-13

    Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by hyperglycemia, hyperinsulinemia and complications, including obesity and osteoporosis. Rodents have been widely used to model human T2DM and investigate its effect on the skeleton. We aimed to investigate skeletal alterations in Yellow Kuo Kondo (KK-Ay) diabetic mice displaying high insulin and glucose levels. Bone mineral density (BMD), micro-architecture and bone metabolism-related genes were analyzed. The total femoral areal BMD (aBMD), cortical volumetric BMD (vBMD) and thickness were significantly increased in KK-Ay mice, while the trabecular vBMD and mineralized bone volume/tissue volume (BV/TV), trabecular thickness and number were decreased compared to C57BL mice. The expression of both osteoblast-related genes, such as osteocalcin (OC), bone sialoprotein, Type I Collagen, osteonectin, RUNX2 and OSX, and osteoclast-related genes, such as TRAP and TCIRG, were up-regulated in KK-Ay mice. Correlation analyses showed that serum insulin levels were positively associated with aBMD, cortical vBMD and thickness and negatively associated with trabecular vBMD and micro-architecture. In addition, serum insulin levels were positively related to osteoblast-related and osteoclast-related gene expression. Our data suggest that high insulin levels in KK-Ay diabetic mice may increase cortical bone mass and impair trabecular micro-structure by up-regulating osteoblast-and osteoclast-related gene expression.

  9. Impaired memory and reduced sensitivity to the circadian period lengthening effects of methamphetamine in mice selected for high methamphetamine consumption.

    PubMed

    Olsen, Reid H J; Allen, Charles N; Derkach, Victor A; Phillips, Tamara J; Belknap, John K; Raber, Jacob

    2013-11-01

    Drug abuse runs in families suggesting the involvement of genetic risk factors. Differences in addiction-related neurobiological systems, including learning and memory and circadian rhythms, may exist prior to developing addiction. We characterized the cognitive phenotypes and the free-running circadian period of mouse lines selectively bred for high methamphetamine (MA) drinking (MA high drinking or MAHDR) and low MA drinking (MA low drinking or MALDR). MA-naïve MALDR mice showed spatial memory retention while MAHDR mice did not. MA-naïve MAHDR mice had elevated hippocampal levels of the AMPA receptor subunits GluA2 (old terminology: GluR2), but not GluA1 (old terminology: GluR1). There were no line differences in the free running period (τ) when only water was available. During a 25 mg/L MA solution access period (vs water), there was an increase in τ in MALDR but not MAHDR mice, although MAHDR mice consumed significantly more MA. During a 50 mg/L MA solution access period (vs water), both lines showed an increased τ. There was a positive correlation between MA consumption and τ from baseline in MALDR, but not MAHDR, mice. Thus, a heritable proclivity for elevated MA self-administration may be associated with impairments in hippocampus-dependent memory and reduced sensitivity to effects of MA on lengthening of the circadian period.

  10. Distinct laterality alterations distinguish mild cognitive impairment and Alzheimer's disease from healthy aging: statistical parametric mapping with high resolution MRI.

    PubMed

    Long, Xiaojing; Zhang, Lijuan; Liao, Weiqi; Jiang, Chunxiang; Qiu, Bensheng

    2013-12-01

    Laterality of human brain varies under healthy aging and diseased conditions. The alterations in hemispheric asymmetry may embed distinct biomarkers linked to the disease dynamics. Statistical parametric mapping based on high-resolution magnetic resonance imaging (MRI) and image processing techniques have allowed automated characterization of morphological features across the entire brain. In this study, 149 subjects grouped in healthy young, healthy elderly, mild cognitive impairment (MCI), and Alzheimer's disease (AD) were investigated using multivariate analysis for regional cerebral laterality indexed by surface area, curvature index, cortical thickness, and subjacent white matter volume measured on high-resolution MR images. Asymmetry alteration of MCI and AD were characterized by marked region-specific reduction, while healthy elderly featured a distinct laterality shift in the limbic system in addition to regional asymmetry loss. Lack of the laterality shift in limbic system and early loss of asymmetry in entorhinal cortex may be biomarkers to identify preclinical AD among other dementia. Multivariate analysis of hemispheric asymmetry may provide information helpful for monitoring the disease progress and improving the management of MCI and AD.

  11. DNA Demethylation Rescues the Impaired Osteogenic Differentiation Ability of Human Periodontal Ligament Stem Cells in High Glucose

    PubMed Central

    Liu, Zhi; Chen, Tian; Sun, Wenhua; Yuan, Zongyi; Yu, Mei; Chen, Guoqing; Guo, Weihua; Xiao, Jingang; Tian, Weidong

    2016-01-01

    Diabetes mellitus, characterized by abnormally high blood glucose levels, gives rise to impaired bone remodeling. In response to high glucose (HG), the attenuated osteogenic differentiation capacity of human periodontal ligament stem cells (hPDLSCs) is associated with the loss of alveolar bone. Recently, DNA methylation was reported to affect osteogenic differentiation of stem cells in pathological states. However, the intrinsic mechanism linking DNA methylation to osteogenic differentiation ability in the presence of HG is still unclear. In this study, we found that diabetic rats with increased DNA methylation levels in periodontal ligaments exhibited reduced bone mass and density. In vitro application of 5-aza-2′-deoxycytidine (5-aza-dC), a DNA methyltransferase inhibitor, to decrease DNA methylation levels in hPDLSCs, rescued the osteogenic differentiation capacity of hPDLSCs under HG conditions. Moreover, we demonstrated that the canonical Wnt signaling pathway was activated during this process and, under HG circumstances, the 5-aza-dC-rescued osteogenic differentiation capacity was blocked by Dickkopf-1, an effective antagonist of the canonical Wnt signaling pathway. Taken together, these results demonstrate for the first time that suppression of DNA methylation is able to facilitate the osteogenic differentiation capacity of hPDLSCs exposed to HG, through activation of the canonical Wnt signaling pathway. PMID:27273319

  12. A maternal diet high in saturated fat impairs offspring hippocampal function in a sex-specific manner.

    PubMed

    Robb, Jamie-Lee; Messa, Isabelle; Lui, Erika; Yeung, Derrick; Thacker, Jonathan; Satvat, Elham; Mielke, John G

    2017-03-01

    While a maternal diet high in saturated fat is likely to affect foetal brain development, whether the effects are the same for male and female offspring is unclear. As a result, we randomly assigned female, Sprague-Dawley rats to either a control, or high-fat diet (HFD; 45% of calories from saturated fat) for 10 weeks. A range of biometrics were collected, and hippocampal function was assessed at both the tissue level (by measuring synaptic plasticity) and at the behavioural level (using the Morris water maze; MWM). Subsequently, a subset of animals was bred and remained on their respective diets throughout gestation and lactation. On post-natal day 21, offspring were weaned and placed onto the control diet; biometrics and spatial learning and memory were then assessed at both adolescence and young adulthood. Although the HFD led to changes in the maternal generation consistent with an obese phenotype, no impairments were noted at the level of hippocampal synaptic plasticity, or MWM performance. Unexpectedly, among the offspring, a sexually dimorphic effect upon MWM performance became apparent. In particular, adolescent male offspring displayed a greater latency to reach the platform during training trials and spent less time in the target quadrant during the probe test; notably, when re-examined during young adulthood, the performance deficit was no longer present. Overall, our work suggests the existence of sexual dimorphism with regard to how a maternal HFD affects hippocampal-dependent function in the offspring brain.

  13. A Novel Marker of Impaired Aortic Elasticity in Never Treated Hypertensive Patients: Monocyte/High-Density Lipoprotein Cholesterol Ratio

    PubMed Central

    Yayla, Kadriye Gayretli; Canpolat, Uğur; Yayla, Çagri; Akboğa, Mehmet Kadri; Akyel, Ahmet; Akdi, Ahmet; Çiçek, Gökhan; Ozcan, Firat; Turak, Osman; Aydoğdu, Sinan

    2017-01-01

    Background Monocyte to high density lipoprotein cholesterol ratio (MHR) is generally understood to be a candidate marker of inflammation and oxidative stress. Therefore, we aimed to assess the association between MHR and aortic elastic properties in hypertensive patients. Methods A total of 114 newly-diagnosed untreated patients with hypertension and 71 healthy subjects were enrolled. Aortic stiffness index, aortic strain and aortic distensibility were measured by using echocardiography. Results Patients with hypertension had a significantly higher MHR compared to the control group (p < 0.001). Also, aortic stiffness index (p < 0.001) was significantly higher and aortic distensibility (p < 0.001) was lower in the hypertensive group. There was a positive correlation of MHR with aortic stiffness index (r = 0.294, p < 0.001) and negative correlation with aortic distensibility (r = -0.281, p < 0.001). In addition, MHR and high sensitivity C-reactive protein have a positive correlation (r = 0.30, p < 0.001). Furthermore, MHR was found to be an independent predictor of aortic distensibility and aortic stiffness index. Conclusions In patients with newly-diagnosed untreated essential hypertension, higher MHR was significantly associated with impaired aortic elastic properties. PMID:28115806

  14. High-Iron Consumption Impairs Growth and Causes Copper-Deficiency Anemia in Weanling Sprague-Dawley Rats

    PubMed Central

    Ha, Jung-Heun; Doguer, Caglar; Wang, Xiaoyu; Flores, Shireen R.; Collins, James F.

    2016-01-01

    Iron-copper interactions were described decades ago; however, molecular mechanisms linking the two essential minerals remain largely undefined. Investigations in humans and other mammals noted that copper levels increase in the intestinal mucosa, liver and blood during iron deficiency, tissues all important for iron homeostasis. The current study was undertaken to test the hypothesis that dietary copper influences iron homeostasis during iron deficiency and iron overload. We thus fed weanling, male Sprague-Dawley rats (n = 6-11/group) AIN-93G-based diets containing high (~8800 ppm), adequate (~80) or low (~11) iron in combination with high (~183), adequate (~8) or low (~0.9) copper for 5 weeks. Subsequently, the iron- and copper-related phenotype of the rats was assessed. Rats fed the low-iron diets grew slower than controls, with changes in dietary copper not further influencing growth. Unexpectedly, however, high-iron (HFe) feeding also impaired growth. Furthermore, consumption of the HFe diet caused cardiac hypertrophy, anemia, low serum and tissue copper levels and decreased circulating ceruloplasmin activity. Intriguingly, these physiologic perturbations were prevented by adding extra copper to the HFe diet. Furthermore, higher copper levels in the HFe diet increased serum nonheme iron concentration and transferrin saturation, exacerbated hepatic nonheme iron loading and attenuated splenic nonheme iron accumulation. Moreover, serum erythropoietin levels, and splenic erythroferrone and hepatic hepcidin mRNA levels were altered by the dietary treatments in unanticipated ways, providing insight into how iron and copper influence expression of these hormones. We conclude that high-iron feeding of weanling rats causes systemic copper deficiency, and further, that copper influences the iron-overload phenotype. PMID:27537180

  15. Impairment of chondrocyte biosynthetic activity by exposure to 3-tesla high-field magnetic resonance imaging is temporary.

    PubMed

    Sunk, Ilse-Gerlinde; Trattnig, Siegfried; Graninger, Winfried B; Amoyo, Love; Tuerk, Birgit; Steiner, Carl-Walter; Smolen, Josef S; Bobacz, Klaus

    2006-01-01

    The influence of magnetic resonance imaging (MRI) devices at high field strengths on living tissues is unknown. We investigated the effects of a 3-tesla electromagnetic field (EMF) on the biosynthetic activity of bovine articular cartilage. Bovine articular cartilage was obtained from juvenile and adult animals. Whole joints or cartilage explants were subjected to a pulsed 3-tesla EMF; controls were left unexposed. Synthesis of sulfated glycosaminoglycans (sGAGs) was measured by using [35S]sulfate incorporation; mRNA encoding the cartilage markers aggrecan and type II collagen, as well as IL-1beta, were analyzed by RT-PCR. Furthermore, effects of the 3-tesla EMF were determined over the course of time directly after exposure (day 0) and at days 3 and 6. In addition, the influence of a 1.5-tesla EMF on cartilage sGAG synthesis was evaluated. Chondrocyte cell death was assessed by staining with Annexin V and TdT-mediated dUTP nick end labelling (TUNEL). Exposure to the EMF resulted in a significant decrease in cartilage macromolecule synthesis. Gene expression of both aggrecan and IL-1beta, but not of collagen type II, was reduced in comparison with controls. Staining with Annexin V and TUNEL revealed no evidence of cell death. Interestingly, chondrocytes regained their biosynthetic activity within 3 days after exposure, as shown by proteoglycan synthesis rate and mRNA expression levels. Cartilage samples exposed to a 1.5-tesla EMF remained unaffected. Although MRI devices with a field strength of more than 1.5 T provide a better signal-to-noise ratio and thereby higher spatial resolution, their high field strength impairs the biosynthetic activity of articular chondrocytes in vitro. Although this decrease in biosynthetic activity seems to be transient, articular cartilage exposed to high-energy EMF may become vulnerable to damage.

  16. Experience with the high-intensity sweetener saccharin impairs glucose homeostasis and GLP-1 release in rats.

    PubMed

    Swithers, Susan E; Laboy, Alycia F; Clark, Kiely; Cooper, Stephanie; Davidson, T L

    2012-07-15

    Previous work from our lab has demonstrated that experience with high-intensity sweeteners in rats leads to increased food intake, body weight gain and adiposity, along with diminished caloric compensation and decreased thermic effect of food. These changes may occur as a result of interfering with learned relations between the sweet taste of food and the caloric or nutritive consequences of consuming those foods. The present experiments determined whether experience with the high-intensity sweetener saccharin versus the caloric sweetener glucose affected blood glucose homeostasis. The results demonstrated that during oral glucose tolerance tests, blood glucose levels were more elevated in animals that had previously consumed the saccharin-sweetened supplements. In contrast, during glucose tolerance tests when a glucose solution was delivered directly into the stomach, no differences in blood glucose levels between the groups were observed. Differences in oral glucose tolerance responses were not accompanied by differences in insulin release; insulin release was similar in animals previously exposed to saccharin and those previously exposed to glucose. However, release of GLP-1 in response to an oral glucose tolerance test, but not to glucose tolerance tests delivered by gavage, was significantly lower in saccharin-exposed animals compared to glucose-exposed animals. Differences in both blood glucose and GLP-1 release in saccharin animals were rapid and transient, and suggest that one mechanism by which exposure to high-intensity sweeteners that interfere with a predictive relation between sweet tastes and calories may impair energy balance is by suppressing GLP-1 release, which could alter glucose homeostasis and reduce satiety.

  17. High-dose statin use does not impair aerobic capacity or skeletal muscle function in older adults

    PubMed Central

    Stock, Anthoney A.; Harman, S. Mitchell

    2008-01-01

    3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are lipid-lowering agents widely employed for atherosclerosis prevention. HMG-CoA reductase blockade reduces skeletal muscle coenzyme Q10 (CoQ10) levels and mitochondrial respiratory chain activities and may produce mild to severe skeletal muscle myopathy. This study investigated whether high-dose statin treatment would result in measurably decreased exercise capacity in older men and women. Maximal oxygen consumption, aerobic endurance, oxygen uptake kinetics, maximal strength, muscular power, and muscular endurance were measured before and after 12 weeks of statin treatment (simvastatin, 80 mg/day) in nine men and one woman, ages 55–76 years, with LDL-cholesterol levels >3.3 mmol/l (mean = 4.2 ± 0.2 mmol/l). Myalgia symptoms were assessed every 4 weeks. As expected, statin treatment resulted in significant decreases in LDL- and total-cholesterol levels (P < 0.01) with no significant changes in HDL-cholesterol or triglyceride levels. No significant changes were observed in aerobic capacity, endurance, oxygen kinetics or any measures of muscle function. No subject reported symptoms of myalgia, cramps, or weakness during the study. In the absence of myalgia or myopathic symptoms, high-dose simvastatin treatment did not impair exercise capacity in hyperlipidemic older individuals. We conclude that decreases in intramuscular CoQ10, in most patients on high dose statin treatment may not be clinically relevant, due to inter-individual variability in the degree of CoQ10 depletion, sensitivity of muscle to decreases in CoQ10, or both. PMID:19424852

  18. Impaired identification of impoverished animate but not inanimate objects in adults with high-functioning autism spectrum disorder.

    PubMed

    Burnett, Hollie G; Panis, Sven; Wagemans, Johan; Jellema, Tjeerd

    2015-02-01

    The ability to identify animate and inanimate objects from impoverished images was investigated in adults with high-functioning autism spectrum disorder (HFA) and in matched typically developed (TD) adults, using a newly developed task. Consecutive frames were presented containing Gabor elements that slightly changed orientation from one frame to the next. For a subset of elements, the changes were such that these elements gradually formed the outline of an object. Elements enclosed within the object's outline gradually adopted one and the same orientation, outside elements adopted random orientations. The subjective experience was that of an object appearing out of a fog. The HFA group required significantly more frames to identify the impoverished objects than the TD group. Crucially, this difference depended on the nature of the objects: the HFA group required significantly more frames to identify animate objects, but with respect to the identification of inanimate objects the groups did not differ. The groups also did not differ with respect to the number and type of incorrect guesses they made. The results suggest a specific impairment in individuals with HFA in identifying animate objects. A number of possible explanations are discussed.

  19. A high-fat diet impairs reproduction by decreasing the IL1β level in mice treated at immature stage.

    PubMed

    Zhang, Jie; Li, Kai; Yuan, Miao; Zhang, Jie; Huang, Guizen; Ao, Jie; Tan, Haoze; Li, Yanyan; Gong, Di; Li, Jun; Kang, Lei; An, Nini; Li, Fei; Lin, Ping; Huang, Lugang

    2017-04-03

    Obesity causes low-grade inflammation that is involved in male infertility. Interleukin 1 beta (IL1β) plays an important role in this process. A high-fat diet (HFD) is the most common cause of obesity. However, the effect of a HFD on IL1β and its consequence in reproduction remain unclear. We established a HFD model in mice treated at immature stage (mice-TIS) and mice treated at mature stage (mice-TMS). Surprisingly, we found that a HFD decreased IL1β levels and was accompanied by an increase in testosterone in mice-TIS, while the reverse results were observed in mice-TMS. In addition, a HFD caused a reduction in testis macrophages and in the expression of inflammasome-related genes and proteins in mice-TIS. Furthermore, we found that IL1β inhibited testosterone secretion through down-regulating the gene expression of P450SCC and P450c17. However, the influence on mice-TIS that were induced by a HFD was recovered by stopping the HFD. In this study, we are the first to report that a HFD impairs the reproductive system by decreasing IL1β and enhancing testosterone levels in mice-TIS, which are different from the effects in mice-TMS. This provides new ideas for the treatment of obesity-induced infertility.

  20. Similar Comparative Low and High Doses of Deltamethrin and Acetamiprid Differently Impair the Retrieval of the Proboscis Extension Reflex in the Forager Honey Bee (Apis mellifera).

    PubMed

    Thany, Steeve H; Bourdin, Céline M; Graton, Jérôme; Laurent, Adèle D; Mathé-Allainmat, Monique; Lebreton, Jacques; Questel, Jean-Yves le

    2015-09-28

    In the present study, the effects of low (10 ng/bee) and high (100 ng/bee) doses of acetamiprid and deltamethrin insecticides on multi-trial learning and retrieval were evaluated in the honey bee Apis mellifera. After oral application, acetamiprid and deltamethrin at the concentrations used were not able to impair learning sessions. When the retention tests were performed 1 h, 6 h, and 24 h after learning, we found a significant difference between bees after learning sessions when drugs were applied 24 h before learning. Deltamethrin-treated bees were found to be more sensitive at 10 ng/bee and 100 ng/bee doses compared to acetamiprid-treated bees, only with amounts of 100 ng/bee and at 6 h and 24 h delays. When insecticides were applied during learning sessions, none of the tested insecticides was able to impair learning performance at 10 ng/bee or 100 ng/bee but retention performance was altered 24 h after learning sessions. Acetamiprid was the only one to impair retrieval at 10 ng/bee, whereas at 100 ng/bee an impairment of retrieval was found with both insecticides. The present results therefore suggest that acetamiprid and deltamethrin are able to impair retrieval performance in the honey bee Apis mellifera.

  1. Impaired Driving

    MedlinePlus

    Impaired driving is dangerous. It's the cause of more than half of all car crashes. It means operating a ... texting Having a medical condition which affects your driving For your safety and the safety of others, ...

  2. Taste - impaired

    MedlinePlus

    ... longer. Causes of impaired taste include: Bell's palsy Common cold Flu and other viral infections Nasal infection, nasal ... your diet. For taste problems due to the common cold or flu, normal taste should return when the ...

  3. Arabidopsis thaliana leaves with altered chloroplast numbers and chloroplast movement exhibit impaired adjustments to both low and high light.

    PubMed

    Königer, Martina; Delamaide, Joy A; Marlow, Elizabeth D; Harris, Gary C

    2008-01-01

    The effects of chloroplast number and size on the capacity for blue light-dependent chloroplast movement, the ability to increase light absorption under low light, and the susceptibility to photoinhibition were investigated in Arabidopsis thaliana. Leaves of wild-type and chloroplast number mutants with mean chloroplast numbers ranging from 120 to two per mesophyll cell were analysed. Chloroplast movement was monitored as changes in light transmission through the leaves. Light transmission was used as an indicator of the ability of leaves to optimize light absorption. The ability of leaves to deal with 3 h of high light stress at 10 degrees C and their capacity to recover in low light was determined by measuring photochemical efficiencies of PSII using chlorophyll a fluorescence. Chloroplast movement was comparable in leaves ranging in chloroplast numbers from 120 to 30 per mesophyll cell: the final light transmission levels after exposure to 0.1 (accumulation response) and 100 micromol photons m(-2) s(-1) (avoidance response) were indistinguishable, the chloroplasts responded quickly to small increases in light intensity and the kinetics of movement were similar. However, when chloroplast numbers per mesophyll cell decreased to 18 or below, the accumulation response was significantly reduced. The avoidance response was only impaired in mutants with nine or fewer chloroplasts, both in terms of final transmission levels and the speed of movement. Only mutants lacking both blue light receptors (phot1/phot2) or those with drastically reduced chloroplast numbers and severely impacted avoidance responses showed a reduced ability to recover from high light stress.

  4. [Deformations of the vertebral column in the visually impaired schoolchildren presenting with complicated high myopia and the possibilities for its correction].

    PubMed

    Egorova, T S; Smirnova, T S; Romashin, O V; Egorova, I V

    2016-01-01

    Complicated high myopia is one of the leading causes responsible for the disablement in the children associated with visual impairment especially when it is combined with other pathological conditions and abnormalities among which are disorders of the musculoskeletal system. In the present study, we for the first time examined visually impaired schoolchildren (n=44) who suffered from high myopia complications making use of the computed optical topographer for the evaluation of the state of their vertebral column. The control group consisted of 60 children attending a secondary school. The study revealed various deformations of the musculoskeletal system including scoliosis, misalignment of the pelvis, kyphosis, hyperlordosis, torsion, platypodia, deformation of the lower extremities and the chest. These deformations were more pronounced in the visually impaired schoolchildren in comparison with the children of the same age comprising the control group (p<0,05). It is concluded that the assessment of the state of the vertebral column with the use of the apparatus yields an important information for the elaboration and application of a series of measures for the timely provision of medical assistance needed for the comprehensive rehabilitation of the visually impaired schoolchildren presenting with high myopia complications.

  5. MicroRNA-134 Contributes to Glucose-Induced Endothelial Cell Dysfunction and This Effect Can Be Reversed by Far-Infrared Irradiation

    PubMed Central

    Wang, Yen-Li; Chang, Shih-Ting; Liao, Ko-Hsun; Lo, Hung-Hao; Chiu, Ya-Lin; Hsieh, Tsung-Han; Huang, Tse-Shun; Lin, Chin-Sheng; Cheng, Shu-Meng; Cheng, Cheng-Chung

    2016-01-01

    Diabetes mellitus (DM) is a metabolic disease that is increasing worldwide. Furthermore, it is associated with the deregulation of vascular-related functions, which can develop into major complications among DM patients. Endothelial colony forming cells (ECFCs) have the potential to bring about medical repairs because of their post-natal angiogenic activities; however, such activities are impaired by high glucose- (HG) and the DM-associated conditions. Far-infrared radiation (FIR) transfers energy as heat that is perceived by the thermoreceptors in human skin. Several studies have revealed that FIR improves vascular endothelial functioning and boost angiogenesis. FIR has been used as anti-inflammatory therapy and as a clinical treatment for peripheral circulation improvement. In addition to vascular repair, there is increasing evidence to show that FIR can be applied to a variety of diseases, including cardiovascular disorders, hypertension and arthritis. Yet mechanism of action of FIR and the biomarkers that indicate FIR effects remain unclear. MicroRNA-134 (miR-134-5p) was identified by small RNA sequencing as being increased in high glucose (HG) treated dfECFCs (HG-dfECFCs). Highly expressed miR-134 was also validated in dmECFCs by RT-qPCR and it is associated with impaired angiogenic activities of ECFCs. The functioning of ECFCs is improved by FIR treatment and this occurs via a reduction in the level of miR-134 and an increase in the NRIP1 transcript, a direct target of miR-134. Using a mouse ischemic hindlimb model, the recovery of impaired blood flow in the presence of HG-dfECFCs was improved by FIR pretreatment and this enhanced functionality was decreased when there was miR-134 overexpression in the FIR pretreated HG-dfECFCs. In conclusion, our results reveal that the deregulation of miR-134 is involved in angiogenic defects found in DM patients. FIR treatment improves the angiogenic activity of HG-dfECFCs and dmECFCs and FIR has potential as a treatment

  6. Biphasic effect of alpha-linolenic acid on glucose-induced dysmorphogenesis and lipoperoxidation in whole rat embryo in culture.

    PubMed

    Chirino-Galindo, Gladys; Barrera-Argüelles, Jorge-Israel; Trejo-González, Ninna-Leslie; Mejía-Zepeda, Ricardo; Palomar-Morales, Martín

    2017-03-18

    Type 1 diabetes mellitus complicated with pregnancy, know as diabetic embryopathy, is the cause of neonatal malformations and low for gestational age neonates. With the use of the whole-embryo culture system, it has been demonstrated that high glucose causes embryo dysmorphogenesis, and that oxidative stress appears to be the main mechanism. In recent years, beneficial effect of omega-3 fatty acids has been demonstrated in various diabetic models, and in diabetic complications. Since diabetic embryopathy is mediated probably through membrane lipoperoxidation, This study was designed to find if omega-3 fatty acids could ameliorate the effect of high glucose over the dysmorphogenesis of whole rat embryo in culture. Postimplantational rat embryos were cultured in hyperglycemic media, with addition of alpha-linolenic acid, and morphologic and morphometric parameters were registered. Also, lipoperoxidation and fatty acids composition were measured in cultured embryos. Growth of embryos cultured in presence of glucose was very affected, whereas lipoperoxidation was increased, and it was found that Triton X-100 causes similar results than glucose. Addition of low micromolar doses of alpha-linolenic acid overcome the effect of high glucose or Triton X-100, but higher doses does not ameliorates the effects of the carbohydrate or the detergent. Paradoxically, there are not significant changes in fatty acids composition, although the U/S fatty acids ratio shows an increasing tendency by high glucose and a normalizing tendency by omega-3 fatty acids. In conclusion, glucose and Triton X-100 induces in vitro dysmorphogenesis in post-implantational rat embryos associated with increased lipoperoxidation; and this nocive effect could be ameliorated by low micromolar doses of ALA.

  7. Resveratrol increases glucose induced GLP-1 secretion in mice: a mechanism which contributes to the glycemic control.

    PubMed

    Dao, Thi-Mai Anh; Waget, Aurélie; Klopp, Pascale; Serino, Matteo; Vachoux, Christelle; Pechere, Laurent; Drucker, Daniel J; Champion, Serge; Barthélemy, Sylvain; Barra, Yves; Burcelin, Rémy; Sérée, Eric

    2011-01-01

    Resveratrol (RSV) is a potent anti-diabetic agent when used at high doses. However, the direct targets primarily responsible for the beneficial actions of RSV remain unclear. We used a formulation that increases oral bioavailability to assess the mechanisms involved in the glucoregulatory action of RSV in high-fat diet (HFD)-fed diabetic wild type mice. Administration of RSV for 5 weeks reduced the development of glucose intolerance, and increased portal vein concentrations of both Glucagon-like peptid-1 (GLP-1) and insulin, and intestinal content of active GLP-1. This was associated with increased levels of colonic proglucagon mRNA transcripts. RSV-mediated glucoregulation required a functional GLP-1 receptor (Glp1r) as neither glucose nor insulin levels were modulated in Glp1r-/- mice. Conversely, levels of active GLP-1 and control of glycemia were further improved when the Dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin was co-administered with RSV. In addition, RSV treatment modified gut microbiota and decreased the inflammatory status of mice. Our data suggest that RSV exerts its actions in part through modulation of the enteroendocrine axis in vivo.

  8. Resveratrol Increases Glucose Induced GLP-1 Secretion in Mice: A Mechanism which Contributes to the Glycemic Control

    PubMed Central

    Dao, Thi-Mai Anh; Waget, Aurélie; Klopp, Pascale; Serino, Matteo; Vachoux, Christelle; Pechere, Laurent; Drucker, Daniel J.; Champion, Serge; Barthélemy, Sylvain; Barra, Yves; Burcelin, Rémy; Sérée, Eric

    2011-01-01

    Resveratrol (RSV) is a potent anti-diabetic agent when used at high doses. However, the direct targets primarily responsible for the beneficial actions of RSV remain unclear. We used a formulation that increases oral bioavailability to assess the mechanisms involved in the glucoregulatory action of RSV in high-fat diet (HFD)-fed diabetic wild type mice. Administration of RSV for 5 weeks reduced the development of glucose intolerance, and increased portal vein concentrations of both Glucagon-like peptid-1 (GLP-1) and insulin, and intestinal content of active GLP-1. This was associated with increased levels of colonic proglucagon mRNA transcripts. RSV-mediated glucoregulation required a functional GLP-1 receptor (Glp1r) as neither glucose nor insulin levels were modulated in Glp1r-/- mice. Conversely, levels of active GLP-1 and control of glycemia were further improved when the Dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin was co-administered with RSV. In addition, RSV treatment modified gut microbiota and decreased the inflammatory status of mice. Our data suggest that RSV exerts its actions in part through modulation of the enteroendocrine axis in vivo. PMID:21673955

  9. FGFR Inhibitor Ameliorates Hypophosphatemia and Impaired Engrailed-1/Wnt Signaling in FGF2 High Molecular Weight Isoform Transgenic Mice.

    PubMed

    Du, Erxia; Xiao, Liping; Hurley, Marja M

    2016-09-01

    High molecular weight FGF2 transgenic (HMWTg) mouse phenocopies the Hyp mouse, homolog of human X-linked hypophosphatemic rickets with hypophosphatemis, and abnormal FGF23, FGFR, Klotho signaling in kidney. Since abnormal Wnt signaling was reported in Hyp mice we assessed whether Wnt signaling was impaired in HMWTg kidneys and the effect of blocking FGF receptor (FGFR) signaling. Bone mineral density and bone mineral content in female HMWTg mice were significantly reduced. HMWTg mice were gavaged with FGFR inhibitor NVP-BGJ398, or vehicle and were euthanized 24 h post treatment. Serum phosphate was significantly reduced and urine phosphate was significantly increased in HMWTg and was rescued by NVP-BGJ398. Analysis of kidneys revealed a significant reduction in Npt2a mRNA in HMWTg that was significantly increased by NVP-BGJ398. Increased FGFR1, KLOTHO, P-ERK1/2, and decreased NPT2a protein in HMWTg were rescued by NVP-BGJ398. Wnt inhibitor Engrailed-1 mRNA and protein was increased in HMWTg and was decreased by BGJ398. Akt mRNA and protein was decreased in HMWTg and was increased by NVP-BGJ398. The active form of glycogen synthase 3 beta (pGSK3-β) and phosphor-β-catenin were increased in HMWTg and were both decreased by NVP-BGJ398 while decreased active-β-catenin in HMWTg was increased by NVP-BGJ398. We conclude that FGFR blockade rescued hypophosphatemia by regulating FGF and WNT signaling in HMWTg kidneys. J. Cell. Biochem. 117: 1991-2000, 2016. © 2016 Wiley Periodicals, Inc.

  10. Oxidized High-Density Lipoprotein Impairs Endothelial Progenitor Cells' Function by Activation of CD36-MAPK-TSP-1 Pathways

    PubMed Central

    Wu, Jianxiang; He, Zhiqing; Gao, Xiang; Wu, Feng; Ding, Ru; Ren, Yusheng; Jiang, Qijun; Fan, Min

    2015-01-01

    Abstract Aims: High-density lipoprotein (HDL) levels inversely correlate with cardiovascular events due to the protective effects on vascular wall and stem cells, which are susceptible to oxidative modifications and then lead to potential pro-atherosclerotic effects. We proposed that oxidized HDL (ox-HDL) might lead to endothelial progenitor cells (EPCs) dysfunction and investigated underlying mechanisms. Results: ox-HDL was shown to increase apoptosis and intracellular reactive oxygen species levels, but to reduce migration, angiogenesis, and cholesterol efflux of EPCs in a dose-dependent manner. p38 mitogen-activated protein kinase (MAPK) and NF-κB were activated after ox-HDL stimulation, which also upregulated thrombospondin-1 (TSP-1) expression without affecting vascular endothelial growth factor. Effects caused by ox-HDL could be significantly attenuated by pretreatment with short hairpin RNA-mediated CD36 knockdown or probucol. Data of in vivo experiments and the inverse correlation of ox-HDL and circulating EPC numbers among patients with coronary artery diseases (CAD) or CAD and type 2 diabetes also supported it. Meanwhile, HDL separated from such patients could significantly increase cultured EPC's caspase 3 activity, further supporting our proposal. Innovation: This is the most complete study to date of how ox-HDL would impair EPCs function, which was involved with activation of CD36-p38 MAPK-TSP-1 pathways and proved by not only the inverse relationship between ox-HDL and circulating EPCs in clinic but also pro-apoptotic effects of HDL separated from patients' serum. Conclusion: Activation of CD36-p38 MAPK-TSP-1 pathways contributes to the pathological effects of ox-HDL on EPCs' dysfunction, which might be one of the potential etiological factors responsible for the disturbed neovascularization in chronic ischemic disease. Antioxid. Redox Signal. 22, 308–324. PMID:25313537

  11. High Mobility Group Box-1 mediates hyperoxia-induced impairment of Pseudomonas aeruginosa clearance and inflammatory lung injury in mice.

    PubMed

    Patel, Vivek S; Sitapara, Ravikumar A; Gore, Ashwini; Phan, Binh; Sharma, Lokesh; Sampat, Vaishali; Li, Jian Hua; Yang, Huan; Chavan, Sangeeta S; Wang, Haichao; Tracey, Kevin J; Mantell, Lin L

    2013-03-01

    Mechanical ventilation with supraphysiological concentrations of oxygen (hyperoxia) is routinely used to treat patients with respiratory distress. However, a significant number of patients on ventilators exhibit enhanced susceptibility to infections and develop ventilator-associated pneumonia (VAP). Pseudomonas aeruginosa (PA) is one of the most common species of bacteria found in these patients. Previously, we demonstrated that prolonged exposure to hyperoxia can compromise the ability of alveolar macrophages (AMs), an essential part of the innate immunity, to phagocytose PA. This study sought to investigate the potential molecular mechanisms underlying hyperoxia-compromised innate immunity against bacterial infection in a murine model of PA pneumonia. Here, we show that exposure to hyperoxia (≥ 99% O2) led to a significant elevation in concentrations of airway high mobility group box-1 (HMGB1) and increased mortality in C57BL/6 mice infected with PA. Treatment of these mice with a neutralizing anti-HMGB1 monoclonal antibody (mAb) resulted in a reduction in bacterial counts, injury, and numbers of neutrophils in the lungs, and an increase in leukocyte phagocytic activity compared with mice receiving control mAb. This improved phagocytic function was associated with reduced concentrations of airway HMGB1. The correlation between phagocytic activity and concentrations of extracellular HMGB1 was also observed in cultured macrophages. These results indicate a pathogenic role for HMGB1 in hyperoxia-induced impairment with regard to a host's ability to clear bacteria and inflammatory lung injury. Thus, HMGB1 may provide a novel molecular target for improving hyperoxia-compromised innate immunity in patients with VAP.

  12. Impact of serum high-mobility group box 1 protein elevation on oxygenation impairment after thoracic aortic aneurysm repair.

    PubMed

    Kohno, Takashi; Anzai, Toshihisa; Shimizu, Hideyuki; Kaneko, Hidehiro; Sugano, Yasuo; Yamada, Shingo; Yoshikawa, Tsutomu; Ishizaka, Akitoshi; Yozu, Ryohei; Ogawa, Satoshi

    2011-05-01

    High-mobility group box 1 protein (HMGB1) is a late mediator of inflammatory responses that can cause acute lung injury. We examined the significance of serum HMGB1 elevation in the development of systemic inflammatory response syndrome (SIRS) and lung oxygenation impairment (LOI) after thoracic aortic aneurysm (TAA) repair. Serial measurements of the serum HMGB1 level and SIRS score for 7 days after surgery were determined in 20 patients with TAA who underwent surgical repair. Arterial oxygen tension was measured serially for at least 4 days after surgery, and LOI was defined as the lowest PaO(2)/FiO(2) ratio ≤ 200 mmHg. The serum HMGB1 level was markedly increased after surgery, peaking on day 2, and remained significantly elevated on day 7. Peak HMGB1 level positively correlated with SIRS duration and the cumulative SIRS score during postoperative days 1-7 (P = 0.0013 and P = 0.0004, respectively). Peak HMGB1 level and cumulative SIRS score were higher in patients with LOI than in those without (P = 0.01 and P = 0.044, respectively). Peak HMGB1 level was negatively correlated with the lowest PaO(2)/FiO(2) ratio (P = 0.0077) and positively correlated with postoperative length of hospitalization (P = 0.042). A greater serum HMGB1 elevation after TAA repair was associated with more severe SIRS and a higher incidence of LOI. HMGB1 might play a key role in the pathogenesis of SIRS and LOI after surgical TAA repair.

  13. Highly Significant Linkage to the SLI1 Locus in an Expanded Sample of Individuals Affected by Specific Language Impairment

    PubMed Central

    2004-01-01

    Specific language impairment (SLI) is defined as an unexplained failure to acquire normal language skills despite adequate intelligence and opportunity. We have reported elsewhere a full-genome scan in 98 nuclear families affected by this disorder, with the use of three quantitative traits of language ability (the expressive and receptive tests of the Clinical Evaluation of Language Fundamentals and a test of nonsense word repetition). This screen implicated two quantitative trait loci, one on chromosome 16q (SLI1) and a second on chromosome 19q (SLI2). However, a second independent genome screen performed by another group, with the use of parametric linkage analyses in extended pedigrees, found little evidence for the involvement of either of these regions in SLI. To investigate these loci further, we have collected a second sample, consisting of 86 families (367 individuals, 174 independent sib pairs), all with probands whose language skills are ⩾1.5 SD below the mean for their age. Haseman-Elston linkage analysis resulted in a maximum LOD score (MLS) of 2.84 on chromosome 16 and an MLS of 2.31 on chromosome 19, both of which represent significant linkage at the 2% level. Amalgamation of the wave 2 sample with the cohort used for the genome screen generated a total of 184 families (840 individuals, 393 independent sib pairs). Analysis of linkage within this pooled group strengthened the evidence for linkage at SLI1 and yielded a highly significant LOD score (MLS = 7.46, interval empirical P<.0004). Furthermore, linkage at the same locus was also demonstrated to three reading-related measures (basic reading [MLS = 1.49], spelling [MLS = 2.67], and reading comprehension [MLS = 1.99] subtests of the Wechsler Objectives Reading Dimensions). PMID:15133743

  14. Physical Impairment

    NASA Astrophysics Data System (ADS)

    Trewin, Shari

    Many health conditions can lead to physical impairments that impact computer and Web access. Musculoskeletal conditions such as arthritis and cumulative trauma disorders can make movement stiff and painful. Movement disorders such as tremor, Parkinsonism and dystonia affect the ability to control movement, or to prevent unwanted movements. Often, the same underlying health condition also has sensory or cognitive effects. People with dexterity impairments may use a standard keyboard and mouse, or any of a wide range of alternative input mechanisms. Examples are given of the diverse ways that specific dexterity impairments and input mechanisms affect the fundamental actions of Web browsing. As the Web becomes increasingly sophisticated, and physically demanding, new access features at the Web browser and page level will be necessary.

  15. Glucose Induces Sensitivity to Oxygen Deprivation and Modulates Insulin/IGF-1 Signaling and Lipid Biosynthesis in Caenorhabditis elegans

    PubMed Central

    Garcia, Anastacia M.; Ladage, Mary L.; Dumesnil, Dennis R.; Zaman, Khadiza; Shulaev, Vladimir; Azad, Rajeev K.; Padilla, Pamela A.

    2015-01-01

    Diet is a central environmental factor that contributes to the phenotype and physiology of individuals. At the root of many human health issues is the excess of calorie intake relative to calorie expenditure. For example, the increasing amount of dietary sugars in the human diet is contributing to the rise of obesity and type 2 diabetes. Individuals with obesity and type 2 diabetes have compromised oxygen delivery, and thus it is of interest to investigate the impact a high-sugar diet has on oxygen deprivation responses. By utilizing the Caenorhabditis elegans genetic model system, which is anoxia tolerant, we determined that a glucose-supplemented diet negatively impacts responses to anoxia and that the insulin-like signaling pathway, through fatty acid and ceramide synthesis, modulates anoxia survival. Additionally, a glucose-supplemented diet alters lipid localization and initiates a positive chemotaxis response. Use of RNA-sequencing analysis to compare gene expression responses in animals fed either a standard or glucose-supplemented diet revealed that glucose impacts the expression of genes involved with multiple cellular processes including lipid and carbohydrate metabolism, stress responses, cell division, and extracellular functions. Several of the genes we identified show homology to human genes that are differentially regulated in response to obesity or type 2 diabetes, suggesting that there may be conserved gene expression responses between C. elegans fed a glucose-supplemented diet and a diabetic and/or obesity state observed in humans. These findings support the utility of the C. elegans model for understanding the molecular mechanisms regulating dietary-induced metabolic diseases. PMID:25762526

  16. HB-EGF release mediates glucose-induced activation of the epidermal growth factor receptor in mesangial cells.

    PubMed

    Uttarwar, L; Peng, F; Wu, D; Kumar, S; Gao, B; Ingram, A J; Krepinsky, J C

    2011-04-01

    Glomerular matrix accumulation is a hallmark of diabetic nephropathy. We showed that transactivation of the epidermal growth factor receptor (EGFR) is an important mediator of matrix upregulation in mesangial cells (MC) in response to high glucose (HG). Here, we study the mechanism of EGFR transactivation. In primary MC, EGFR transactivation by 1 h of HG (30 mM) was unaffected by inhibitors of protein kinase C, reactive oxygen species, or the angiotensin II AT1 receptor. However, general metalloprotease inhibition, as well as specific inhibitors of heparin-binding EGF-like growth factor (HB-EGF), prevented both EGFR and downstream Akt activation. HB-EGF was released into the medium by 30 min of HG, and this depended on metalloprotease activity. One of the metalloproteases shown to cleave proHB-EGF is ADAM17 (TACE). HG, but not an osmotic control, activated ADAM17, and its inhibition prevented EGFR and Akt activation and HB-EGF release into the medium. siRNA to either ADAM17 or HB-EGF prevented HG-induced EGFR transactivation. We previously showed that EGFR/Akt signaling increases transforming growth factor (TGF)-β1 transcription through the transcription factor activator protein (AP)-1. HG-induced AP-1 activation, as assessed by EMSA, was abrogated by inhibitors of metalloproteases, HB-EGF and ADAM17. HB-EGF and ADAM17 siRNA also prevented AP-1 activation. Finally, these inhibitors and siRNA prevented TGF-β1 upregulation by HG. Thus, HG-induced EGFR transactivation in MC is mediated by the release of HB-EGF, which requires activity of the metalloprotease ADAM17. The mechanism of ADAM17 activation awaits identification. Targeting upstream mediators of EGFR transactivation including HB-EGF or ADAM17 provides novel therapeutic targets for the treatment of diabetic nephropathy.

  17. Toll-like receptor 2 mediates high-fat diet-induced impairment of vasodilator actions of insulin

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Rationale - Obesity is characterized by a chronic pro-inflammatory state that promotes insulin resistance in liver, adipose tissue, and skeletal muscle as well as impairing insulin action in vascular endothelium that contributes to endothelial dysfunction. Cadiovascular complications of obesity are ...

  18. Metformin Ameliorates Dysfunctional Traits of Glibenclamide- and Glucose-Induced Insulin Secretion by Suppression of Imposed Overactivity of the Islet Nitric Oxide Synthase-NO System.

    PubMed

    Lundquist, Ingmar; Mohammed Al-Amily, Israa; Meidute Abaraviciene, Sandra; Salehi, Albert

    2016-01-01

    Metformin lowers diabetic blood glucose primarily by reducing hepatic gluconeogenesis and increasing peripheral glucose uptake. However, possible effects by metformin on beta-cell function are incompletely understood. We speculated that metformin might positively influence insulin secretion through impacting the beta-cell nitric oxide synthase (NOS)-NO system, a negative modulator of glucose-stimulated insulin release. In short-time incubations with isolated murine islets either glibenclamide or high glucose augmented insulin release associated with increased NO production from both neural and inducible NOS. Metformin addition suppressed the augmented NO generation coinciding with amplified insulin release. Islet culturing with glibenclamide or high glucose revealed pronounced fluorescence of inducible NOS in the beta-cells being abolished by metformin co-culturing. These findings were reflected in medium nitrite-nitrate levels. A glucose challenge following islet culturing with glibenclamide or high glucose revealed markedly impaired insulin response. Metformin co-culturing restored this response. Culturing murine islets and human islets from controls and type 2 diabetics with high glucose or high glucose + glibenclamide induced a pronounced decrease of cell viability being remarkably restored by metformin co-culturing. We show here, that imposed overactivity of the beta-cell NOS-NO system by glibenclamide or high glucose leads to insulin secretory dysfunction and reduced cell viability and also, importantly, that these effects are relieved by metformin inhibiting beta-cell NO overproduction from both neural and inducible NOS thus ameliorating a concealed negative influence by NO induced by sulfonylurea treatment and/or high glucose levels. This double-edged effect of glibenclamide on the beta-cellsuggests sulfonylurea monotherapy in type 2 diabetes being avoided.

  19. Metformin Ameliorates Dysfunctional Traits of Glibenclamide- and Glucose-Induced Insulin Secretion by Suppression of Imposed Overactivity of the Islet Nitric Oxide Synthase-NO System

    PubMed Central

    Lundquist, Ingmar; Mohammed Al-Amily, Israa; Meidute Abaraviciene, Sandra

    2016-01-01

    Metformin lowers diabetic blood glucose primarily by reducing hepatic gluconeogenesis and increasing peripheral glucose uptake. However, possible effects by metformin on beta-cell function are incompletely understood. We speculated that metformin might positively influence insulin secretion through impacting the beta-cell nitric oxide synthase (NOS)-NO system, a negative modulator of glucose-stimulated insulin release. In short-time incubations with isolated murine islets either glibenclamide or high glucose augmented insulin release associated with increased NO production from both neural and inducible NOS. Metformin addition suppressed the augmented NO generation coinciding with amplified insulin release. Islet culturing with glibenclamide or high glucose revealed pronounced fluorescence of inducible NOS in the beta-cells being abolished by metformin co-culturing. These findings were reflected in medium nitrite-nitrate levels. A glucose challenge following islet culturing with glibenclamide or high glucose revealed markedly impaired insulin response. Metformin co-culturing restored this response. Culturing murine islets and human islets from controls and type 2 diabetics with high glucose or high glucose + glibenclamide induced a pronounced decrease of cell viability being remarkably restored by metformin co-culturing. We show here, that imposed overactivity of the beta-cell NOS-NO system by glibenclamide or high glucose leads to insulin secretory dysfunction and reduced cell viability and also, importantly, that these effects are relieved by metformin inhibiting beta-cell NO overproduction from both neural and inducible NOS thus ameliorating a concealed negative influence by NO induced by sulfonylurea treatment and/or high glucose levels. This double-edged effect of glibenclamide on the beta-cellsuggests sulfonylurea monotherapy in type 2 diabetes being avoided. PMID:27820841

  20. All Vision Impairment

    MedlinePlus

    ... Home > Statistics and Data > All Vision Impairment All Vision Impairment Vision Impairment Defined Vision impairment is defined as the ... Ethnicity 2010 U.S. Age-Specific Prevalence Rates for Vision Impairment by Age and Race/Ethnicity Table for ...

  1. Ameliorating effect and potential mechanism of Rehmannia glutinosa oligosaccharides on the impaired glucose metabolism in chronic stress rats fed with high-fat diet.

    PubMed

    Zhang, Ruxue; Zhou, Jun; Li, Maoxing; Ma, Haigang; Qiu, Jianguo; Luo, Xiaohong; Jia, Zhengping

    2014-04-15

    The aim of this study was to determine whether the Rehmannia glutinosa oligosaccharides (ROS) ameliorate the impaired glucose metabolism and the potential mechanism in chronic stress rats fed with high-fat diet. The rats were fed by a high-fat diet and simultaneously stimulated by chronic stress over 5 weeks. Body weight, fasting plasma glucose, intraperitoneal glucose tolerance test (IPGTT), plasma lipids, gluconeogenesis test (GGT), glycogen content, and corticosterone, insulin and leptin levels were measured. The results showed that ROS administration (100, 200 mg/kg, i.g.) for 5 weeks exerted the effects of increasing the organ weights of thymus and spleen, lowering the fasting plasma glucose level, improving impaired glucose tolerance, increasing the contents of liver and muscle glycogen, decreasing the gluconeogenesis ability, plasma-free fatty acid's level, as well as plasma triglyceride and total cholesterol levels in chronic stress and high-fat fed rats, especially in the group of 200mg/kg; while the plasma corticosterone level was decreased, and plasma leptin level was increased. These results suggest that ROS exert an ameliorating effect of impaired glucose metabolism in chronic stress rats fed with high-fat diet, and the potential mechanism may be mediated through rebuilding the glucose homeostasis in the neuroendocrine immuno-modulation (NIM) network through multilinks and multitargets.

  2. Frequency of diabetes, impaired fasting glucose, and glucose intolerance in high-risk groups identified by a FINDRISC survey in Puebla City, Mexico

    PubMed Central

    García-Alcalá, Hector; Genestier-Tamborero, Christelle Nathalie; Hirales-Tamez, Omara; Salinas-Palma, Jorge; Soto-Vega, Elena

    2012-01-01

    Background As a first step in the prevention of diabetes, the International Diabetes Federation recommends identification of persons at risk using the Finnish type 2 Diabetes Risk Assessment (FINDRISC) survey. The frequency of diabetes mellitus, impaired fasting glucose, and glucose intolerance in high-risk groups identified by FINDRISC is unknown in our country. The aim of this study was to determine the frequency of diabetes mellitus, impaired fasting glucose, and glucose intolerance in higher-risk groups using a FINDRISC survey in an urban population. Methods We used a television program to invite interested adults to fill out a survey at a television station. An oral glucose tolerance test was performed in all persons with a FINDRISC score ≥ 15 points (high-risk and very high-risk groups). Patients were classified as normal (fasting glucose < 100 mg/dL and 2-hour glucose < 140 mg/dL), or having impaired fasting glucose (fasting glucose 100–125 mg/dL and 2-hour glucose < 140 mg/dL), glucose intolerance (fasting glucose < 126 mg/dL and 2-hour glucose 140–199 mg/dL), and diabetes mellitus (fasting glucose ≥ 126 mg/dL or 2-hour glucose ≥ 200 mg/dL). We describe the frequency of each diagnostic category in this selected population according to gender and age. Results A total of 186 patients had a score ≥ 15. The frequencies of diabetes mellitus, impaired fasting glucose, glucose intolerance, and normal glucose levels were 28.6%, 25.9%, 29.2%, and 16.2%, respectively. We found a higher frequency of diabetes mellitus and impaired fasting glucose in men than in women (33% versus 27% and 40% versus 21%, respectively) and more glucose intolerance in women than in men (34% versus 16%, P < 0.05). Patients with diabetes mellitus (52.55 ± 9.2 years) were older than those with impaired fasting glucose (46.19 ± 8.89 years), glucose intolerance (46.15 ± 10.9 years), and normal levels (41.9 ± 10.45 years, P < 0.05). We found a higher frequency of diabetes

  3. Enhanced glucose-induced intracellular signaling promotes insulin hypersecretion: pancreatic beta-cell functional adaptations in a model of genetic obesity and prediabetes.

    PubMed

    Irles, Esperanza; Ñeco, Patricia; Lluesma, Mónica; Villar-Pazos, Sabrina; Santos-Silva, Junia Carolina; Vettorazzi, Jean F; Alonso-Magdalena, Paloma; Carneiro, Everardo M; Boschero, Antonio C; Nadal, Ángel; Quesada, Ivan

    2015-03-15

    Obesity is associated with insulin resistance and is known to be a risk factor for type-2 diabetes. In obese individuals, pancreatic beta-cells try to compensate for the increased insulin demand in order to maintain euglycemia. Most studies have reported that this adaptation is due to morphological changes. However, the involvement of beta-cell functional adaptations in this process needs to be clarified. For this purpose, we evaluated different key steps in the glucose-stimulated insulin secretion (GSIS) in intact islets from female ob/ob obese mice and lean controls. Obese mice showed increased body weight, insulin resistance, hyperinsulinemia, glucose intolerance and fed hyperglycemia. Islets from ob/ob mice exhibited increased glucose-induced mitochondrial activity, reflected by enhanced NAD(P)H production and mitochondrial membrane potential hyperpolarization. Perforated patch-clamp examination of beta-cells within intact islets revealed several alterations in the electrical activity such as increased firing frequency and higher sensitivity to low glucose concentrations. A higher intracellular Ca(2+) mobilization in response to glucose was also found in ob/ob islets. Additionally, they displayed a change in the oscillatory pattern and Ca(2+) signals at low glucose levels. Capacitance experiments in intact islets revealed increased exocytosis in individual ob/ob beta-cells. All these up-regulated processes led to increased GSIS. In contrast, we found a lack of beta-cell Ca(2+) signal coupling, which could be a manifestation of early defects that lead to beta-cell malfunction in the progression to diabetes. These findings indicate that beta-cell functional adaptations are an important process in the compensatory response to obesity.

  4. Influence of high carbohydrate versus high fat diet in ozone induced pulmonary injury and systemic metabolic impairment in a Brown Norway (BN) rat model of healthy aging

    EPA Science Inventory

    Rationale: Air pollution has been recently linked to the increased prevalence of metabolic syndrome. It has been postulated that dietary risk factors might exacerbate air pollution-induced metabolic impairment. We have recently reported that ozone exposure induces acute systemic ...

  5. Spatial navigation impairments among intellectually high-functioning adults with autism spectrum disorder: exploring relations with theory of mind, episodic memory, and episodic future thinking.

    PubMed

    Lind, Sophie E; Williams, David M; Raber, Jacob; Peel, Anna; Bowler, Dermot M

    2013-11-01

    Research suggests that spatial navigation relies on the same neural network as episodic memory, episodic future thinking, and theory of mind (ToM). Such findings have stimulated theories (e.g., the scene construction and self-projection hypotheses) concerning possible common underlying cognitive capacities. Consistent with such theories, autism spectrum disorder (ASD) is characterized by concurrent impairments in episodic memory, episodic future thinking, and ToM. However, it is currently unclear whether spatial navigation is also impaired. Hence, ASD provides a test case for the scene construction and self-projection theories. The study of spatial navigation in ASD also provides a test of the extreme male brain theory of ASD, which predicts intact or superior navigation (purportedly a systemizing skill) performance among individuals with ASD. Thus, the aim of the current study was to establish whether spatial navigation in ASD is impaired, intact, or superior. Twenty-seven intellectually high-functioning adults with ASD and 28 sex-, age-, and IQ-matched neurotypical comparison adults completed the memory island virtual navigation task. Tests of episodic memory, episodic future thinking, and ToM were also completed. Participants with ASD showed significantly diminished performance on the memory island task, and performance was positively related to ToM and episodic memory, but not episodic future thinking. These results suggest that (contra the extreme male brain theory) individuals with ASD have impaired survey-based navigation skills--that is, difficulties generating cognitive maps of the environment--and adds weight to the idea that scene construction/self-projection are impaired in ASD. The theoretical and clinical implications of these results are discussed.

  6. Short-Term High-Fat Diet (HFD) Induced Anxiety-Like Behaviors and Cognitive Impairment Are Improved with Treatment by Glyburide

    PubMed Central

    Gainey, Stephen J.; Kwakwa, Kristin A.; Bray, Julie K.; Pillote, Melissa M.; Tir, Vincent L.; Towers, Albert E.; Freund, Gregory G.

    2016-01-01

    Obesity-associated comorbidities such as cognitive impairment and anxiety are increasing public health burdens that have gained prevalence in children. To better understand the impact of childhood obesity on brain function, mice were fed with a high-fat diet (HFD) from weaning for 1, 3 or 6 weeks. When compared to low-fat diet (LFD)-fed mice (LFD-mice), HFD-fed mice (HFD-mice) had impaired novel object recognition (NOR) after 1 week. After 3 weeks, HFD-mice had impaired NOR and object location recognition (OLR). Additionally, these mice displayed anxiety-like behavior by measure of both the open-field and elevated zero maze (EZM) testing. At 6 weeks, HFD-mice were comparable to LFD-mice in NOR, open-field and EZM performance but they remained impaired during OLR testing. Glyburide, a second-generation sulfonylurea for the treatment of type 2 diabetes, was chosen as a countermeasure based on previous data exhibiting its potential as an anxiolytic. Interestingly, a single dose of glyburide corrected deficiencies in NOR and mitigated anxiety-like behaviors in mice fed with HFD-diet for 3-weeks. Taken together these results indicate that a HFD negatively impacts a subset of hippocampal-independent behaviors relatively rapidly, but such behaviors normalize with age. In contrast, impairment of hippocampal-sensitive memory takes longer to develop but persists. Since single-dose glyburide restores brain function in 3-week-old HFD-mice, drugs that block ATP-sensitive K+ (KATP) channels may be of clinical relevance in the treatment of obesity-associated childhood cognitive issues and psychopathologies. PMID:27563288

  7. Development of a Novel, Highly Quantitative In Vivo Model for the Study of Biofilm-Impaired Cutaneous Wound Healing

    DTIC Science & Technology

    2011-01-01

    that in addition to hypoxia, ischemia- reperfusion injury, and intrinsic host factors, bacterial biofilms represent a fourth major pillar in chronic ...specifically contributes to profound cutaneous wound healing impairment. Our model highlights the importance of bacterial biofilms in chronic wound...The result is a chronic inflammatory cycle causing injury to host tissues over time.2 In recent years the wound bed of compromised skin has been

  8. Environmental stimulation rescues maternal high fructose intake-impaired learning and memory in female offspring: Its correlation with redistribution of histone deacetylase 4.

    PubMed

    Wu, Kay L H; Wu, Chih-Wei; Tain, You-Lin; Huang, Li-Tung; Chao, Yung-Mei; Hung, Chun-Ying; Wu, Jin-Cheng; Chen, Siang-Ru; Tsai, Pei-Chia; Chan, Julie Y H

    2016-04-01

    Impairment of learning and memory has been documented in the later life of offspring to maternal consumption with high energy diet. Environmental stimulation enhances the ability of learning and memory. However, potential effects of environmental stimulation on the programming-associated deficit of learning and memory have not been addressed. Here, we examined the effects of enriched-housing on hippocampal learning and memory in adult female offspring rats from mother fed with 60% high fructose diet (HFD) during pregnancy and lactation. Impairment of spatial learning and memory performance in HFD group was observed in offspring at 3-month-old. Hippocampal brain-derived neurotrophic factor (BDNF) was decreased in the offspring. Moreover, the HFD group showed an up-regulation of histone deacetylase 4 (HDAC4) in the nuclear fractions of hippocampal neurons. Stimulation to the offspring for 4weeks after winning with an enriched-housing environment effectively rescued the decrease in cognitive function and hippocampal BDNF level; alongside a reversal of the increased distribution of nuclear HDAC4. Together these results suggest that later life environmental stimulation effectively rescues the impairment of hippocampal learning and memory in female offspring to maternal HFD intake through redistributing nuclear HDAC4 to increase BDNF expression.

  9. Serum high-molecular weight adiponectin decreases abruptly after an oral glucose load in subjects with normal glucose tolerance or impaired fasting glucose, but not those with impaired glucose tolerance or diabetes mellitus.

    PubMed

    Ozeki, Noriyuki; Hara, Kenji; Yatsuka, Chikako; Nakano, Tomoki; Matsumoto, Sachiko; Suetsugu, Mariko; Nakamachi, Takafumi; Takebayashi, Kohzo; Inukai, Toshihiko; Haruki, Kohsuke; Aso, Yoshimasa

    2009-10-01

    Adiponectin exists in the blood as 3 forms, which are a trimer, a hexamer, and a high-molecular weight (HMW) form. We investigated whether circulating HMW adiponectin levels were altered by oral glucose or fat ingestion. Forty male subjects underwent a 75-g oral glucose loading test (OGTT), and 11 healthy subjects (5 women and 6 men) received a fat loading test. Serum levels of HMW and total adiponectin were measured during the OGTT and the fat loading test. The fat loading test was performed for at least 8 hours. Among the 40 male subjects, 11 had normal glucose tolerance (NGT), 9 had impaired fasting glucose (IFG), 11 had impaired glucose tolerance, and 9 had diabetes mellitus (DM). In all 40 subjects, the serum total adiponectin level did not change significantly, whereas serum HMW adiponectin decreased significantly after a glucose load and reached 92.2% of the basal level at 120 minutes after the OGTT (P < .01). The HMW to total adiponectin ratio decreased significantly from 0.47 +/- 0.15 at baseline to 0.43 +/- 0.13 at 120 minutes after a glucose load (P < .05). Serum HMW adiponectin measured at 120 minutes after the OGTT decreased significantly to 86.0% and 85.6% of the basal level in subjects with NGT or IFG, respectively (both P < .01). In subjects with impaired glucose tolerance or DM, however, serum HMW adiponectin did not change. The area under the curve for insulin at 30 minutes after a glucose load during the OGTT was significantly larger in subjects with NGT or IFG than in those with DM (P < .05). In addition, the insulinogenic index (DeltaI(0-30)/DeltaG(0-30)) was significantly higher in subjects with NGT or IFG than in those with DM (P < .001). Percentage changes in serum HMW adiponectin of the baseline at 120 minutes correlated negatively with those in serum insulin (r = -0.468, P = .0023), but not plasma glucose, of the baseline at 30 minutes in 40 subjects. On the other hand, serum triglycerides increased significantly after an oral fat load in

  10. Pharmacokinetics of acyclovir and its metabolites in cerebrospinal fluid and systemic circulation after administration of high-dose valacyclovir in subjects with normal and impaired renal function.

    PubMed

    Smith, James P; Weller, Stephen; Johnson, Benjamin; Nicotera, Janet; Luther, James M; Haas, David W

    2010-03-01

    Valacyclovir, the L-valyl ester prodrug of acyclovir (ACV), is widely prescribed to treat infections caused by varicella-zoster virus or herpes simplex virus. Rarely, treatment is complicated by reversible neuropsychiatric symptoms. By mechanisms not fully understood, this occurs more frequently in the setting of renal impairment. We characterized the steady-state pharmacokinetics of ACV and its metabolites 9-[(carboxymethoxy)methyl]guanine (CMMG) and 8-hydroxy-acyclovir (8-OH-ACV) in cerebrospinal fluid (CSF) and the systemic circulation. We administered multiple doses of high-dose valacyclovir to 6 subjects with normal renal function and 3 subjects with chronic renal impairment (creatinine clearance [CrCl], approximately 15 to 30 ml/min). Dosages were 2,000 mg every 6 h and 1,500 mg every 12 h, respectively. Indwelling intrathecal catheters allowed serial CSF sampling throughout the dosing interval. The average steady-state concentrations of acyclovir, CMMG, and 8-OH-ACV were greater in both the systemic circulation and the CSF among subjects with impaired renal function than among subjects with normal renal function. However, the CSF penetration of each analyte, reflected by the CSF-to-plasma area under the concentration-time curve over the 6- or 12-h dosing interval (AUC(tau)) ratio, did not differ based on renal function. Renal impairment does not alter the propensity for ACV or its metabolites to distribute to the CSF, but the higher concentrations in the systemic circulation, as a result of reduced elimination, are associated with proportionally higher concentrations in CSF.

  11. [Multilingualism and specific language impairment].

    PubMed

    Arkkila, Eva; Smolander, Sini; Laasonen, Marja

    2013-01-01

    Specific language impairment is one of the most common developmental disturbances in childhood. With the increase of the foreign language population group an increasing number of children assimilating several languages and causing concern in language development attend clinical examinations. Knowledge of factors underlying the specific language impairment and the specific impairment in general, special features of language development of those learning several languages, as well as the assessment and support of the linguistic skills of a multilingual child is essential. The risk of long-term problems and marginalization is high for children having specific language impairment.

  12. High antigen levels induce an exhausted phenotype in a chronic infection without impairing T cell expansion and survival

    PubMed Central

    Alfei, Francesca; Roelli, Patrick; Delorenzi, Mauro; Pinschewer, Daniel D.

    2016-01-01

    Chronic infections induce T cells showing impaired cytokine secretion and up-regulated expression of inhibitory receptors such as PD-1. What determines the acquisition of this chronic phenotype and how it impacts T cell function remain vaguely understood. Using newly generated recombinant antigen variant-expressing chronic lymphocytic choriomeningitis virus (LCMV) strains, we uncovered that T cell differentiation and acquisition of a chronic or exhausted phenotype depend critically on the frequency of T cell receptor (TCR) engagement and less significantly on the strength of TCR stimulation. In fact, we noted that low-level antigen exposure promotes the formation of T cells with an acute phenotype in chronic infections. Unexpectedly, we found that T cell populations with an acute or chronic phenotype are maintained equally well in chronic infections and undergo comparable primary and secondary expansion. Thus, our observations contrast with the view that T cells with a typical chronic infection phenotype are severely functionally impaired and rapidly transition into a terminal stage of differentiation. Instead, our data unravel that T cells primarily undergo a form of phenotypic and functional differentiation in the early phase of a chronic LCMV infection without inheriting a net survival or expansion deficit, and we demonstrate that the acquired chronic phenotype transitions into the memory T cell compartment. PMID:27455951

  13. A Bayesian approach of high impaired river reaches identification and total nitrogen load estimation in a sparsely monitored basin.

    PubMed

    Li, Xue; Feng, Jianfeng; Wellen, Christopher; Wang, Yuqiu

    2017-01-01

    In this study, a modeling framework based on the theory of SPAtially Referenced Regression On Watershed attributes (SPARROW) model was developed to identify impaired river reaches with respect to total nitrogen (TN) and estimate the TN sources in the Xin'anjiang River basin, which had limited monitoring sites. A Bayesian approach was applied to estimate the mean values and uncertainties of parameters, including land use export coefficients and in-stream attention rates. Based on the parameters, the midranges (25-75 %) of annual TN concentrations were assessed by the model and 4.5 % of river reaches in the basin were found to be with higher impaired probabilities (namely [TN] > 1.5 mg/l) than other reaches. The amount and yields of TN discharged from diffuse sources were estimated for each county in the basin. The results suggested that Tunxi City had the highest TN yields from farm land and population, while the highest TN yields in Huangshan City were from tea plantations. The outcomes of this study will guide the implementation of practical management measures to reduce TN loads.

  14. Women with elevated food addiction symptoms show accelerated reactions, but no impaired inhibitory control, in response to pictures of high-calorie food-cues.

    PubMed

    Meule, Adrian; Lutz, Annika; Vögele, Claus; Kübler, Andrea

    2012-12-01

    Addictive behaviors are accompanied by a lack of inhibitory control, specifically when individuals are confronted with substance-related cues. Thus, we expected women with symptoms of food addiction to be impaired in inhibitory control, when confronted with palatable, high-calorie food-cues. Female college students (N=50) were divided in low and high food addiction groups based on the symptom count of the Yale Food Addiction Scale. Participants performed a Go/No-go-task with high-calorie food-cues or neutral pictures presented behind the targets. Self-reported impulsivity was also assessed. The high food addiction group had faster reaction times in response to food-cues as compared to neutral cues and reported higher attentional impulsivity than the low food addiction group. Commission and omission errors did not differ between groups or picture types. Hence, women with food addiction symptoms reported higher attentional impulsivity and reacted faster in response to food-cues, although neither increased self-reported motor impulsivity nor impaired behavioral inhibition was found. Food addiction symptoms seem to be related to attentional aspects of impulsivity but not other facets of impulsivity.

  15. High dietary folate in pregnant mice leads to pseudo-MTHFR deficiency and altered methyl metabolism, with embryonic growth delay and short-term memory impairment in offspring.

    PubMed

    Bahous, Renata H; Jadavji, Nafisa M; Deng, Liyuan; Cosín-Tomás, Marta; Lu, Jessica; Malysheva, Olga; Leung, Kit-Yi; Ho, Ming-Kai; Pallàs, Mercè; Kaliman, Perla; Greene, Nicholas DE; Bedell, Barry J; Caudill, Marie A; Rozen, Rima

    2017-01-09

    Methylenetetrahydrofolate reductase (MTHFR) generates methyltetrahydrofolate for methylation reactions. Severe MTHFR deficiency results in homocystinuria and neurologic impairment. Mild MTHFR deficiency (677C>T polymorphism) increases risk for complex traits, including neuropsychiatric disorders. Although low dietary folate impacts brain development, recent concerns have focused on high folate intake following food fortification and increased vitamin use. Our goal was to determine whether high dietary folate during pregnancy affects brain development in murine offspring. Female mice were placed on control diet (CD) or folic acid-supplemented diet (FASD) throughout mating, pregnancy and lactation. Three-week-old male pups were evaluated for motor and cognitive function. Tissues from E17.5 embryos, pups and dams were collected for choline/methyl metabolite measurements, immunoblotting or gene expression of relevant enzymes. Brains were examined for morphology of hippocampus and cortex.Pups of FASD mothers displayed short-term memory impairment, decreased hippocampal size and decreased thickness of the dentate gyrus. MTHFR protein levels were reduced in FASD pup livers, with lower concentrations of phosphocholine and glycerophosphocholine in liver and hippocampus, respectively. FASD pup brains showed evidence of altered acetylcholine availability and Dnmt3a mRNA was reduced in cortex and hippocampus. E17.5 embryos and placentas from FASD dams were smaller. MTHFR protein and mRNA were reduced in embryonic liver, with lower concentrations of choline, betaine and phosphocholine. Embryonic brain displayed altered development of cortical layers. In summary, high folate intake during pregnancy leads to pseudo-MTHFR 3 deficiency, disturbed choline/methyl metabolism, embryonic growth delay and memory impairment in offspring. These findings highlight the unintended negative consequences of supplemental folic acid.

  16. Heme oxygenase (HO)-1 induction prevents Endoplasmic Reticulum stress-mediated endothelial cell death and impaired angiogenic capacity.

    PubMed

    Maamoun, Hatem; Zachariah, Matshediso; McVey, John H; Green, Fiona R; Agouni, Abdelali

    2017-03-01

    Most of diabetic cardiovascular complications are attributed to endothelial dysfunction and impaired angiogenesis. Endoplasmic Reticulum (ER) and oxidative stresses were shown to play a pivotal role in the development of endothelial dysfunction in diabetes. Hemeoxygenase-1 (HO-1) was shown to protect against oxidative stress in diabetes; however, its role in alleviating ER stress-induced endothelial dysfunction remains not fully elucidated. We aim here to test the protective role of HO-1 against high glucose-mediated ER stress and endothelial dysfunction and understand the underlying mechanisms with special emphasis on oxidative stress, inflammation and cell death. Human Umbilical Vein Endothelial Cells (HUVECs) were grown in either physiological or intermittent high concentrations of glucose for 5days in the presence or absence of Cobalt (III) Protoporphyrin IX chloride (CoPP, HO-1 inducer) or 4-Phenyl Butyric Acid (PBA, ER stress inhibitor). Using an integrated cellular and molecular approach, we then assessed ER stress and inflammatory responses, in addition to apoptosis and angiogenic capacity in these cells. Our results show that HO-1 induction prevented high glucose-mediated increase of mRNA and protein expression of key ER stress markers. Cells incubated with high glucose exhibited high levels of oxidative stress, activation of major inflammatory and apoptotic responses [nuclear factor (NF)-κB and c-Jun N-terminal kinase (JNK)] and increased rate of apoptosis; however, cells pre-treated with CoPP or PBA were fully protected. In addition, high glucose enhanced caspases 3 and 7 cleavage and activity and augmented cleaved poly ADP ribose polymerase (PARP) expression whereas HO-1 induction prevented these effects. Finally, HO-1 induction and ER stress inhibition prevented high glucose-induced reduction in NO release and impaired the angiogenic capacity of HUVECs, and enhanced vascular endothelial growth factor (VEGF)-A expression. Altogether, we show here the

  17. Negative regulatory responses to metabolically triggered inflammation impair renal epithelial immunity in diabetes mellitus.

    PubMed

    Chen, Nelson K F; Chong, Tsung Wen; Loh, Hwai-Liang; Lim, Kiat Hon; Gan, Valerie H L; Wang, Marian; Kon, Oi Lian

    2013-05-01

    Diabetes mellitus is characterized by chronic inflammation and increased risk of infections, particularly of tissues exposed to the external environment. However, the causal molecular mechanisms that affect immune cells and their functions in diabetes are unclear. Here we show, by transcript and protein analyses, signatures of glucose-induced tissue damage, chronic inflammation, oxidative stress, and dysregulated expression of multiple inflammation- and immunity-related molecules in diabetic kidneys compared with non-diabetic controls. Abnormal signaling involving cytokines, G-protein coupled receptors, protein kinase C isoforms, mitogen-activated protein kinases, nuclear factor-κB (NFκB), and Toll-like receptors (TLR) were evident. These were accompanied by overexpression of negative regulators of NFκB, TLR, and other proinflammatory pathways, e.g., A20, SOCS1, IRAK-M, IκBα, Triad3A, Tollip, SIGIRR, and ST2L. Anti-inflammatory and immunomodulatory molecules, e.g., IL-10, IL-4, and TSLP that favor TH2 responses were strongly induced. These molecular indicators of immune dysfunction led us to detect the cryptic presence of bacteria and human cytomegalovirus in more than one third of kidneys of diabetic subjects but none in non-diabetic kidneys. Similar signaling abnormalities could be induced in primary human renal tubular epithelial (but not mesangial) cell cultures exposed to high glucose, proinflammatory cytokines and methylglyoxal, and were reversed by combined pharmacological treatment with an antioxidant and a PKC inhibitor. Our results suggest that diabetes impairs epithelial immunity as a consequence of chronic and inappropriate activation of counter-regulatory immune responses, which are otherwise physiological protective mechanisms against inflammation. The immune abnormalities and cryptic renal infections described here may contribute to progression of diabetic nephropathy.

  18. High Salt Intake Increases Blood Pressure via BDNF-Mediated Downregulation of KCC2 and Impaired Baroreflex Inhibition of Vasopressin Neurons

    PubMed Central

    Choe, Katrina Y.; Han, Su Y.; Gaub, Perrine; Shell, Brent; Voisin, Daniel L.; Knapp, Blayne A.; Barker, Philip A.; Brown, Colin H.; Cunningham, J. Thomas

    2015-01-01

    Summary The mechanisms by which dietary salt promotes hypertension are unknown. Previous work established that plasma [Na+] and osmolality rise in proportion with salt intake and thus promote release of vasopressin (VP) from the neurohypophysis. Although high levels of circulating VP can increase blood pressure, this effect is normally prevented by a potent GABAergic inhibition of VP neurons by aortic baroreceptors. Here we show that chronic high salt intake impairs baroreceptor inhibition of rat VP neurons through a brain-derived neurotrophic factor (BDNF)-dependent activation of TrkB receptors and downregulation of KCC2 expression, which prevents inhibitory GABAergic signaling. We show that high salt intake increases the spontaneous firing rate of VP neurons in vivo and that circulating VP contributes significantly to the elevation of arterial pressure under these conditions. These results provide the first demonstration that dietary salt can affect blood pressure through neurotrophin-induced plasticity in a central homeostatic circuit. PMID:25619659

  19. “8 Plate”: An Alternative Device to Fix Highly Recurrent Traumatic Anterior Gleno-Humeral Instability in Patients with Severe Impairment of the Anterior Capsule

    PubMed Central

    Tudisco, C; Bisicchia, S; Savarese, E; Ippolito, E

    2014-01-01

    Background: There is still debate about the best treatment option for highly recurrent anterior shoulder dislocation in patients with severe impairment of the anterior capsule and/or recurrence after either arthroscopic or open capsulorrhaphy. Materials and Methods: The clinical and radiological findings of 7 patients treated with an open capsulorrhaphy stabilized with an “8 plate” for a highly recurrent traumatic anterior shoulder dislocation with severe impairment of the anterior capsule and a large Bankart lesion were retrospectively reviewed. Follow-up evaluation included VAS for pain, Constant-Murley, Simple Shoulder Test, ASES, UCLA, Quick DASH, Rowe, Walsch-Duplay scores, as well as X-rays of the operated shoulder. Results: At follow-up none of the patients reported subsequent dislocations. Range of motion of the shoulder was complete in all cases, but one. Results of the functional scoring systems were satisfactory. X-rays showed no osteolysis and good position of the plate. Conclusion: To our knowledge, this is the first report in the literature about an open capsular tensioning and Bankart lesion repair performed with an “8 plate”. We believe that this is a reliable and effective procedure to address traumatic anterior re-dislocation of the gleno-humeral joint when the capsule is extensively torn and frayed or in revision cases. Moreover the “8 plate” is ideal to be applied in such a narrow space on the slant surface of the scapular neck close to the glenoid rim. PMID:25621080

  20. Synapsin knockdown is associated with decreased neurite outgrowth, functional synaptogenesis impairment, and fast high-frequency neurotransmitter release.

    PubMed

    Brenes, Oscar; Giachello, Carlo Natale Giuseppe; Corradi, Anna Margherita; Ghirardi, Mirella; Montarolo, Pier Giorgio

    2015-10-01

    Synapsins (Syns) are an evolutionarily conserved family of synaptic vesicle-associated proteins related to fine tuning of synaptic transmission. Studies with mammals have partially clarified the different roles of Syns; however, the presence of different genes and isoforms and the development of compensatory mechanisms hinder accurate data interpretation. Here, we use a simple in vitro monosynaptic Helix neuron connection, reproducing an in vivo physiological connection as a reliable experimental model to investigate the effects of Syn knockdown. Cells overexpressing an antisense construct against Helix Syn showed a time-dependent decrease of Syn immunostaining, confirming protein loss. At the morphological level, Syn-silenced cells showed a reduction in neurite linear outgrowth and branching and in the size and number of synaptic varicosities. Functionally, Syn-silenced cells presented a reduced ability to form synaptic connections; however, functional chemical synapses showed similar basal excitatory postsynaptic potentials and similar short-term plasticity paradigms. In addition, Syn-silenced cells presented faster neurotransmitter release and decreased postsynaptic response toward the end of long tetanic presynaptic stimulations, probably related to an impairment of the synaptic vesicle trafficking resulting from a different vesicle handling, with an increased readily releasable pool and a compromised reserve pool.

  1. Episodic Memory and Episodic Future Thinking Impairments in High-Functioning Autism Spectrum Disorder: An Underlying Difficulty With Scene Construction or Self-Projection?

    PubMed Central

    2013-01-01

    Objective: There appears to be a common network of brain regions that underlie the ability to recall past personal experiences (episodic memory) and the ability to imagine possible future personal experiences (episodic future thinking). At the cognitive level, these abilities are thought to rely on “scene construction” (the ability to bind together multimodal elements of a scene in mind—dependent on hippocampal functioning) and temporal “self-projection” (the ability to mentally project oneself through time—dependent on prefrontal cortex functioning). Although autism spectrum disorder (ASD) is characterized by diminished episodic memory, it is unclear whether episodic future thinking is correspondingly impaired. Moreover, the underlying basis of such impairments (difficulties with scene construction, self-projection, or both) is yet to be established. The current study therefore aimed to elucidate these issues. Method: Twenty-seven intellectually high-functioning adults with ASD and 29 age- and IQ-matched neurotypical comparison adults were asked to describe (a) imagined atemporal, non-self-relevant fictitious scenes (assessing scene construction), (b) imagined plausible self-relevant future episodes (assessing episodic future thinking), and (c) recalled personally experienced past episodes (assessing episodic memory). Tests of narrative ability and theory of mind were also completed. Results: Performances of participants with ASD were significantly and equally diminished in each condition and, crucially, this diminution was independent of general narrative ability. Conclusions: Given that participants with ASD were impaired in the fictitious scene condition, which does not involve self-projection, we suggest the underlying difficulty with episodic memory/future thinking is one of scene construction. PMID:24015827

  2. In utero exposure to prepregnancy maternal obesity and postweaning high-fat diet impair regulators of mitochondrial dynamics in rat placenta and offspring.

    PubMed

    Borengasser, Sarah J; Faske, Jennifer; Kang, Ping; Blackburn, Michael L; Badger, Thomas M; Shankar, Kartik

    2014-12-01

    The proportion of pregnant women who are obese at conception continues to rise. Compelling evidence suggests the intrauterine environment is an important determinant of offspring health. Maternal obesity and unhealthy diets are shown to promote metabolic programming in the offspring. Mitochondria are maternally inherited, and we have previously shown impaired mitochondrial function in rat offspring exposed to maternal obesity in utero. Mitochondrial health is maintained by mitochondrial dynamics, or the processes of fusion and fission, which serve to repair damaged mitochondria, remove irreparable mitochondria, and maintain mitochondrial morphology. An imbalance between fusion and fission has been associated with obesity, insulin resistance, and reproduction complications. In the present study, we examined the influence of maternal obesity and postweaning high-fat diet (HFD) on key regulators of mitochondrial fusion and fission in rat offspring at important developmental milestones which included postnatal day (PND)35 (2 wk HFD) and PND130 (∼16 wk HFD). Our results indicate HFD-fed offspring had reduced mRNA expression of presenilin-associated rhomboid-like (PARL), optic atrophy (OPA)1, mitofusin (Mfn)1, Mfn2, fission (Fis)1, and nuclear respiratory factor (Nrf)1 at PND35, while OPA1 and Mfn2 remained decreased at PND130. Putative transcriptional regulators of mitochondrial dynamics were reduced in rat placenta and offspring liver and skeletal muscle [peroxisome proliferator-activated receptor gamma coactivator (PGC1)α, PGC1β, and estrogen-related receptor (ERR)α], consistent with indirect calorimetry findings revealing reduced energy expenditure and impaired fat utilization. Overall, maternal obesity detrimentally alters mitochondrial targets that may contribute to impaired mitochondrial health and increased obesity susceptibility in later life.

  3. Skeletal development of mice lacking bone sialoprotein (BSP)--impairment of long bone growth and progressive establishment of high trabecular bone mass.

    PubMed

    Bouleftour, Wafa; Boudiffa, Maya; Wade-Gueye, Ndeye Marième; Bouët, Guénaëlle; Cardelli, Marco; Laroche, Norbert; Vanden-Bossche, Arnaud; Thomas, Mireille; Bonnelye, Edith; Aubin, Jane E; Vico, Laurence; Lafage-Proust, Marie Hélène; Malaval, Luc

    2014-01-01

    Adult Ibsp-knockout mice (BSP-/-) display shorter stature, lower bone turnover and higher trabecular bone mass than wild type, the latter resulting from impaired bone resorption. Unexpectedly, BSP knockout also affects reproductive behavior, as female mice do not construct a proper "nest" for their offsprings. Multiple crossing experiments nonetheless indicated that the shorter stature and lower weight of BSP-/- mice, since birth and throughout life, as well as their shorter femur and tibia bones are independent of the genotype of the mothers, and thus reflect genetic inheritance. In BSP-/- newborns, µCT analysis revealed a delay in membranous primary ossification, with wider cranial sutures, as well as thinner femoral cortical bone and lower tissue mineral density, reflected in lower expression of bone formation markers. However, trabecular bone volume and osteoclast parameters of long bones do not differ between genotypes. Three weeks after birth, osteoclast number and surface drop in the mutants, concomitant with trabecular bone accumulation. The growth plates present a thinner hypertrophic zone in newborns with lower whole bone expression of IGF-1 and higher IHH in 6 days old BSP-/- mice. At 3 weeks the proliferating zone is thinner and the hypertrophic zone thicker in BSP-/- than in BSP+/+ mice of either sex, maybe reflecting a combination of lower chondrocyte proliferation and impaired cartilage resorption. Six days old BSP-/- mice display lower osteoblast marker expression but higher MEPE and higher osteopontin(Opn)/Runx2 ratio. Serum Opn is higher in mutants at day 6 and in adults. Thus, lack of BSP alters long bone growth and membranous/cortical primary bone formation and mineralization. Endochondral development is however normal in mutant mice and the accumulation of trabecular bone observed in adults develops progressively in the weeks following birth. Compensatory high Opn may allow normal endochondral development in BSP-/- mice, while impairing

  4. Long-term ambient air pollution and lung function impairment in Chinese children from a high air pollution range area: The Seven Northeastern Cities (SNEC) study

    NASA Astrophysics Data System (ADS)

    Zeng, Xiao-Wen; Vivian, Elaina; Mohammed, Kahee A.; Jakhar, Shailja; Vaughn, Michael; Huang, Jin; Zelicoff, Alan; Xaverius, Pamela; Bai, Zhipeng; Lin, Shao; Hao, Yuan-Tao; Paul, Gunther; Morawska, Lidia; Wang, Si-Quan; Qian, Zhengmin; Dong, Guang-Hui

    2016-08-01

    Epidemiological studies have reported inconsistent and inconclusive associations between long-term exposure to ambient air pollution and lung function in children from Europe and America, where air pollution levels were typically low. The aim of the present study is to examine the relationship between air pollutants and lung function in children selected from heavily industrialized and polluted cities in northeastern China. During 2012, 6740 boys and girls aged 7-14 years were recruited in 24 districts of seven northeastern cities. Portable electronic spirometers were used to measure lung function. Four-year average concentrations of particulate matter with an aerodynamic diameter ≤10 μm (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2), and ozone (O3) were measured at monitoring stations in the 24 districts. Two-staged regression models were used in the data analysis, controlling for covariates. Overall, for all subjects, the increased odds of lung function impairment associated with exposure to air pollutants, ranged from 5% (adjusted odds ratio [aOR] = 1.05; 95% confidence interval [CI] = 1.01, 1.10) for FVC < 85% predicted per 46.3 μg/m3 for O3 to 81% (aOR = 1.81; 95%CI = 1.44, 2.28) for FEV1 < 85% predicted per 30.6 μg/m3 for PM10. The linear regression models consistently showed a negative relationship between all air pollutants and lung function measures across subjects. There were significant interaction terms indicating gender differences for lung function impairment and pulmonary function from exposure to some pollutants (P < 0.10). In conclusion, long term exposure to high concentrations of ambient air pollution is associated with decreased pulmonary function and lung function impairment, and females appear to be more susceptible than males.

  5. Low- and high-intensity treadmill exercise attenuates chronic morphine-induced anxiogenesis and memory impairment but not reductions in hippocampal BDNF in female rats.

    PubMed

    Ghodrati-Jaldbakhan, Shahrbanoo; Ahmadalipour, Ali; Rashidy-Pour, Ali; Vafaei, Abbas Ali; Miladi-Gorji, Hossein; Alizadeh, Maryam

    2017-03-05

    Previous studies from our laboratory have shown that treadmill exercise alleviates the deficits in cognitive functions and anxiety behaviors induced by chronic exposure to morphine in male rats. In this study, we investigated the effects of low and high intensities of treadmill exercise on spatial memory, anxiety-like behaviors, and biochemical changes in the hippocampus and serum of morphine-treated female rats. The adult virgin female rats were injected with bi-daily doses (10 mg/kg, at 12 h intervals) of morphine over a period of 10 days. Following these injections, the rats were exercised under low or high intensities for 30 min per session on five days a week for four weeks. After exercise training, object location memory, anxiety profile, hippocampal BDNF, and serum corticosterone and BDNF were examined. Morphine-treated animals exhibited increased anxiety levels, impaired object location memory, and reduced hippocampal BDNF. Exercise alleviated these impairing effects on anxiety profile and memory but not hippocampal BDNF. The high-intensity exercise even further reduced the hippocampal BDNF. Additionally, both exercise regimens in the morphine group and the high exercise in the saline group reduced serum BDNF. Finally, the high-intensity exercise enhanced corticosterone serum. These findings indicate that the negative cognitive and behavioral effects of chronic exposure to morphine could be relieved by forced exercise in female rats. However, the exercise intensity is an important factor to be considered during exercise training. Finally, the correlation between changes of brain and serum BDNF and cognitive functions following morphine exposure needs further research.

  6. P2X7R-Panx1 Complex Impairs Bone Mechanosignaling under High Glucose Levels Associated with Type-1 Diabetes

    PubMed Central

    Maung, Stephanie; Schaffler, Mitchell B.; Spray, David C.; Suadicani, Sylvia O.; Thi, Mia M.

    2016-01-01

    Type 1 diabetes (T1D) causes a range of skeletal problems, including reduced bone density and increased risk for bone fractures. However, mechanisms underlying skeletal complications in diabetes are still not well understood. We hypothesize that high glucose levels in T1D alters expression and function of purinergic receptors (P2Rs) and pannexin 1 (Panx1) channels, and thereby impairs ATP signaling that is essential for proper bone response to mechanical loading and maintenance of skeletal integrity. We first established a key role for P2X7 receptor-Panx1 in osteocyte mechanosignaling by showing that these proteins are co-expressed to provide a major pathway for flow-induced ATP release. To simulate in vitro the glucose levels to which bone cells are exposed in healthy vs. diabetic bones, we cultured osteoblast and osteocyte cell lines for 10 days in medium containing 5.5 or 25 mM glucose. High glucose effects on expression and function of P2Rs and Panx1 channels were determined by Western Blot analysis, quantification of Ca2+ responses to P2R agonists and oscillatory fluid shear stress (± 10 dyne/cm2), and measurement of flow-induced ATP release. Diabetic C57BL/6J-Ins2Akita mice were used to evaluate in vivo effects of high glucose on P2R and Panx1. Western blotting indicated altered P2X7R, P2Y2R and P2Y4R expression in high glucose exposed bone cells, and in diabetic bone tissue. Moreover, high glucose blunted normal P2R- and flow-induced Ca2+ signaling and ATP release from osteocytes. These findings indicate that T1D impairs load-induced ATP signaling in osteocytes and affects osteoblast function, which are essential for maintaining bone health. PMID:27159053

  7. Impaired drug absorption due to high stomach pH: a review of strategies for mitigation of such effect to enable pharmaceutical product development.

    PubMed

    Mitra, Amitava; Kesisoglou, Filippos

    2013-11-04

    Published reports have clearly shown that weakly basic drugs which have low solubility at high pH could have impaired absorption in patients with high gastric pH thus leading to reduced and variable bioavailability. Since such reduction in exposure can lead to significant loss of efficacy, it is imperative to (1) understand the behavior of the compound as a function of stomach pH to inform of any risk of bioavailability loss in clinical studies and (2) develop a robust formulation which can provide adequate exposure in achlorhydric patients. In this review paper, we provide an overview of the factors that can cause high gastric pH in human, discuss clinical and preclinical pharmacokinetic data for weak bases under conditions of normal and high gastric pH, and give examples of formulation strategies to minimize or mitigate the reduced absorption of weakly basic drugs under high gastric pH conditions. It should be noted that the ability to overcome pH sensitivity issues is highly compound dependent and there are no obvious and general solutions to overcome such effect. Further, we discuss, along with several examples, the use of biopharmaceutical tools such as in vitro dissolution, absorption modeling, and gastric pH modified animal models to assess absorption risk of weak bases in high gastric pH and also the use of these tools to enable development of formulations to mitigate such effects.

  8. Symptoms of ADHD in children with high-functioning autism are related to impaired verbal working memory and verbal delayed recall.

    PubMed

    Andersen, Per Normann; Hovik, Kjell Tore; Skogli, Erik Winther; Egeland, Jens; Oie, Merete

    2013-01-01

    Symptoms similar to those found in Attention-Deficit/Hyperactivity Disorder (ADHD) often occur in children with Autism Spectrum Disorders (ASD). The objective of the current study was to compare verbal working memory, acquisition and delayed recall in children with High-Functioning Autism (HFA) to children with ADHD and typically developing children (TDC). Thirty-eight children with HFA, 79 with ADHD and 50 TDC (age 8-17) were assessed with a letter/number sequencing task and a verbal list-learning task. To investigate the possible influence of attention problems in children with HFA, we divided the HFA group into children with (HFA+) or without (HFA-) "attention problems" according to the Child Behaviour Checklist 6-18. The children with HFA+ displayed significant impairment compared to TDC on all three neurocognitive measures, while the children with HFA- were significantly impaired compared to TDC only on the working memory and acquisition measures. In addition, the HFA+ group scored significantly below the HFA- group and the ADHD group on the verbal working memory and delayed recall measures. The results support the proposition that children with HFA+, HFA-, and ADHD differ not only on a clinical level but also on a neurocognitive level which may have implications for treatment.

  9. Impaired Social and Role Function in Ultra-High Risk for Psychosis and First-Episode Schizophrenia: Its Relations with Negative Symptoms

    PubMed Central

    Lee, So Jung; Kim, Kyung Ran; Lee, Su Young

    2017-01-01

    Objective Psychosocial dysfunction was a nettlesome of schizophrenia even in their prodromal phase as well as first episode and its relations with psychopathology were not determined. The aim of the present study was to examine whether the social and role function impairment was found in ultra-high risk for psychosis (UHR) individuals as well as first-episode schizophrenia patients and to explore its relations with psychopathology. Methods Thirty-seven normal controls, 63 UHR participants and 28 young, first-episode schizophrenia patients were recruited. Psychosocial functioning was examined by using Global function: Social and Role scale. Psychopathologies of positive, negative and depressive symptom were also measured. Results Social and role functioning in UHR were compromised at the equivalent level of those of first-episode schizophrenia patients. Multiple linear regression analysis revealed that social and role dysfunction was associated with negative symptoms in each UHR and first-episode schizophrenia group. Conclusion These findings suggest that the significant impairment of social and role function may be appeared before the active psychosis onset at the level of extent to those of first-episode schizophrenia patients. The psychosocial intervention strategy especially targeting the negative symptoms should be developed and provided to individuals from their prepsychotic stage of schizophrenia. PMID:28326117

  10. High avidity HSV-1 antibodies correlate with absence of amnestic Mild Cognitive Impairment conversion to Alzheimer's disease.

    PubMed

    Agostini, Simone; Mancuso, Roberta; Baglio, Francesca; Cabinio, Monia; Hernis, Ambra; Costa, Andrea Saul; Calabrese, Elena; Nemni, Raffaello; Clerici, Mario

    2016-11-01

    Amnestic Mild Cognitive Impairment (aMCI) is an alteration in cognitive abilities that can progress to Alzheimer's disease (AD), a condition in which herpes simplex type 1 (HSV-1) infection might play a pathogenetic role. Prognostic indexes capable of predicting aMCI conversion to AD are only partially understood. The objective of the present work is to verify whether HSV-1 immune responses is involved in conversion of aMCI to AD and correlate with grey matter brain morphometry. Two homogeneous groups of individuals who did or did not convert to AD over a 24-months period were selected after retrospective analysis of a cohort of patients with a diagnosis of aMCI. The selection of subjects was based on: a) clinical follow-up; b) neurocognitive evaluation at baseline and after 24months; c) availability of serum and DNA samples at baseline. 36 aMCI individuals, 21 of whom did (aMCI-converters) and 15 of whom did not (aMCI-non-converters) convert to AD, were included in the study. HSV-1 antibody (Ab) titers, avidity index and APOE genotyping were performed in all the enrolled individuals at baseline. Brain magnetic resonance imaging (MRI) by 1.5T scanner results at baseline were available as well in most (29/36) of these individuals. HSV-1-specific Ab titers were increased at baseline in aMCI-non-converters, and the avidity of these Ab was significantly higher in aMCI-non-converter compared to aMCI-converter (p=0.0018). Receiver operating characteristics analysis showed that HSV-1 avidity had a predictive value in distinguishing between aMCI-non-converters and aMCI-converters (p<0.0001). Notably, a positive correlation was detected as well between HSV-1 antibody titers and MRI-evaluated cortical volumes in the left hippocampus and amigdala (pcorr<0.05). In conclusion, stronger HSV-1-specific humoral responses associate with protection against AD conversion and better-preserved cortical volumes. These results reinforce the hypothesis for a role for HSV-1 in the

  11. Long-Term Feeding of Chitosan Ameliorates Glucose and Lipid Metabolism in a High-Fructose-Diet-Impaired Rat Model of Glucose Tolerance.

    PubMed

    Liu, Shing-Hwa; Cai, Fang-Ying; Chiang, Meng-Tsan

    2015-12-10

    This study was designed to investigate the effects of long-term feeding of chitosan on plasma glucose and lipids in rats fed a high-fructose (HF) diet (63.1%). Male Sprague-Dawley rats aged seven weeks were used as experimental animals. Rats were divided into three groups: (1) normal group (normal); (2) HF group; (3) chitosan + HF group (HF + C). The rats were fed the experimental diets and drinking water ad libitum for 21 weeks. The results showed that chitosan (average molecular weight was about 3.8 × 10⁵ Dalton and degree of deacetylation was about 89.8%) significantly decreased body weight, paraepididymal fat mass, and retroperitoneal fat mass weight, but elevated the lipolysis rate in retroperitoneal fats of HF diet-fed rats. Supplementation of chitosan causes a decrease in plasma insulin, tumor necrosis factor (TNF)-α, Interleukin (IL)-6, and leptin, and an increase in plasma adiponectin. The HF diet increased hepatic lipids. However, intake of chitosan reduced the accumulation of hepatic lipids, including total cholesterol (TC) and triglyceride (TG) contents. In addition, chitosan elevated the excretion of fecal lipids in HF diet-fed rats. Furthermore, chitosan significantly decreased plasma TC, low-density lipoprotein cholesterol (LDL-C), very-low-density lipoprotein cholesterol (VLDL-C), the TC/high-density lipoprotein cholesterol (HDL-C) ratio, and increased the HDL-C/(LDL-C + VLDL-C) ratio, but elevated the plasma TG and free fatty acids concentrations in HF diet-fed rats. Plasma angiopoietin-like 4 (ANGPTL4) protein expression was not affected by the HF diet, but it was significantly increased in chitosan-supplemented, HF-diet-fed rats. The high-fructose diet induced an increase in plasma glucose and impaired glucose tolerance, but chitosan supplementation decreased plasma glucose and improved impairment of glucose tolerance and insulin tolerance. Taken together, these results indicate that supplementation with chitosan can improve the impairment of

  12. Effects of Low versus High Glycemic Index Sugar-Sweetened Beverages on Postprandial Vasodilatation and Inactivity-Induced Impairment of Glucose Metabolism in Healthy Men.

    PubMed

    Keller, Judith; Kahlhöfer, Julia; Peter, Andreas; Bosy-Westphal, Anja

    2016-12-10

    Intake of sugar-sweetened beverages (SSB) may contribute to cardiovascular risk. The aim of this study was to investigate whether functional sugars with low compared to high glycemic index (GI) have beneficial effects on arterial stiffness during a period of low-physical activity. In a controlled cross-over dietary intervention (55% CHO, 30% fat, 15% protein), 13 healthy men (age: 23.7 ± 2.2 years, body mass index: 23.6 ± 1.9 kg/m²) completed 2 × 1 week of low physical activity following 1 week of normal physical activity (2363 ± 900 vs. 11,375 ± 3124 steps/day). During inactive phases participants consumed either low-GI (isomaltulose) or high-GI SSB (maltodextrin-sucrose), providing 20% of energy requirements. Postprandial vasodilatation (augmentation index, AIx), insulin sensitivity (IS) and Glucagon-like-peptide 1 (GLP-1) responses were measured during a meal test before and after SSB-intervention. Compared to maltodextrin-sucrose-SSB, postprandial vasodilatation was prolonged (AIx after 120 min: 9.9% ± 4.3% vs. 11.4% ± 3.7%, p < 0.05) and GLP-1 secretion was higher with isomaltulose-SSB (total area under the GLP-1 curve (tAUCGLP)-1: 8.0 ± 4.4 vs. 5.4 ± 3.4 pM × 3 h; p < 0.05). One week of low-physical activity led to impaired IS that was attenuated with low-GI SSB consumption, but did not affect arterial stiffness (p > 0.05). Higher postprandial GLP-1 secretion after intake of low compared to high-GI beverages may contribute to improved postprandial vasodilatation. Although one week of low-physical activity led to marked impairment in IS, it had no effect on arterial stiffness in healthy men.

  13. Effects of Low versus High Glycemic Index Sugar-Sweetened Beverages on Postprandial Vasodilatation and Inactivity-Induced Impairment of Glucose Metabolism in Healthy Men

    PubMed Central

    Keller, Judith; Kahlhöfer, Julia; Peter, Andreas; Bosy-Westphal, Anja

    2016-01-01

    Intake of sugar-sweetened beverages (SSB) may contribute to cardiovascular risk. The aim of this study was to investigate whether functional sugars with low compared to high glycemic index (GI) have beneficial effects on arterial stiffness during a period of low-physical activity. In a controlled cross-over dietary intervention (55% CHO, 30% fat, 15% protein), 13 healthy men (age: 23.7 ± 2.2 years, body mass index: 23.6 ± 1.9 kg/m2) completed 2 × 1 week of low physical activity following 1 week of normal physical activity (2363 ± 900 vs. 11,375 ± 3124 steps/day). During inactive phases participants consumed either low-GI (isomaltulose) or high-GI SSB (maltodextrin-sucrose), providing 20% of energy requirements. Postprandial vasodilatation (augmentation index, AIx), insulin sensitivity (IS) and Glucagon-like-peptide 1 (GLP-1) responses were measured during a meal test before and after SSB-intervention. Compared to maltodextrin-sucrose-SSB, postprandial vasodilatation was prolonged (AIx after 120 min: 9.9% ± 4.3% vs. 11.4% ± 3.7%, p < 0.05) and GLP-1 secretion was higher with isomaltulose-SSB (total area under the GLP-1 curve (tAUCGLP)-1: 8.0 ± 4.4 vs. 5.4 ± 3.4 pM × 3 h; p < 0.05). One week of low-physical activity led to impaired IS that was attenuated with low-GI SSB consumption, but did not affect arterial stiffness (p > 0.05). Higher postprandial GLP-1 secretion after intake of low compared to high-GI beverages may contribute to improved postprandial vasodilatation. Although one week of low-physical activity led to marked impairment in IS, it had no effect on arterial stiffness in healthy men. PMID:27973411

  14. Effects of long-term feeding of chitosan on postprandial lipid responses and lipid metabolism in a high-sucrose-diet-impaired glucose-tolerant rat model.

    PubMed

    Liu, Shing-Hwa; He, Sih-Pin; Chiang, Meng-Tsan

    2012-05-02

    This study was designed to investigate the effects of long-term feeding of chitosan on postprandial lipid response and lipid metabolism in a high-sucrose (HS)-diet-impaired glucose-tolerant rat model. As the results, HS-diet-fed rats supplemented with 5 and 7% chitosan in diets for 9 weeks had lower postprandial plasma total cholesterol (TC) levels, but 7% chitosan in the diet had higher postprandial plasma triglyceride (TG) and TG-rich lipoprotein TG levels. Supplementation of chitosan significantly decreased the postprandial ratio of apolipoprotein B (apoB)48/apoB100 in TG-rich lipoprotein fractions of HS-diet-fed rats. Long-term supplementation of 5 and 7% chitosan in diets for 16 weeks had lower plasma TC, low-density lipoprotein cholesterol (LDL-C) + very low density lipoprotein cholesterol (VLDL-C), TC/high-density lipoprotein (HDL-C) ratio, leptin, and tumor necrosis factor-α (TNF-α) levels in HS-diet-fed rats. Moreover, it was noticed that the VLDL receptor (VLDLR) protein expression in skeletal muscles of HS-diet-fed rats was significantly decreased, which could be significantly reversed by supplementation of 5 and 7% chitosan. Rats supplemented with 7% chitosan in the diet significantly elevated the lipolysis rate and decreased the accumulation of TG in epididymal fat pads of HS-diet-fed rats. The plasma angiopoietin-like 4 (ANGPTL4) protein expression was not affected in HS-diet-fed rats, but it was significantly increased in 7% chitosan-supplemented HS-diet-fed rats. Taken together, these results indicate that supplementation of chitosan in the diet can improve the impairment of lipid metabolism in a HS-diet-fed rat model, but long-term high-dose chitosan feeding may enhance postprandial plasma TG and TG-rich lipoprotein TG levels in HS-diet-fed rats through an ANGPTL4-regulated pathway.

  15. Cortical Visual Impairment

    MedlinePlus

    ... Frequently Asked Questions Español Condiciones Chinese Conditions Cortical Visual Impairment En Español Read in Chinese What is cortical visual impairment? Cortical visual impairment (CVI) is a decreased ...

  16. Unimpaired Perception of Social and Physical Causality, but Impaired Perception of Animacy in High Functioning Children with Autism

    ERIC Educational Resources Information Center

    Congiu, Sara; Schlottmann, Anne; Ray, Elizabeth

    2010-01-01

    We investigated perception of social and physical causality and animacy in simple motion events, for high-functioning children with autism (CA = 13, VMA = 9.6). Children matched 14 different animations to pictures showing physical, social or non-causality. In contrast to previous work, children with autism performed at a high level similar to…

  17. Mice lacking C1q are protected from high fat diet-induced hepatic insulin resistance and impaired glucose homeostasis.

    PubMed

    Hillian, Antoinette D; McMullen, Megan R; Sebastian, Becky M; Roychowdhury, Sanjoy; Rowchowdhury, Sanjoy; Kashyap, Sangeeta R; Schauer, Philip R; Kirwan, John P; Feldstein, Ariel E; Nagy, Laura E

    2013-08-02

    Complement activation is implicated in the development of obesity and insulin resistance, and loss of signaling by the anaphylatoxin C3a prevents obesity-induced insulin resistance in mice. Here we have identified C1q in the classical pathway as required for activation of complement in response to high fat diets. After 8 weeks of high fat diet, wild-type mice became obese and developed glucose intolerance. This was associated with increased apoptotic cell death and accumulation of complement activation products (C3b/iC3b/C3c) in liver and adipose tissue. Previous studies have shown that high fat diet-induced apoptosis is dependent on Bid; here we report that Bid-mediated apoptosis was required for complement activation in adipose and liver. Although C1qa deficiency had no effect on high fat diet-induced apoptosis, accumulation of complement activation products and the metabolic complications of high fat diet-induced obesity were dependent on C1q. When wild-type mice were fed a high fat diet for only 3 days, hepatic insulin resistance was associated with the accumulation of C3b/iC3b/C3c in the liver. Mice deficient in C3a receptor were protected against this early high fat diet-induced hepatic insulin resistance, whereas mice deficient in the negative complement regulator CD55/DAF were more sensitive to the high fat diet. C1qa(-/-) mice were also protected from high fat diet-induced hepatic insulin resistance and complement activation. Evidence of complement activation was also detected in adipose tissue of obese women compared with lean women. Together, these studies reveal an important role for C1q in the classical pathway of complement activation in the development of high fat diet-induced insulin resistance.

  18. High-fat diet with stress impaired islets' insulin secretion by reducing plasma estradiol and pancreatic GLUT2 protein levels in rats' proestrus phase.

    PubMed

    Salimi, M; Zardooz, H; Khodagholi, F; Rostamkhani, F; Shaerzadeh, F

    2016-10-01

    This study was conducted to determine whether two estrus phases (proestrus and diestrus) in female rats may influence the metabolic response to a high-fat diet and/or stress, focusing on pancreatic insulin secretion and content. Animals were divided into high-fat and normal diet groups, then each group was subdivided into stress and non-stress groups, and finally, each one of these was divided into proestrus and diestrus subgroups. At the end of high-fat diet treatment, foot-shock stress was applied to the animals. Then, blood samples were taken to measure plasma factors. Finally, the pancreas was removed for determination of glucose transporter 2 (GLUT2) protein levels and assessment of insulin content and secretion of the isolated islets. In the normal and high-fat diet groups, stress increased plasma corticosterone concentration in both phases. In both study phases, high-fat diet consumption decreased estradiol and increased leptin plasma levels. In the high-fat diet group in response to high glucose concentration, a reduction in insulin secretion was observed in the proestrus phase compared with the same phase in the normal diet group in the presence and absence of stress. Also, high-fat diet decreased the insulin content of islets in the proestrus phase compared with the normal diet. High-fat diet and/or stress caused a reduction in islet GLUT2 protein levels in both phases. In conclusion, it seems possible that high-fat diet alone or combined with foot-shock, predispose female rats to impaired insulin secretion, at least in part, by interfering with estradiol levels in the proestrus phase and decreasing pancreatic GLUT2 protein levels.

  19. The contribution of childhood parental rejection and early androgen exposure to impairments in socio-cognitive skills in intimate partner violence perpetrators with high alcohol consumption.

    PubMed

    Romero-Martínez, Ángel; Lila, Marisol; Catalá-Miñana, Alba; Williams, Ryan K; Moya-Albiol, Luis

    2013-08-20

    Alcohol consumption, a larger history of childhood parental rejection, and high prenatal androgen exposure have been linked with facilitation and high risk of recidivism in intimate partner violence (IPV) perpetrators. Participants were distributed into two groups according to their alcohol consumption scores as high (HA) and low (LA). HA presented a higher history of childhood parental rejection, prenatal masculinization (smaller 2D:4D ratio), and violence-related scores than LA IPV perpetrators. Nonetheless, the former showed poor socio-cognitive skills performance (cognitive flexibility, emotional recognition and cognitive empathy). Particularly in HA IPV perpetrators, the history of childhood parental rejection was associated with high hostile sexism and low cognitive empathy. Moreover, a masculinized 2D:4D ratio was associated with high anger expression and low cognitive empathy. Parental rejection during childhood and early androgen exposure are relevant factors for the development of violence and the lack of adequate empathy in adulthood. Furthermore, alcohol abuse plays a key role in the development of socio-cognitive impairments and in the proneness to violence and its recidivism. These findings contribute to new coadjutant violence intervention programs, focused on the rehabilitation of basic executive functions and emotional decoding processes and on the treatment of alcohol dependence.

  20. The Contribution of Childhood Parental Rejection and Early Androgen Exposure to Impairments in Socio-Cognitive Skills in Intimate Partner Violence Perpetrators with High Alcohol Consumption

    PubMed Central

    Romero-Martínez, Ángel; Lila, Marisol; Catalá-Miñana, Alba; Williams, Ryan K.; Moya-Albiol, Luis

    2013-01-01

    Alcohol consumption, a larger history of childhood parental rejection, and high prenatal androgen exposure have been linked with facilitation and high risk of recidivism in intimate partner violence (IPV) perpetrators. Participants were distributed into two groups according to their alcohol consumption scores as high (HA) and low (LA). HA presented a higher history of childhood parental rejection, prenatal masculinization (smaller 2D:4D ratio), and violence-related scores than LA IPV perpetrators. Nonetheless, the former showed poor socio-cognitive skills performance (cognitive flexibility, emotional recognition and cognitive empathy). Particularly in HA IPV perpetrators, the history of childhood parental rejection was associated with high hostile sexism and low cognitive empathy. Moreover, a masculinized 2D:4D ratio was associated with high anger expression and low cognitive empathy. Parental rejection during childhood and early androgen exposure are relevant factors for the development of violence and the lack of adequate empathy in adulthood. Furthermore, alcohol abuse plays a key role in the development of socio-cognitive impairments and in the proneness to violence and its recidivism. These findings contribute to new coadjutant violence intervention programs, focused on the rehabilitation of basic executive functions and emotional decoding processes and on the treatment of alcohol dependence. PMID:23965927

  1. Titanium Implant Impairment and Surrounding Muscle Cell Death Following High-Salt Diet: An In Vivo Study

    PubMed Central

    Lecocq, Mathieu; Felix, Marie-Solenne; Linares, Jean-Marc; Chaves-Jacob, Julien; Decherchi, Patrick; Dousset, Erick

    2016-01-01

    Aim of the study High-salt consumption has been widely described as a risk factor for cardiovascular, renal and bone functions. In the present study, the extent to which high-salt diet could influence Ti6Al4V implant surface characteristic, its adhesion to rat tibial crest, and could modify muscle cell viability of two surrounding muscles, was investigated in vivo. These parameters have also been assessed following a NMES (neuro-myoelectrostimulation) program similar to that currently used in human care following arthroplasty. Results After a three-week diet, a harmful effect on titanium implant surface and muscle cell viability was noted. This is probably due to salt corrosive effect on metal and then release of toxic substance around biologic tissue. Moreover, if the use of NMES with high-salt diet induced muscles damages, the latter were higher when implant was added. Unexpectedly, higher implant-to-bone adhesion was found for implanted animals receiving salt supplementation. Conclusion Our in vivo study highlights the potential dangerous effect of high-salt diet in arthroplasty based on titanium prosthesis. This effect appears to be more important when high-salt diet is combined with NMES. PMID:26761710

  2. Hearing Impairment

    MedlinePlus

    ... known as noise-induced hearing loss (NIHL) . Personal music players are among the chief culprits of NIHL ... exposure to high noise levels (such as loud music) over time can cause permanent damage to the ...

  3. Selective overexpression of Toll-like receptor-4 in skeletal muscle impairs metabolic adaptation to high-fat feeding

    PubMed Central

    McMillan, Ryan P.; Wu, Yaru; Voelker, Kevin; Fundaro, Gabrielle; Kavanaugh, John; Stevens, Joseph R.; Shabrokh, Elika; Ali, Mostafa; Harvey, Mordecai; Anderson, Angela S.; Boutagy, Nabil E.; Mynatt, Randall L.; Frisard, Madlyn I.

    2015-01-01

    Toll-like receptor-4 (TLR-4) is elevated in skeletal muscle of obese humans, and data from our laboratory have shown that activation of TLR-4 in skeletal muscle via LPS results in decreased fatty acid oxidation (FAO). The purpose of this study was to determine whether overexpression of TLR-4 in skeletal muscle alters mitochondrial function and whole body metabolism in the context of a chow and high-fat diet. C57BL/6J mice (males, 6–8 mo of age) with skeletal muscle-specific overexpression of the TLR-4 (mTLR-4) gene were created and used for this study. Isolated mitochondria and whole muscle homogenates from rodent skeletal muscle (gastrocnemius and quadriceps) were investigated. TLR-4 overexpression resulted in a significant reduction in FAO in muscle homogenates; however, mitochondrial respiration and reactive oxygen species (ROS) production did not appear to be affected on a standard chow diet. To determine the role of TLR-4 overexpression in skeletal muscle in response to high-fat feeding, mTLR-4 mice and WT control mice were fed low- and high-fat diets for 16 wk. The high-fat diet significantly decreased FAO in mTLR-4 mice, which was observed in concert with elevated body weight and fat, greater glucose intolerance, and increase in production of ROS and cellular oxidative damage compared with WT littermates. These findings suggest that TLR-4 plays an important role in the metabolic response in skeletal muscle to high-fat feeding. PMID:26084695

  4. Selective overexpression of Toll-like receptor-4 in skeletal muscle impairs metabolic adaptation to high-fat feeding.

    PubMed

    McMillan, Ryan P; Wu, Yaru; Voelker, Kevin; Fundaro, Gabrielle; Kavanaugh, John; Stevens, Joseph R; Shabrokh, Elika; Ali, Mostafa; Harvey, Mordecai; Anderson, Angela S; Boutagy, Nabil E; Mynatt, Randall L; Frisard, Madlyn I; Hulver, Matthew W

    2015-08-01

    Toll-like receptor-4 (TLR-4) is elevated in skeletal muscle of obese humans, and data from our laboratory have shown that activation of TLR-4 in skeletal muscle via LPS results in decreased fatty acid oxidation (FAO). The purpose of this study was to determine whether overexpression of TLR-4 in skeletal muscle alters mitochondrial function and whole body metabolism in the context of a chow and high-fat diet. C57BL/6J mice (males, 6-8 mo of age) with skeletal muscle-specific overexpression of the TLR-4 (mTLR-4) gene were created and used for this study. Isolated mitochondria and whole muscle homogenates from rodent skeletal muscle (gastrocnemius and quadriceps) were investigated. TLR-4 overexpression resulted in a significant reduction in FAO in muscle homogenates; however, mitochondrial respiration and reactive oxygen species (ROS) production did not appear to be affected on a standard chow diet. To determine the role of TLR-4 overexpression in skeletal muscle in response to high-fat feeding, mTLR-4 mice and WT control mice were fed low- and high-fat diets for 16 wk. The high-fat diet significantly decreased FAO in mTLR-4 mice, which was observed in concert with elevated body weight and fat, greater glucose intolerance, and increase in production of ROS and cellular oxidative damage compared with WT littermates. These findings suggest that TLR-4 plays an important role in the metabolic response in skeletal muscle to high-fat feeding.

  5. High Working Memory Load Impairs Language Processing during a Simulated Piloting Task: An ERP and Pupillometry Study

    PubMed Central

    Causse, Mickaël; Peysakhovich, Vsevolod; Fabre, Eve F.

    2016-01-01

    Given the important amount of visual and auditory linguistic information that pilots have to process, operating an aircraft generates a high working-memory load (WML). In this context, the ability to focus attention on relevant information and to remain responsive to concurrent stimuli might be altered. Consequently, understanding the effects of WML on the processing of both linguistic targets and distractors is of particular interest in the study of pilot performance. In the present work, participants performed a simplified piloting task in which they had to follow one of three colored aircraft, according to specific written instructions (i.e., the written word for the color corresponding to the color of one of the aircraft) and to ignore either congruent or incongruent concurrent auditory distractors (i.e., a spoken name of color). The WML was manipulated with an n-back sub-task. Participants were instructed to apply the current written instruction in the low WML condition, and the 2-back written instruction in the high WML condition. Electrophysiological results revealed a major effect of WML at behavioral (i.e., decline of piloting performance), electrophysiological, and autonomic levels (i.e., greater pupil diameter). Increased WML consumed resources that could not be allocated to the processing of the linguistic stimuli, as indexed by lower P300/P600 amplitudes. Also, significantly, lower P600 responses were measured in incongruent vs. congruent trials in the low WML condition, showing a higher difficulty reorienting attention toward the written instruction, but this effect was canceled in the high WML condition. This suppression of interference in the high load condition is in line with the engagement/distraction trade-off model. We propose that P300/P600 components could be reliable indicators of WML and that they allow an estimation of its impact on the processing of linguistic stimuli. PMID:27252639

  6. High Working Memory Load Impairs Language Processing during a Simulated Piloting Task: An ERP and Pupillometry Study.

    PubMed

    Causse, Mickaël; Peysakhovich, Vsevolod; Fabre, Eve F

    2016-01-01

    Given the important amount of visual and auditory linguistic information that pilots have to process, operating an aircraft generates a high working-memory load (WML). In this context, the ability to focus attention on relevant information and to remain responsive to concurrent stimuli might be altered. Consequently, understanding the effects of WML on the processing of both linguistic targets and distractors is of particular interest in the study of pilot performance. In the present work, participants performed a simplified piloting task in which they had to follow one of three colored aircraft, according to specific written instructions (i.e., the written word for the color corresponding to the color of one of the aircraft) and to ignore either congruent or incongruent concurrent auditory distractors (i.e., a spoken name of color). The WML was manipulated with an n-back sub-task. Participants were instructed to apply the current written instruction in the low WML condition, and the 2-back written instruction in the high WML condition. Electrophysiological results revealed a major effect of WML at behavioral (i.e., decline of piloting performance), electrophysiological, and autonomic levels (i.e., greater pupil diameter). Increased WML consumed resources that could not be allocated to the processing of the linguistic stimuli, as indexed by lower P300/P600 amplitudes. Also, significantly, lower P600 responses were measured in incongruent vs. congruent trials in the low WML condition, showing a higher difficulty reorienting attention toward the written instruction, but this effect was canceled in the high WML condition. This suppression of interference in the high load condition is in line with the engagement/distraction trade-off model. We propose that P300/P600 components could be reliable indicators of WML and that they allow an estimation of its impact on the processing of linguistic stimuli.

  7. Sustained High Protein-tyrosine Phosphatase 1B Activity in the Sperm of Obese Males Impairs the Sperm Acrosome Reaction*

    PubMed Central

    Shi, Lei; Zhang, Qipeng; Xu, Binqiang; Jiang, Xiaohong; Dai, Yutian; Zhang, Chen-Yu; Zen, Ke

    2014-01-01

    Evidence of a causal link between male obesity and subfertility or infertility has been demonstrated previously. However, the mechanism underlying this link is incompletely understood. Here, we report that sustained high protein-tyrosine phosphatase 1B (PTP1B) activity in sperm of obese donors plays an essential role in coupling male obesity and subfertility or infertility. First, PTP1B level and activity were significantly higher in sperm from ob/ob mice than in wild-type littermates. High PTP1B level and activity in sperm was also observed in obese patients compared with non-obese donors. The enhanced sperm PTP1B level and activity in ob/ob mice and obese patients correlated with a defect of the sperm acrosome reaction (AR). Second, treating sperm from male ob/ob mice or obese men with a specific PTP1B inhibitor largely restored the sperm AR. Finally, blockade of sperm AR by enhanced PTP1B activity in male ob/ob mice or obese men was due to prolonged dephosphorylation of N-ethylmaleimide-sensitive factor by PTP1B, leading to the inability to reassemble the trans-SNARE complexes, which is a critical step in sperm acrosomal exocytosis. In summary, our study demonstrates for the first time that a sustained high PTP1B level or activity in the sperm of obese donors causes a defect of sperm AR and that PTP1B is a novel potential therapeutic target for male infertility treatment. PMID:24519936

  8. Long-term, but not short-term high-fat diet induces fiber composition changes and impaired contractile force in mouse fast-twitch skeletal muscle.

    PubMed

    Eshima, Hiroaki; Tamura, Yoshifumi; Kakehi, Saori; Kurebayashi, Nagomi; Murayama, Takashi; Nakamura, Kyoko; Kakigi, Ryo; Okada, Takao; Sakurai, Takashi; Kawamori, Ryuzo; Watada, Hirotaka

    2017-04-01

    In this study, we investigated the effects of a short-term and long-term high-fat diet (HFD) on morphological and functional features of fast-twitch skeletal muscle. Male C57BL/6J mice were fed a HFD (60% fat) for 4 weeks (4-week HFD) or 12 weeks (12-week HFD). Subsequently, the fast-twitch extensor digitorum longus muscle was isolated, and the composition of muscle fiber type, expression levels of proteins involved in muscle contraction, and force production on electrical stimulation were analyzed. The 12-week HFD, but not the 4-week HFD, resulted in a decreased muscle tetanic force on 100 Hz stimulation compared with control (5.1 ± 1.4 N/g in the 12-week HFD vs. 7.5 ± 1.7 N/g in the control group; P < 0.05), whereas muscle weight and cross-sectional area were not altered after both HFD protocols. Morphological analysis indicated that the percentage of type IIx myosin heavy chain fibers, mitochondrial oxidative enzyme activity, and intramyocellular lipid levels increased in the 12-week HFD group, but not in the 4-week HFD group, compared with controls (P < 0.05). No changes in the expression levels of calcium handling-related proteins and myofibrillar proteins (myosin heavy chain and actin) were detected in the HFD models, whereas fast-troponin T-protein expression was decreased in the 12-week HFD group, but not in the 4-week HFD group (P < 0.05). These findings indicate that a long-term HFD, but not a short-term HFD, impairs contractile force in fast-twitch muscle fibers. Given that skeletal muscle strength largely depends on muscle fiber type, the impaired muscle contractile force by a HFD might result from morphological changes of fiber type composition.

  9. Knockdown of neuropeptide Y in the dorsomedial hypothalamus reverses high-fat diet-induced obesity and impaired glucose tolerance in rats.

    PubMed

    Kim, Yonwook J; Bi, Sheng

    2016-01-15

    Neuropeptide Y (NPY) in the dorsomedial hypothalamus (DMH) plays an important role in the regulation of energy balance. While DMH NPY overexpression causes hyperphagia and obesity in rats, knockdown of NPY in the DMH via adeno-associated virus (AAV)-mediated RNAi (AAVshNPY) ameliorates these alterations. Whether this knockdown has a therapeutic effect on obesity and glycemic disorder has yet to be determined. The present study sought to test this potential using a rat model of high-fat diet (HFD)-induced obesity and insulin resistance, mimicking human obesity with impaired glucose homeostasis. Rats had ad libitum access to rodent regular chow (RC) or HFD. Six weeks later, an oral glucose tolerance test (OGTT) was performed for verifying HFD-induced glucose intolerance. After verification, obese rats received bilateral DMH injections of AAVshNPY or the control vector AAVshCTL, and OGTT and insulin tolerance test (ITT) were performed at 16 and 18 wk after viral injection (23 and 25 wk on HFD), respectively. Rats were killed at 26 wk on HFD. We found that AAVshCTL rats on HFD remained hyperphagic, obese, glucose intolerant, and insulin resistant relative to lean control RC-fed rats receiving DMH injection of AAVshCTL, whereas these alterations were reversed in NPY knockdown rats fed a HFD. NPY knockdown rats exhibited normal food intake, body weight, glucose tolerance, and insulin sensitivity, as seen in lean control rats. Together, these results demonstrate a therapeutic action of DMH NPY knockdown against obesity and impaired glucose homeostasis in rats, providing a potential target for the treatment of obesity and diabetes.

  10. Investigation of thymol effect on learning and memory impairment induced by intrahippocampal injection of amyloid beta peptide in high fat diet- fed rats.

    PubMed

    Asadbegi, Masoumeh; Yaghmaei, Parichehreh; Salehi, Iraj; Komaki, Alireza; Ebrahim-Habibi, Azadeh

    2017-03-02

    Obesity and consumption of a high fat diet (HFD) are known to increase the risk of Alzheimer's disease (AD). In the present study, we have examined the protective and therapeutic effects of thymol (main monoterpene phenol found in thyme essential oil) on a HFD-fed rat model of AD. Fourty adult male Wistar rats were randomly assigned to 5 groups:(n = 8 rats/group): group 1, control, consumed an ordinary diet, group 2 consumed a HFD for 8 weeks, then received phosphate-buffered saline (PBS) via intrahippocampal (IHP) injection, group 3 consumed HFD for 8 weeks, then received beta-amyloid (Aβ)1-42 via IHP injections to induce AD, group 4 consumed HFD for 8 weeks, then received Aβ1-42, and was treated by thymol (30 mg/kg in sunflower oil) daily for 4 weeks, and group 5 consumed HFD for 8 week, then received Aβ1-42 after what sunflower oil was administered by oral gavage daily for 4 weeks. Biochemical tests showed an impaired lipid profile and higher glucose levels upon consumption of HFD, which was ameliorated by thymol treatment. In behavioral results, spatial memory in group 3 was significantly impaired, but groups treated with thymol showed better spatial memory compared to group 3 (p ≤ 0.01). In histological results, formation of Aβ plaque in hippocampus of group 3 increased significantly compared to group 1 and group 2 (p ≤ 0.05), but group 4 showed decreased Aβ plaques compared to group 3 (p ≤ 0.01). In conclusion, thymol decreased the effects of Aβ on memory and could be considered as neuroprotective.

  11. Does long-term creatine supplementation impair kidney function in resistance-trained individuals consuming a high-protein diet?

    PubMed Central

    2013-01-01

    Background The aim of this study was to determine the effects of creatine supplementation on kidney function in resistance-trained individuals ingesting a high-protein diet. Methods A randomized, double-blind, placebo-controlled trial was performed. The participants were randomly allocated to receive either creatine (20 g/d for 5 d followed by 5 g/d throughout the trial) or placebo for 12 weeks. All of the participants were engaged in resistance training and consumed a high-protein diet (i.e., ≥ 1.2 g/Kg/d). Subjects were assessed at baseline (Pre) and after 12 weeks (Post). Glomerular filtration rate was measured by 51Cr-EDTA clearance. Additionally, blood samples and a 24-h urine collection were obtained for other kidney function assessments. Results No significant differences were observed for 51Cr-EDTA clearance throughout the trial (Creatine: Pre 101.42 ± 13.11, Post 108.78 ± 14.41 mL/min/1.73m2; Placebo: Pre 103.29 ± 17.64, Post 106.68 ± 16.05 mL/min/1.73m2; group x time interaction: F = 0.21, p = 0.64). Creatinine clearance, serum and urinary urea, electrolytes, proteinuria, and albuminuria remained virtually unchanged. Conclusions A 12-week creatine supplementation protocol did not affect kidney function in resistance-trained healthy individuals consuming a high-protein diet; thus reinforcing the safety of this dietary supplement. Trial registration ClinicalTrials.gov NCT01817673 PMID:23680457

  12. Impaired learning and memory in rats induced by a high-fat diet: involvement with the imbalance of nesfatin-1 abundance and copine 6 expression.

    PubMed

    Chen, Zheng; Xu, Ya-Yun; Wu, Rui; Han, Yin-Xiu; Yu, Yue; Ge, Jin-Fang; Chen, Fei-Hu

    2017-02-17

    Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease, resulting not only in liver dysfunction, glucose and lipid metabolism disorder, but also in neuropsychiatric damage. In the present study, a NAFLD rat model was established via feeding of a high-fat diet, and the behavior was observed via the open field test (OFT), the sucrose preference test (SPT), the elevated plus maze (EPM), the forced swimming test (FST), and the Morris water maze (MWM). The plasma concentrations of alanine aminotransferase (ALT), glucose, free fatty acid (FFA), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were detected using chemiluminescence technique. The plasma levels of nesfatin-1, leptin, and insulin were measured via enzyme-linked immunosorbent assay (ELISA), and the protein expressions of p-GSK-3β, GSK-3β, p-β-catenin, β-catenin, cyclinD, and copine 6 in the hippocampus and prefrontal cortex (PFC) were detected using western blotting. After 4 consecutive weeks of feeding with a high-fat diet, the rats showed obesity; increased plasma concentrations of ALT, glucose, FFA, TC, TG, HDL-C, and LDL-C; decreased plasma levels of leptin and insulin; and inflammation and mild hepatocyte steatosis in the liver. Although there was no significant difference between groups with regard to performance in the OFT, EPM, or FST, the NAFLD rats showed a decreased sucrose preference index in the SPT and impaired learning and memory in the MWM task. Moreover, the present study provides the first evidence of an increased plasma nesfatin-1 concentration in the NAFLD rats, which was significantly correlated with the plasma lipid concentrations and the behavioral performance. Furthermore, copine 6 and p-β-catenin protein expression decreased and p-GSK-3β increased in the hippocampus and PFC of NAFLD rats. These results suggested that consuming of a high-fat diet for 4

  13. High working memory load impairs the effect of cognitive reappraisal on emotional response: Evidence from an event-related potential study.

    PubMed

    Gan, Shuzhen; Yang, Jianfeng; Chen, Xuhai; Zhang, Xiuping; Yang, Yufang

    2017-02-03

    This study investigates how the working memory (WM) load influenced the efficacy of cognitive reappraisal, a frequently used strategy for emotion regulation. In a dual-task paradigm, the participants were required to perform a high-load or a low-load memory task and simultaneously reappraise aversive pictures with a negative or a neutral meaning. In the low-load condition, we found that the amplitude of emotion-enhanced late positive potential (LPP) was significantly decreased by neutral reappraisal compared to negative reappraisal. In the high-load condition, this regulatory effect of reappraisal disappeared. These results suggest that successful reappraisal relies on cognitive resources and WM processes. If the necessary resources involved in reappraisal are over-depleted by a concurrent memory task, the reappraisal effect will be impaired. Moreover, we found that emotion-enhanced LPP was significant in both of the high-load and low-load tasks, which suggests that emotional electrocortical response may not be susceptible to the available resources.

  14. Impaired Transcriptional Response of the Murine Heart to Cigarette Smoke in the Setting of High Fat Diet and Obesity

    SciTech Connect

    Tilton, Susan C.; Karin, Norman J.; Webb-Robertson, Bobbie-Jo M.; Waters, Katrina M.; Mikheev, Vladimir B.; Lee, K. M.; Corley, Richard A.; Pounds, Joel G.; Bigelow, Diana J.

    2013-07-01

    Smoking and obesity are each well-established risk factors for cardiovascular heart disease, which together impose earlier onset and greater severity of disease. To identify early signaling events in the response of the heart to cigarette smoke exposure within the setting of obesity, we exposed normal weight and high fat diet-induced obese (DIO) C57BL/6 mice to repeated inhaled doses of mainstream (MS) or sidestream (SS) cigarette smoke administered over a two week period, monitoring effects on both cardiac and pulmonary transcriptomes. MS smoke (250 μg wet total particulate matter (WTPM)/L, 5 h/day) exposures elicited robust cellular and molecular inflammatory responses in the lung with 1466 differentially expressed pulmonary genes (p < 0.01) in normal weight animals and a much-attenuated response (463 genes) in the hearts of the same animals. In contrast, exposures to SS smoke (85 μg WTPM/L) with a CO concentration equivalent to that of MS smoke (250 CO ppm) induced a weak pulmonary response (328 genes) but an extensive cardiac response (1590 genes). SS smoke and to a lesser extent MS smoke preferentially elicited hypoxia- and stress-responsive genes as well as genes predicting early changes of vascular smooth muscle and endothelium, precursors of cardiovascular disease. The most sensitive smoke-induced cardiac transcriptional changes of normal weight mice were largely absent in DIO mice after smoke exposure, while genes involved in fatty acid utilization were unaffected. At the same time, smoke exposure suppressed multiple proteome maintenance genes induced in the hearts of DIO mice. Together, these results underscore the sensitivity of the heart to SS smoke and reveal adaptive responses in healthy individuals that are absent in the setting of high fat diet and obesity.

  15. High heterogeneity and low reliability in the diagnosis of major depression will impair the development of new drugs

    PubMed Central

    Castle, David J.; Pantelis, Christos; Hopwood, Malcolm; Young, Allan Hunter; Everall, Ian P.

    2015-01-01

    Summary Major depressive disorder is a common diagnosis associated with a high burden of disease that has proven to be highly heterogeneous and unreliable. Treatments currently available demonstrate limited efficacy and effectiveness. New drug development is urgently required but is likely to be hindered by diagnostic limitations. Declarations of interest D.J.C. has received grants and personal fees from Eli Lilly, Janssen-Cilag, Roche, Allergen, Bristol-Myers Squibb, Pfizer, Lundbeck, AstraZeneca, Hospira, Organon, Sanofi-Aventis, and Wyeth during the writing of this review. C.P. has received grant support from Janssen-Cilag, Eli Lilly, Hospira (Mayne), AstraZeneca, and received honoraria for consultancy to Janssen-Cilag, Eli Lilly, Hospira (Mayne), AstraZeneca, Pfizer, Schering Plough, and Lundbeck. Over the past 2 years he has participated on advisory boards for Janssen-Cilag and Lundbeck, and received honoraria for talks presented at educational meetings organised by AstraZeneca, Janssen-Cilag and Lundbeck. M.H. has received personal fees or grants from Lundbeck, AstraZeneca and Servier during the writing of this review. A.H.Y. reports personal fees from Lundbeck, Sunovion, AstraZeneca and Janssen outside the submitted work. I.P.E. has received personal fees or grants from Lundbeck, AstraZeneca, and Abbvie during the writing of this review. Copyright and usage © The Royal College of Psychiatrists 2015. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence. PMID:27703745

  16. Umbelliferone Improves an Impaired Glucose and Lipid Metabolism in High-Fat Diet/Streptozotocin-Induced Type 2 Diabetic Rats.

    PubMed

    Naowaboot, Jarinyaporn; Somparn, Nuntiya; Saentaweesuk, Suphaket; Pannangpetch, Patchareewan

    2015-06-08

    Umbelliferone (UMB) is a natural product that has several pharmacological effects including antihyperglycemic activity in diabetic rats. Thus, the objective of this study was to investigate the effect of UMB on insulin resistance and on the regulation of glucose and lipid metabolism in type 2 diabetic rats. Type 2 diabetes was induced in rats by feeding a high-fat diet (45 kcal% fat) and a single dose of streptozotocin injection. After 8 weeks of treatment, UMB significantly reduced the elevated blood glucose levels and insulin resistance and increased the liver glycogen and serum adiponectin. Moreover, the serum lipid and the storages of triglyceride and non-esterified fatty acid in liver tissue were reduced. From histological examination, the lipid droplets in liver tissue were clearly decreased, and the fat cell size in the fat tissue was smaller in diabetic rats treated with UMB. Interestingly, UMB increased fat cell adiponectin, plasma membrane glucose transporter 4 (GLUT4) and peroxisome proliferator-activated receptor gamma (PPARγ), and liver PPARα protein expressions. Our findings demonstrate that UMB improves glucose and lipid metabolism in type 2 diabetes by stimulating the insulin secretion and the related mechanisms via stimulating expression of adiponectin, GLUT4, PPARγ, and PPARα-protein expressions. Copyright © 2015 John Wiley & Sons, Ltd.

  17. High Doses of Caffeine during the Peripubertal Period in the Rat Impair the Growth and Function of the Testis

    PubMed Central

    Park, Minji; Choi, Hyeonhae; Yim, Ju-Yearn

    2015-01-01

    Prenatal caffeine exposure adversely affects the development of the reproductive organs of male rat offspring. Thus, it is conceivable that peripubertal caffeine exposure would also influence physiologic gonadal changes and function during this critical period for sexual maturation. This study investigated the impact of high doses of caffeine on the testes of prepubertal male rats. A total of 45 immature male rats were divided randomly into three groups: a control group and 2 groups fed 120 and 180 mg/kg/day of caffeine, respectively, via the stomach for 4 weeks. Caffeine caused a significant decrease in body weight gain, accompanied by proportional decreases in lean body mass and body fat. The caffeine-fed animals had smaller and lighter testes than those of the control that were accompanied by negative influences on the histologic parameters of the testes. In addition, stimulated-testosterone ex vivo production was reduced in Leydig cells retrieved from the caffeine-fed animals. Our results demonstrate that peripubertal caffeine consumption can interfere with the maturation and function of the testis, possibly by interrupting endogenous testosterone secretion and reducing the sensitivity of Leydig cells to gonadotrophic stimulation. In addition, we confirmed that pubertal administration of caffeine reduced testis growth and altered testis histomorphology. PMID:25983753

  18. Tenacious D: Symbiodinium in clade D remain in reef corals at both high and low temperature extremes despite impairment.

    PubMed

    Silverstein, Rachel N; Cunning, Ross; Baker, Andrew C

    2017-04-01

    Reef corals are sensitive to thermal stress, which induces coral bleaching (the loss of algal symbionts), often leading to coral mortality. However, corals hosting certain symbionts (notably some members of Symbiodinium clade D) resist bleaching when exposed to high temperatures. To determine whether these symbionts are also cold tolerant, we exposed corals hosting either Symbiodinium C3 or D1a to incremental warming (+1°C week(-1) to 35°C) and cooling (-1°C week(-1) to 15°C), and measured photodamage and symbiont loss. During warming to 33°C, C3 corals were photodamaged and lost >99% of symbionts, while D1a corals experienced photodamage but did not bleach. During cooling, D1a corals suffered more photodamage than C3 corals but still did not bleach, while C3 corals lost 94% of symbionts. These results indicate that photodamage does not always lead to bleaching, suggesting alternate mechanisms exist by which symbionts resist bleaching, and helping explain the persistence of D1a symbionts on recently bleached reefs, with implications for the future of these ecosystems.

  19. Young to Middle-Aged Dogs with High Amyloid-β Levels in Cerebrospinal Fluid are Impaired on Learning in Standard Cognition tests

    PubMed Central

    Borghys, Herman; Van Broeck, Bianca; Dhuyvetter, Deborah; Jacobs, Tom; de Waepenaert, Katja; Erkens, Tim; Brooks, Melissa; Thevarkunnel, Sandy; Araujo, Joseph A.

    2016-01-01

    Understanding differences in Alzheimer’s disease biomarkers before the pathology becomes evident can contribute to an improved understanding of disease pathogenesis and treatment. A decrease in amyloid-β (Aβ)42 in cerebrospinal fluid (CSF) is suggested to be a biomarker for Aβ deposition in brain. However, the relevance of CSF Aβ levels prior to deposition is not entirely known. Dogs are similar to man with respect to amyloid-β protein precursor (AβPP)-processing, age-related amyloid plaque deposition, and cognitive dysfunction. In the current study, we evaluated the relation between CSF Aβ42 levels and cognitive performance in young to middle-aged dogs (1.5–7 years old). Additionally, CSF sAβPPα and sAβPPβ were measured to evaluate AβPP processing, and CSF cytokines were measured to determine the immune status of the brain. We identified two groups of dogs showing consistently low or high CSF Aβ42 levels. Based on prior studies, it was assumed that at this age no cerebral amyloid plaques were likely to be present. The cognitive performance was evaluated in standard cognition tests. Low or high Aβ concentrations coincided with low or high sAβPPα, sAβPPβ, and CXCL-1 levels, respectively. Dogs with high Aβ concentrations showed significant learning impairments on delayed non-match to position (DNMP), object discrimination, and reversal learning compared to dogs with low Aβ concentrations. Our data support the hypothesis that high levels of CSF Aβ in dogs coincide with lower cognitive performance prior to amyloid deposition. Further experiments are needed to investigate this link, as well as the relevance with respect to Alzheimer’s disease pathology progression. PMID:28035921

  20. Young to Middle-Aged Dogs with High Amyloid-β Levels in Cerebrospinal Fluid are Impaired on Learning in Standard Cognition tests.

    PubMed

    Borghys, Herman; Van Broeck, Bianca; Dhuyvetter, Deborah; Jacobs, Tom; de Waepenaert, Katja; Erkens, Tim; Brooks, Melissa; Thevarkunnel, Sandy; Araujo, Joseph A

    2017-01-01

    Understanding differences in Alzheimer's disease biomarkers before the pathology becomes evident can contribute to an improved understanding of disease pathogenesis and treatment. A decrease in amyloid-β (Aβ)42 in cerebrospinal fluid (CSF) is suggested to be a biomarker for Aβ deposition in brain. However, the relevance of CSF Aβ levels prior to deposition is not entirely known. Dogs are similar to man with respect to amyloid-β protein precursor (AβPP)-processing, age-related amyloid plaque deposition, and cognitive dysfunction. In the current study, we evaluated the relation between CSF Aβ42 levels and cognitive performance in young to middle-aged dogs (1.5-7 years old). Additionally, CSF sAβPPα and sAβPPβ were measured to evaluate AβPP processing, and CSF cytokines were measured to determine the immune status of the brain. We identified two groups of dogs showing consistently low or high CSF Aβ42 levels. Based on prior studies, it was assumed that at this age no cerebral amyloid plaques were likely to be present. The cognitive performance was evaluated in standard cognition tests. Low or high Aβ concentrations coincided with low or high sAβPPα, sAβPPβ, and CXCL-1 levels, respectively. Dogs with high Aβ concentrations showed significant learning impairments on delayed non-match to position (DNMP), object discrimination, and reversal learning compared to dogs with low Aβ concentrations. Our data support the hypothesis that high levels of CSF Aβ in dogs coincide with lower cognitive performance prior to amyloid deposition. Further experiments are needed to investigate this link, as well as the relevance with respect to Alzheimer's disease pathology progression.

  1. High-intensity physical activity modulates diet effects on cerebrospinal amyloid-β levels in normal aging and mild cognitive impairment.

    PubMed

    Baker, Laura D; Bayer-Carter, Jennifer L; Skinner, Jeannine; Montine, Thomas J; Cholerton, Brenna A; Callaghan, Maureen; Leverenz, James B; Walter, Brooke K; Tsai, Elaine; Postupna, Nadia; Lampe, Johanna; Craft, Suzanne

    2012-01-01

    We previously showed that amyloid-β 1-42 (Aβ(42)) levels in cerebrospinal fluid (CSF) were markedly altered in response to a 4-week dietary intervention in normal aging and mild cognitive impairment (MCI). Here, we re-examined the data to assess whether diet-induced effects on CSF Aβ(42) were modulated by high intensity physical activity (hi-PA). Normal older adults (n = 18, mean age = 68.6 ± 7.4 y) and adults with amnestic MCI (n = 23, mean age = 68.0 ± 6.5 y) received a low saturated fat/low glycemic index (LOW) diet or a high saturated fat/high glycemic index (HIGH) diet, and CSF levels of Aβ(42), tau, and IL-8 were measured at baseline and week 4. Pre-study activity levels were assessed using a 7-d questionnaire, and weekly duration of hi-PA was quantified. At baseline, increased hi-PA in normals predicted lower CSF levels of tau (r = -0.54, p = 0.020) and IL-8 (r = -0.70, p = 0.025). Diet-induced effects on CSF Aβ(42) during the intervention study were modulated by hi-PA, and the nature of this effect differed for normals and MCI (ANOVA, p = 0.039). That is, for normal adults, increased hi-PA attenuated the effects of the HIGH diet on CSF Aβ(42) whereas in MCI, increased hi-PA potentiated the effects of the LOW diet. Our results suggest that normal adults who engage in hi-PA are less vulnerable to the pathological effects of an unhealthy diet, while in MCI, the benefit of a healthy diet on Aβ modulation is greatest when paired with hi-PA. Exercise may thus interact with diet to alter pathological processes that ultimately modify risk of Alzheimer's disease.

  2. Rats with metabolic syndrome resist the protective effects of N-acetyl l-cystein against impaired spermatogenesis induced by high-phosphorus/zinc-free diet.

    PubMed

    Suzuki, Yuka; Ichihara, Gaku; Sahabudeen, Sheik Mohideen; Kato, Ai; Yamaguchi, Takanori; Imanaka-Yoshida, Kyoko; Yoshida, Toshimichi; Yamada, Yoshiji; Ichihara, Sahoko

    2013-11-01

    Consumption of relatively high amounts of processed food can result in abnormal nutritional status, such as zinc deficiency or phosphorus excess. Moreover, hyperphosphatemia and hypozincemia are found in some patients with diabetic nephropathy and metabolic syndrome. The present study investigated the effects of high-phosphorus/zinc-free diet on the reproductive function of spontaneously hypertensive rats/NDmcr-cp (SHR/cp), a model of the metabolic syndrome. We also investigated the effects of antioxidant, N-acetyl-l-cysteine (NAC), on testicular dysfunction under such conditions. Male SHR/cp and control rats (Wistar Kyoto rats, WKY) were divided into three groups; rats fed control diet (P 0.3%, w/w; Zn 0.2%, w/w), high-phosphorus and zinc-deficient diet (P 1.2%, w/w; Zn 0.0%, w/w) with vehicle, or high-phosphorus and zinc-deficient diet with NAC (1.5mg/g/day) for 12 weeks (n=6 or 8 rats/group). The weights of testis and epididymis were significantly reduced by high-phosphate/zinc-free diet in both SHR/cp and WKY. The same diet significantly reduced caudal epididymal sperm count and motility and induced histopathological changes in the testis in both strains. Treatment with NAC provided significant protection against the toxic effects of the diet on testicular function in WKY, but not in SHR/cp. The lack of the protective effects of NAC on impaired spermatogenesis in SHR/cp could be due to the more pronounced state of oxidative stress observed in these rats compared with WKY.

  3. Prion-Protein-interacting Amyloid-β Oligomers of High Molecular Weight Are Tightly Correlated with Memory Impairment in Multiple Alzheimer Mouse Models.

    PubMed

    Kostylev, Mikhail A; Kaufman, Adam C; Nygaard, Haakon B; Patel, Pujan; Haas, Laura T; Gunther, Erik C; Vortmeyer, Alexander; Strittmatter, Stephen M

    2015-07-10

    Alzheimer disease (AD) is characterized by amyloid-β accumulation, with soluble oligomers (Aβo) being the most synaptotoxic. However, the multivalent and unstable nature of Aβo limits molecular characterization and hinders research reproducibility. Here, we characterized multiple Aβo forms throughout the life span of various AD mice and in post-mortem human brain. Aβo exists in several populations, where prion protein (PrP(C))-interacting Aβo is a high molecular weight Aβ assembly present in multiple mice and humans with AD. Levels of PrP(C)-interacting Aβo match closely with mouse memory and are equal or superior to other Aβ measures in predicting behavioral impairment. However, Aβo metrics vary considerably between mouse strains. Deleting PrP(C) expression in mice with relatively low PrP(C)-interacting Aβo (Tg2576) results in partial rescue of cognitive performance as opposed to complete recovery in animals with a high percentage of PrP(C)-interacting Aβo (APP/PSEN1). These findings highlight the relative contributions and interplay of Aβo forms in AD.

  4. Emotional Abilities in Children with Oppositional Defiant Disorder (ODD): Impairments in Perspective-Taking and Understanding Mixed Emotions are Associated with High Callous-Unemotional Traits.

    PubMed

    O'Kearney, Richard; Salmon, Karen; Liwag, Maria; Fortune, Clare-Ann; Dawel, Amy

    2017-04-01

    Most studies of emotion abilities in disruptive children focus on emotion expression recognition. This study compared 74 children aged 4-8 years with ODD to 45 comparison children (33 healthy; 12 with an anxiety disorder) on behaviourally assessed measures of emotion perception, emotion perspective-taking, knowledge of emotions causes and understanding ambivalent emotions and on parent-reported cognitive and affective empathy. Adjusting for child's sex, age and expressive language ODD children showed a paucity in attributing causes to emotions but no other deficits relative to the comparison groups. ODD boys with high levels of callous-unemotional traits (CU) (n = 22) showed deficits relative to low CU ODD boys (n = 25) in emotion perspective-taking and in understanding ambivalent emotions. Low CU ODD boys did not differ from the healthy typically developing boys (n = 12). Impairments in emotion perceptive-taking and understanding mixed emotions in ODD boys are associated with the presence of a high level of CU.

  5. Prion-Protein-interacting Amyloid-β Oligomers of High Molecular Weight Are Tightly Correlated with Memory Impairment in Multiple Alzheimer Mouse Models*

    PubMed Central

    Kostylev, Mikhail A.; Kaufman, Adam C.; Nygaard, Haakon B.; Patel, Pujan; Haas, Laura T.; Gunther, Erik C.; Vortmeyer, Alexander; Strittmatter, Stephen M.

    2015-01-01

    Alzheimer disease (AD) is characterized by amyloid-β accumulation, with soluble oligomers (Aβo) being the most synaptotoxic. However, the multivalent and unstable nature of Aβo limits molecular characterization and hinders research reproducibility. Here, we characterized multiple Aβo forms throughout the life span of various AD mice and in post-mortem human brain. Aβo exists in several populations, where prion protein (PrPC)-interacting Aβo is a high molecular weight Aβ assembly present in multiple mice and humans with AD. Levels of PrPC-interacting Aβo match closely with mouse memory and are equal or superior to other Aβ measures in predicting behavioral impairment. However, Aβo metrics vary considerably between mouse strains. Deleting PrPC expression in mice with relatively low PrPC-interacting Aβo (Tg2576) results in partial rescue of cognitive performance as opposed to complete recovery in animals with a high percentage of PrPC-interacting Aβo (APP/PSEN1). These findings highlight the relative contributions and interplay of Aβo forms in AD. PMID:26018073

  6. Reductions in laminin beta2 mRNA translation are responsible for impaired IGFBP-5-mediated mesangial cell migration in the presence of high glucose.

    PubMed

    Schaeffer, Valerie; Hansen, Kim M; Morris, David R; Abrass, Christine K

    2010-02-01

    Insulin-like growth factor binding protein-5 (IGFBP-5) mediates mesangial cell migration through activation of cdc42, and laminin421 binding to alpha(6)beta(1)-integrin (Berfield AK, Hansen KM, Abrass CK. Am J Physiol Cell Physiol 291: C589-C599, 2006). Because glomerular expression of laminin beta(2) is reduced in diabetic rats (Abrass CK, Spicer D, Berfield AK, St. John PL, Abrahamson DR. Am J Pathol 151: 1131-1140, 1997), we directly examined the effect of hyperglycemia on mesangial cell migration and laminin beta2 expression. Migration mediated by IGFBP-5 is impaired in the presence of 25 mM glucose. This reduction in migration was found to result from a loss in mesangial cell synthesis of laminin421, and IGFBP-5-induced migration could be restored by replacing laminin421. Additional studies showed that there was selective reduction in mRNA translation of laminin beta2 in the presence of high glucose. Preserved synthesis of laminin beta1 indicates that not all proteins are reduced by high glucose and confirms prior data showing that laminin411 cannot substitute for laminin421 in IGFBP-5-mediated migration. Given the importance of mesangial migration in the reparative response to diabetes-associated mesangiolysis, these findings provide new insights into abnormalities associated with diabetic nephropathy and the potential importance of differential control of protein translation in determination of alterations of protein expression.

  7. Nitrosamine exposure exacerbates high fat diet-mediated type 2 diabetes mellitus, non-alcoholic steatohepatitis, and neurodegeneration with cognitive impairment

    PubMed Central

    2009-01-01

    Background The current epidemics of type 2 diabetes mellitus (T2DM), non-alcoholic steatohepatitis (NASH), and Alzheimer's disease (AD) all represent insulin-resistance diseases. Previous studies linked insulin resistance diseases to high fat diets or exposure to streptozotocin, a nitrosamine-related compound that causes T2DM, NASH, and AD-type neurodegeneration. We hypothesize that low-level exposure to nitrosamines that are widely present in processed foods, amplifies the deleterious effects of high fat intake in promoting T2DM, NASH, and neurodegeneration. Methods Long Evans rat pups were treated with N-nitrosodiethylamine (NDEA) by i.p. Injection, and upon weaning, they were fed with high fat (60%; HFD) or low fat (5%; LFD) chow for 6 weeks. Rats were evaluated for cognitive impairment, insulin resistance, and neurodegeneration using behavioral, biochemical, molecular, and histological methods. Results NDEA and HFD ± NDEA caused T2DM, NASH, deficits in spatial learning, and neurodegeneration with hepatic and brain insulin and/or IGF resistance, and reductions in tau and choline acetyltransferase levels in the temporal lobe. In addition, pro-ceramide genes, which promote insulin resistance, were increased in livers and brains of rats exposed to NDEA, HFD, or both. In nearly all assays, the adverse effects of HFD+NDEA were worse than either treatment alone. Conclusions Environmental and food contaminant exposures to low, sub-mutagenic levels of nitrosamines, together with chronic HFD feeding, function synergistically to promote major insulin resistance diseases including T2DM, NASH, and AD-type neurodegeneration. Steps to minimize human exposure to nitrosamines and consumption of high-fat content foods are needed to quell these costly and devastating epidemics. PMID:20034403

  8. Moderately Low Magnesium Intake Impairs Growth of Lean Body Mass in Obese-Prone and Obese-Resistant Rats Fed a High-Energy Diet

    PubMed Central

    Bertinato, Jesse; Lavergne, Christopher; Rahimi, Sophia; Rachid, Hiba; Vu, Nina A.; Plouffe, Louise J.; Swist, Eleonora

    2016-01-01

    The physical and biochemical changes resulting from moderately low magnesium (Mg) intake are not fully understood. Obesity and associated co-morbidities affect Mg metabolism and may exacerbate Mg deficiency and physiological effects. Male rats selectively bred for diet-induced obesity (OP, obese-prone) or resistance (OR, obese-resistant) were fed a high-fat, high-energy diet containing moderately low (LMg, 0.116 ± 0.001 g/kg) or normal (NMg, 0.516 ± 0.007 g/kg) Mg for 13 weeks. The growth, body composition, mineral homeostasis, bone development, and glucose metabolism of the rats were examined. OP and OR rats showed differences (p < 0.05) in many physical and biochemical measures regardless of diet. OP and OR rats fed the LMg diet had decreased body weight, lean body mass, decreased femoral size (width, weight, and volume), and serum Mg and potassium concentrations compared to rats fed the NMg diet. The LMg diet increased serum calcium (Ca) concentration in both rat strains with a concomitant decrease in serum parathyroid hormone concentration only in the OR strain. In the femur, Mg concentration was reduced, whereas concentrations of Ca and sodium were increased in both strains fed the LMg diet. Plasma glucose and insulin concentrations in an oral glucose tolerance test were similar in rats fed the LMg or NMg diets. These results show that a moderately low Mg diet impairs the growth of lean body mass and alters femoral geometry and mineral metabolism in OP and OR rats fed a high-energy diet. PMID:27136580

  9. High water temperature impairs ovarian activity and gene expression in the brain-pituitary-gonadal axis in female red seabream during the spawning season.

    PubMed

    Okuzawa, Koichi; Gen, Koichiro

    2013-12-01

    Temperature plays a pivotal role in the control of seasonal reproduction in temperate fish species. It is well known that temperatures that exceed a certain threshold impair gonadal development, maturation, and spawning. However, the endocrine mechanisms that underlie these effects are poorly understood. We evaluated the effect of high water temperature on the brain-pituitary-gonadal (B-P-G) axis of a perciform fish, red seabream, Pagrus (Chrysophrys) major during its spawning season (April-May). Fish were reared at either high (24 °C: H-group) or optimal/control (17 °C: C-group) temperatures for 5 or 10 d. After 5 d, the transcript abundance of gonadotropin-releasing hormone-1 (GnRH1) in the brain and GnRH receptor (GnRH-R) and FSH-β in the pituitary were significantly lower in H-group than in C-group. Conversely, there was no difference in pituitary LH-β mRNA levels, serum concentrations of estradiol-17β (E₂), or the gonadosomatic index (GSIs) between H- and C-groups on Day 5. After 10 d, the ovaries of all H-group fish had completely regressed and were filled with only perinucleolar stage primary oocytes and atretic oocytes. The brain GnRH1 expression, pituitary GnRH-R and pituitary LH-β expression, serum E₂ concentrations, and the GSI were significantly lower in the H-group on Day 10. Our results suggest that high water temperature is the proximate driver of the termination of the spawning season of female red seabream. The effect appears to be mediated by suppression of gene expression in the B-P-G axis.

  10. Abnormal white matter tractography of visual pathways detected by high-angular-resolution diffusion imaging (HARDI) corresponds to visual dysfunction in cortical/cerebral visual impairment.

    PubMed

    Bauer, Corinna M; Heidary, Gena; Koo, Bang-Bon; Killiany, Ronald J; Bex, Peter; Merabet, Lotfi B

    2014-08-01

    Cortical (cerebral) visual impairment (CVI) is characterized by visual dysfunction associated with damage to the optic radiations and/or visual cortex. Typically it results from pre- or perinatal hypoxic damage to postchiasmal visual structures and pathways. The neuroanatomical basis of this condition remains poorly understood, particularly with regard to how the resulting maldevelopment of visual processing pathways relates to observations in the clinical setting. We report our investigation of 2 young adults diagnosed with CVI and visual dysfunction characterized by difficulties related to visually guided attention and visuospatial processing. Using high-angular-resolution diffusion imaging (HARDI), we characterized and compared their individual white matter projections of the extrageniculo-striate visual system with a normal-sighted control. Compared to a sighted control, both CVI cases revealed a striking reduction in association fibers, including the inferior frontal-occipital fasciculus as well as superior and inferior longitudinal fasciculi. This reduction in fibers associated with the major pathways implicated in visual processing may provide a neuroanatomical basis for the visual dysfunctions observed in these patients.

  11. Ameliorative effects of α-lipoic acid on high-fat diet-induced oxidative stress and glucose uptake impairment of T cells.

    PubMed

    Cui, Jue; Huang, Dejian; Zheng, Yi

    2016-10-01

    The incidence of obesity and metabolic disease continues to rise, mainly associated with consumption of a high-fat diet (HFD). Previous studies have indicated that HFD could disturb the immune system, leading to immunodeficiency and inflammation. Several mechanisms have been postulated to account for immunodeficiency associated with HFD, one being oxidative stress. To further investigate the effects of HFD on glucose metabolism and proliferative capability of T cells and the protective effects of α-lipoic acid (LA), male C57BL/6J mice were fed a normal chow (10% fat), an HFD (60% fat), an LA supplement (HFD +0.1%LA), and a N-acetyl-L-cysteine supplement (HFD +0.1% NAC) for 10 weeks. Results showed that 10-week HFD increased intracellular reactive oxygen species (ROS) production, induced oxidative stress state formation, inhibited glucose uptake, decreased ATP concentration, reduced proliferative rate, and dampened IL-2 production of T cells of mice. Administration of LA significantly alleviated these changes induced by HFD. These findings reveal that oxidative stress of T cells caused by HFD may be a key factor leading to glucose metabolism reduction and proliferative capability and function impairment of T cells. LA, as a potent agonist, could promote Nrf2 nuclear translocation and up-regulate expression of Nrf2 target genes (Ho-1 and Prdx1), which can eliminate excess ROS and restore redox balance of cells.

  12. Heterozygous Hfe gene deletion leads to impaired glucose homeostasis, but not liver injury in mice fed a high-calorie diet.

    PubMed

    Britton, Laurence; Jaskowski, Lesley; Bridle, Kim; Santrampurwala, Nishreen; Reiling, Janske; Musgrave, Nick; Subramaniam, V Nathan; Crawford, Darrell

    2016-06-01

    Heterozygous mutations of the Hfe gene have been proposed as cofactors in the development and progression of nonalcoholic fatty liver disease (NAFLD). Homozygous Hfe deletion previously has been shown to lead to dysregulated hepatic lipid metabolism and accentuated liver injury in a dietary mouse model of NAFLD We sought to establish whether heterozygous deletion of Hfe is sufficient to promote liver injury when mice are exposed to a high-calorie diet (HCD). Eight-week-old wild-type and Hfe(+/-) mice received 8 weeks of a control diet or HCD Liver histology and pathways of lipid and iron metabolism were analyzed. Liver histology demonstrated that mice fed a HCD had increased NAFLD activity score (NAS), steatosis, and hepatocyte ballooning. However, liver injury was unaffected by Hfe genotype. Hepatic iron concentration (HIC) was increased in Hfe(+/-) mice of both dietary groups. HCD resulted in a hepcidin-independent reduction in HIC Hfe(+/-) mice demonstrated raised fasting serum glucose concentrations and HOMA-IR score, despite unaltered serum adiponectin concentrations. Downstream regulators of hepatic de novo lipogenesis (pAKT, SREBP-1, Fas, Scd1) and fatty acid oxidation (AdipoR2, Pparα, Cpt1) were largely unaffected by genotype. In summary, heterozygous Hfe gene deletion is associated with impaired iron and glucose metabolism. However, unlike homozygous Hfe deletion, heterozygous gene deletion did not affect lipid metabolism pathways or liver injury in this model.

  13. Decreased osteoclastogenesis and high bone mass in mice with impaired insulin clearance due to liver-specific inactivation to CEACAM1.

    PubMed

    Huang, S; Kaw, M; Harris, M T; Ebraheim, N; McInerney, M F; Najjar, S M; Lecka-Czernik, B

    2010-04-01

    Type 2 diabetes is associated with normal-to-higher bone mineral density (BMD) and increased rate of fracture. Hyperinsulinemia and hyperglycemia may affect bone mass and quality in the diabetic skeleton. In order to dissect the effect of hyperinsulinemia from the hyperglycemic impact on bone homeostasis, we have analyzed L-SACC1 mice, a murine model of impaired insulin clearance in liver causing hyperinsulinemia and insulin resistance without fasting hyperglycemia. Adult L-SACC1 mice exhibit significantly higher trabecular and cortical bone mass, attenuated bone formation as measured by dynamic histomorphometry, and reduced number of osteoclasts. Serum levels of bone formation (BALP) and bone resorption markers (TRAP5b and CTX) are decreased by approximately 50%. The L-SACC1 mutation in the liver affects myeloid cell lineage allocation in the bone marrow: the (CD3(-)CD11b(-)CD45R(-)) population of osteoclast progenitors is decreased by 40% and the number of (CD3(-)CD11b(-)CD45R(+)) B-cell progenitors is increased by 60%. L-SACC1 osteoclasts express lower levels of c-fos and RANK and their differentiation is impaired. In vitro analysis corroborated a negative effect of insulin on osteoclast recruitment, maturation and the expression levels of c-fos and RANK transcripts. Although bone formation is decreased in L-SACC1 mice, the differentiation potential and expression of the osteoblast-specific gene markers in L-SACC1-derived mesenchymal stem cells (MSC) remain unchanged as compared to the WT. Interestingly, however, MSC from L-SACC1 mice exhibit increased PPARgamma2 and decreased IGF-1 transcript levels. These data suggest that high bone mass in L-SACC1 animals results, at least in part, from a negative regulatory effect of insulin on bone resorption and formation, which leads to decreased bone turnover. Because low bone turnover contributes to decreased bone quality and an increased incidence of fractures, studies on L-SACC1 mice may advance our understanding of

  14. Impaired Waters and TMDLs

    EPA Pesticide Factsheets

    The 303(d) program provides guidance and technical resources to assist States in submitting lists of impaired waterbodies and the development of Total Maximum Daily Loads of the pollutant causing the impairment.

  15. Early adaptive response of the retina to a pro-diabetogenic diet: Impairment of cone response and gene expression changes in high-fructose fed rats.

    PubMed

    Thierry, Magalie; Pasquis, Bruno; Buteau, Bénédicte; Fourgeux, Cynthia; Dembele, Doulaye; Leclere, Laurent; Gambert-Nicot, Ségolène; Acar, Niyazi; Bron, Alain M; Creuzot-Garcher, Catherine P; Bretillon, Lionel

    2015-06-01

    The lack of plasticity of neurons to respond to dietary changes, such as high fat and high fructose diets, by modulating gene and protein expression has been associated with functional and behavioral impairments that can have detrimental consequences. The inhibition of high fat-induced rewiring of hypothalamic neurons induced obesity. Feeding rodents with high fructose is a recognized and widely used model to trigger obesity and metabolic syndrome. However the adaptive response of the retina to short term feeding with high fructose is poorly documented. We therefore aimed to characterize both the functional and gene expression changes in the neurosensory retina of Brown Norway rats fed during 3 and 8 days with a 60%-rich fructose diet (n = 16 per diet and per time point). Glucose, insulin, leptin, triacylglycerols, total cholesterol, HDL-cholesterol, LDL-cholesterol and fructosamine were quantified in plasma (n = 8 in each group). Functionality of the inner retina was studied using scotopic single flash electroretinography (n = 8 in each group) and the individual response of rod and cone photoreceptors was determined using 8.02 Hz Flicker electroretinography (n = 8 in each group). Analysis of gene expression in the neurosensory retina was performed by Affymetrix genechips, and confirmed by RT-qPCR (n = 6 in each group). Elevated glycemia (+13%), insulinemia (+83%), and leptinemia (+172%) was observed after 8 days of fructose feeding. The cone photoreceptor response was altered at day 8 in high fructose fed rats (Δ = 0.5 log unit of light stimulus intensity). Affymetrix analysis of gene expression highlighted significant modulation of the pathways of eIF2 signaling and endoplasmic reticulum stress, regulation of eIF4 and p70S6K signaling, as well as mTOR signaling and mitochondrial dysfunction. RT-qPCR analysis confirmed the down regulation of Crystallins, Npy, Nid1 and Optc genes after 3 days of fructose feeding, and up regulation of End2. Meanwhile, a trend

  16. Impaired fear extinction retention and increased anxiety-like behaviours induced by limited daily access to a high-fat/high-sugar diet in male rats: Implications for diet-induced prefrontal cortex dysregulation.

    PubMed

    Baker, Kathryn D; Reichelt, Amy C

    2016-12-01

    Anxiety disorders and obesity are both common in youth and young adults. Despite increasing evidence that over-consumption of palatable high-fat/high-sugar "junk" foods leads to adverse neurocognitive outcomes, little is known about the effects of palatable diets on emotional memories and fear regulation. In the present experiments we examined the effects of daily 2h consumption of a high-fat/high-sugar (HFHS) food across adolescence on fear inhibition and anxiety-like behaviour in young adult rats. Rats exposed to the HFHS diet exhibited impaired retention of fear extinction and increased anxiety-like behaviour in an emergence test compared to rats fed a standard diet. The HFHS-fed rats displayed diet-induced changes in prefrontal cortex (PFC) function which were detected by altered expression of GABAergic parvalbumin-expressing inhibitory interneurons and the stable transcription factor ΔFosB which accumulates in the PFC in response to chronic stimuli. Immunohistochemical analyses of the medial PFC revealed that animals fed the HFHS diet had fewer parvalbumin-expressing cells and increased levels of FosB/ΔFosB expression in the infralimbic cortex, a region implicated in the consolidation of fear extinction. There was a trend towards increased IBA-1 immunoreactivity, a marker of microglial activation, in the infralimbic cortex after HFHS diet exposure but expression of the extracellular glycoprotein reelin was unaffected. These findings demonstrate that a HFHS diet during adolescence is associated with reductions of prefrontal parvalbumin neurons and impaired fear inhibition in adulthood. Adverse effects of HFHS diets on the mechanisms of fear regulation may precipitate a vulnerability in obese individuals to the development of anxiety disorders.

  17. High glucose suppresses embryonic stem cell differentiation into neural lineage cells

    PubMed Central

    Yang, Penghua; Shen, Wei-bin; Reece, E. Albert; Chen, Xi; Yang, Peixin

    2017-01-01

    Abnormal neurogenesis occurs during embryonic development in human diabetic pregnancies and in animal models of diabetic embryopathy. Our previous studies in a mouse model of diabetic embryopathy have implicated that high glucose of maternal diabetes delays neurogenesis in the developing neuroepithelium leading to neural tube defects. However, the underlying process in high glucose-impaired neurogenesis is uncharacterized. Neurogenesis from embryonic stem (ES) cells provides a valuable model for understanding the abnormal neural lineage development under high glucose conditions. ES cells are commonly generated and maintained in high glucose (approximately 25 mM glucose). Here, the mouse ES cell line, E14, was gradually adapted to and maintained in low glucose (5 mM), and became a glucose responsive E14 (GR-E14) line. High glucose induced the endoplasmic reticulum stress marker, CHOP, in GR-E14 cells. Under low glucose conditions, the GR-E14 cells retained their pluripotency and capability to differentiate into neural lineage cells. GR-E14 cell differentiation into neural stem cells (Sox1 and nestin positive cells) was inhibited by high glucose. Neuron (Tuj1 positive cells) and glia (GFAP positive cells) differentiation from GR-E14 cells was also suppressed by high glucose. In addition, high glucose delayed GR-E14 differentiation into neural crest cells by decreasing neural crest markers, paired box 3 (Pax3) and paired box 7 (Pax7). Thus, high glucose impairs ES cell differentiation into neural lineage cells. The low glucose adapted and high glucose responsive GR-E14 cell line is a useful in vitro model for assessing the adverse effect of high glucose on the development of the central nervous system. PMID:26940741

  18. High glucose suppresses embryonic stem cell differentiation into neural lineage cells.

    PubMed

    Yang, Penghua; Shen, Wei-bin; Reece, E Albert; Chen, Xi; Yang, Peixin

    2016-04-01

    Abnormal neurogenesis occurs during embryonic development in human diabetic pregnancies and in animal models of diabetic embryopathy. Our previous studies in a mouse model of diabetic embryopathy have implicated that high glucose of maternal diabetes delays neurogenesis in the developing neuroepithelium leading to neural tube defects. However, the underlying process in high glucose-impaired neurogenesis is uncharacterized. Neurogenesis from embryonic stem (ES) cells provides a valuable model for understanding the abnormal neural lineage development under high glucose conditions. ES cells are commonly generated and maintained in high glucose (approximately 25 mM glucose). Here, the mouse ES cell line, E14, was gradually adapted to and maintained in low glucose (5 mM), and became a glucose responsive E14 (GR-E14) line. High glucose induced the endoplasmic reticulum stress marker, CHOP, in GR-E14 cells. Under low glucose conditions, the GR-E14 cells retained their pluripotency and capability to differentiate into neural lineage cells. GR-E14 cell differentiation into neural stem cells (Sox1 and nestin positive cells) was inhibited by high glucose. Neuron (Tuj1 positive cells) and glia (GFAP positive cells) differentiation from GR-E14 cells was also suppressed by high glucose. In addition, high glucose delayed GR-E14 differentiation into neural crest cells by decreasing neural crest markers, paired box 3 (Pax3) and paired box 7 (Pax7). Thus, high glucose impairs ES cell differentiation into neural lineage cells. The low glucose adapted and high glucose responsive GR-E14 cell line is a useful in vitro model for assessing the adverse effect of high glucose on the development of the central nervous system.

  19. Adapting for Impaired Patrons.

    ERIC Educational Resources Information Center

    Schuyler, Michael

    1999-01-01

    Describes how a library, with an MCI Corporation grant, approached the process of setting up computers for the visually impaired. Discusses preparations, which included hiring a visually-impaired user as a consultant and contacting the VIP (Visually Impaired Persons) group; equipment; problems with the graphical user interface; and training.…

  20. Working Memory Impairment in Calcineurin Knock-out Mice Is Associated with Alterations in Synaptic Vesicle Cycling and Disruption of High-Frequency Synaptic and Network Activity in Prefrontal Cortex

    PubMed Central

    Cottrell, Jeffrey R.; Levenson, Jonathan M.; Kim, Sung Hyun; Gibson, Helen E.; Richardson, Kristen A.; Sivula, Michael; Li, Bing; Ashford, Crystle J.; Heindl, Karen A.; Babcock, Ryan J.; Rose, David M.; Hempel, Chris M.; Wiig, Kjesten A.; Laeng, Pascal; Levin, Margaret E.; Ryan, Timothy A.

    2013-01-01

    Working memory is an essential component of higher cognitive function, and its impairment is a core symptom of multiple CNS disorders, including schizophrenia. Neuronal mechanisms supporting working memory under normal conditions have been described and include persistent, high-frequency activity of prefrontal cortical neurons. However, little is known about the molecular and cellular basis of working memory dysfunction in the context of neuropsychiatric disorders. To elucidate synaptic and neuronal mechanisms of working memory dysfunction, we have performed a comprehensive analysis of a mouse model of schizophrenia, the forebrain-specific calcineurin knock-out mouse. Biochemical analyses of cortical tissue from these mice revealed a pronounced hyperphosphorylation of synaptic vesicle cycling proteins known to be necessary for high-frequency synaptic transmission. Examination of the synaptic vesicle cycle in calcineurin-deficient neurons demonstrated an impairment of vesicle release enhancement during periods of intense stimulation. Moreover, brain slice and in vivo electrophysiological analyses showed that loss of calcineurin leads to a gene dose-dependent disruption of high-frequency synaptic transmission and network activity in the PFC, correlating with selective working memory impairment. Finally, we showed that levels of dynamin I, a key presynaptic protein and calcineurin substrate, are significantly reduced in prefrontal cortical samples from schizophrenia patients, extending the disease relevance of our findings. Our data provide support for a model in which impaired synaptic vesicle cycling represents a critical node for disease pathologies underlying the cognitive deficits in schizophrenia. PMID:23825400

  1. IMPAIRED NATURAL KILLER CELL LYSIS IN BREAST CANCER PATIENTS WITH HIGH LEVELS OF PSYCHOLOGICAL STRESS IS ASSOCIATED WITH ALTERED EXPRESSION OF KILLER IMMUNOGLOBULIN-LIKE RECEPTORS

    PubMed Central

    Varker, Kimberly A.; Terrell, Catherine E.; Welt, Marilyn; Suleiman, Samer; Thornton, Lisa; Andersen, Barbara L.; Carson, William E.

    2007-01-01

    expression was significantly lower in Group I after incubation with IL-2. Conclusions In this study of a small subset of breast cancer patients chosen from a previous clinical trial of psychosocial intervention for breast cancer, impaired NK lysis in breast cancer patients with high levels of psychological stress was associated with alterations in surface expression of killer immunoglobulin-like receptors. However, immune effectors retained the ability to lyse antibody-coated targets and to initiate lymphokine-activated killer activity, irrespective of stress levels or baseline NK50. PMID:17292412

  2. An index of reservoir habitat impairment

    USGS Publications Warehouse

    Miranda, L.E.; Hunt, K.M.

    2011-01-01

    Fish habitat impairment resulting from natural and anthropogenic watershed and in-lake processes has in many cases reduced the ability of reservoirs to sustain native fish assemblages and fisheries quality. Rehabilitation of impaired reservoirs is hindered by the lack of a method suitable for scoring impairment status. To address this limitation, an index of reservoir habitat impairment (IRHI) was developed by merging 14 metrics descriptive of common impairment sources, with each metric scored from 0 (no impairment) to 5 (high impairment) by fisheries scientists with local knowledge. With a plausible range of 5 to 25, distribution of the IRHI scores ranged from 5 to 23 over 482 randomly selected reservoirs dispersed throughout the USA. The IRHI reflected five impairment factors including siltation, structural habitat, eutrophication, water regime, and aquatic plants. The factors were weakly related to key reservoir characteristics including reservoir area, depth, age, and usetype, suggesting that common reservoir descriptors are poor predictors of fish habitat impairment. The IRHI is rapid and inexpensive to calculate, provides an easily understood measure of the overall habitat impairment, allows comparison of reservoirs and therefore prioritization of restoration activities, and may be used to track restoration progress. The major limitation of the IRHI is its reliance on unstandardized professional judgment rather than standardized empirical measurements. ?? 2010 US Government.

  3. Memory Impairment in Children with Language Impairment

    ERIC Educational Resources Information Center

    Baird, Gillian; Dworzynski, Katharina; Slonims, Vicky; Simonoff, Emily

    2010-01-01

    Aim: The aim of this study was to assess whether any memory impairment co-occurring with language impairment is global, affecting both verbal and visual domains, or domain specific. Method: Visual and verbal memory, learning, and processing speed were assessed in children aged 6 years to 16 years 11 months (mean 9y 9m, SD 2y 6mo) with current,…

  4. Visual impairment in the hearing impaired students

    PubMed Central

    Gogate, Parikshit; Rishikeshi, Nikhil; Mehata, Reshma; Ranade, Satish; Kharat, Jitesh; Deshpande, Madan

    2009-01-01

    Background: Ocular problems are more common in children with hearing problems than in normal children. Neglected visual impairment could aggravate educational and social disability. Aim: To detect and treat visual impairment, if any, in hearing-impaired children. Setting and Design: Observational, clinical case series of hearing-impaired children in schools providing special education. Materials and Methods: Hearing-impaired children in selected schools underwent detailed visual acuity testing, refraction, external ocular examination and fundoscopy. Ocular motility testing was also performed. Teachers were sensitized and trained to help in the assessment of visual acuity using Snellen's E charts. Refractive errors and squint were treated as per standard practice. Statistical Analysis: Excel software was used for data entry and SSPS for analysis. Results: The study involved 901 hearing-impaired students between four and 21 years of age, from 14 special education schools. A quarter of them (216/901, 24%) had ocular problems. Refractive errors were the most common morbidity 167(18.5%), but only 10 children were using appropriate spectacle correction at presentation. Fifty children had visual acuity less than 20/80 at presentation; after providing refractive correction, this number reduced to three children, all of whom were provided low-vision aids. Other common conditions included strabismus in 12 (1.3%) children, and retinal pigmentary dystrophy in five (0.6%) children. Conclusion: Ocular problems are common in hearing-impaired children. Screening for ocular problems should be made mandatory in hearing-impaired children, as they use their visual sense to compensate for the poor auditory sense. PMID:19861747

  5. Shooting history and presence of high-frequency hearing impairment in swedish hunters: A cross-sectional internet-based observational study.

    PubMed

    Honeth, Louise; Ström, Peter; Ploner, Alexander; Bagger-Sjöbäck, Dan; Rosenhall, Ulf; Nyrén, Olof

    2015-01-01

    The aim of this cross-sectional study among Swedish hunters was to examine the association between shooting history and presence of high-frequency hearing impairment (HFHI). All hunters registered with an e-mail address in the membership roster of the Swedish Hunters' Association were invited via e-mail to a secure website with a questionnaire and an Internet-based audiometry test. Associations, expressed as prevalence ratio (PR), were multivariately modelled using Poisson regression. The questionnaire was answered by 1771 hunters (age 11-91 years), and 202 of them also completed the audiometry test. Subjective severe hearing loss was reported by 195/1771 (11%), while 23/202 (11%) exhibited HFHI upon testing with Internet-based audiometry. As many as 328/1771 (19%) had never used hearing protection during hunting. In the preceding 5 years, 785/1771 (45%), had fired >6 unprotected gunshots with hunting rifle calibers. The adjusted PR of HFHI when reporting 1-6 such shots, relative to 0, was 1.5 [95% confidence interval (CI) 1.1-2.1; P = 0.02]. We could not verify any excessive HFHI prevalence among 89 hunters reporting unprotected exposure to such gunshot noise >6 times. Nor did the total number of reported rifle shots seem to matter. These findings support the notion of a wide variation in individual susceptibility to impulse noise; that significant sound energy, corresponding to unprotected noise from hunting rifle calibers, seems to be required; that susceptible individuals may sustain irreversible damage to the inner ear from just one or a few shots; and that use of hearing protection should be encouraged from the first shot with such weapons.

  6. Greater default-mode network abnormalities compared to high order visual processing systems in amnestic mild cognitive impairment: an integrated multi-modal MRI study.

    PubMed

    Sala-Llonch, Roser; Bosch, Beatriz; Arenaza-Urquijo, Eider M; Rami, Lorena; Bargalló, Núria; Junqué, Carme; Molinuevo, José-Luis; Bartrés-Faz, David

    2010-01-01

    We conducted an integrated multi-modal magnetic resonance imaging (MRI) study based on functional MRI (fMRI) data during a complex but cognitively preserved visual task in 15 amnestic mild cognitive impairment (a-MCI) patients and 15 Healthy Elders (HE). Independent Component Analysis of fMRI data identified a functional network containing an Activation Task Related Pattern (ATRP), including regions of the dorsal and ventral visual stream, and a Deactivation Task Related Pattern network (DTRP), with high spatial correspondence with the default-mode network (DMN). Gray matter (GM) volumes of the underlying ATRP and DTRP cortical areas were measured, and probabilistic tractography (based on diffusion MRI) identified fiber pathways within each functional network. For the ATRP network, a-MCI patients exhibited increased fMRI responses in inferior-ventral visual areas, possibly reflecting compensatory activations for more compromised dorsal regions. However, no significant GM or white matter group differences were observed within the ATRP network. For the DTRP/DMN, a-MCI showed deactivation deficits and reduced GM volumes in the posterior cingulate/precuneus, excessive deactivations in the inferior parietal lobe, and less fiber tract integrity in the cingulate bundles. Task performance correlated with DTRP-functionality in the HE group. Besides allowing the identification of functional reorganizations in the cortical network directly processing the task-stimuli, these findings highlight the importance of conducting integrated multi-modal MRI studies in MCI based on spared cognitive domains in order to identify functional abnormalities in critical areas of the DMN and their precise anatomical substrates. These latter findings may reflect early neuroimaging biomarkers in dementia.

  7. Vibrotactile Presentation of Musical Notes to the Glabrous Skin for Adults with Normal Hearing or a Hearing Impairment: Thresholds, Dynamic Range and High-Frequency Perception

    PubMed Central

    Maté-Cid, Saúl; Fulford, Robert; Seiffert, Gary; Ginsborg, Jane

    2016-01-01

    Presentation of music as vibration to the skin has the potential to facilitate interaction between musicians with hearing impairments and other musicians during group performance. Vibrotactile thresholds have been determined to assess the potential for vibrotactile presentation of music to the glabrous skin of the fingertip, forefoot and heel. No significant differences were found between the thresholds for sinusoids representing notes between C1 and C6 when presented to the fingertip of participants with normal hearing and with a severe or profound hearing loss. For participants with normal hearing, thresholds for notes between C1 and C6 showed the characteristic U-shape curve for the fingertip, but not for the forefoot and heel. Compared to the fingertip, the forefoot had lower thresholds between C1 and C3, and the heel had lower thresholds between C1 and G2; this is attributed to spatial summation from the Pacinian receptors over the larger contactor area used for the forefoot and heel. Participants with normal hearing assessed the perception of high-frequency vibration using 1s sinusoids presented to the fingertip and were found to be more aware of transient vibration at the beginning and/or end of notes between G4 and C6 when stimuli were presented 10dB above threshold, rather than at threshold. An average of 94% of these participants reported feeling continuous vibration between G4 and G5 with stimuli presented 10dB above threshold. Based on the experimental findings and consideration of health effects relating to vibration exposure, a suitable range of notes for vibrotactile presentation of music is identified as being from C1 to G5. This is more limited than for human hearing but the fundamental frequencies of the human voice, and the notes played by many instruments, lie within it. However, the dynamic range might require compression to avoid the negative effects of amplitude on pitch perception. PMID:27191400

  8. Low MMP-8/TIMP-1 reflects left ventricle impairment in takotsubo cardiomyopathy and high TIMP-1 may help to differentiate it from acute coronary syndrome

    PubMed Central

    Parkkonen, Olavi; Nieminen, Mikko T.; Vesterinen, Paula; Tervahartiala, Taina; Perola, Markus; Salomaa, Veikko; Jousilahti, Pekka; Sorsa, Timo; Pussinen, Pirkko J.; Sinisalo, Juha

    2017-01-01

    Background Matrix metalloproteinase 8 (MMP-8) is the most potent type-I collagen protease. Such collagen mainly constitutes the transient fibrosis in takotsubo cardiomyopathy (TTC) endomyocardial biopsies. High MMP-8 and tissue-inhibitor of matrix metalloproteinase-1 (TIMP-1) levels are implicated in acute coronary syndrome (ACS). We compared MMP-8 and TIMP-1 levels in consecutive TTC and ACS patients, and their association to TTC severity. Methods and results In 45 acute serum samples of TTC, 2072 ACS and 1000 controls, TIMP-1 differed between ACS 146.7ng/mL (115.0–186.3) (median (interquartile range)), TTC 115.7 (94.3–137.7) and controls 80.9 (73.2–90.4), (p<0.0001). MMP-8 levels were similar between ACS and TTC. In receiver-operating characteristics analysis, TIMP-1 differentiated TTC from ACS with an area under the curve (AUC) of 0.679 (p<0.0001) surpassing troponin T (TnT) at 0.522 (p = 0.66). Compared to other differing factors (age, sex, smoking), TIMP-1 improved diagnostic specificity and sensitivity from AUC of 0.821 to 0.844 (p = 0.007). The MMP8/TIMP-1 molar ratio differentiated normal ejection fraction (EF) at 0.27 (0.13–0.51) from decreased EF<50% at 0.08 (0.05–0.20), (p = 0.04) in TTC, but not in ACS. Conclusions Even with other differing factors considered, TIMP-1 differentiated TTC from ACS better than TnT. In TTC, the low MMP-8/TIMP-1 molar ratio may reflect decreased proteolysis and increased transient fibrosis, perhaps in part explaining the left-ventricle impairment. PMID:28278213

  9. Effects of rosglitazone on plasma adiponectin, insulin sensitivity, and insulin secretion in high-risk African Americans with impaired glucose tolerance test and type 2 diabetes.

    PubMed

    Osei, Kwame; Gaillard, Trudy; Kaplow, June; Bullock, Matthew; Schuster, Dara

    2004-12-01

    We examined the metabolic effects of rosiglitazone therapy on glucose control, insulin sensitivity, insulin secretion, and adiponectin in first-degree relatives of African Americans with type 2 diabetes (DM) with impaired glucose tolerance (IGT) and DM for 3 months. The study was comprised of 12 first-degree relatives with IGT, 17 newly diagnosed DM, and 19 healthy relatives with normal glucose tolerance (NGT). Oral glucose tolerance test (OGTT) was performed before and after 3 months of rosiglitazone therapy (4 to 8 mg/d) in patients with IGT and DM. Serum glucose, insulin, C-peptide, and adiponectin levels were measured before and 2 hours during OGTT in the NGT and patients with IGT and DM. Insulin resistance index (HOMA-IR) and beta-cell function (HOMA-%B) were calculated in each subject using homeostasis model assessment (HOMA). Rosglitazone improved the overall glycemic control in the IGT and DM groups. Following rosiglitazone, the beta-cell secretion remained unchanged, while HOMR-IR was reduced in DM by 30% (4.12 +/- 1.95 v 6.33 +/- 3.54, P < .05) and the IGT group (3.78 +/- 2.45 v 4.81 +/- 3.49, P = not significant [NS]). Mean plasma adiponectin levels were significantly (P < .05) lower in the DM (6.74 +/- 1.95 microg/mL) when compared with the NGT group(9.61 +/- 5.09). Rosiglitazone significantly (P < .001) increased adiponectin levels by 2-fold in patients with IGT (22.2 +/- 10.97 microg/mL) and 2.5-fold greater in DM (15.68 +/- 8.23 microg/mL) at 3 months when compared with the 0 month. We conclude that adiponectin could play a significant role (1) in the pathogenesis of IGT and DM and (2) the beneficial metabolic effects of thiazolidinediones (TZDs) in high-risk African American patients.

  10. Cognitive impairments in progression of Parkinson's disease.

    PubMed

    Stepkina, D A; Zakharov, V V; Yakhno, N N

    2010-01-01

    A total of 88 patients with progression of Parkinson's disease (PD) were studied. Cognitive impairments (CI) in PD were in most cases progressive in nature, predominantly because of increases in the severity of dysregulatory and neurodynamic disorders, impairments to visuospatial functions, and, in some cases, deficits in nominative speech function. A high frequency of transformation of moderate cognitive impairments to dementia was demonstrated over periods of 2-5 years. Predictors of the progression of CI in PD were identified: elderly age, later onset of disease, and the severity of PD. The greatest rate of progression of CI was seen in patients with initially more severe impairments of regulatory and visuospatial functions.

  11. High frequency of diabetes and impaired fasting glucose in patients with glucose-6-phosphate dehydrogenase deficiency in the Western brazilian Amazon.

    PubMed

    Santana, Marli S; Monteiro, Wuelton M; Costa, Mônica R F; Sampaio, Vanderson S; Brito, Marcelo A M; Lacerda, Marcus V G; Alecrim, Maria G C

    2014-07-01

    Glucose-6-phosphate dehydrogenase (G6PD) deficiency is one of the most common human genetic abnormalities, and it has a significant prevalence in the male population (X chromosome linked). The purpose of this study was to estimate the frequency of impaired fasting glucose and diabetes among G6PD-deficient persons in Manaus, Brazil, an area in the Western Brazilian Amazon to which malaria is endemic. Glucose-6-phosphate dehydrogenase-deficient males had more impaired fasting glucose and diabetes. This feature could be used as a screening tool for G6PD-deficient persons who are unable to use primaquine for the radical cure of Plasmodium vivax malaria.

  12. A combination of high stress-induced tense and energetic arousal compensates for impairing effects of stress on memory retrieval in men.

    PubMed

    Boehringer, Andreas; Schwabe, Lars; Schachinger, Hartmut

    2010-09-01

    Stress can both impair and enhance memory retrieval. Glucocorticoids mediate impairing effects of stress on memory retrieval. Little is known, however, about factors that facilitate post-stress memory performance. Here, we asked whether stress-induced arousal mediates facilitative stress effects on memory retrieval. Two arousal dimensions were separated: tense arousal, which is characterized by feelings ranging from tension and anxiety to calmness and quietness, and energetic arousal, which is associated with feelings ranging from energy and vigor to states of fatigue and tiredness. Fifty-one men (mean age +/- SEM: 24.57 +/- 0.61 years) learned emotional and neutral words. Memory for these words was tested 165 min later, after participants were exposed to a psychosocial stress or a non-arousing control condition. Changes in heart rate, self-reported (energetic and tense) arousal, and saliva cortisol in response to the stress/control condition were measured. Overall, stress impaired memory retrieval. However, stressed participants with large increases in both tense and energetic arousal performed comparably to controls. Neither salivary cortisol level nor autonomic arousal predicted memory performance after controlling for changes in energetic and tense arousal. The present data indicate that stress-induced concurrent changes in tense and energetic arousal can compensate for impairing effects of stress on memory retrieval. This finding could help to explain some of the discrepancies in the literature on stress and memory.

  13. Using Early Standardized Language Measures to Predict Later Language and Early Reading Outcomes in Children at High Risk for Language-Learning Impairments

    ERIC Educational Resources Information Center

    Flax, Judy F.; Realpe-Bonilla, Teresa; Roesler, Cynthia; Choudhury, Naseem; Benasich, April

    2009-01-01

    The aim of the study was to examine the profiles of children with a family history (FH+) of language-learning impairments (LLI) and a control group of children with no reported family history of LLI (FH-) and identify which language constructs (receptive or expressive) and which ages (2 or 3 years) are related to expressive and receptive language…

  14. Carnitine protects the nematode Caenorhabditis elegans from glucose-induced reduction of survival depending on the nuclear hormone receptor DAF-12.

    PubMed

    Deusing, Dorothé Jenni; Beyrer, Melanie; Fitzenberger, Elena; Wenzel, Uwe

    2015-05-08

    Besides its function in transport of fatty acids into mitochondria in order to provide substrates for β-oxidation, carnitine has been shown to affect also glucose metabolism and to inhibit several mechanisms associated with diabetic complications. In the present study we used the mev-1 mutant of the nematode Caenorhabditis elegans fed on a high glucose concentration in liquid media as a diabetes model and tested the effects of carnitine supplementation on their survival under heat-stress. Carnitine at 100 μM completely prevented the survival reduction that was caused by the application of 10 mM glucose. RNA-interference for sir-2.1, a candidate genes mediating the effects of carnitine revealed no contribution of the sirtuin for the rescue of survival. Under daf-12 RNAi rescue of survival by carnitine was abolished. RNA-interference for γ-butyrobetaine hydroxylase 2, encoding the key enzyme for carnitine biosynthesis did neither increase glucose toxicity nor prevent the rescue of survival by carnitine, suggesting that the effects of carnitine supplementation on carnitine levels were significant. Finally, it was demonstrated that neither the amount of lysosomes nor the proteasomal activity were increased by carnitine, excluding that protein degradation pathways, such as autophagy or proteasomal degradation, are involved in the protective carnitine effects. In conclusion, carnitine supplementation prevents the reduction of survival caused by glucose in C. elegans in dependence on a nuclear hormone receptor which displays high homologies to the vertebrate peroxisomal proliferator activated receptors.

  15. Cooperation between HMGA1, PDX-1, and MafA is Essential for Glucose-Induced Insulin Transcription in Pancreatic Beta Cells

    PubMed Central

    Arcidiacono, Biagio; Iiritano, Stefania; Chiefari, Eusebio; Brunetti, Francesco S.; Gu, Guoqiang; Foti, Daniela Patrizia; Brunetti, Antonio

    2014-01-01

    The high-mobility group AT-hook 1 (HMGA1) protein is a nuclear architectural factor that can organize chromatin structures. It regulates gene expression by controlling the formation of stereospecific multiprotein complexes called “enhanceosomes” on the AT-rich regions of target gene promoters. Previously, we reported that defects in HMGA1 caused decreased insulin receptor expression and increased susceptibility to type 2 diabetes mellitus in humans and mice. Interestingly, mice with disrupted HMGA1 gene had significantly smaller islets and decreased insulin content in their pancreata, suggesting that HMGA1 may have a direct role in insulin transcription and secretion. Herein, we investigate the regulatory roles of HMGA1 in insulin transcription. We provide evidence that HMGA1 physically interacts with PDX-1 and MafA, two critical transcription factors for insulin gene expression and beta-cell function, both in vitro and in vivo. We then show that the overexpression of HMGA1 significantly improves the transactivating activity of PDX-1 and MafA on human and mouse insulin promoters, while HMGA1 knockdown considerably decreased this transactivating activity. Lastly, we demonstrate that high glucose stimulus significantly increases the binding of HMGA1 to the insulin (INS) gene promoter, suggesting that HMGA1 may act as a glucose-sensitive element controlling the transcription of the INS gene. Together, our findings provide evidence that HMGA1, by regulating PDX-1- and MafA-induced transactivation of the INS gene promoter, plays a critical role in pancreatic beta-cell function and insulin production. PMID:25628604

  16. Infection with a Mouse-Adapted Strain of the 2009 Pandemic Virus Causes a Highly Severe Disease Associated with an Impaired T Cell Response

    PubMed Central

    Meunier, Isabelle; Morisseau, Olivier; Garneau, Émilie; Marois, Isabelle; Cloutier, Alexandre; Richter, Martin V.

    2015-01-01

    Despite a relatively low fatality rate, the 2009 H1N1 pandemic virus differed from other seasonal viruses in that it caused mortality and severe pneumonia in the young and middle-aged population (18–59 years old). The mechanisms underlying this increased disease severity are still poorly understood. In this study, a human isolate of the 2009 H1N1 pandemic virus was adapted to the mouse (MAp2009). The pathogenicity of the MAp2009 virus and the host immune responses were evaluated in the mouse model and compared to the laboratory H1N1 strain A/Puerto Rico/8/1934 (PR8). The MAp2009 virus reached consistently higher titers in the lungs over 14 days compared to the PR8 virus, and caused severe disease associated with high morbidity and 85% mortality rate, contrasting with the 0% death rate in the PR8 group. During the early phase of infection, both viruses induced similar pathology in the lungs. However, MAp2009-induced lung inflammation was sustained until the end of the study (day 14), while there was no sign of inflammation in the PR8-infected group by day 10. Furthermore, at day 3 post-infection, MAp2009 induced up to 10- to 40-fold more cytokine and chemokine gene expression, respectively. More importantly, the numbers of CD4+ T cells and virus-specific CD8+ T cells were significantly lower in the lungs of MAp2009-infected mice compared to PR8-infected mice. Interestingly, there was no difference in the number of dendritic cells in the lung and in the draining lymph node. Moreover, mice infected with PR8 or MAp2009 had similar numbers of CCR5 and CXCR3-expressing T cells, suggesting that the impaired T cell response was not due to a lack of chemokine responsiveness or priming of T cells. This study demonstrates that a mouse-adapted virus from an isolate of the 2009 pandemic virus interferes with the adaptive immune response leading to a more severe disease. PMID:26381265

  17. Are fetal growth impairment and preterm birth causally related to child attention problems and ADHD? Evidence from a comparison between high-income and middle-income cohorts

    PubMed Central

    Murray, Elizabeth; Pearson, Rebecca; Fernandes, Michelle; Santos, Iná S; Barros, Fernando C; Victora, Cesar G; Stein, Alan; Matijasevich, Alicia

    2016-01-01

    Background Cross-cohort comparison is an established method for improving causal inference. This study compared 2 cohorts, 1 from a high-income country and another from a middle-income country, to (1) establish whether birth exposures may play a causal role in the development of childhood attention problems; and (2) identify whether confounding structures play a different role in parent-reported attention difficulties compared with attention deficit hyperactivity disorder (ADHD) diagnoses. Methods Birth exposures included low birth weight (LBW), small-for-gestational age (SGA), small head circumference (HC) and preterm birth (PTB)). Outcomes of interest were attention difficulties (Strengths and Difficulties Questionnaire, SDQ) and ADHD (Development and Well-Being Assessment, DAWBA). Associations between exposures and outcomes were compared between 7-year-old children from the Avon Longitudinal Study of Parents and Children (ALSPAC) in the UK (N=6849) and the 2004 Pelotas cohort in Brazil (N=3509). Results For attention difficulties (SDQ), the pattern of association with birth exposures was similar between cohorts: following adjustment, attention difficulties were associated with SGA (OR=1.59, 95% CI 1.20 to 2.19) and small HC (OR=1.64, 95% CI 1.11 to 2.41) in ALSPAC and SGA (OR=1.35, 95% CI 1.04 to 1.75) in Pelotas. For ADHD, however, the pattern of association following adjustment differed markedly between cohorts. In ALSPAC, ADHD was associated with LBW (OR=2.29, 95% CI 1.09 to 4.80) and PTB (OR=2.33, 95% CI 1.23 to 4.42). In the Pelotas cohort, however, ADHD was associated with SGA (OR=1.69, 95% CI 1.02 to 2.82). Conclusions The findings suggest that fetal growth impairment may play a causal role in the development of attention difficulties in childhood, as similar associations were identified across both cohorts. Confounding structures, however, appear to play a greater role in determining whether a child meets the full diagnostic criteria for ADHD. PMID

  18. A high-salt diet further impairs age-associated declines in cognitive, behavioral, and cardiovascular functions in male Fischer brown Norway rats.

    PubMed

    Chugh, Gaurav; Asghar, Mohammad; Patki, Gaurav; Bohat, Ritu; Jafri, Faizan; Allam, Farida; Dao, An T; Mowrey, Christopher; Alkadhi, Karim; Salim, Samina

    2013-09-01

    Aging-associated declines in cognitive, emotional, and cardiovascular function are well known. Environmental stress triggers critical changes in the brain, further compromising cardiovascular and behavioral health during aging. Excessive dietary salt intake is one such stressor. Here, we tested the effect of high salt (HS) on anxiety, learning-memory function, and blood pressure (BP) in male Fischer brown Norway (FBN) rats. Adult (A; 2 mo) and old (O; 20 mo) male rats were fed normal-salt (NS; 0.4% NaCl) or HS (8% NaCl) diets for 4 wk after being implanted with telemeter probes for conscious BP measurement. Thereafter, tests to assess anxiety-like behavior and learning-memory were conducted. The rats were then killed, and samples of plasma, urine, and brain tissue were collected. We found that systolic BP was higher in O-NS (117 ± 1.2 mm Hg) than in A-NS (105 ± 0.8 mm Hg) rats (P < 0.05). Furthermore, BP was higher in O-HS (124 ± 1.4 mm Hg) than in O-NS (117 ± 1.2 mm Hg) rats (P < 0.05). Moreover, anxiety-like behavior (light-dark and open-field tests) was not different between A-NS and O-NS rats but was greater in O-HS rats than in A-NS, O-NS, or A-HS rats (P < 0.05). Short-term memory (radial arm water maze test) was similar in A-NS and O-NS rats but was significantly impaired in O-HS rats compared with A-NS, O-NS, or A-HS rats (P < 0.05). Furthermore, oxidative stress variables (in plasma, urine, and brain) as well as corticosterone (plasma) were greater in O-HS rats when compared with A-NS, O-NS, or A-HS rats (P < 0.05). The antioxidant enzyme glyoxalase-1 expression was selectively reduced in the hippocampus and amygdala of O-HS rats compared with A-NS, O-NS, or A-HS rats (P < 0.05), whereas other antioxidant enzymes, glutathione reductase 1, manganese superoxide dismutase (SOD), and Cu/Zn SOD remained unchanged. We suggest that salt-sensitive hypertension and behavioral derangement are associated with a redox imbalance in the brain of aged FBN rats.

  19. Prevalence and pattern of neuropsychological impairment in human immunodeficiency virus-infected/acquired immunodeficiency syndrome (HIV/AIDS) patients across pre- and post-highly active antiretroviral therapy eras: a combined study of two cohorts.

    PubMed

    Cysique, Lucette A; Maruff, Paul; Brew, Bruce J

    2004-12-01

    The objective of this study was to assess the prevalence and pattern of neuropsychological impairment in cohorts of human immunodeficiency virus (HIV)-infected individuals across pre- and post-HAART (highly active antiretroviral therapy) eras. Two cohorts of HIV-infected individuals attending tertiary referral hospital outpatient clinics were studied. The cohorts represented two eras of antiretroviral medication: monotherapy (n = 51) and HAART (n = 90). Each was compared in nine neuropsychological domains in regard to the prevalence as well as pattern of neuropsychological impairment. Because the authors intended to characterize the prevalence and pattern of neuropsychological deficits in nondemented advanced HIV-infected individuals, patients with a current diagnosis of acquired immunodeficiency syndrome (AIDS) dementia complex were not included. The prevalence of impairment was not significantly different across pre-HAART and HAART eras using a standard criterion to define impairment: -2 SD in two neuropsychological measures (41.1%/38.8%). Prevalence of deficits was not significantly reduced in patients with undetectable plasma viral load. The pattern of neuropsychological impairment was different across pre-HAART and HAART eras, with an improvement in attention, verbal fluency, visuoconstruction deficits, but a deterioration in learning efficiency and complex attention. This change remained even in patients with an undetectable plasma viral load, although the severity was partially diminished. Neuropsychological deficits remain common in the HAART era, essentially uninfluenced by HAART. The finding that some neuropsychological functions are improving while other are deteriorating indicates that these deficits do not reflect "burnt out" damage but rather that there is an active intracerebral process occurring, the nature of which is still to be determined.

  20. Osteocalcin protects pancreatic beta cell function and survival under high glucose conditions

    SciTech Connect

    Kover, Karen; Yan, Yun; Tong, Pei Ying; Watkins, Dara; Li, Xiaoyu; Tasch, James; Hager, Melissa; Clements, Mark; Moore, Wayne V.

    2015-06-19

    Diabetes is characterized by progressive beta cell dysfunction and loss due in part to oxidative stress that occurs from gluco/lipotoxicity. Treatments that directly protect beta cell function and survival in the diabetic milieu are of particular interest. A growing body of evidence suggests that osteocalcin, an abundant non-collagenous protein of bone, supports beta cell function and proliferation. Based on previous gene expression data by microarray, we hypothesized that osteocalcin protects beta cells from glucose-induced oxidative stress. To test our hypothesis we cultured isolated rat islets and INS-1E cells in the presence of normal, high, or high glucose ± osteocalcin for up to 72 h. Oxidative stress and viability/mitochondrial function were measured by H{sub 2}O{sub 2} assay and Alamar Blue assay, respectively. Caspase 3/7 activity was also measured as a marker of apoptosis. A functional test, glucose stimulated insulin release, was conducted and expression of genes/protein was measured by qRT-PCR/western blot/ELISA. Osteocalcin treatment significantly reduced high glucose-induced H{sub 2}O{sub 2} levels while maintaining viability/mitochondrial function. Osteocalcin also significantly improved glucose stimulated insulin secretion and insulin content in rat islets after 48 h of high glucose exposure compared to untreated islets. As expected sustained high glucose down-regulated gene/protein expression of INS1 and BCL2 while increasing TXNIP expression. Interestingly, osteocalcin treatment reversed the effects of high glucose on gene/protein expression. We conclude that osteocalcin can protect beta cells from the negative effects of glucose-induced oxidative stress, in part, by reducing TXNIP expression, thereby preserving beta cell function and survival. - Highlights: • Osteocalcin reduces glucose-induced oxidative stress in beta cells. • Osteocalcin preserves beta cell function and survival under stress conditions. • Osteocalcin reduces glucose-induced

  1. miR-146a regulates glucose induced upregulation of inflammatory cytokines extracellular matrix proteins in the retina and kidney in diabetes

    PubMed Central

    Chen, Shali; Feng, Biao; Thomas, Anu Alice

    2017-01-01

    Hyperglycemic damage to the endothelial cells (ECs) leads to increased synthesis of inflammatory cytokines. We have previously shown miR-146a downregulation in ECs and in the tissues of diabetic mice. Here we investigated the role of miR-146a, in the production of specific inflammatory cytokines and extracellular matrix (ECM) proteins in retina and kidneys in diabetes. We generated an endothelial specific miR-146a overexpressing transgenic mice (TG). We investigated these mice and wild type (WT) controls with or without streptozotocin (STZ) induced diabetes. Retinal and renal cortical tissues from the mice were examined for mRNAs for specific inflammatory markers, (ECM) proteins and inflammation inducible transcription factor by real time RT-PCR. Corresponding proteins, where possible, were examined using immunofluorescence or ELISA. In parallel, we examined ECs following incubation with various levels of glucose with or without miR-146a mimic transfection. In the retina and kidneys of WT mice with diabetes, increased expression of inflammatory markers (IL-6, TNFα, IL1β) in association augmented expression of ECM proteins (collagen 1αIV, fibronectin) and NF κB-P65 were observed, compared to WT non-diabetic controls. These changes were prevented in diabetic miR-146a TG mice along with retinal and renal functional and structural changes. In vitro studies showed similar changes in the ECs exposed to high glucose. Such changes were corrected in the cells following miR-146a mimic transfection. Further analyses of renal cortical tissues showed diabetes induced significant upregulation of two regulators of NFκB, namely Interleukin-1 associated Kinase 1 and tumour necrosis factor receptor associated factor. Such changes were prevented in diabetic TG animals. These data indicate that augmented production of inflammatory cytokines and ECM proteins in the retina and kidneys in diabetes are regulated through endothelium derived miR-146a. Identification of such novel

  2. Education for the Hearing Impaired (Auditorily Impaired).

    ERIC Educational Resources Information Center

    World Federation of the Deaf, Rome (Italy).

    Education for the hearing impaired is discussed in nine conference papers. J. N. Howarth describes "The Education of Deaf Children in Schools for Hearing Pupils in the United Kingdom" and A.I.Dyachkov of the U.S.S.R. outlines Didactical Principles of Educating the Deaf in the Light of their Rehabilitation Goal." Seven papers from…

  3. Development or Impairment?

    ERIC Educational Resources Information Center

    Hakansson, Gisela

    2010-01-01

    Joanne Paradis' Keynote Article on bilingualism and specific language impairment (SLI) is an impressive overview of research in language acquisition and language impairment. Studying different populations is crucial both for theorizing about language acquisition mechanisms, and for practical purposes of diagnosing and supporting children with…

  4. The Impact of Visual Impairment on Perceived School Climate

    ERIC Educational Resources Information Center

    Schade, Benjamin; Larwin, Karen H.

    2015-01-01

    The current investigation examines whether visual impairment has an impact on a student's perception of the school climate. Using a large national sample of high school students, perceptions were examined for students with vision impairment relative to students with no visual impairments. Three factors were examined: self-reported level of…

  5. Vascular Cognitive Impairment.

    PubMed

    Dichgans, Martin; Leys, Didier

    2017-02-03

    Cerebrovascular disease typically manifests with stroke, cognitive impairment, or both. Vascular cognitive impairment refers to all forms of cognitive disorder associated with cerebrovascular disease, regardless of the specific mechanisms involved. It encompasses the full range of cognitive deficits from mild cognitive impairment to dementia. In principle, any of the multiple causes of clinical stroke can cause vascular cognitive impairment. Recent work further highlights a role of microinfarcts, microhemorrhages, strategic white matter tracts, loss of microstructural tissue integrity, and secondary neurodegeneration. Vascular brain injury results in loss of structural and functional connectivity and, hence, compromise of functional networks within the brain. Vascular cognitive impairment is common both after stroke and in stroke-free individuals presenting to dementia clinics, and vascular pathology frequently coexists with neurodegenerative pathology, resulting in mixed forms of mild cognitive impairment or dementia. Vascular dementia is now recognized as the second most common form of dementia after Alzheimer's disease, and there is increasing awareness that targeting vascular risk may help to prevent dementia, even of the Alzheimer type. Recent advances in neuroimaging, neuropathology, epidemiology, and genetics have led to a deeper understanding of how vascular disease affects cognition. These new findings provide an opportunity for the present reappraisal of vascular cognitive impairment. We further briefly address current therapeutic concepts.

  6. Defining Neurocognitive Impairment in HIV: Deficit Scores versus Clinical Ratings

    PubMed Central

    Blackstone, K.; Moore, D. J.; Franklin, D. R.; Clifford, D. B.; Collier, A. C.; Marra, C. M.; Gelman, B. B.; McArthur, J. C.; Morgello, S.; Simpson, D. M.; Ellis, R. J.; Atkinson, J. H.; Grant, I.; Heaton, R. K.

    2012-01-01

    Background Because HIV-related neurocognitive impairment is usually mild and variable, clinical ratings (CR) and global deficit scores (GDS) are recommended for detecting HIV-associated neurocognitive disorders (HAND). The CR-approach requires impairment in at least two ability domains; GDS considers number and severity of impairments across all measures. We examined classification agreement and clinical correlates of the two methods. Method Neurocognitive functioning of 1574 HIV-infected participants was assessed via a comprehensive, seven-domain neuropsychological battery. Global neurocognitive impairment was defined for each participant independently by CR and GDS. Participants were classified into four categories (Dually-normal, impaired by CR-only, impaired by GDS-only, or Dually-impaired). Results There was 83% concordance between CR and GDS classifications; in total, 56% of participants were deemed impaired by CR and 41% were classified as impaired by GDS. Impairment by GDS virtually guaranteed CR impairment, but 16% of participants were additionally classified as impaired only by CR. As compared to Dually-normal participants, those classified as Dually and CR-only impaired were more likely to have AIDS, have more severe co-occurring conditions, have more severe depressive symptoms, be unemployed, and have more everyday functioning complaints (ps < 0.05). Conclusion Impairment classifications of the two methods were in high agreement; however, more people were classified as impaired using the CR-approach compared to the GDS approach, and those impaired according to CR-only showed fewer neurocognitive and functional deficits than the Dually-impaired participants. The CR approach may be most appropriate for detecting more subtle forms of neurocognitive impairment. Clinicians and researchers should recognize the strengths and weaknesses of each method when evaluating neurocognitive complications in HIV. PMID:22708483

  7. Impairment in Non-Word Repetition: A Marker for Language Impairment or Reading Impairment?

    ERIC Educational Resources Information Center

    Baird, Gillian; Slonims, Vicky; Simonoff, Emily; Dworzynski, Katharina

    2011-01-01

    Aim: A deficit in non-word repetition (NWR), a measure of short-term phonological memory proposed as a marker for language impairment, is found not only in language impairment but also in reading impairment. We evaluated the strength of association between language impairment and reading impairment in children with current, past, and no language…

  8. Hearing or speech impairment - resources

    MedlinePlus

    Resources - hearing or speech impairment ... The following organizations are good resources for information on hearing impairment or speech impairment: Alexander Graham Bell Association for the Deaf and Hard of Hearing -- www.agbell. ...

  9. The visually impaired patient.

    PubMed

    Rosenberg, Eric A; Sperazza, Laura C

    2008-05-15

    Blindness or low vision affects more than 3 million Americans 40 years and older, and this number is projected to reach 5.5 million by 2020. In addition to treating a patient's vision loss and comorbid medical issues, physicians must be aware of the physical limitations and social issues associated with vision loss to optimize health and independent living for the visually impaired patient. In the United States, the four most prevalent etiologies of vision loss in persons 40 years and older are age-related macular degeneration, cataracts, glaucoma, and diabetic retinopathy. Exudative macular degeneration is treated with laser therapy, and progression of nonexudative macular degeneration in its advanced stages may be slowed with high-dose antioxidant and zinc regimens. The value of screening for glaucoma is uncertain; management of this condition relies on topical ocular medications. Cataract symptoms include decreased visual acuity, decreased color perception, decreased contrast sensitivity, and glare disability. Lifestyle and environmental interventions can improve function in patients with cataracts, but surgery is commonly performed if the condition worsens. Diabetic retinopathy responds to tight glucose control, and severe cases marked by macular edema are treated with laser photocoagulation. Vision-enhancing devices can help magnify objects, and nonoptical interventions include special filters and enhanced lighting.

  10. Sulforaphane Protects against High Cholesterol-Induced Mitochondrial Bioenergetics Impairments, Inflammation, and Oxidative Stress and Preserves Pancreatic β-Cells Function

    PubMed Central

    Tan, Kah Ni; Gotteland, Martin

    2017-01-01

    Cholesterol plays an important role in inducing pancreatic β-cell dysfunction, leading to an impaired insulin secretory response to glucose. This study aimed to determine the protective effects of sulforaphane, a natural isothiocyanate Nrf2-inducer, against cholesterol-induced pancreatic β-cells dysfunction, through molecular and cellular mechanisms involving mitochondrial bioenergetics. Sulforaphane prevented cholesterol-induced alterations in the coupling efficiency of mitochondrial respiration, improving ATP turnover and spare capacity, and averted the impairment of the electron flow at complexes I, II, and IV. Sulforaphane also attenuated the cholesterol-induced activation of the NFκB pathway, normalizing the expression of pro- and anti-inflammatory cytokines. In addition, it also inhibited the decrease in sirtuin 1 expression and greatly increased Pgc-1α expression in Min6 cells. Sulforaphane increased the expression of antioxidant enzymes downstream of the Nrf2 pathway and prevented lipid peroxidation induced by cholesterol. The antioxidant and anti-inflammatory properties of sulforaphane and its ability to protect and improve mitochondrial bioenergetic function contribute to its protective action against cholesterol-induced pancreatic β-cell dysfunction. Our data provide a scientifically tested foundation upon which sulforaphane can be developed as nutraceutical to preserve β-cell function and eventually control hyperglycemia. PMID:28386307

  11. Speech impairment (adult)

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/003204.htm Speech impairment (adult) To use the sharing features on ... 2017, A.D.A.M., Inc. Duplication for commercial use must be authorized in writing by ADAM ...

  12. Kids' Quest: Vision Impairment

    MedlinePlus

    ... most important job. Return to Steps World-Wide Web Search Kids Health: What is Vision Impairment What ... for the Blind (AFB) created the Braille Bug web site to teach sighted children about braille, and ...

  13. Evaluation of hearing impairment.

    PubMed

    Zadeh, M H; Selesnick, S H

    2001-01-01

    Hearing impairment is among the most common medical condition presenting to health care professionals. Ear anatomy, physiology, and pathology resulting in hearing loss are discussed. A systematic approach to evaluation, diagnosis, and treatment is presented.

  14. A Short-Term Incubation with High Glucose Impairs VASP Phosphorylation at Serine 239 in response to the Nitric Oxide/cGMP Pathway in Vascular Smooth Muscle Cells: Role of Oxidative Stress

    PubMed Central

    Russo, Isabella; Viretto, Michela; Doronzo, Gabriella; Barale, Cristina; Mattiello, Luigi; Anfossi, Giovanni; Trovati, Mariella

    2014-01-01

    A reduction of the nitric oxide (NO) action in vascular smooth muscle cells (VSMC) could play a role in the vascular damage induced by the glycaemic excursions occurring in diabetic patients; in this study, we aimed to clarify whether a short-term incubation of cultured VSMC with high glucose reduces the NO ability to increase cGMP and the cGMP ability to phosphorylate VASP at Ser-239. We observed that a 180 min incubation of rat VSMC with 25 mmol/L glucose does not impair the NO-induced cGMP increase but reduces VASP phosphorylation in response to both NO and cGMP with a mechanism blunted by antioxidants. We further demonstrated that high glucose increases radical oxygen species (ROS) production and that this phenomenon is prevented by the PKC inhibitor chelerythrine and the NADPH oxidase inhibitor apocynin. The following sequence of events is supported by these results: (i) in VSMC high glucose activates PKC; (ii) PKC activates NADPH oxidase; (iii) NADPH oxidase induces oxidative stress; (iv) ROS impair the signalling of cGMP, which is involved in the antiatherogenic actions of NO. Thus, high glucose, via oxidative stress, can reduce the cardiovascular protection conferred by the NO/cGMP pathway via phosphorylation of the cytoskeleton protein VASP in VSMC. PMID:24779009

  15. Occupational noise, smoking, and a high body mass index are risk factors for age-related hearing impairment and moderate alcohol consumption is protective: a European population-based multicenter study.

    PubMed

    Fransen, Erik; Topsakal, Vedat; Hendrickx, Jan-Jaap; Van Laer, Lut; Huyghe, Jeroen R; Van Eyken, Els; Lemkens, Nele; Hannula, Samuli; Mäki-Torkko, Elina; Jensen, Mona; Demeester, Kelly; Tropitzsch, Anke; Bonaconsa, Amanda; Mazzoli, Manuela; Espeso, Angeles; Verbruggen, Katia; Huyghe, Joke; Huygen, Patrick L M; Kunst, Sylvia; Manninen, Minna; Diaz-Lacava, Amalia; Steffens, Michael; Wienker, Thomas F; Pyykkö, Ilmari; Cremers, Cor W R J; Kremer, Hannie; Dhooge, Ingeborg; Stephens, Dafydd; Orzan, Eva; Pfister, Markus; Bille, Michael; Parving, Agnete; Sorri, Martti; Van de Heyning, Paul; Van Camp, Guy

    2008-09-01

    A multicenter study was set up to elucidate the environmental and medical risk factors contributing to age-related hearing impairment (ARHI). Nine subsamples, collected by nine audiological centers across Europe, added up to a total of 4,083 subjects between 53 and 67 years. Audiometric data (pure-tone average [PTA]) were collected and the participants filled out a questionnaire on environmental risk factors and medical history. People with a history of disease that could affect hearing were excluded. PTAs were adjusted for age and sex and tested for association with exposure to risk factors. Noise exposure was associated with a significant loss of hearing at high sound frequencies (>1 kHz). Smoking significantly increased high-frequency hearing loss, and the effect was dose-dependent. The effect of smoking remained significant when accounting for cardiovascular disease events. Taller people had better hearing on average with a more pronounced effect at low sound frequencies (<2 kHz). A high body mass index (BMI) correlated with hearing loss across the frequency range tested. Moderate alcohol consumption was inversely correlated with hearing loss. Significant associations were found in the high as well as in the low frequencies. The results suggest that a healthy lifestyle can protect against age-related hearing impairment.

  16. Occupational Noise, Smoking, and a High Body Mass Index are Risk Factors for Age-related Hearing Impairment and Moderate Alcohol Consumption is Protective: A European Population-based Multicenter Study

    PubMed Central

    Fransen, Erik; Topsakal, Vedat; Hendrickx, Jan-Jaap; Van Laer, Lut; Huyghe, Jeroen R.; Van Eyken, Els; Lemkens, Nele; Hannula, Samuli; Mäki-Torkko, Elina; Jensen, Mona; Demeester, Kelly; Tropitzsch, Anke; Bonaconsa, Amanda; Mazzoli, Manuela; Espeso, Angeles; Verbruggen, Katia; Huyghe, Joke; Huygen, Patrick L. M.; Kunst, Sylvia; Manninen, Minna; Diaz-Lacava, Amalia; Steffens, Michael; Wienker, Thomas F.; Pyykkö, Ilmari; Cremers, Cor W. R. J.; Kremer, Hannie; Dhooge, Ingeborg; Stephens, Dafydd; Orzan, Eva; Pfister, Markus; Bille, Michael; Parving, Agnete; Sorri, Martti; Van de Heyning, Paul

    2008-01-01

    A multicenter study was set up to elucidate the environmental and medical risk factors contributing to age-related hearing impairment (ARHI). Nine subsamples, collected by nine audiological centers across Europe, added up to a total of 4,083 subjects between 53 and 67 years. Audiometric data (pure-tone average [PTA]) were collected and the participants filled out a questionnaire on environmental risk factors and medical history. People with a history of disease that could affect hearing were excluded. PTAs were adjusted for age and sex and tested for association with exposure to risk factors. Noise exposure was associated with a significant loss of hearing at high sound frequencies (>1 kHz). Smoking significantly increased high-frequency hearing loss, and the effect was dose-dependent. The effect of smoking remained significant when accounting for cardiovascular disease events. Taller people had better hearing on average with a more pronounced effect at low sound frequencies (<2 kHz). A high body mass index (BMI) correlated with hearing loss across the frequency range tested. Moderate alcohol consumption was inversely correlated with hearing loss. Significant associations were found in the high as well as in the low frequencies. The results suggest that a healthy lifestyle can protect against age-related hearing impairment. Electronic supplementary material The online version of this article (doi: 10.1007/s10162-008-0123-1) contains supplementary material, which is available to authorized users. PMID:18543032

  17. Concentrations of alprazolam in blood from impaired drivers and forensic autopsies were not much different but showed a high prevalence of co-ingested illicit drugs.

    PubMed

    Jones, Alan Wayne; Holmgren, Anita

    2013-03-01

    Alprazolam is a benzodiazepine anxiolytic widely prescribed for treatment of panic-disorder and social phobias, although this medication is also subject to abuse. In this paper, the concentrations of alprazolam in venous blood samples from impaired drivers were compared with femoral blood samples from forensic autopsies classified as intoxication or other causes of death (e.g. natural, trauma). After liquid-liquid extraction (n-butyl acetate) alprazolam was determined in blood by capillary gas chromatography with a nitrogen-phosphorous detector. The mean (median) and range of alprazolam concentrations in blood from impaired drivers (n = 773) were 0.08 mg/L (0.05 mg/L) and 0.02-3.9 mg/L, respectively. Many traffic offenders had co-ingested ethanol (13%), amphetamine (46%), cannabis (32%), or heroin (14%), as well as other drugs. In deaths attributed to drug intoxication, the mean (median) and range of alprazolam concentrations in blood (n = 438) were 0.10 mg/L (0.06 mg/L) and 0.02-1.6 mg/L, respectively, which were not much different from other causes of death (n = 278); 0.08 mg/L (0.05 mg/L) and 0.02-0.9 mg/L. Median concentrations of alprazolam in blood from living and deceased persons did not seem to depend on the number of co-ingested substances. The result of this pharmacoepidemiological study suggests that alprazolam is a fairly innocent drug when used as monotherapy, but toxicity problems arise when co-ingested with illicit drugs and/or psychoactive medication.

  18. Trainable Mentally Impaired/Severely Multiply Impaired/Autistic Impaired/Severely Mentally Impaired. Product Evaluation Report 1989-1990.

    ERIC Educational Resources Information Center

    Claus, Richard N.; And Others

    The evaluation report describes special education services provided to trainable mentally impaired (TMI), autistic impaired (AI), severely multiply impaired (SXI), and severely mentally impaired (SMI) students at and through the Melvin G. Millet Learning Center (Bridgeport, Michigan). The eight program components are described individually and…

  19. Mandatory notification of impaired doctors.

    PubMed

    Beran, R G

    2014-12-01

    Mandatory reporting of impaired doctors is compulsory in Australasia. Australian Health Practitioner Regulation Agency guidelines for notification claim high benchmark though the Royal Australasian College of Surgeons and the Royal Australasian College of Physicians suggest they still obstruct doctors seeking help. Western Australia excludes mandatory reporting of practitioner-patients. This study examines reporting, consequences and international experiences with notification. Depressed doctors avoid diagnosis and treatment, fearing consequences, yet are more prone to marital problems, substance dependence and needing psychotherapy. South African research confirms isolation of impaired doctors and delayed seeking help with definable characteristics of those at risk. New Zealand data acknowledge: errors occur; questionable contribution from mandatory reporting; issues concerning competence assessment; favouring reporting to senior colleagues or self-intervention to compliance with mandatory reporting. UK found an anaesthetist guilty of professional misconduct for not reporting and sanctioned doctors regarding Harold Shipman. Australians are reluctant to report, fearing legalistic intrusion into care. Australian research confirmed definable characteristics for doctors with psychiatric illness or alcohol abuse. Exposure to legal medicine evokes personal disenchantment for doctors involved. Medicine poses barriers for impaired doctors. Spanish and UK doctors do not use general practitioners and may have suboptimal care. US and European doctors self-medicate using samples. US drug-dependent doctors also prescribe for spouses. Junior doctors are losing empathy with the profession. UK doctors favour private care, avoiding public scrutiny. NZ and Brazil created specific services for doctors, which appear effective. Mandatory reporting may be counterproductive requiring reappraisal.

  20. Social communication impairments: pragmatics.

    PubMed

    Russell, Robert L

    2007-06-01

    Social communication or pragmatic impairments are characterized and illustrated as involving inappropriate or ineffective use of language and gesture in social contexts. Three clinical vignettes illustrate different pragmatic impairments and the wealth of diagnostic information that can be garnered from observation of a child's social communication behavior. Definitions of, and developmental milestones in, domains of pragmatic competence are provided. Several screening instruments are suggested for use in assessing pragmatic competence within the time-frame of a pediatric examination. Frequent comorbid psychiatric conditions are described and a sample of current neurobiologic research is briefly summarized.

  1. Using early standardized language measures to predict later language and early reading outcomes in children at high risk for language-learning impairments.

    PubMed

    Flax, Judy F; Realpe-Bonilla, Teresa; Roesler, Cynthia; Choudhury, Naseem; Benasich, April

    2009-01-01

    The aim of the study was to examine the profiles of children with a family history (FH+) of language-learning impairments (LLI) and a control group of children with no reported family history of LLI (FH-) and identify which language constructs (receptive or expressive) and which ages (2 or 3 years) are related to expressive and receptive language abilities, phonological awareness, and reading abilities at ages 5 and 7 years. Participants included 99 children (40 FH+ and 59 FH-) who received a standardized neuropsychological battery at 2, 3, 5, and 7 years of age. As a group, the FH+ children had significantly lower scores on all language measures at 2 and 3 years, on selected language and phonological awareness measures at 5 years, and on phonological awareness and nonword reading at 7 years. Language comprehension at 3 years was the best predictor of later language and early reading for both groups. These results support past work suggesting that children with a positive family history of LLI are at greater risk for future language and reading problems through their preschool and early school-age years. Furthermore, language comprehension in the early years is a strong predictor of future language-learning status.

  2. Impairment of ovarian function and associated health-related abnormalities are attributable to low social status in premenopausal monkeys and not mitigated by a high-isoflavone soy diet

    PubMed Central

    Kaplan, J.R.; Chen, H.; Appt, S.E.; Lees, C.J.; Franke, A.A.; Berga, S.L.; Wilson, M.E.; Manuck, S.B.; Clarkson, T.B.

    2010-01-01

    BACKGROUND Psychological stress may impair premenopausal ovarian function and contribute to risk for chronic disease. Soy isoflavones may also influence ovarian function and affect health. Here, we report the effects of a psychological stressor (subordinate social status) and dietary soy on reproductive function and related health indices in female monkeys. We hypothesized that reproductive compromise and adverse health outcomes would be induced in subordinate when compared with dominant monkeys and be mitigated by exposure to soy. METHODS Subjects were 95 adult cynomolgus monkeys (Macaca fascicularis) housed in social groups of five or six. Animals consumed a soy-free, animal protein-based diet during an 8-month Baseline phase and then, during a 32-month Treatment phase, consumed either the baseline diet or an identical diet that substituted high-isoflavone soy protein for animal protein. RESULTS Across more than 1200 menstrual cycles, subordinate monkeys consistently exhibited ovarian impairment [increased cycle length (P < 0.02) and variability (P < 0.02) and reduced levels of progesterone (P < 0.04) and estradiol (P < 0.04)]. Subordinate status was confirmed behaviorally and was associated with elevated cortisol (P < 0.04) and relative osteopenia (P < 0.05). Consumption of the soy diet had no significant effects. CONCLUSIONS (i) Psychological stress adversely affects ovarian function and related health indices in a well-accepted animal model of women's health; (ii) Similar effects may extend to women experiencing reproductive impairment of psychogenic origin; (iii) soy protein and isoflavones neither exacerbate nor mitigate the effects of an adverse psychosocial environment; and (iv) this study was limited by an inability to investigate the genetic and developmental determinants of social status. PMID:20956266

  3. "They Think They Know What's Best for Me": An Interpretative Phenomenological Analysis of the Experience of Inclusion and Support in High School for Vision-Impaired Students with Albinism

    ERIC Educational Resources Information Center

    Thurston, Mhairi

    2014-01-01

    The challenges of social inclusion and access to the curriculum facing students with visual impairment in schools are well documented. The refreshed UK Vision Strategy (2013) seeks to improve education for students with vision impairment. In order to do this, it is important to understand how students with visual impairment experience education.…

  4. Emotionally Impaired Elementary Curriculum.

    ERIC Educational Resources Information Center

    Taulbee, Dianne R.; And Others

    A curriculum is presented for teaching emotionally impaired elementary students. The curriculum document describes program management techniques, strategies for developing and maintaining teacher-student relationships, and therapy/change systems. It outlines referral and eligibility procedures and exit criteria. It contains job descriptions for…

  5. Emotionally Impaired Elementary Curriculum.

    ERIC Educational Resources Information Center

    Taulbee, Dianne R.; And Others

    The Jackson County (Michigan) Intermediate School District curriculum for teaching emotionally impaired elementary students is presented. The curriculum document describes program management techniques, strategies for developing and maintaining teacher-student relationships, and therapy/change systems. It outlines referral and eligibility…

  6. Anarthria impairs subvocal counting.

    PubMed

    Cubelli, R; Nichelli, P; Pentore, R

    1993-12-01

    We studied subvocal counting in two pure anarthric patients. Analysis showed that they performed definitively worse than normal subjects free to articulate subvocally and their scores were in the lower bounds of the performances of subjects suppressing articulation. These results suggest that subvocal counting is impaired after anarthria.

  7. Specific Language Impairment

    MedlinePlus

    ... children with true language impairments. After studying a large group of Hispanic children who speak English as a ... trying out an intervention program with a small group of bilingual first graders with SLI to find techniques and strategies to help them succeed academically. Diagnostic ...

  8. Neurodegeneration Alters Metabolic Profile and Sirt 1 Signaling in High-Fat-Induced Obese Mice.

    PubMed

    Lima, Leandro Ceotto Freitas; Saliba, Soraya Wilke; Andrade, João Marcus Oliveira; Cunha, Maria Luisa; Cassini-Vieira, Puebla; Feltenberger, John David; Barcelos, Lucíola Silva; Guimarães, André Luiz Sena; de-Paula, Alfredo Mauricio Batista; de Oliveira, Antônio Carlos Pinheiro; Santos, Sérgio Henrique Sousa

    2016-05-16

    Different factors may contribute to the development of neurodegenerative diseases. Among them, metabolic syndrome (MS), which has reached epidemic proportions, has emerged as a potential element that may be involved in neurodegeneration. Furthermore, studies have shown the importance of the sirtuin family in neuronal survival and MS, which opens the possibility of new pharmacological targets. This study investigates the influence of sirtuin metabolic pathways by examining the functional capacities of glucose-induced obesity in an excitotoxic state induced by a quinolinic acid (QA) animal model. Mice were divided into two groups that received different diets for 8 weeks: one group received a regular diet, and the other group received a high-fat diet (HF) to induce MS. The animals were submitted to a stereotaxic surgery and subdivided into four groups: Standard (ST), Standard-QA (ST-QA), HF and HF-QA. The QA groups were given a 250 nL quinolinic acid injection in the right striatum and PBS was injected in the other groups. Obese mice presented with a weight gain of 40 % more than the ST group beyond acquiring an insulin resistance. QA induced motor impairment and neurodegeneration in both ST-QA and HF-QA, although no difference was observed between these groups. The HF-QA group showed a reduction in adiposity when compared with the groups that received PBS. Therefore, the HF-QA group demonstrated a commitment-dependent metabolic pathway. The results suggest that an obesogenic diet does not aggravate the neurodegeneration induced by QA. However, the excitotoxicity induced by QA promotes a sirtuin pathway impairment that contributes to metabolic changes.

  9. Severe hypertriglyceridemia, reduced high density lipoprotein, and neonatal death in lipoprotein lipase knockout mice. Mild hypertriglyceridemia with impaired very low density lipoprotein clearance in heterozygotes.

    PubMed Central

    Weinstock, P H; Bisgaier, C L; Aalto-Setälä, K; Radner, H; Ramakrishnan, R; Levak-Frank, S; Essenburg, A D; Zechner, R; Breslow, J L

    1995-01-01

    Lipoprotein lipase (LPL)-deficient mice have been created by gene targeting in embryonic stem cells. At birth, homozygous knockout pups have threefold higher triglycerides and sevenfold higher VLDL cholesterol levels than controls. When permitted to suckle, LPL-deficient mice become pale, then cyanotic, and finally die at approximately 18 h of age. Before death, triglyceride levels are severely elevated (15,087 +/- 3,805 vs 188 +/- 71 mg/dl in controls). Capillaries in tissues of homozygous knockout mice are engorged with chylomicrons. This is especially significant in the lung where marginated chylomicrons prevent red cell contact with the endothelium, a phenomenon which is presumably the cause of cyanosis and death in these mice. Homozygous knockout mice also have diminished adipose tissue stores as well as decreased intracellular fat droplets. By crossbreeding with transgenic mice expressing human LPL driven by a muscle-specific promoter, mouse lines were generated that express LPL exclusively in muscle but not in any other tissue. This tissue-specific LPL expression rescued the LPL knockout mice and normalized their lipoprotein pattern. This supports the contention that hypertriglyceridemia caused the death of these mice and that LPL expression in a single tissue was sufficient for rescue. Heterozygous LPL knockout mice survive to adulthood and have mild hypertriglyceridemia, with 1.5-2-fold elevated triglyceride levels compared with controls in both the fed and fasted states on chow, Western-type, or 10% sucrose diets. In vivo turnover studies revealed that heterozygous knockout mice had impaired VLDL clearance (fractional catabolic rate) but no increase in transport rate. In summary, total LPL deficiency in the mouse prevents triglyceride removal from plasma, causing death in the neonatal period, and expression of LPL in a single tissue alleviates this problem. Furthermore, half-normal levels of LPL cause a decrease in VLDL fractional catabolic rate and mild

  10. Grammatical Impairments in PPA

    PubMed Central

    Thompson, Cynthia K.; Mack, Jennifer E.

    2015-01-01

    Background Grammatical impairments are commonly observed in the agrammatic subtype of primary progressive aphasia (PPA-G), whereas grammatical processing is relatively preserved in logopenic (PPA-L) and semantic (PPA-S) subtypes. Aims We review research on grammatical deficits in PPA and associated neural mechanisms, with discussion focused on production and comprehension of four aspects of morphosyntactic structure: grammatical morphology, functional categories, verbs and verb argument structure, and complex syntactic structures. We also address assessment of grammatical deficits in PPA, with emphasis on behavioral tests of grammatical processing. Finally, we address research examining the effects of treatment for progressive grammatical impairments. Main Contribution PPA-G is associated with grammatical deficits that are evident across linguistic domains in both production and comprehension. PPA-G is associated with damage to regions including the left inferior frontal gyrus (IFG) and dorsal white matter tracts, which have been linked to impaired comprehension and production of complex sentences. Detailing grammatical deficits in PPA is important for estimating the trajectory of language decline and associated neuropathology. We, therefore, highlight several new assessment tools for examining different aspects of morphosyntactic processing in PPA. Conclusions Individuals with PPA-G present with agrammatic deficit patterns distinct from those associated with PPA-L and PPA-S, but similar to those seen in agrammatism resulting from stroke, and patterns of cortical atrophy and white matter changes associated with PPA-G have been identified. Methods for clinical evaluation of agrammatism, focusing on comprehension and production of grammatical morphology, functional categories, verbs and verb argument structure, and complex syntactic structures are recommended and tools for this are emerging in the literature. Further research is needed to investigate the real

  11. Antioxidant effects of JM-20 on rat brain mitochondria and synaptosomes: mitoprotection against Ca²⁺-induced mitochondrial impairment.

    PubMed

    Nuñez-Figueredo, Yanier; Pardo-Andreu, Gilberto L; Ramírez-Sánchez, Jeney; Delgado-Hernández, René; Ochoa-Rodríguez, Estael; Verdecia-Reyes, Yamila; Naal, Zeki; Muller, Alexandre Pastoris; Portela, Luis Valmor; Souza, Diogo O

    2014-10-01

    Because mitochondrial oxidative stress and impairment are important mediators of neuronal damage in neurodegenerative diseases and in brain ischemia/reperfusion, in the present study, we evaluated the antioxidant and mitoprotective effect of a new promising neuroprotective molecule, JM-20, in mitochondria and synaptosomes isolated from rat brains. JM-20 inhibited succinate-mediated H₂O₂ generation in both mitochondria and synaptosomes incubated in depolarized (high K(+)) medium at extremely low micromolar concentration and with identical IC₅₀ values of 0.91 μM. JM-20 also repressed glucose-induced H₂O₂ generation stimulated by rotenone or by antimycin A in synaptosomes incubated in high sodium-polarized medium at extremely low IC₅₀ values of 0.395 μM and 2.452 μM, respectively. JM-20 was unable to react directly with H₂O₂ or with superoxide anion radicals but displayed a cathodic reduction peak at -0.71V, which is close to that of oxygen (-0.8V), indicating high electron affinity. JM-20 also inhibited uncoupled respiration in mitochondria or synaptosomes and was a more effective inhibitor in the presence of the respiratory substrates glutamate/malate than in the presence of succinate. JM-20 also prevented Ca(2+)-induced mitochondrial permeability transition pore opening, membrane potential dissipation and cytochrome c release, which are key pathogenic events during stroke. This molecule also prevented Ca(2+) influx into synaptosomes and mitochondria; the former effect was a consequence of the latter because JM-20 inhibition followed the patterns of carbonyl cyanide p-trifluoromethoxyphenyl hydrazone (FCCP), which is a classic mitochondrial uncoupler. Because the mitochondrion is considered an important source and target of neuronal cell death signaling after an ischemic insult, the antioxidant and protective effects of JM-20 against the deleterious effects of Ca(2+) observed at the mitochondrial level in this study may endow this molecule

  12. Butalbital and driving impairment.

    PubMed

    Yeakel, Jillian K; Logan, Barry K

    2013-07-01

    Butalbital (Fiorinal(®)), used in the treatment of migraines and muscle pain, is the most commonly encountered barbiturate in impaired driving cases. It has central nervous system (CNS) depressant properties, including sedation, drowsiness, and feelings of intoxication, which can contribute to driving impairment. Twenty-six driving under the influence cases are reviewed including results from field sobriety tests and toxicology testing. Blood samples were screened using enzyme multiplied immunoassay technique immunoassay, and the presence of butalbital was confirmed and quantified using gas chromatography/mass spectrometry, gas chromatography with flame ionization detection, or gas chromatography nitrogen/phosphorus detection. Butalbital concentrations ranged from 1.0 to 30.2 mg/L, with a mean and median of 16.0 mg/L. General impairment indicators in these cases included horizontal and vertical nystagmus, lack of convergence, poor motor coordination, and balance and speech problems, which are common to CNS depressant intoxication, similar to that associated with alcohol. These findings indicate the importance of toxicological testing for butalbital in cases where CNS depressants are indicated.

  13. Neurological Impairment: Nomenclature and Consequences.

    ERIC Educational Resources Information Center

    Spears, Catherine E.; Weber, Robert E.

    Neurological impairment as discussed includes a range of disabilities referred to as neurological impairment: minimal brain dysfunction/damage, developmental disability, perceptual handicap, learning disability, hyperkinetic behavioral syndrome, and others. Defined are causes of neurological impairment and methods of diagnosis. Symptoms…

  14. Assessment of Hearing Impaired Youth.

    ERIC Educational Resources Information Center

    Hicks, Doin E., Ed.; And Others

    1980-01-01

    The issue of Directions contains 11 articles on assessment of hearing impaired individuals. Entries have the following titles and authors: "Classroom Assessment Techniques for Hearing Impaired Students--A Literature Review" (B. McKee, M. Hausknecht); "Informal Assessment of Hearing Impaired Students In the Classroom" (B. Culhane, R. Hein);…

  15. Single high-dose irradiation aggravates eosinophil-mediated fibrosis through IL-33 secreted from impaired vessels in the skin compared to fractionated irradiation

    SciTech Connect

    Lee, Eun-Jung; Kim, Jun Won; Yoo, Hyun; Kwak, Woori; Choi, Won Hoon; Cho, Seoae; Choi, Yu Jeong; Lee, Yoon-Jin; Cho, Jaeho

    2015-08-14

    We have revealed in a porcine skin injury model that eosinophil recruitment was dose-dependently enhanced by a single high-dose irradiation. In this study, we investigated the underlying mechanism of eosinophil-associated skin fibrosis and the effect of high-dose-per-fraction radiation. The dorsal skin of a mini-pig was divided into two sections containing 4-cm{sup 2} fields that were irradiated with 30 Gy in a single fraction or 5 fractions and biopsied regularly over 14 weeks. Eosinophil-related Th2 cytokines such as interleukin (IL)-4, IL-5, and C–C motif chemokine-11 (CCL11/eotaxin) were evaluated by quantitative real-time PCR. RNA-sequencing using 30 Gy-irradiated mouse skin and functional assays in a co-culture system of THP-1 and irradiated-human umbilical vein endothelial cells (HUVECs) were performed to investigate the mechanism of eosinophil-mediated radiation fibrosis. Single high-dose-per-fraction irradiation caused pronounced eosinophil accumulation, increased profibrotic factors collagen and transforming growth factor-β, enhanced production of eosinophil-related cytokines including IL-4, IL-5, CCL11, IL-13, and IL-33, and reduced vessels compared with 5-fraction irradiation. IL-33 notably increased in pig and mouse skin vessels after single high-dose irradiation of 30 Gy, as well as in irradiated HUVECs following 12 Gy. Blocking IL-33 suppressed the migration ability of THP-1 cells and cytokine secretion in a co-culture system of THP-1 cells and irradiated HUVECs. Hence, high-dose-per-fraction irradiation appears to enhance eosinophil-mediated fibrotic responses, and IL-33 may be a key molecule operating in eosinophil-mediated fibrosis in high-dose-per fraction irradiated skin. - Highlights: • Single high-dose irradiation aggravates eosinophil-mediated fibrosis through IL-33. • Vascular endothelial cells damaged by high-dose radiation secrete IL-33. • Blocking IL-33 suppressed migration of inflammatory cells and cytokine secretion. • IL

  16. Sleep, Torpor and Memory Impairment

    NASA Astrophysics Data System (ADS)

    Palchykova, S.; Tobler, I.

    It is now well known that daily torpor induces a sleep deficit. Djungarian hamsters emerging from this hypometabolic state spend most of the time in sleep. This sleep is characterized by high initial values of EEG slow-wave activity (SWA) that monotonically decline during recovery sleep. These features resemble the changes seen in numerous species during recovery after prolonged wakefulness or sleep deprivation (SD). When hamsters are totally or partially sleep deprived immediately after emerging from torpor, an additional increase in SWA can be induced. It has been therefore postulated, that these slow- waves are homeostatically regulated, as predicted by the two-process model of sleep regulation, and that during daily torpor a sleep deficit is accumulated as it is during prolonged waking. The predominance of SWA in the frontal EEG observed both after SD and daily torpor provides further evidence for the similarity of these conditions. It has been shown in several animal and human studies that sleep can enhance memory consolidation, and that SD leads to memory impairment. Preliminary data obtained in the Djungarian hamster showed that both SD and daily torpor result in object recognition deficits. Thus, animals subjected to SD immediately after learning, or if they underwent an episode of daily torpor between learning and retention, displayed impaired recognition memory for complex object scenes. The investigation of daily torpor can reveal mechanisms that could have important implications for hypometabolic state induction in other mammalian species, including humans.

  17. Circulating progenitors following high-dose sequential (HDS) chemotherapy with G-CSF: short intervals between drug courses severely impair progenitor mobilization.

    PubMed

    Tarella, C; Caracciolo, D; Gavarotti, P; Bondesan, P; Cherasco, C; Omedè, P; Bregni, M; Siena, S; Gianni, A M; Pileri, A

    1995-08-01

    Sequential administration of high-dose chemotherapy courses possibly allows extensive in vivo purging before circulating progenitor collection for autograft. To evaluate whether progenitor cell mobilization was negatively affected by repeated high-dose chemotherapy courses, we studied 23 lymphoma patients undergoing the HDS regimen. The scheme includes the sequential administration of cyclophosphamide (CY) given at 7 g/m2 and etoposide (VP16) given at 2 g/m2, each followed by G-CSF (filgrastim) at 5 micrograms/kg/day. Eleven patients received the standard HDS sequence, with a short interval between first and second myelotoxic courses of less than 45 days (median: 30 days); the remaining 12 patients received a modified HDS where the interval between first and second high-dose course was protracted over 2 months (median: 70 days); in this latter group, 2 to 4 conventional debulking courses were delivered prior to HDS. In patients receiving the standard HDS, progenitor mobilization following the first course was consistently high (median circulating CFU-GM/ml peak value: 29,022); however, significantly lower values were observed at the second course (median CFU-GM/ml peak value 3757, P = 0.002). Circulating BFU-E and CD34+ cell values paralleled those of CFU-GM. No significant difference was observed in progenitor mobilization following either course in patients receiving HDS with extended interval (median circulating CFU-GM/ml peak value: 14,363 vs 9208, at first and second course respectively, P = 0.27). Eleven patients had their progenitor cells harvested following the second delayed course and 2-4 leucaphereses allowed very satisfactory harvests in all of them (CFU-GM/kg ranging from 39-340 x 10(4)).(ABSTRACT TRUNCATED AT 250 WORDS)

  18. Language Learning Impairment in Sequential Bilingual Children

    ERIC Educational Resources Information Center

    Ebert, Kerry Danahy; Kohnert, Kathryn

    2016-01-01

    We review and synthesize empirical evidence at the intersection of two populations: children with language learning impairment (LLI) and children from immigrant families who learn a single language from birth and a second language beginning in early childhood. LLI is a high incidence disorder that, in recent years, has been referred to by…

  19. Cognitive impairment and stroke in elderly patients

    PubMed Central

    Lo Coco, Daniele; Lopez, Gianluca; Corrao, Salvatore

    2016-01-01

    We reviewed current knowledge about the interaction between stroke and vascular risk factors and the development of cognitive impairment and dementia. Stroke is increasingly recognized as an important cause of cognitive problems and has been implicated in the development of both Alzheimer’s disease and vascular dementia. The prevalence of cognitive impairment after stroke is high, and their combined effects significantly increase the cost of care and health resource utilization, with reflections on hospital readmissions and increased mortality rates. There is also substantial evidence that vascular risk factors (such as hypertension, diabetes, obesity, dyslipidemia, and tobacco smoking) are independently associated with an increased risk of cognitive decline and dementia. Thus, a successful management of these factors, as well as optimal acute stroke management, might have a great impact on the development of cognitive impairment. Notwithstanding, the pathological link between cognitive impairment, stroke, and vascular risk factors is complex and still partially unclear so that further studies are needed to better elucidate the boundaries of this relationship. Many specific pharmacological treatments, including anticholinergic drugs and antihypertensive medications, and nonpharmacological approaches, such as diet, cognitive rehabilitation, and physical activity, have been studied for patients with vascular cognitive impairment, but the optimal care is still far away. Meanwhile, according to the most recent knowledge, optimal stroke care should also include cognitive assessment in the short and long term, and great efforts should be oriented toward a multidisciplinary approach, including quality-of-life assessment and support of caregivers. PMID:27069366

  20. Facilitating Transition from High School and Special Education to Adult Life: Focus on Youth with Learning Disorders, Attention-Deficit/Hyperactivity Disorder, and Speech/Language Impairments.

    PubMed

    Ascherman, Lee I; Shaftel, Julia

    2017-04-01

    Youth with learning disorders, speech/language disorders, and/or attention-deficit/hyperactivity disorder may experience significant struggles during the transition from high school to postsecondary education and employment. These disorders often occur in combination or concurrently with behavioral and emotional difficulties. Incomplete evaluation may not fully identify the factors underlying academic and personal challenges. This article reviews these disorders, the role of special education law for transitional age youth in public schools, and the Americans with Disabilities Act in postsecondary educational and employment settings. The role of the child and adolescent psychiatrist and the importance of advocacy for these youth are presented.