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  1. 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

  2. Rice bran protein hydrolysates prevented interleukin-6- and high glucose-induced insulin resistance in HepG2 cells.

    PubMed

    Boonloh, Kampeebhorn; Kukongviriyapan, Upa; Pannangpetch, Patchareewan; Kongyingyoes, Bunkerd; Senggunprai, Laddawan; Prawan, Auemduan; Thawornchinsombut, Supawan; Kukongviriyapan, Veerapol

    2015-02-01

    Rice bran, which is a byproduct of rice milling process, contains various nutrients and biologically active compounds. Rice bran protein hydrolysates have various pharmacological activities such as antidiabetic and antidyslipidemic effects. However, there are limited studies about the mechanisms of rice bran protein hydrolysates (RBP) on insulin resistance and lipid metabolism. RBP used in this study were prepared from Thai Jasmine rice. When HepG2 cells were treated with IL-6, the IRS-1 expression and Akt phosphorylation were suppressed. This effect of IL-6 was prevented by RBP in association with inhibition of STAT3 phosphorylation and SOCS3 expression. RBP could increase the phospho-AMPK levels and inhibit IL-6- or high glucose-induced suppression of AMPK and Akt activation. High glucose-induced dysregulation of the expression of lipogenic genes, including SREBP-1c, FASN and CPT-1, was normalized by RBP treatment. Moreover, impaired glucose utilization in insulin resistant HepG2 cells was significantly alleviated by concurrent treatment with RBP. Our results suggested that RBP suppresses inflammatory cytokine signaling and activates AMPK, and thereby these effects may underlie the insulin sensitizing effect. PMID:25518891

  3. Anthocyanin inhibits high glucose-induced hepatic mtGPAT1 activation and prevents fatty acid synthesis through PKCζ.

    PubMed

    Guo, Honghui; Li, Dan; Ling, Wenhua; Feng, Xiang; Xia, Min

    2011-05-01

    Mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase 1 (mtGPAT1) controls the first step of triacylglycerol (TAG) synthesis and is critical to the understanding of chronic metabolic disorders such as primary nonalcoholic fatty liver disease (NAFLD). Anthocyanin, a large group of polyphenols, was negatively correlated with hepatic lipid accumulation, but its impact on mtGPAT1 activity and NAFLD has yet to be determined. Hepatoma cell lines and KKAy mice were used to investigate the impact of anthocyanin on high glucose-induced mtGPAT1 activation and hepatic steatosis. Treatment with anthocyanin cyanidin-3-O-β-glucoside (Cy-3-g) reduced high glucose-induced GPAT1 activity through the prevention of mtGPAT1 translocation from the endoplasmic reticulum to the outer mitochondrial membrane (OMM), thereby suppressing intracellular de novo lipid synthesis. Cy-3-g treatment also increased protein kinase C ζ phosphorylation and membrane translocation in order to phosphorylate the mtF0F1-ATPase β-subunit, reducing its enzymatic activity and thus inhibiting mtGPAT1 activation. In vivo studies further showed that Cy-3-g treatment significantly decreases hepatic mtGPAT1 activity and its presence in OMM isolated from livers, thus ameliorating hepatic steatosis in diabetic KKAy mice. Our findings reveal a novel mechanism by which anthocyanin regulates lipogenesis and thereby inhibits hepatic steatosis, suggesting its potential therapeutic application in diabetes and related steatotic liver diseases. PMID:21343633

  4. Astragaloside IV prevents high glucose-induced podocyte apoptosis via downregulation of TRPC6.

    PubMed

    Yao, Xing-Mei; Liu, Yu-Jun; Wang, Yun-Man; Wang, Hao; Zhu, Bing-Bing; Liang, Yong-Ping; Yao, Wei-Guo; Yu, Hui; Wang, Nian-Song; Zhang, Xue-Mei; Peng, Wen

    2016-06-01

    Diabetic nephropathy (DN) is one of the most important causes of end‑stage renal disease. Astragaloside IV (AS-IV) is a saponin isolated from Astragalus membranaceus, which possesses various pharmacological activities. AS‑IV prevents podocyte apoptosis and ameliorates renal injury in DN; however, few studies have focused on its effects on ion channels. The transient receptor potential channel 6 (TRPC6) is an important Ca2+‑permeable ion channel in podocytes, which is involved in high glucose (HG)-induced podocyte apoptosis. The aim of the present study was to investigate whether AS‑IV prevented HG‑induced podocyte apoptosis via TRPC6. Cultured podocytes were pre‑treated with 10, 20 or 40 µM AS‑IV for 1 h prior to HG exposure for 24 h. Apoptosis, cell viability, expression of TRPC6, nuclear factor of activated T cells (NFAT2) and B‑cell lymphoma 2‑associated X protein (Bax), as well as the intracellular Ca2+ concentration were subsequently analyzed. The results indicated that HG induced podocyte apoptosis and upregulation of TRPC6, and increased intracellular Ca2+. Furthermore, enhanced NFAT2 and Bax expression was detected. Conversely, AS‑IV protected HG‑induced podocyte apoptosis, downregulated TRPC6 expression and suppressed intracellular Ca2+ in HG-stimulated podocytes. AS‑IV also suppressed NFAT2 and Bax expression. These results suggest that AS‑IV may prevent HG-induced podocyte apoptosis via downregulation of TRPC6, which is possibly mediated via the calcineurin/NFAT signaling pathway. PMID:27109610

  5. Delphinidin prevents high glucose-induced cell proliferation and collagen synthesis by inhibition of NOX-1 and mitochondrial superoxide in mesangial cells.

    PubMed

    Song, Seung Eun; Jo, Hye Jun; Kim, Yong-Woon; Cho, Young-Je; Kim, Jae-Ryong; Park, So-Young

    2016-04-01

    This study examined the effect of delphinidin on high glucose-induced cell proliferation and collagen synthesis in mesangial cells. Glucose dose-dependently (5.6-25 mM) increased cell proliferation and collagen I and IV mRNA levels, whereas pretreatment with delphinidin (50 μM) prevented cell proliferation and the increased collagen mRNA levels induced by high glucose (25 mM). High glucose increased reactive oxygen species (ROS) generation, and this was suppressed by pretreating delphinidin or the antioxidant N-acetyl cysteine. NADPH oxidase (NOX) 1 was upregulated by high glucose, but pretreatment with delphinidin abrogated this upregulation. Increased mitochondrial superoxide by 25 mM glucose was also suppressed by delphinidin. The NOX inhibitor apocynin and mitochondria-targeted antioxidant Mito TEMPO inhibited ROS generation and cell proliferation induced by high glucose. Phosphorylation of extracellular signal regulated kinase (ERK)1/2 was increased by high glucose, which was suppressed by delphinidin, apocynin or Mito TEMPO. Furthermore, PD98059 (an ERK1/2 inhibitor) prevented the high glucose-induced cell proliferation and increased collagen mRNA levels. Transforming growth factor (TGF)-β protein levels were elevated by high glucose, and pretreatment with delphinidin or PD98059 prevented this augmentation. These results suggest that delphinidin prevents high glucose-induced cell proliferation and collagen synthesis by inhibition of NOX-1 and mitochondrial superoxide in mesangial cells. PMID:27103328

  6. Serelaxin (recombinant human relaxin-2) prevents high glucose-induced endothelial dysfunction by ameliorating prostacyclin production in the mouse aorta.

    PubMed

    Ng, Hooi Hooi; Leo, Chen Huei; Parry, Laura J

    2016-05-01

    Diabetes-induced endothelial dysfunction is a critical initiating factor in the development of cardiovascular complications. Treatment with relaxin improves tumour necrosis factor α-induced endothelial dysfunction by enhancing endothelial nitric oxide synthase (eNOS) activity and restoring superoxide dismutase 1 protein in rat aortic rings ex vivo. It is, therefore, possible that relaxin treatment could alleviate endothelial dysfunction in diabetes. This study aimed to test the hypothesis that serelaxin (recombinant human relaxin-2) prevents high glucose-induced vascular dysfunction in the mouse aorta. Abdominal aortae were isolated from C57BL/6 male mice and incubated in M199 media for 3days with either normal glucose (5.5mM) or high glucose (30mM), and co-incubated with placebo (20mM sodium acetate) or 10nM serelaxin at 37°C in 5% CO2. Vascular function was analysed using wire-myography. High glucose significantly reduced the sensitivity to the endothelium-dependent agonist, acetylcholine (ACh) (pEC50; normal glucose=7.66±0.10 vs high glucose=7.29±0.10, n=11-12, P<0.05) and the contraction induced by NOS inhibitor, L-NAME (200μM) (normal glucose=59.9±8.3% vs high glucose=38.7±4.3%, n=6, P<0.05), but had no effect on the endothelium-independent agonist, sodium nitroprusside (SNP)-mediated relaxation. Treatment with serelaxin restored endothelial function (pEC50; 7.83±0.11, n=11) but not NO availability. The presence of the cyclooxygenase (COX) inhibitor, indomethacin (1μM) (pEC50; control=7.29±0.10 vs indo=7.74±0.18, n=6-12, P<0.05) and a superoxide dismutase mimetic, tempol (10μM) (pEC50; control=7.29±0.10 vs tempol=7.82±0.05, n=6-12, P<0.01) significantly improved sensitivity to ACh in high glucose treated aortae, but had no effect in serelaxin treated aortae. This suggests that high glucose incubation alters the superoxide and COX-sensitive pathway, which was normalized by co-incubation with serelaxin. Neither high glucose incubation nor serelaxin

  7. Anthocyanin inhibits high glucose-induced hepatic mtGPAT1 activation and prevents fatty acid synthesis through PKCζ[S

    PubMed Central

    Guo, Honghui; Li, Dan; Ling, Wenhua; Feng, Xiang; Xia, Min

    2011-01-01

    Mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase 1 (mtGPAT1) controls the first step of triacylglycerol (TAG) synthesis and is critical to the understanding of chronic metabolic disorders such as primary nonalcoholic fatty liver disease (NAFLD). Anthocyanin, a large group of polyphenols, was negatively correlated with hepatic lipid accumulation, but its impact on mtGPAT1 activity and NAFLD has yet to be determined. Hepatoma cell lines and KKAy mice were used to investigate the impact of anthocyanin on high glucose-induced mtGPAT1 activation and hepatic steatosis. Treatment with anthocyanin cyanidin-3-O-β-glucoside (Cy-3-g) reduced high glucose-induced GPAT1 activity through the prevention of mtGPAT1 translocation from the endoplasmic reticulum to the outer mitochondrial membrane (OMM), thereby suppressing intracellular de novo lipid synthesis. Cy-3-g treatment also increased protein kinase C ζ phosphorylation and membrane translocation in order to phosphorylate the mtF0F1-ATPase β-subunit, reducing its enzymatic activity and thus inhibiting mtGPAT1 activation. In vivo studies further showed that Cy-3-g treatment significantly decreases hepatic mtGPAT1 activity and its presence in OMM isolated from livers, thus ameliorating hepatic steatosis in diabetic KKAy mice. Our findings reveal a novel mechanism by which anthocyanin regulates lipogenesis and thereby inhibits hepatic steatosis, suggesting its potential therapeutic application in diabetes and related steatotic liver diseases. PMID:21343633

  8. Rosiglitazone Prevents High Glucose-Induced Vascular Endothelial Growth Factor and Collagen IV Expression in Cultured Mesangial Cells

    PubMed Central

    Whiteside, Catharine; Wang, Hong; Xia, Ling; Munk, Snezana; Goldberg, Howard J.; Fantus, I. George

    2009-01-01

    Peroxisome proliferator-activated receptor (PPARγ), a ligand-dependent transcription factor, negatively modulates high glucose effects. We postulated that rosiglitazone (RSG), an activator of PPARγ prevents the upregulation of vascular endothelial growth factor (VEGF) and collagen IV by mesangial cells exposed to high glucose. Primary cultured rat mesangial cells were growth-arrested in 5.6 mM (NG) or 25 mM D-glucose (HG) for up to 48 hours. In HG, PPARγ mRNA and protein were reduced within 3 h, and enhanced ROS generation, expression of p22phox, VEGF and collagen IV, and PKC-ζ membrane association were prevented by RSG. In NG, inhibition of PPARγ caused ROS generation and VEGF expression that were unchanged by RSG. Reduced AMP-activated protein kinase (AMPK) phosphorylation in HG was unchanged with RSG, and VEGF expression was unaffected by AMPK inhibition. Hence, PPARγ is a negative modulator of HG-induced signaling that acts through PKC-ζ but not AMPK and regulates VEGF and collagen IV expression by mesangial cells. PMID:19609456

  9. Inhibition of Src kinase blocks high glucose-induced EGFR transactivation and collagen synthesis in mesangial cells and prevents diabetic nephropathy in mice.

    PubMed

    Taniguchi, Kanta; Xia, Ling; Goldberg, Howard J; Lee, Ken W K; Shah, Anu; Stavar, Laura; Masson, Elodie A Y; Momen, Abdul; Shikatani, Eric A; John, Rohan; Husain, Mansoor; Fantus, I George

    2013-11-01

    Chronic exposure to high glucose leads to diabetic nephropathy characterized by increased mesangial matrix protein (e.g., collagen) accumulation. Altered cell signaling and gene expression accompanied by oxidative stress have been documented. The contribution of the tyrosine kinase, c-Src (Src), which is sensitive to oxidative stress, was examined. Cultured rat mesangial cells were exposed to high glucose (25 mmol/L) in the presence and absence of Src inhibitors (PP2, SU6656), Src small interfering RNA (siRNA), and the tumor necrosis factor-α-converting enzyme (TACE) inhibitor, TAPI-2. Src was investigated in vivo by administration of PP2 to streptozotocin (STZ)-induced diabetic DBA2/J mice. High glucose stimulated Src, TACE, epidermal growth factor receptor (EGFR), mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK1/2, p38), and collagen IV accumulation in mesangial cells. PP2 and SU6656 blocked high glucose-stimulated phosphorylation of Src Tyr-416, EGFR, and MAPKs. These inhibitors and Src knockdown by siRNA, as well as TAPI-2, also abrogated high glucose-induced phosphorylation of these targets and collagen IV accumulation. In STZ-diabetic mice, albuminuria, increased Src pTyr-416, TACE activation, ERK and EGFR phosphorylation, glomerular collagen accumulation, and podocyte loss were inhibited by PP2. These data indicate a role for Src in a high glucose-Src-TACE-heparin-binding epidermal growth factor-EGFR-MAPK-signaling pathway to collagen accumulation. Thus, Src may provide a novel therapeutic target for diabetic nephropathy. PMID:23942551

  10. 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. PMID:26453010

  11. The antioxidant edaravone prevents cardiac dysfunction by suppressing oxidative stress in type 1 diabetic rats and in high-glucose-induced injured H9c2 cardiomyoblasts.

    PubMed

    Ji, Lei; Liu, Yingying; Zhang, Ying; Chang, Wenguang; Gong, Junli; Wei, Shengnan; Li, Xudong; Qin, Ling

    2016-09-01

    Edaravone, a radical scavenger, has been recognized as a potential protective agent for cardiovascular diseases. However, little is known about the effect of edaravone in cardiac complications associated with diabetes. Here, we have demonstrated that edaravone prevents cardiac dysfunction and apoptosis in the streptozotocin-induced type 1 diabetic rat heart. Mechanistic studies revealed that edaravone treatment improved cardiac function and restored superoxide dismutase levels. In addition, treatment of diabetic animals by edaravone increased protein expressions of sirtuin-1 (SIRT-1), peroxisome proliferator activated receptor γ coactivator α (PGC-1α), nuclear factor like-2 (NRF-2), and B cell lymphoma 2 (Bcl-2), and reduced protein expressions of Bax and Caspase-3 compared to the control group. High glucose incubation resulted in the production of reactive oxygen species (ROS) and cell death. Treatment of high-glucose-incubated H9c2 cells by edaravone reduced ROS production and cell death. In addition, the treatment of high-glucose-incubated H9c2 cells by edaravone increased the activity of antioxidative stress by increasing SIRT-1, PGC-1α, and NRF-2, and this treatment also reduced apoptosis by increasing Bcl-2 expression and reducing Bax and Caspase-3 expressions. Knockdown SIRT-1 with small interferer RNA abolished the effects of edaravone. Overall, our data demonstrated that edaravone may be an effective agent against the development of diabetic cardiomyopathy. PMID:27376621

  12. Inhibitory Effects of Ecklonia cava Extract on High Glucose-Induced Hepatic Stellate Cell Activation

    PubMed Central

    Yokogawa, Kumiko; Matsui-Yuasa, Isao; Tamura, Akiko; Terada, Masaki; Kojima-Yuasa, Akiko

    2011-01-01

    Nonalcoholic steatohepatitis (NASH) is a disease closely associated with obesity and diabetes. A prevalence of type 2 diabetes and a high body mass index in cryptogenic cirrhosis may imply that obesity leads to cirrhosis. Here, we examined the effects of an extract of Ecklonia cava, a brown algae, on the activation of high glucose-induced hepatic stellate cells (HSCs), key players in hepatic fibrosis. Isolated HSCs were incubated with or without a high glucose concentration. Ecklonia cava extract (ECE) was added to the culture simultaneously with the high glucose. Treatment with high glucose stimulated expression of type I collagen and α-smooth muscle actin, which are markers of activation in HSCs, in a dose-dependent manner. The activation of high glucose-treated HSCs was suppressed by the ECE. An increase in the formation of intracellular reactive oxygen species (ROS) and a decrease in intracellular glutathione levels were observed soon after treatment with high glucose, and these changes were suppressed by the simultaneous addition of ECE. High glucose levels stimulated the secretion of bioactive transforming growth factor-β (TGF-β) from the cells, and the stimulation was also suppressed by treating the HSCs with ECE. These results suggest that the suppression of high glucose-induced HSC activation by ECE is mediated through the inhibition of ROS and/or GSH and the downregulation of TGF-β secretion. ECE is useful for preventing the development of diabetic liver fibrosis. PMID:22363250

  13. 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

  14. 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

  15. Blockade of chronic high glucose-induced endothelial apoptosis by Sasa borealis bamboo extract.

    PubMed

    Choi, Yean-Jung; Lim, Hyeon-Sook; Choi, Jung-Suk; Shin, Seung-Yong; Bae, Ji-Young; Kang, Sang-Wook; Kang, Il-Jun; Kang, Young-Hee

    2008-05-01

    Hyperglycemia is a causal factor in the development of diabetic vascular complications including impaired vascular smooth muscle contractility and increased cell proliferation. The present study was designed to investigate the effects of Sasa borealis water-extract (SBwE) on chronic hyperglycemia-induced oxidative stress and apoptosis in human umbilical endothelial cells (HUVEC). HUVEC were cultured in 5.5 mM low glucose, 5.5 mM glucose plus 27.5 mM mannitol as an osmotic control, or 33 mM high glucose for 5 days in the absence and presence of 1-30 microg/ ml SBwE. Caspase-3 activation and Annexin V staining revealed chronic high glucose-induced endothelial apoptotic toxicity with a generation of oxidants detected by DCF-fluorescence, and these effects were reversed by SBwE at > or =1 microg/ml in a dose-dependent manner. Cytoprotective SBwE substantially reduced the sustained high glucose-induced expression of endothelial nitric oxide synthase and attenuated the formation of peroxynitrite radicals. The suppressive effects of SBwE were most likely mediated through blunting activation of PKC beta 2 and NADPH oxidase promoted by high glucose. In addition, this bamboo extract modulated the high glucose-triggered mitogen-activated protein kinase-dependent upregulation of heat-shock proteins. Our results suggest that SBwE suppressed these detrimental effects caused by PKC-dependent peroxynitrite formation via activation of NADPH oxidase and induction of nitric oxide synthase and heat-shock protein family that may be essential mechanisms responsible for increased apoptotic oxidative stress in diabetic vascular complications. Moreover, the blockade of high glucose-elicited heat-shock protein induction appeared to be responsible for SBwE-alleviated endothelial apoptosis. Therefore, SBwE may be a therapeutic agent for the prevention and treatment of diabetic endothelial dysfunction and related complications. PMID:18375828

  16. Pyrroloquinoline quinone protects mouse brain endothelial cells from high glucose-induced damage in vitro

    PubMed Central

    Wang, Zhong; Chen, Guo-qiang; Yu, Gui-ping; Liu, Chang-jian

    2014-01-01

    Aim: To investigate the effects of pyrroloquinoline quinone (PQQ), an oxidoreductase cofactor, on high glucose-induced mouse endothelial cell damage in vitro. Methods: Mouse brain microvascular endothelial bEND.3 cells were exposed to different glucose concentrations (5.56, 25 and 40 mmol/L) for 24 or 48 h. The cell viability was examined using MTT assay. Flow cytometry was used to analyze the apoptosis and ROS levels in the cells. MitoTracker Green staining was used to examine the mitochondria numbers in the cells. Western blot analysis was used to analyze the expression of HIF-1α and the proteins in JNK pathway. Results: Treatment of bEND.3 cells with high glucose significantly decreased the cell viability, while addition of PQQ (1 and 10 μmol/L) reversed the high glucose-induced cell damage in a concentration-dependent manner. Furthermore, PQQ (100 μmol/L) significantly suppressed the high glucose-induced apoptosis and ROS production in the cells. PQQ significantly reversed the high glucose-induced reduction in both the mitochondrial membrane potential and mitochondria number in the cells. The high glucose treatment significantly increased the expression of HIF-1α and JNK phosphorylation in the cells, and addition of PQQ led to a further increase of HIF-1α level and a decrease of JNK phosphorylation. Addition of JNK inhibitor SP600125 (10 μmol/L) also significantly suppressed high glucose-induced apoptosis and JNK phosphorylation in bEND.3 cells. Conclusion: PQQ protects mouse brain endothelial cells from high glucose damage in vitro by suppressing intracellular ROS and apoptosis via inhibiting JNK signaling pathway. PMID:25283505

  17. Glucose induces intestinal human UDP-glucuronosyltransferase (UGT) 1A1 to prevent neonatal hyperbilirubinemia.

    PubMed

    Aoshima, Naoya; Fujie, Yoshiko; Itoh, Tomoo; Tukey, Robert H; Fujiwara, Ryoichi

    2014-01-01

    Inadequate calorie intake or starvation has been suggested as a cause of neonatal jaundice, which can further cause permanent brain damage, kernicterus. This study experimentally investigated whether additional glucose treatments induce the bilirubin-metabolizing enzyme--UDP-glucuronosyltransferase (UGT) 1A1--to prevent the onset of neonatal hyperbilirubinemia. Neonatal humanized UGT1 (hUGT1) mice physiologically develop jaundice. In this study, UGT1A1 expression levels were determined in the liver and small intestine of neonatal hUGT1 mice that were orally treated with glucose. In the hUGT1 mice, glucose induced UGT1A1 in the small intestine, while it did not affect the expression of UGT1A1 in the liver. UGT1A1 was also induced in the human intestinal Caco-2 cells when the cells were cultured in the presence of glucose. Luciferase assays demonstrated that not only the proximal region (-1300/-7) of the UGT1A1 promoter, but also distal region (-6500/-4050) were responsible for the induction of UGT1A1 in the intestinal cells. Adequate calorie intake would lead to the sufficient expression of UGT1A1 in the small intestine to reduce serum bilirubin levels. Supplemental treatment of newborns with glucose solution can be a convenient and efficient method to treat neonatal jaundice while allowing continuous breastfeeding. PMID:25209391

  18. Tetramethylpyrazine ameliorates high glucose-induced endothelial dysfunction by increasing mitochondrial biogenesis.

    PubMed

    Xu, Qiong; Xia, Pu; Li, Xi; Wang, Wei; Liu, Zhenqi; Gao, Xin

    2014-01-01

    Tetramethylpyrazine (TMP) is an active compound isolated from a Chinese herbal prescription that is widely used in traditional Chinese medicine for the treatment of inflammatory and cardiovascular diseases. We have previously reported that TMP acts as a potent antioxidant protecting endothelial cells against high glucose-induced damages. However, the molecular mechanism responsible for the antioxidant effect of TMP remains to be elucidated. In this study, we show that TMP increases nitric oxide production in endothelial cells and promotes endothelium-dependent relaxation in rate aortic rings. The antioxidant effect of TMP appears attributable to its ability to activate the mitochondrial biogenesis, as reflected in an up-regulation of complex III and amelioration of mitochondrial membrane potential. Furthermore, TMP is able to reverse high glucose-induced suppression of SIRT1 and the biogenesis-related factors, including PGC-1α, NRF1 and TFAM, suggesting a new molecular mechanism underlying the protective effect of TMP on the endothelium. PMID:24505445

  19. Tetramethylpyrazine Ameliorates High Glucose-Induced Endothelial Dysfunction by Increasing Mitochondrial Biogenesis

    PubMed Central

    Xu, Qiong; Xia, Pu; Li, Xi; Wang, Wei; Liu, Zhenqi; Gao, Xin

    2014-01-01

    Tetramethylpyrazine (TMP) is an active compound isolated from a Chinese herbal prescription that is widely used in traditional Chinese medicine for the treatment of inflammatory and cardiovascular diseases. We have previously reported that TMP acts as a potent antioxidant protecting endothelial cells against high glucose-induced damages. However, the molecular mechanism responsible for the antioxidant effect of TMP remains to be elucidated. In this study, we show that TMP increases nitric oxide production in endothelial cells and promotes endothelium-dependent relaxation in rate aortic rings. The antioxidant effect of TMP appears attributable to its ability to activate the mitochondrial biogenesis, as reflected in an up-regulation of complex III and amelioration of mitochondrial membrane potential. Furthermore, TMP is able to reverse high glucose-induced suppression of SIRT1 and the biogenesis-related factors, including PGC-1α, NRF1 and TFAM, suggesting a new molecular mechanism underlying the protective effect of TMP on the endothelium. PMID:24505445

  20. Protective effects of andrographolide derivative AL-1 on high glucose-induced oxidative stress in RIN-m cells.

    PubMed

    Yan, Hui; Li, Yongmei; Yang, Yali; Zhang, Zaijun; Zhang, Gaoxiao; Sun, Yewei; Yu, Pei; Wang, Yuqiang; Xu, Lipeng

    2016-01-01

    AL-1 is a novel andrographolide derivative synthesized by conjugating andrographolide and alpha lipoic acid. AL-1 has been found to increase insulin secretion, decrease blood glucose level and protect β-cell mass and function in alloxan-induced diabetic mouse model. However, the protective mechanism of AL-1 on high glucose-induced pancreatic β-cell injury is still not clear. In the present study, we found that AL-1 reduced reactive oxygen species (ROS) and nitric oxide (NO) generation induced by high glucose in RIN-m cells, and which elevated the activities of superoxide dismutase (SOD) and catalase (CAT). In addition, AL-1 increased the expression of NF-E2-related factor 2 (Nrf2), thioredoxin-1 (Trx-1) and heme oxygenase-1 (HO- 1) proteins in RIN-m cells. These results suggest that AL-1 prevented RIN-m cells from high glucose-induced oxidative damage via upregulation of Nrf2 signaling pathway. PMID:26391852

  1. 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.

  2. Blockade of store-operated calcium entry alleviates high glucose-induced neurotoxicity via inhibiting apoptosis in rat neurons.

    PubMed

    Xu, Zhenkuan; Xu, Wenzhe; Song, Yan; Zhang, Bin; Li, Feng; Liu, Yuguang

    2016-07-25

    Altered store-operated calcium entry (SOCE) has been suggested to be involved in many diabetic complications. However, the association of altered SOCE and diabetic neuronal damage remains unclear. This study aimed to investigate the effects of altered SOCE on primary cultured rat neuron injury induced by high glucose. Our data demonstrated that high glucose increased rat neuron injury and upregulated the expression of store-operated calcium channel (SOC). Inhibition of SOCE by a pharmacological inhibitor and siRNA knockdown of stromal interaction molecule 1 weakened the intracellular calcium overload, restored mitochondrial membrane potential, downregulated cytochrome C release and inhibited cell apoptosis. As well, treatment with the calcium chelator BAPTA-AM prevented cell apoptosis by ameliorating the high glucose-increased intracellular calcium level. These findings suggest that SOCE blockade may alleviate high glucose-induced neuronal damage by inhibiting apoptosis. SOCE might be a promising therapeutic target in diabetic neurotoxicity. PMID:27234048

  3. Curcumin ameliorates high glucose-induced neural tube defects by suppressing cellular stress and apoptosis

    PubMed Central

    Wu, Yanqing; Wang, Fang; Reece, E. Albert; Yang, Peixin

    2015-01-01

    Objectives Curcumin is a naturally occurring polyphenol present in the roots of the Curcuma longa plant (turmeric), which possesses antioxidant, anti-tumorigenic and anti-inflammatory properties. Here, we test whether curcumin treatment reduces high glucose-induced neural tube defects (NTDs), and if this occurs via blocking cellular stress and caspase activation. Study Design Embryonic day 8.5 mouse embryos were collected for use in whole embryo culture under normal glucose (100 mg/dl glucose) or high glucose (300 mg/dl glucose) conditions, with or without curcumin treatment. After 24 h in culture, protein levels of oxidative stress makers, nitrosative stress makers, endoplasmic reticulum (ER) stress makers, cleaved caspase 3 and 8 and the level of lipid peroxides (LPO) were determined in the embryos. After 36 h in culture, embryos were examined for evidence of NTD formation. Results Although 10 μM curcumin did not significantly reduce the rate of NTDs caused by high glucose, 20 μM curcumin significantly ameliorated high glucose-induced NTD formation. Curcumin suppressed oxidative stress in embryos cultured under high glucose conditions. Treatment reduced the levels of the lipid peroxidation marker, 4-hydroxynonenal(4-HNE), nitrotyrosine-modified protein, and LPO. Curcumin also blocked ER 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, curcumin abolished caspase 3 and caspase 8 cleavage in embryos cultured under high glucose conditions. Conclusions Curcumin reduces high glucose-induced NTD formation by blocking cellular stress and caspase activation, suggesting that curcumin supplements could reduce the negative effects of diabetes on the embryo. Further

  4. High glucose induces adipogenic differentiation of muscle-derived stem cells

    PubMed Central

    Aguiari, Paola; Leo, Sara; Zavan, Barbara; Vindigni, Vincenzo; Rimessi, Alessandro; Bianchi, Katiuscia; Franzin, Chiara; Cortivo, Roberta; Rossato, Marco; Vettor, Roberto; Abatangelo, Giovanni; Pozzan, Tullio; Pinton, Paolo; Rizzuto, Rosario

    2008-01-01

    Regeneration of mesenchymal tissues depends on a resident stem cell population, that in most cases remains elusive in terms of cellular identity and differentiation signals. We here show that primary cell cultures derived from adipose tissue or skeletal muscle differentiate into adipocytes when cultured in high glucose. High glucose induces ROS production and PKCβ activation. These two events appear crucial steps in this differentiation process that can be directly induced by oxidizing agents and inhibited by PKCβ siRNA silencing. The differentiated adipocytes, when implanted in vivo, form viable and vascularized adipose tissue. Overall, the data highlight a previously uncharacterized differentiation route triggered by high glucose that drives not only resident stem cells of the adipose tissue but also uncommitted precursors present in muscle cells to form adipose depots. This process may represent a feed-forward cycle between the regional increase in adiposity and insulin resistance that plays a key role in the pathogenesis of diabetes mellitus. PMID:18212116

  5. The Nrf2 Activator Vinylsulfone Reduces High Glucose-Induced Neural Tube Defects by Suppressing Cellular Stress and Apoptosis.

    PubMed

    Dong, Daoyin; Reece, E Albert; Yang, Peixin

    2016-08-01

    The nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway is one of the primary pathways responsible for the cellular defense system against oxidative stress. Oxidative stress-induced apoptosis is a causal event in diabetic embryopathy. Thus, the Nrf2 pathway may play an important role in the induction of diabetic embryopathy. In the present study, we investigated the potentially protective effect of the Nrf2 activator, vinylsulfone, on high glucose-induced cellular stress, apoptosis, and neural tube defects (NTDs). Embryonic day 8.5 (E8.5) whole mouse embryos were cultured in normal (5 mmol/L) or high (16.7 mmol/L) glucose conditions, with or without vinylsulfone. At a concentration of 10 μmol/L, vinylsulfone had an inhibitory effect on high glucose-induced NTD formation, but it was not significant. At a concentration of 20 μmol/L, vinylsulfone significantly reduced high glucose-induced NTDs. In addition, 20 μmol/L vinylsulfone abrogated the high glucose-induced oxidative stress markers lipid hydroperoxide (LPO), 4-hydroxynonenal (4-HNE), and nitrotyrosine-modified proteins. The high glucose-induced endoplasmic reticulum (ER) stress biomarkers were also suppressed by 20 μmol/L vinylsulfone through the inhibition of phosphorylated protein kinase RNA-like ER kinase (PERK), inositol requiring protein 1α (IRE1a), eukaryotic initiation factor 2α (eIF2a), upregulated C/EBP-homologous protein (CHOP), binding immunoglobulin protein (BiP), and x-box binding protein 1 (XBP1) messenger RNA splicing. Furthermore, 20 μmol/L vinylsulfone abolished caspase 3 and caspase 8 cleavage, markers of apoptosis, in embryos cultured under high glucose conditions. The Nrf2 activator, vinylsulfone, is protective against high glucose-induced cellular stress, caspase activation, and subsequent NTD formation. Our data suggest that vinylsulfone supplementation is a potential therapy for diabetes-associated neurodevelopmental defects. PMID:26802109

  6. Aflibercept, bevacizumab and ranibizumab prevent glucose-induced damage in human retinal pericytes in vitro, through a PLA2/COX-2/VEGF-A pathway.

    PubMed

    Giurdanella, Giovanni; Anfuso, Carmelina Daniela; Olivieri, Melania; Lupo, Gabriella; Caporarello, Nunzia; Eandi, Chiara M; Drago, Filippo; Bucolo, Claudio; Salomone, Salvatore

    2015-08-01

    Diabetic retinopathy, a major cause of vision loss, is currently treated with anti-VEGF agents. Here we tested two hypotheses: (i) high glucose damages retinal pericytes, the cell layer surrounding endothelial cells, via VEGF induction, which may be counteracted by anti-VEGFs and (ii) activation of PLA2/COX-2 pathway by high glucose might be upstream and/or downstream of VEGF in perycites, as previously observed in endothelial cells. Human retinal pericytes were treated with high glucose (25mM) for 48h and/or anti-VEGFs (40μg/ml aflibercept, 25μg/ml bevacizumab, 10μg/ml ranibizumab). All anti-VEGFs significantly prevented high glucose-induced cell damage (assessed by LDH release) and improved cell viability (assessed by MTT and Evans blue). High glucose-induced VEGF-A expression, as detected both at mRNA (qPCR) and protein (ELISA) level, while receptor (VEGFR1 and VEGFR2) expression, detected in control condition, was unaffected by treatments. High glucose induced also activation of PLA2/COX-2 pathway, as revealed by increased phosphorylation of cPLA2, COX-2 expression and PGE2 release. Treatment with cPLA2 (50μM AACOCF3) and COX-2 (5μM NS-392) inhibitors prevented both cell damage and VEGF-A induced by high glucose. Finally, challenge with exogenous VEGF-A (10ng/ml) induced VEGF-A expression, while anti-VEGFs reduced VEGF-A expression induced by either high glucose or exogenous VEGF-A. These data indicate that high glucose directly damages pericytes through activation of PLA2/COX-2/VEGF-A pathway. Furthermore, a kind of feed-forward loop between cPLA2/COX-2/PG axis and VEGF appears to operate in this system. Thus, anti-VEGFs afford protection of pericytes from high glucose by inhibiting this loop. PMID:26056075

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

    PubMed

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

    2016-08-01

    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

  8. 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

  9. Curcumin Protects Neonatal Rat Cardiomyocytes against High Glucose-Induced Apoptosis via PI3K/Akt Signalling Pathway

    PubMed Central

    Yu, Wei; Zha, Wenliang; Ke, Zhiqiang; Min, Qing; Li, Cairong; Sun, Huirong; Liu, Chao

    2016-01-01

    The function of curcumin on NADPH oxidase-related ROS production and cardiac apoptosis, together with the modulation of protein signalling pathways, was investigated in cardiomyocytes. Primary cultures of neonatal rat cardiomyocytes were exposed to 30 mmol/L high glucose with or without curcumin. Cell viability, apoptosis, superoxide formation, the expression of NADPH oxidase subunits, and potential regulatory molecules, Akt and GSK-3β, were assessed in cardiomyocytes. Cardiomyocytes exposure to high glucose led to an increase in both cell apoptosis and intracellular ROS levels, which were strongly prevented by curcumin treatment (10 μM). In addition, treatment with curcumin remarkably suppressed the increased activity of Rac1, as well as the enhanced expression of gp91phox and p47phox induced by high glucose. Lipid peroxidation and SOD were reversed in the presence of curcumin. Furthermore, curcumin treatment markedly inhibited the reduced Bcl-2/Bax ratio elicited by high glucose exposure. Moreover, curcumin significantly increased Akt and GSK-3β phosphorylation in cardiomyocytes treated with high glucose. In addition, LY294002 blocked the effects of curcumin on cardiomyocytes exposure to high glucose. In conclusion, these results demonstrated that curcumin attenuated high glucose-induced cardiomyocyte apoptosis by inhibiting NADPH-mediated oxidative stress and this protective effect is most likely mediated by PI3K/Akt-related signalling pathway. PMID:26989696

  10. Autophagy is involved in high glucose-induced heart tube malformation

    PubMed Central

    Wang, Guang; Huang, Wen-qing; Cui, Shu-dan; Li, Shuai; Wang, Xiao-yu; Li, Yan; Chuai, Manli; Cao, Liu; Li, Jiang-chao; Lu, Da-xiang; Yang, Xuesong

    2015-01-01

    Both pre-gestational and gestational diabetes have an adverse impact on heart development, but little is known about the influence on the early stage of heart tube formation. Using early gastrulating chick embryos, we investigated the influence of high glucose on the process of heart tube formation, specifically during the primary heart field phase. We demonstrated that high-glucose exposure resulted in 3 types of heart tube malformation: 1) ventricular hypertrophy, 2) ventricular hypertrophy with dextrocardia and 3) ventricular hypertrophy and dextrocardia with the fusion anomaly of a bilateral primary heart tube. Next, we found that these malformation phenotypes of heart tubes might mainly originate from the migratory anomaly of gastrulating precardiac mesoderm cells rather than cell proliferation in the developmental process of bilateral primary heart field primordia. The treatment of rapamycin (RAPA), an autophagy inducer, led to a similar heart tube malformation phenotype as high glucose. Additionally, high-glucose exposure promoted the expression of the key autophagy protein LC3B in early chick tissue. Atg7 is strongly expressed in the fusion site of bilateral primary heart tubes. All of these data imply that autophagy could be involved in the process of high-glucose-induced malformation of the heart tube. PMID:25738919

  11. 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

  12. Myricitrin Attenuates High Glucose-Induced Apoptosis through Activating Akt-Nrf2 Signaling in H9c2 Cardiomyocytes.

    PubMed

    Zhang, Bin; Chen, Yaping; Shen, Qiang; Liu, Guiyan; Ye, Jingxue; Sun, Guibo; Sun, Xiaobo

    2016-01-01

    Hyperglycemia, as well as diabetes mellitus, has been shown to trigger cardiac cell apoptosis. We have previously demonstrated that myricitrin prevents endothelial cell apoptosis. However, whether myricitrin can attenuate H9c2 cell apoptosis remains unknown. In this study, we established an experiment model in H9c2 cells exposed to high glucose. We tested the hypothesis that myricitrin may inhibit high glucose (HG)-induced cardiac cell apoptosis as determined by TUNEL staining. Furthermore, myricitrin promoted antioxidative enzyme production, suppressed high glucose-induced reactive oxygen species (ROS) production and decreased mitochondrial membrane potential (MMP) in H9c2 cells. This agent significantly inhibited apoptotic protein expression, activated Akt and facilitated the transcription of NF-E2-related factor 2 (Nrf2)-mediated protein (heme oxygenase-1 (HO-1) and quinone oxidoreductase 1 (NQO-1) expression as determined by Western blotting. Significantly, an Akt inhibitor (LY294002) or HO-1 inhibitor (ZnPP) not only inhibited myricitrin-induced HO-1/NQO-1 upregulation but also alleviated its anti-apoptotic effects. In summary, these observations demonstrate that myricitrin activates Nrf2-mediated anti-oxidant signaling and attenuates H9c2 cell apoptosis induced by high glucose via activation of Akt signaling. PMID:27399653

  13. Glucose-induced changes in protein kinase C and nitric oxide are prevented by vitamin E.

    PubMed

    Ganz, M B; Seftel, A

    2000-01-01

    Changes in activity or expression of protein kinase C (PKC), reactive oxygen products, and nitric oxide (NO) may account for the alteration in cell behavior seen in diabetes. These changes have been proposed to be part of the pathophysiology of erectile dysfunction. We sought to ascertain if corpus cavernosal vascular smooth muscle cells (CCSMC) grown in a high glucose milieu exhibit changes in the activity and expression of PKC isoforms, NO, and reactive oxygen products and to find out if these changes are prevented by alpha-tocopherol. Rat CCSMC were grown in 5, 15, and 30 mM glucose concentrations for 3, 7, and 14 days. PKC isoform expression was assayed with isoform-specific antibodies. In CCSMCs grown in 30 mM glucose for 2-wk, PKC-beta(2)-isoform was upregulated (n = 4; P < 0.01), whereas the expression of alpha-, delta-, epsilon-, and beta(1)-isoforms was unchanged. NO as measured by nitrate-to-nitrite ratio was greatly diminished at 14 days in 30 mM (n = 4; P < 0.002) compared with 5 mM glucose. Reactive oxygen products were upregulated at 14 days when they were assayed by the fluorescent probe dichlorofluorescein diacetate bis(acetoxy-methyl) (DCFH-DA) (n = 5; P < 0.01). When these same cells were exposed to alpha-tocopherol for 14 days, there was a reduction of PKC-beta(2) (57.8%; P < 0.01; n = 4) and a reduction in reactive oxygen product formation (71.1%; P < 0.001; n = 4), along with an increase in nitrate-to-nitrite ratio (43.9%; P < 0.01, n = 4). These results suggest that there may be an interrelationship between PKC, NO, and reactive oxygen product formation in CCSMC exposed to a high glucose environment. PMID:10644549

  14. Endoplasmic Reticulum Stress-Mediated Apoptosis Contributing to High Glucose-Induced Vascular Smooth Muscle Cell Calcification.

    PubMed

    Zhu, Qiang; Guo, Runmin; Liu, Chang; Fu, Duguan; Liu, Fuyuan; Hu, Jiefen; Jiang, Hong

    2015-01-01

    Vascular calcification (VC) is a common feature in patients with type 2 diabetes mellitus, a metabolic disorder that is characterized by hyperglycemia (high blood glucose) in the context of insulin resistance and a relative lack of insulin. Recently, a few studies have indicated that a high concentration of glucose amplifies the osteogenesis of vascular smooth muscle cells (VSMCs). Some previous reports state that endoplasmic reticulum (ER) stress-mediated apoptosis was activated in and contributed to VC. However, whether or not high glucose could induce ER stress-mediated apoptosis and then involve the pathogenesis of VC remains unclear. The purpose of the present study was to investigate whether high blood glucose-induced VC in diabetes mellitus is caused by the ER response and subsequent apoptosis. We examined the effects of high glucose on the ER stress response of VSMCs. High glucose treatment drastically increased the ER stress response in VSMCs. The high glucose-induced osteoblastic differentiation of VSMCs was significantly attenuated by pretreatment with 500 μM of 4-PBA (an ER stress inhibitor) prior to the exposure to high glucose, as evidenced by decreases in the expression of Runx2 and activity of alkaline phosphatase, as well as calcium nodules. These results suggest that high glucose induces the ER stress response and apoptosis, leading to high glucose-elicited VC. PMID:26890314

  15. High glucose-induced apoptosis in human coronary artery endothelial cells involves up-regulation of death receptors

    PubMed Central

    2011-01-01

    Background High glucose can induce apoptosis in vascular endothelial cells, which may contribute to the development of vascular complications in diabetes. We evaluated the role of the death receptor pathway of apoptotic signaling in high glucose-induced apoptosis in human coronary artery endothelial cells (HCAECs). Methods HCAECs were treated with media containing 5.6, 11.1, and 16.7 mM of glucose for 24 h in the presence or absence of tumor necrosis factor (TNF)-α. For detection of apoptosis, DNA fragmentation assay was used. HCAEC expression of death receptors were analyzed by the PCR and flow cytometry methods. Also, using immunohistochemical techniques, coronary expression of death receptors was assessed in streptozotocin-nicotinamide-induced type 2 diabetic mice. Results Exposure of HCAECs to high glucose resulted in a significant increase in TNF-R1 and Fas expression, compared with normal glucose. High glucose increased TNF-α production by HCAECs and exogenous TNF-α up-regulated TNF-R1 and Fas expression in HCAECs. High glucose-induced up-regulation of TNF-R1 and Fas expression was undetectable in the presence of TNF-α. Treatment with TNF-R1 neutralizing peptides significantly inhibited high glucose-induced endothelial cell apoptosis. Type 2 diabetic mice displayed appreciable expression of TNF-R1 and Fas in coronary vessels. Conclusions In association with increased TNF-α levels, the death receptors, TNF-R1 and Fas, are up-regulated in HCAECs under high glucose conditions, which could in turn play a role in high glucose-induced endothelial cell apoptosis. PMID:21816064

  16. Myt3 suppression sensitizes islet cells to high glucose-induced cell death via Bim induction.

    PubMed

    Tennant, B R; Vanderkruk, B; Dhillon, J; Dai, D; Verchere, C B; Hoffman, B G

    2016-01-01

    Diabetes is a chronic disease that results from the body's inability to properly control circulating blood glucose levels. The loss of glucose homoeostasis can arise from a loss of β-cell mass because of immune-cell-mediated attack, as in type 1 diabetes, and/or from dysfunction of individual β-cells (in conjunction with target organ insulin resistance), as in type 2 diabetes. A better understanding of the transcriptional pathways regulating islet-cell survival is of great importance for the development of therapeutic strategies that target β-cells for diabetes. To this end, we previously identified the transcription factor Myt3 as a pro-survival factor in islets following acute suppression of Myt3 in vitro. To determine the effects of Myt3 suppression on islet-cell survival in vivo, we used an adenovirus to express an shRNA targeting Myt3 in syngeneic optimal and marginal mass islet transplants, and demonstrate that suppression of Myt3 impairs the function of marginal mass grafts. Analysis of grafts 5 weeks post-transplant revealed that grafts transduced with the shMyt3 adenovirus contained ~20% the number of transduced cells as grafts transduced with a control adenovirus. In fact, increased apoptosis and significant cell loss in the shMyt3-transduced grafts was evident after only 5 days, suggesting that Myt3 suppression sensitizes islet cells to stresses present in the early post-transplant period. Specifically, we find that Myt3 suppression sensitizes islet cells to high glucose-induced cell death via upregulation of the pro-apoptotic Bcl2 family member Bim. Taken together these data suggest that Myt3 may be an important link between glucotoxic and immune signalling pathways. PMID:27195679

  17. Myt3 suppression sensitizes islet cells to high glucose-induced cell death via Bim induction

    PubMed Central

    Tennant, B R; Vanderkruk, B; Dhillon, J; Dai, D; Verchere, C B; Hoffman, B G

    2016-01-01

    Diabetes is a chronic disease that results from the body's inability to properly control circulating blood glucose levels. The loss of glucose homoeostasis can arise from a loss of β-cell mass because of immune-cell-mediated attack, as in type 1 diabetes, and/or from dysfunction of individual β-cells (in conjunction with target organ insulin resistance), as in type 2 diabetes. A better understanding of the transcriptional pathways regulating islet-cell survival is of great importance for the development of therapeutic strategies that target β-cells for diabetes. To this end, we previously identified the transcription factor Myt3 as a pro-survival factor in islets following acute suppression of Myt3 in vitro. To determine the effects of Myt3 suppression on islet-cell survival in vivo, we used an adenovirus to express an shRNA targeting Myt3 in syngeneic optimal and marginal mass islet transplants, and demonstrate that suppression of Myt3 impairs the function of marginal mass grafts. Analysis of grafts 5 weeks post-transplant revealed that grafts transduced with the shMyt3 adenovirus contained ~20% the number of transduced cells as grafts transduced with a control adenovirus. In fact, increased apoptosis and significant cell loss in the shMyt3-transduced grafts was evident after only 5 days, suggesting that Myt3 suppression sensitizes islet cells to stresses present in the early post-transplant period. Specifically, we find that Myt3 suppression sensitizes islet cells to high glucose-induced cell death via upregulation of the pro-apoptotic Bcl2 family member Bim. Taken together these data suggest that Myt3 may be an important link between glucotoxic and immune signalling pathways. PMID:27195679

  18. 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

  19. MicroRNA-24 inhibits high glucose-induced vascular smooth muscle cell proliferation and migration by targeting HMGB1.

    PubMed

    Yang, Jian; Chen, Lihua; Ding, Jiawang; Fan, Zhixing; Li, Song; Wu, Hui; Zhang, Jing; Yang, Chaojun; Wang, Huibo; Zeng, Ping; Yang, Jun

    2016-07-25

    Dysfunction of vascular smooth muscle cells (VSMCs) performs a key role in the pathogenesis of diabetic vascular disease. Recent studies have reported that microRNA-24 (miR-24) may be implicated in diabetes and atherosclerotic vascular diseases. This study was designed to explore the role of miR-24 on VSMC proliferation and migration under high glucose conditions mimicking diabetes, and reveal the underlying mechanism. VSMCs were isolated from rat thoracic aortas, treated with normal glucose (NG, 5.5mM) or high glucose (HG, 30mM) during an incubation period. Cell viability, proliferation and migration were detected by trypan blue staining, BrdU incorporation assay and transwell chamber assay. Gene and protein expression were analyzed by qRT-PCR and Western blot respectively. We also used electrophoretic mobility shift assay (EMSA) to detect nuclear factor kappaB (NF-κB) DNA binding. TNF-α and IL-6 levels were determined by enzyme-linked immunosorbent assay. The results showed that adenovirus-mediated miR-24 overexpression significantly inhibited HG-stimulated VSMC proliferation and migration. Meanwhile, high mobility group box-1 (HMGB1) as a target of miR-24, was also markedly suppressed after miR-24 transfection. Additionally, NF-κB nuclear translocation and DNA binding, TNF-α and IL-6 production were all decreased associated with the down-regulation of HMGB1. The above data indicated that miR-24 is a crucial regulator of high glucose-induced proliferation and migration in VSMCs, and suggests that elevation of miR-24 in vascular system may be a novel therapeutic strategy to prevent the development of diabetic atherosclerosis. PMID:27085480

  20. O-GlcNAcylation involvement in high glucose-induced cardiac hypertrophy via ERK1/2 and cyclin D2.

    PubMed

    Ding, Fang; Yu, Lu; Wang, Meihui; Xu, Shengjie; Xia, Qiang; Fu, Guosheng

    2013-08-01

    Continuous hyperglycemia is considered to be the most significant pathogenesis of diabetic cardiomyopathy, which manifests as cardiac hypertrophy and subsequent heart failure. O-GlcNAcylation has attracted attention as a post-translational protein modification in the past decade. The role of O-GlcNAcylation in high glucose-induced cardiomyocyte hypertrophy remains unclear. We studied the effect of O-GlcNAcylation on neonatal rat cardiomyocytes that were exposed to high glucose and myocardium in diabetic rats induced by streptozocin. High glucose (30 mM) incubation induced a greater than twofold increase in cell size and increased hypertrophy marker gene expression accompanied by elevated O-GlcNAcylation protein levels. High glucose increased ERK1/2 but not p38 MAPK or JNK activity, and cyclin D2 expression was also increased. PUGNAc, an inhibitor of β-N-acetylglucosaminidase, enhanced O-GlcNAcylation and imitated the effects of high glucose. OGT siRNA and ERK1/2 inhibition with PD98059 treatment blunted the hypertrophic response and cyclin D2 upregulation. OGT inhibition also prevented ERK1/2 activation. We also observed concentric hypertrophy and similar changes of O-GlcNAcylation level, ERK1/2 activation and cyclin D2 expression in myocardium of diabetic rats induced by streptozocin. In conclusion, O-GlcNAcylation plays a role in high glucose-induced cardiac hypertrophy via ERK1/2 and cyclin D2. PMID:23665912

  1. Ergothioneine oxidation in the protection against high-glucose induced endothelial senescence: Involvement of SIRT1 and SIRT6.

    PubMed

    D'Onofrio, Nunzia; Servillo, Luigi; Giovane, Alfonso; Casale, Rosario; Vitiello, Milena; Marfella, Raffaele; Paolisso, Giuseppe; Balestrieri, Maria Luisa

    2016-07-01

    Ergothioneine (Egt), the betaine of 2-mercapto-L-histidine, is a dietary antioxidant protecting against many diseases, including cardiovascular disease (CVD), through a redox mechanism different from alkylthiols. Here, experiments were designed to evaluate the mechanisms underlying the beneficial effect of Egt against hyperglycaemia-induced senescence in endothelial cells. To this end, cells were incubated with increasing concentrations of Egt (0.01-1.00mM) for 12h followed by incubation for 48h with high-glucose (25mM). Cell evaluation indicated that viability was not affected by mM concentrations of Egt and that the high-glucose cytotoxicity was prevented with the highest efficacy at 0.5mM Egt. The cytoprotective effect of Egt was paralleled by reduced ROS production, cell senescence, and, interestingly, the formation of hercynine (EH), a betaine we recently found to be produced during the Egt oxidation pathway. Notably, the Egt beneficial effect was exerted through the upregulation of sirtuin 1 (SIRT1) and sirtuin 6 (SIRT6) expression and the downregulation of p66Shc and NF-κB. SIRT1 activity inhibition and SIRT6 gene silencing by small interfering RNA abolished the protective effect of Egt against the high-glucose-induced endothelial senescence. These data provide the first evidence of the Egt ability to interfere with endothelial senescence linked to hyperglycaemia through the regulation of SIRT1 and SIRT6 signaling, thus further strengthening the already assessed role of these two histone deacetylases in type 2 diabetes. PMID:27101740

  2. DSePA Antagonizes High Glucose-Induced Neurotoxicity: Evidences for DNA Damage-Mediated p53 Phosphorylation and MAPKs and AKT Pathways.

    PubMed

    Wang, Kun; Fu, Xiao-Yan; Fu, Xiao-Ting; Hou, Ya-Jun; Fang, Jie; Zhang, Shuai; Yang, Ming-Feng; Li, Da-Wei; Mao, Lei-Lei; Sun, Jing-Yi; Yuan, Hui; Yang, Xiao-Yi; Fan, Cun-Dong; Zhang, Zong-Yong; Sun, Bao-Liang

    2016-09-01

    Hyperglycemia as the major hallmark of diabetic neuropathy severely limited its therapeutic efficiency. Evidences have revealed that selenium (Se) as an essential trace element could effectively reduce the risk of neurological diseases. In the present study, 3,3'-diselenodipropionic acid (DSePA), a derivative of selenocystine, was employed to investigate its protective effect against high glucose-induced neurotoxicity in PC12 cells and evaluate the underlying mechanism. The results suggested that high glucose showed significant cytotoxicity through launching mitochondria-mediated apoptosis in PC12 cells, accompanied by poly (ADP-ribose) polymerase (PARP) cleavage, caspase activation, and mitochondrial dysfunction. Moreover, high glucose also triggered DNA damage and dysregulation of MAPKs and AKT pathways through reactive oxygen species (ROS) overproduction. p53 RNA interference partially suppressed high glucose-induced cytotoxicity and apoptosis, indicating the role of p53 in high glucose-induced signal. However, DSePA pretreatment effectively attenuated high glucose-induced cytotoxicity, inhibited the mitochondrial dysfunction through regulation of Bcl-2 family, and ultimately reversed high glucose-induced apoptotic cell death in PC12 cells. Attenuation of caspase activation, PARP cleavage, DNA damage, and ROS accumulation all confirmed its protective effects. Moreover, DSePA markedly alleviated the dysregulation of AKT and MAPKs pathways induced by high glucose. Our findings revealed that the strategy of using DSePA to antagonize high glucose-induced neurotoxicity may be a highly effective strategy in combating high glucose-mediated neurological diseases. PMID:26232068

  3. 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.

  4. 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.

  5. 6,6'-Bieckol protects insulinoma cells against high glucose-induced glucotoxicity by reducing oxidative stress and apoptosis.

    PubMed

    Park, Mi-Hwa; Heo, Soo-Jin; Kim, Kil-Nam; Ahn, Ginnae; Park, Pyo-Jam; Moon, Sang-Ho; Jeon, Byong-Tae; Lee, Seung-Hong

    2015-10-01

    Pancreatic β cells are highly sensitive to oxidative stress, which might play an important role in β cell death in diabetes. The protective effect of 6,6'-bieckol, a phlorotannin polyphenol compound purified from Ecklonia cava, against high glucose-induced glucotoxicity was investigated in rat insulinoma cells. High glucose (30 mM) treatment induced the death of rat insulinoma cells, but treatment with 10 or 50 μg/mL 6,6'-bieckol significantly inhibited the high glucose-induced glucotoxicity. Furthermore, treatment with 6,6'-bieckol dose-dependently reduced the level of thiobarbituric acid reactive substances, generation of intracellular reactive oxygen species, and the level of nitric oxide, all of which were increased by high glucose concentration. In addition, 6,6'-bieckol protected rat insulinoma cells from apoptosis under high-glucose conditions. These effects were associated with increased expression of the anti-apoptotic protein Bcl-2 and reduced expression of the pro-apoptotic protein Bax. These findings indicate that 6,6'-bieckol could be used as a potential nutraceutical agent offering protection against the glucotoxicity caused by hyperglycemia-induced oxidative stress associated with diabetes. PMID:26343533

  6. The protective effect of daidzein on high glucose-induced oxidative stress in human umbilical vein endothelial cells.

    PubMed

    Park, Mi Hwa; Ju, Jae-Won; Kim, Mihyang; Han, Ji-Sook

    2016-01-01

    Endothelial cell dysfunction is considered a major cause of vascular complications in diabetes. In the present study, we investigated the protective effect of daidzein, a natural isoflavonoid, against high-glucose-induced oxidative damage in human umbilical vein endothelial cells (HUVECs). Treatment with a high concentration of glucose (30 mM) induced oxidative stress in the endothelial cells, against which daidzein protected the cells as demonstrated by significantly increased cell viability. In addition, lipid peroxidation, intracellular reactive oxygen species (ROS) generation, and indirect nitric oxide levels induced by the high glucose treatment were significantly reduced in the presence of daidzein (0.02-0.1 mM) in a dose-dependent manner. High glucose levels induced the overexpression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and NF-κB proteins in HUVECs, which was suppressed by treatment with 0.04 mM daidzein. These findings indicate the potential of daidzein to reduce high glucose-induced oxidative stress. PMID:26756092

  7. ZLN005 protects cardiomyocytes against high glucose-induced cytotoxicity by promoting SIRT1 expression and autophagy.

    PubMed

    Li, Wenju; Li, Xiaoli; Wang, Bin; Chen, Yan; Xiao, Aiping; Zeng, Di; Ou, Dongbo; Yan, Song; Li, Wei; Zheng, Qiangsun

    2016-07-01

    Diabetic cardiomyopathy increases the risk for the development of heart failure independent of coronary artery disease and hypertension. Either type 1 or type 2 diabetes is often accompanied by varying degrees of hyperglycemia, which has been proven to induce myocardial apoptosis in animal models. Recently, a novel small molecule, ZLN005, has been reported to show antidiabetic efficacy in a mouse model, possibly by induction of PGC-1α expression. In this study, we investigated whether ZLN005 protects cardiomyocytes against high glucose-induced cytotoxicity and the mechanisms involved. Neonatal mouse cardiomyocytes were incubated with media containing 5.5 or 33mM glucose for 24h in the presence or absence of ZLN005. ZLN005 treatment led to ameliorated cardiomyocyte oxidative injury, enhanced cell viability, and reduced apoptosis in the high glucose environment. Western blot analysis revealed that high glucose suppressed cardiomyocyte autophagy, whereas ZLN005 increased the expression of autophagy marker proteins ATG5, beclin1, and LC3 II/LC3 I; this increase was accompanied by increased expression of SIRT1. Furthermore, EX527, a SIRT1-specific inhibitor, weakened the protective effects of ZLN005 on cardiomyocytes subjected to high glucose. Taken together, these results suggest that ZLN005 suppresses high glucose-induced cardiomyocyte injury by promoting SIRT1 expression and autophagy. PMID:27208585

  8. Saikosaponin-d protects renal tubular epithelial cell against high glucose induced injury through modulation of SIRT3

    PubMed Central

    Zhao, Lichang; Zhang, Hui; Bao, Jingfang; Liu, Jun; Ji, Zhongning

    2015-01-01

    Saikosaponin-d (Ssd) is one of the major pharmacologically active molecules present in Bupleurum falcatum L, a medical herb against inflammatory diseases in the traditional Chinese medicine. In the current study, we investigated the protective activity of Ssd on diabetic nephropathy along with the underlying mechanisms using renal tubular epithelial cell line (NRK-52E). Our study showed that high glucose stimulation significantly increased NRK-52E cell proliferation. Ssd administration dramatically inhibited high glucose-induced proliferation and DNA synthesis in NRK-52E cell. In addition, high glucose treatment resulted in oxidative stress as shown by increased production of ROS, higher concentration of MDA, and decreased activity of SOD. However, incubation with Ssd reversed such changes in NRK-52E cells. On the molecular level, Ssd also increased the mRNA levels of IDH2 and MnSOD. Moreover, Ssd-treated NRK-52E cells displayed a dramatic enhancement in SIRT3 expression both at mRNA and protein levels. Down-regulation of SIRT3 abolished the protective effects of Ssd on NRK-52E cells. These findings demonstrated that Ssd protected renal tubular epithelial cell against high glucose induced injury via upregulation of SIRT3. PMID:26131275

  9. 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. PMID:26899161

  10. Fyn Mediates High Glucose-Induced Actin Cytoskeleton Reorganization of Podocytes via Promoting ROCK Activation In Vitro.

    PubMed

    Lv, Zhimei; Hu, Mengsi; Ren, Xiaoxu; Fan, Minghua; Zhen, Junhui; Chen, Liqun; Lin, Jiangong; Ding, Nannan; Wang, Qun; Wang, Rong

    2016-01-01

    Fyn, a member of the Src family of tyrosine kinases, is a key regulator in cytoskeletal remodeling in a variety of cell types. Recent studies have demonstrated that Fyn is responsible for nephrin tyrosine phosphorylation, which will result in polymerization of actin filaments and podocyte damage. Thus detailed involvement of Fyn in podocytes is to be elucidated. In this study, we investigated the potential role of Fyn/ROCK signaling and its interactions with paxillin. Our results presented that high glucose led to filamentous actin (F-actin) rearrangement in podocytes, accompanied by paxillin phosphorylation and increased cell motility, during which Fyn and ROCK were markedly activated. Gene knockdown of Fyn by siRNA showed a reversal effect on high glucose-induced podocyte damage and ROCK activation; however, inhibition of ROCK had no significant effects on Fyn phosphorylation. These observations demonstrate that in vitro Fyn mediates high glucose-induced actin cytoskeleton remodeling of podocytes via promoting ROCK activation and paxillin phosphorylation. PMID:26881253

  11. Fyn Mediates High Glucose-Induced Actin Cytoskeleton Reorganization of Podocytes via Promoting ROCK Activation In Vitro

    PubMed Central

    Lv, Zhimei; Hu, Mengsi; Ren, Xiaoxu; Fan, Minghua; Zhen, Junhui; Chen, Liqun; Lin, Jiangong; Ding, Nannan; Wang, Qun; Wang, Rong

    2016-01-01

    Fyn, a member of the Src family of tyrosine kinases, is a key regulator in cytoskeletal remodeling in a variety of cell types. Recent studies have demonstrated that Fyn is responsible for nephrin tyrosine phosphorylation, which will result in polymerization of actin filaments and podocyte damage. Thus detailed involvement of Fyn in podocytes is to be elucidated. In this study, we investigated the potential role of Fyn/ROCK signaling and its interactions with paxillin. Our results presented that high glucose led to filamentous actin (F-actin) rearrangement in podocytes, accompanied by paxillin phosphorylation and increased cell motility, during which Fyn and ROCK were markedly activated. Gene knockdown of Fyn by siRNA showed a reversal effect on high glucose-induced podocyte damage and ROCK activation; however, inhibition of ROCK had no significant effects on Fyn phosphorylation. These observations demonstrate that in vitro Fyn mediates high glucose-induced actin cytoskeleton remodeling of podocytes via promoting ROCK activation and paxillin phosphorylation. PMID:26881253

  12. Rosmarinic Acid suppressed high glucose-induced apoptosis in H9c2 cells by ameliorating the mitochondrial function and activating STAT3.

    PubMed

    Diao, Jiayu; Wei, Jin; Yan, Rui; Liu, Xin; Li, Qing; Lin, Lin; Zhu, Yanhe; Li, Hong

    2016-09-01

    Mitochondrial injury characterized by intracellular reactive oxygen species (ROS) accumulation plays a critical role in hyperglycemia-induced myocardium dysfunction. Previous studies have demonstrated that Rosmarinic Acid (RA) treatment and activating Signal transducer and activator of transcription 3 (STAT3) signaling pathway have protective effects on mitochondrial dysfunction in cardiomyocyte, but there is little data regarding cardiomyocyte under condition of high-glucose. The present study was undertaken to determine the relationship between RA and STAT3 activation, as well as their effects on high glucose-induced mitochondrial injury and apoptosis in H9c2 cardiomyocyte. Our results revealed that RA pretreatment suppressed high glucose-induced apoptosis in H9c2 cells. Moreover, the effect of RA on apoptosis was related with improved mitochondrial function, which was demonstrated by that RA attenuated high glucose-induced ROS generation, inhibited mitochondrial permeability transition pore (MPTP) activation, suppressed cytochrome c release and caspase-3 activation. In addition, the phosphorylation of STAT3 in H9c2 cells was inhibited under condition of high-glucose, but RA improved STAT3 phosphorylation. Importantly, inhibition of STAT3 expression by using STAT3-siRNA partly suppressed the effect of RA on high glucose-induced apoptosis. Taken together, pretreatment with RA suppressed high glucose-induced apoptosis in cardiomyocyte by ameliorating mitochondrial function and activating STAT3. PMID:27402269

  13. Tadalafil Integrates Nitric Oxide-Hydrogen Sulfide Signaling to Inhibit High Glucose-induced Matrix Protein Synthesis in Podocytes*

    PubMed Central

    Lee, Hak Joo; Feliers, Denis; Mariappan, Meenalakshmi M.; Sataranatarajan, Kavithalakshmi; Choudhury, Goutam Ghosh; Gorin, Yves; Kasinath, Balakuntalam S.

    2015-01-01

    Diabetes-induced kidney cell injury involves an increase in matrix protein expression that is only partly alleviated by current treatment, prompting a search for new modalities. We have previously shown that hydrogen sulfide (H2S) inhibits high glucose-induced protein synthesis in kidney podocytes. We tested whether tadalafil, a phosphodiesterase 5 inhibitor used to treat erectile dysfunction, ameliorates high glucose stimulation of matrix proteins by generating H2S in podocytes. Tadalafil abrogated high glucose stimulation of global protein synthesis and matrix protein laminin γ1. Tadalafil inhibited high glucose-induced activation of mechanistic target of rapamycin complex 1 and laminin γ1 accumulation in an AMP-activated protein kinase (AMPK)-dependent manner. Tadalafil increased AMPK phosphorylation by stimulating calcium-calmodulin kinase kinase β. Tadalafil rapidly increased the expression and activity of the H2S-generating enzyme cystathionine γ-lyase (CSE) by promoting its translation. dl-Propargylglycine, a CSE inhibitor, and siRNA against CSE inhibited tadalafil-induced AMPK phosphorylation and abrogated the tadalafil effect on high glucose stimulation of laminin γ1. In tadalafil-treated podocytes, we examined the interaction between H2S and nitric oxide (NO). Nω-Nitro-l-arginine methyl ester and 1H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one, inhibitors of NO synthase (NOS) and soluble guanylyl cyclase, respectively, abolished tadalafil induction of H2S and AMPK phosphorylation. Tadalafil rapidly augmented inducible NOS (iNOS) expression by increasing its mRNA, and siRNA for iNOS and 1400W, an iNOS blocker, inhibited tadalafil stimulation of CSE expression and AMPK phosphorylation. We conclude that tadalafil amelioration of high glucose stimulation of synthesis of proteins including matrix proteins in podocytes requires integration of the NO-H2S-AMPK axis leading to the inhibition of high glucose-induced mechanistic target of rapamycin complex 1

  14. Effect of Baechu Kimchi Added Ecklonia cava Extracts on High Glucose-induced Oxidative Stress in Human Umbilical Vein Endothelial Cells

    PubMed Central

    Lee, Hyun-Ah; Song, Yeong-Ok; Jang, Mi-Soon; Han, Ji-Sook

    2014-01-01

    Endothelial cell dysfunction is considered to be a major cause of vascular complications in diabetes. In the present study, we investigated the protective effect of a baechu kimchi added Ecklonia cava extract (BKE) against high glucose induced oxidative damage in human umbilical vein endothelial cells (HUVECs). Treatment with a high concentration of glucose (30 mM) induced cytotoxicity, whereas treatment with BKE protected HUVECs from high glucose induced damage; by restoring cell viability. In addition, BKE reduced lipid peroxidation, intracellular reactive oxygen species and nitric oxide levels in a dose dependent manner. Treatment with high glucose concentrations also induced the overexpression of inducible nitric oxide synthase, cyclooxygenase-2 and NF-κB proteins in HUVECs, but BKE treatment significantly reduced the overexpression of these proteins. These findings indicate that BKE may be a valuable treatment against high glucose-induced oxidative stress HUVECs. PMID:25320714

  15. Effect of Baechu Kimchi Added Ecklonia cava Extracts on High Glucose-induced Oxidative Stress in Human Umbilical Vein Endothelial Cells.

    PubMed

    Lee, Hyun-Ah; Song, Yeong-Ok; Jang, Mi-Soon; Han, Ji-Sook

    2014-09-01

    Endothelial cell dysfunction is considered to be a major cause of vascular complications in diabetes. In the present study, we investigated the protective effect of a baechu kimchi added Ecklonia cava extract (BKE) against high glucose induced oxidative damage in human umbilical vein endothelial cells (HUVECs). Treatment with a high concentration of glucose (30 mM) induced cytotoxicity, whereas treatment with BKE protected HUVECs from high glucose induced damage; by restoring cell viability. In addition, BKE reduced lipid peroxidation, intracellular reactive oxygen species and nitric oxide levels in a dose dependent manner. Treatment with high glucose concentrations also induced the overexpression of inducible nitric oxide synthase, cyclooxygenase-2 and NF-κB proteins in HUVECs, but BKE treatment significantly reduced the overexpression of these proteins. These findings indicate that BKE may be a valuable treatment against high glucose-induced oxidative stress HUVECs. PMID:25320714

  16. 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.

  17. Protective Effects of Ferulic Acid on High Glucose-Induced Protein Glycation, Lipid Peroxidation, and Membrane Ion Pump Activity in Human Erythrocytes

    PubMed Central

    Sompong, Weerachat; Cheng, Henrique; Adisakwattana, Sirichai

    2015-01-01

    Ferulic acid (FA) is the ubiquitous phytochemical phenolic derivative of cinnamic acid. Experimental studies in diabetic models demonstrate that FA possesses multiple mechanisms of action associated with anti-hyperglycemic activity. The mechanism by which FA prevents diabetes-associated vascular damages remains unknown. The aim of study was to investigate the protective effects of FA on protein glycation, lipid peroxidation, membrane ion pump activity, and phosphatidylserine exposure in high glucose-exposed human erythrocytes. Our results demonstrated that FA (10-100 μM) significantly reduced the levels of glycated hemoglobin (HbA1c) whereas 0.1-100 μM concentrations inhibited lipid peroxidation in erythrocytes exposed to 45 mM glucose. This was associated with increased glucose consumption. High glucose treatment also caused a significant reduction in Na+/K+-ATPase activity in the erythrocyte plasma membrane which could be reversed by FA. Furthermore, we found that FA (0.1-100 μM) prevented high glucose-induced phosphatidylserine exposure. These findings provide insights into a novel mechanism of FA for the prevention of vascular dysfunction associated with diabetes. PMID:26053739

  18. Cytoprotective mechanism of ferulic acid against high glucose-induced oxidative stress in cardiomyocytes and hepatocytes

    PubMed Central

    Song, Yuan; Wen, Luona; Sun, Jianxia; Bai, Weibin; Jiao, Rui; Hu, Yunfeng; Peng, Xichun; He, Yong; Ou, Shiyi

    2016-01-01

    Background Ferulic acid (FA), a phenolic acid, is a potential therapy for diabetes mellitus. FA has been shown to protect against hepatic and myocardial injury and oxidative stress in obese rats with late-stage diabetes, but the mechanism of the antioxidative activity of FA is still unclear. Objective The aim of this study was to elucidate whether FA can prevent damage to cardiomyocytes and hepatocytes caused by high glucose (HG)-induced oxidative stress and whether the protection effects of FA on these cells are related to the Keap1-Nrf2-ARE signaling pathways. Design Cells were divided into four groups: a control group (cultured with normal medium), an HG group (medium containing 80 mmol/L glucose), an FA+HG group (medium containing 80 mmol/L glucose and 1, 5, or 10 µg/mL FA), and a dimethylbiguanide (DMBG)+HG group (medium containing 80 mmol/L glucose and 50 µg/mL DMBG). Results FA treatment significantly increased cell viability and significantly decreased cell apoptosis compared with the HG-treated group. Moreover, FA down-regulated the expression of Keap1 protein and up-regulated the expression of Nrf2 protein and gene transcription of HO-1 and glutathione S-transferase (GST) in a dose-dependent manner. Conclusion FA alleviated the HG-induced oxidative stress and decreased cell apoptosis in hepatocytes and cardiomyocytes. These effects were associated with the Keap1-Nrf2-ARE signaling pathway. PMID:26869273

  19. 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

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

    PubMed

    Fan, Yue; Qiao, Yuan; Huang, Jianmei; Tang, Minke

    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

  1. 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

  2. Identification of compounds from the water soluble extract of Cinnamomum cassia barks and their inhibitory effects against high-glucose-induced mesangial cells.

    PubMed

    Luo, Qi; Wang, Shu-Mei; Lu, Qing; Luo, Jie; Cheng, Yong-Xian

    2013-01-01

    The difficulty of diabetic nephropathy (DN) treatment makes prevention the best choice. Cinnamomum cassia barks, known as Chinese cinnamon or Chinese cassia, is one of the most popular natural spices and flavoring agents in many parts of the World. Since previous reports indicated that Chinese cinnamon extract could be used for the treatment of diabetes, we proposed that this spice may be beneficial for the prevention of DN. However, the responsible compounds need to be further identified. In this study, we isolated three new phenolic glycosides, cinnacassosides A-C (1-3), together with fifteen known compounds from the water soluble extract of Chinese cinnamon. The structures of the new compounds were identified by comprehensive spectroscopic evidence. Eleven compounds (6-9, 11, 13-18) were isolated from this spice for the first time, despite extensive research on this species in the past, which added new facets for the chemical profiling of this spice. These isolates were purposely evaluated for their inhibitory effects on IL-6 and extracellular matrix production in mesangial cells which are definitely implicated in DN. The results showed that compounds 4-8 could inhibit over secretion of IL-6, collagen IV and fibronectin against high-glucose-induced mesangial cells at 10 mM, suggesting that Chinese cinnamon could be used as a functional food against DN. PMID:24013407

  3. 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. PMID:25710929

  4. Effects of methanolic extracts of edible plants on RAGE in high-glucose-induced human endothelial cells.

    PubMed

    Okada, Mizue; Okada, Yoshinori

    2015-01-01

    Advanced glycation end products' (AGEs) engagement of a cell-surface receptor for AGEs (RAGE) has been causally implicated in the pathogenesis of vascular complications in diabetic patients. Methanolic extracts from edible plants (MEEP) are naturally occurring phenolic compounds. The phenolic compounds have been reported to possess potent radical-scavenging properties. We investigated whether MEEP could inhibit high glucose-induced RAGE production through interference with reactive oxygen species generation in endothelial cells (ECs). ECs were incubated with 4.5 g/l of glucose in culture medium treated with 21 MEEP. Determination of RAGE production in the culture supernatants was performed by colorimetric ELISA. DNA damage was determined by using the 8-hydroxydeoxyguanosine ELISA kit. Because peroxynitrite radicals with stronger toxicity were produced by nitric oxide radical (NO), the NO scavenging activity of MEEP was assessed as nitrite generation. Peroxynitrite radical-dependent oxidation inhibition by MEEP was estimated by the Crow method. The results showed that four extracts reduced RAGE production. The extract from onion peel showed the highest RAGE production inhibition activity, followed by that of onion rhizome, cow pea and burdock. The results showed that RAGE production is correlated with the above-mentioned indicators. This study supports the utilization of four extracts for improved treatment of diabetic complications. PMID:26407112

  5. 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.

  6. Quercetin protects against high glucose-induced damage in bone marrow-derived endothelial progenitor cells.

    PubMed

    Zhao, Li-Rong; Du, Yu-Jun; Chen, Lei; Liu, Zhi-Gang; Pan, Yue-Hai; Liu, Jian-Feng; Liu, Bin

    2014-10-01

    Endothelial progenitor cells (EPCs), a group of bone marrow-derived pro-angiogenic cells, contribute to vascular repair after damage. EPC dysfunction exists in diabetes and results in poor wound healing in diabetic patients with trauma or surgery. The aim of the present study was to determine the effect of quercetin, a natural flavonoid on high glucose‑induced damage in EPCs. Treatment with high glucose (40 mM) decreased cell viability and migration, and increased oxidant stress, as was evidenced by the elevated levels of reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase in bone marrow-derived EPCs. Moreover, high glucose reduced the levels of endothelial nitric oxide synthase (eNOS) phosphorylation, nitric oxide (NO) production and intracellular cyclic guanosine monophosphate (cGMP). Quercetin supplement protected against high glucose‑induced impairment in cell viability, migration, oxidant stress, eNOS phosphorylation, NO production and cGMP levels. Quercetin also increased Sirt1 expression in EPCs. Inhibition of Sirt1 by a chemical antagonist sirtinol abolished the protective effect of quercetin on eNOS phosphorylation, NO production and cGMP levels following high glucose stress. To the best of our knowledge, the results provide the first evidence that quercetin protects against high glucose‑induced damage by inducing Sirt1-dependent eNOS upregulation in EPCs, and suggest that quercetin is a promising therapeutic agent for diabetic patients undergoing surgery or other invasive procedures. PMID:25197782

  7. c-Src tyrosine kinase mediates high glucose-induced endothelin-1 expression.

    PubMed

    Manea, Simona-Adriana; Fenyo, Ioana Madalina; Manea, Adrian

    2016-06-01

    Endothelin-1 (ET-1) plays an important role in the pathophysiology of diabetes-associated cardiovascular disorders. The molecular mechanisms leading to ET-1 upregulation in diabetes are not entirely defined. c-Src tyrosine kinase regulates important pathophysiological aspects of vascular response to insults. In this study, we aimed to elucidate whether high glucose-activated c-Src signaling plays a role in the regulation of ET-1 expression. Human endothelial cells EAhy926 (ECs) were exposed to normal or high levels of glucose for 24h. Male C57BL/6J mice were rendered diabetic with streptozotocin and then treated with a specific c-Src inhibitor (Src I1) or c-Src siRNA. Real-time PCR, Western blot, and ELISA, were used to investigate ET-1 regulation. The c-Src activity and expression were selectively downregulated by pharmacological inhibition and siRNA-mediated gene silencing, respectively. High glucose dose-dependently up-regulated c-Src phosphorylation and ET-1 gene and protein expression levels in human ECs. Chemical inhibition or silencing of c-Src significantly decreased the high-glucose augmented ET-1 expression in cultured ECs. In vivo studies showed significant elevations in the aortic ET-1 mRNA expression and plasma ET-1 concentration in diabetic mice compared to non-diabetic animals. Treatment with Src I1, as well as in vivo silencing of c-Src, significantly reduced the upregulated ET-1 expression in diabetic mice. These data provide new insights into the regulation of ET-1 expression in endothelial cells in diabetes. Pharmacological targeting of c-Src activity and/or expression may represent a potential therapeutic strategy to reduce ET-1 level and to counteract diabetes-induced deleterious vascular effects. PMID:27102411

  8. 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. PMID:24011924

  9. 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.

  10. 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. PMID:24609927

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

    SciTech Connect

    Chao, Louis Kuoping; Chang, W.-T.; Shih, Y.-W.; Huang, J.-S.

    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.

  12. 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. PMID:26902399

  13. Aralia taibaiensis Protects Cardiac Myocytes against High Glucose-Induced Oxidative Stress and Apoptosis.

    PubMed

    Duan, Jialin; Wei, Guo; Guo, Chao; Cui, Jia; Yan, Jiajia; Yin, Ying; Guan, Yue; Weng, Yan; Zhu, Yanrong; Wu, Xiaoxiao; Wang, Yanhua; Xi, Miaomiao; Wen, Aidong

    2015-01-01

    Patients with type 2 diabetes have increased cardiovascular disease risk compared with those without diabetes. Hyperglycemia can induce reactive oxygen species (ROS) generation, which contributes to the development of diabetic cardiomyopathy. Our previous study has demonstrated that the total saponins of Aralia taibaiensis (sAT), a frequently-used antidiabetic medicine in traditional Chinese medicine (TCM), can scavenge free radicals in vitro and have good anti-oxidant ability on lipid peroxidation of rat liver microsomes. This work was designed to investigate whether sAT could protect the heart while it was used in the treatment of diabetes. Oxidative stress was induced in H9c2 cells by high glucose (33 mM) and glucose oxidase (15 mU, G/GO) and the protective effects of sAT were evaluated. Treatment of H9c2 cells with G/GO resulted in an increase in cell death, intracellular ROS level and cell oxidative injury, which were markedly reduced by sAT treatment. Further study revealed that sAT induced the nuclear translocation of Nrf2 and expression of its downstream targets. Moreover, Nrf2 siRNA markedly abolished the cytoprotective effects of sAT. sAT exerted cytoprotective effects against oxidative stress induced by hyperglycemia and the cardioprotective effects of sAT might be through the Nrf2/ARE pathway. Thus, sAT might be a promising candidate for the treatment of diabetic cardiomyopathy. PMID:26446201

  14. Sphingosine kinase-1 pathway mediates high glucose-induced fibronectin expression in glomerular mesangial cells.

    PubMed

    Lan, Tian; Liu, Weihua; Xie, Xi; Xu, Suowen; Huang, Kaipeng; Peng, Jing; Shen, Xiaoyan; Liu, Peiqing; Wang, Lijing; Xia, Pu; Huang, Heqing

    2011-12-01

    Diabetic nephropathy is characterized by accumulation of glomerular extracellular matrix proteins, such as fibronectin (FN). Here, we investigated whether sphingosine kinase (SphK)1 pathway is responsible for the elevated FN expression in diabetic nephropathy. The SphK1 pathway and FN expression were examined in streptozotocin-induced diabetic rat kidney and glomerular mesangial cells (GMC) exposed to high glucose (HG). FN up-regulation was concomitant with activation of the SphK1 pathway as reflected in an increase in the expression and activity of SphK1 and sphingosine 1-phosphate (S1P) production in both diabetic kidney and HG-treated GMC. Overexpression of wild-type SphK1 (SphK(WT)) significantly induced FN expression, whereas treatment with a SphK inhibitor, N,N-dimethylsphingosine, or transfection of SphK1 small interference RNA or dominant-negative SphK1 (SphK(G82D)) abolished HG-induced FN expression. Furthermore, addition of exogenous S1P significantly induced FN expression in GMC with an induction of activator protein 1 (AP-1) activity. Inhibition of AP-1 activity by curcumin attenuated the S1P-induced FN expression. Finally, by inhibiting SphK1 activity, both N,N-dimethylsphingosine and SphK(G82D) markedly attenuated the HG-induced AP-1 activity. Taken together, these results demonstrated that the SphK1 pathway plays a critical role in matrix accumulation in GMC under diabetic condition, suggesting that the SphK1 pathway could be a potential therapeutic target for diabetic nephropathy. PMID:21998146

  15. Sphingosine Kinase-1 Pathway Mediates High Glucose-Induced Fibronectin Expression in Glomerular Mesangial Cells

    PubMed Central

    Lan, Tian; Liu, Weihua; Xie, Xi; Xu, Suowen; Huang, Kaipeng; Peng, Jing; Shen, Xiaoyan; Liu, Peiqing; Wang, Lijing; Xia, Pu

    2011-01-01

    Diabetic nephropathy is characterized by accumulation of glomerular extracellular matrix proteins, such as fibronectin (FN). Here, we investigated whether sphingosine kinase (SphK)1 pathway is responsible for the elevated FN expression in diabetic nephropathy. The SphK1 pathway and FN expression were examined in streptozotocin-induced diabetic rat kidney and glomerular mesangial cells (GMC) exposed to high glucose (HG). FN up-regulation was concomitant with activation of the SphK1 pathway as reflected in an increase in the expression and activity of SphK1 and sphingosine 1-phosphate (S1P) production in both diabetic kidney and HG-treated GMC. Overexpression of wild-type SphK1 (SphKWT) significantly induced FN expression, whereas treatment with a SphK inhibitor, N,N-dimethylsphingosine, or transfection of SphK1 small interference RNA or dominant-negative SphK1 (SphKG82D) abolished HG-induced FN expression. Furthermore, addition of exogenous S1P significantly induced FN expression in GMC with an induction of activator protein 1 (AP-1) activity. Inhibition of AP-1 activity by curcumin attenuated the S1P-induced FN expression. Finally, by inhibiting SphK1 activity, both N,N-dimethylsphingosine and SphKG82D markedly attenuated the HG-induced AP-1 activity. Taken together, these results demonstrated that the SphK1 pathway plays a critical role in matrix accumulation in GMC under diabetic condition, suggesting that the SphK1 pathway could be a potential therapeutic target for diabetic nephropathy. PMID:21998146

  16. High glucose induces autophagy of MC3T3-E1 cells via ROS-AKT-mTOR axis.

    PubMed

    Wang, Xiaoju; Feng, Zhengping; Li, Jiling; Chen, Lixue; Tang, Weixue

    2016-07-01

    In the present study, we investigate the function of ROS-AKT-mTOR axis on the apoptosis, proliferation and autophagy of MC3T3-E1 cells, and the proliferation of MC3T3-E1 cells after autophagy inhibition under high glucose conditions. MC3T3-E1 cells cultured in vitro were divided into the following groups: normal control group, N-acetylcysteine (NAC) group, 11.0 mM high glucose group, 11.0 mM high glucose + NAC group, 22.0 mM high glucose group, 22.0 mM high glucose + NAC group, CQ group, 22.0 mM high glucose + CQ group, 3-MA group and 3-MA + 22.0 mM high glucose group. ROS production was measured by DCFH-DA fluorescent probe. Cell proliferation was measured by MTT assay. Cells in different groups were stained with Annexin V-FITC/PI, and then apoptosis rate was detected by flow cytometry. Nucleus morphology was observed under fluorescence microscope after being incubated with Honchest33258. Protein expression was measured using Western blotting and immunofluorescence. Cell apoptosis and proliferation in high glucose group were increased and decreased, respectively, in a dose-dependent manner. Autophagy was significantly induced in high glucose group, even though different concentration of glucose induced autophagy in different stages of autophagy. ROS production in MC3T3-E1 cells was remarkably increased in high glucose group, but not in a dose-dependent manner. NAC, as an antioxidant, reduced ROS production and ameliorated cell apoptosis, proliferation abnormity and autophagy caused by high glucose. Expression of p-AKT and p-mTOR proteins were dramatically decreased in high glucose group, and NAC reversed their expression. In addition, 3-MA, an inhibitor of autophagy, significantly decreased the proliferation of MC3T3-E1 cells. When cocultured with 22.0 mM glucose that induced autophagy, proliferation of MC3T3-E1 cells was not affected compared to 22.0 mM high glucose group. Our present findings reveal that high glucose affects apoptosis

  17. Curcumin attenuates high glucose-induced podocyte apoptosis by regulating functional connections between caveolin-1 phosphorylation and ROS

    PubMed Central

    Sun, Li-na; Liu, Xiang-chun; Chen, Xiang-jun; Guan, Guang-ju; Liu, Gang

    2016-01-01

    Aim: Caveolin-1 (cav-1) is a major multifunctional scaffolding protein of caveolae. Cav-1 is primarily expressed in mesangial cells, renal proximal tubule cells and podocytes in kidneys. Recent evidence shows that the functional connections between cav-1 and ROS play a key role in many diseases. In this study we investigated whether regulating the functional connections between cav-1 and ROS in kidneys contributed to the beneficial effects of curcumin in treating diabetic nephropathy in vitro and in vivo. Methods: Cultured mouse podocytes (mpc5) were incubated in a high glucose (HG, 30 mmol/L) medium for 24, 48 or 72 h. Male rats were injected with STZ (60 mg/kg, ip) to induce diabetes. ROS generation, SOD activity, MDA content and caspase-3 activity in the cultured cells and kidney cortex homogenate were determined. Apoptotic proteins and cav-1 phosphorylation were analyzed using Western blot analyses. Results: Incubation in HG-containing medium time-dependently increased ROS production, oxidative stress, apoptosis, and cav-1 phosphorylation in podocytes. Pretreatment with curcumin (1, 5, and 10 μmol/L) dose-dependently attenuated these abnormalities in HG-treated podocytes. Furthermore, in HG-containing medium, the podocytes transfected with a recombinant plasmid GFP-cav-1 Y14F (mutation at a cav-1 phosphorylation site) exhibited significantly decreased ROS production and apoptosis compared with the cells transfected with empty vector. In diabetic rats, administration of curcumin (100 or 200 mg/kg body weight per day, ig, for 8 weeks) not only significantly improved the renal function, but also suppressed ROS levels, oxidative stress, apoptosis and cav-1 phosphorylation in the kidneys. Conclusion: Curcumin attenuates high glucose-induced podocyte apoptosis in vitro and diabetic nephropathy in vivo partly through regulating the functional connections between cav-1 phosphorylation and ROS. PMID:26838071

  18. Ramipril protects the endothelium from high glucose-induced dysfunction through CaMKKβ/AMPK and heme oxygenase-1 activation.

    PubMed

    Tian, Shiliu; Ge, Xinfa; Wu, Ke; Yang, Huabing; Liu, Yu

    2014-07-01

    This study aims to investigate the effects of ramipril (RPL) on endothelial dysfunction associated with diabetes mellitus using cultured human aortic endothelial cells (HAECs) and a type 2 diabetic animal model. The effect of RPL on vasodilatory function in fat-fed, streptozotocin-treated rats was assessed. RPL treatment of 8 weeks alleviated insulin resistance and inhibited the decrease in endothelium-dependent vasodilation in diabetic rats. RPL treatment also reduced serum advanced glycation end products (AGE) concentration and rat aorta reactive oxygen species formation and increased aorta endothelium heme oxygenase-1 (HO-1) expression. Exposure of HAECs to high concentrations of glucose induced prolonged oxidative stress, apoptosis, and accumulation of AGEs. These effects were abolished by incubation of ramiprilat (RPT), the active metabolite of RPL. However, treatment of HAECs with STO-609, a CaMKKβ (Ca(2+)/calmodulin-dependent protein kinase kinase-β) inhibitor; compound C, an AMPK (AMP-activated protein kinase) inhibitor; and Zn(II)PPIX, a selective HO-1 inhibitor, blocked these beneficial effects of RPT. In addition, RPT increased nuclear factor erythroid 2-related factor-2 (Nrf-2) nuclear translocation and activation in a CaMKKβ/AMPK pathway-dependent manner, leading to increased expression of the Nrf-2-regulated antioxidant enzyme, HO-1. The inhibition of CaMKKβ or AMPK by pharmaceutical approach ablated RPT-induced HO-1 expression. Taken together, RPL ameliorates insulin resistance and endothelial dysfunction in diabetes via reducing oxidative stress. These effects are mediated by RPL activation of CaMKK-β, which in turn activates the AMPK-Nrf-2-HO-1 pathway for enhanced endothelial function. PMID:24741076

  19. 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

  20. 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. PMID:25816073

  1. 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. PMID:26739493

  2. Saponins from Platycodon grandiflorum inhibit hepatic lipogenesis through induction of SIRT1 and activation of AMP-activated protein kinase in high-glucose-induced HepG2 cells.

    PubMed

    Hwang, Yong Pil; Choi, Jae Ho; Kim, Hyung Gyun; Lee, Hyun-Sun; Chung, Young Chul; Jeong, Hye Gwang

    2013-09-01

    Saponins from the roots of Platycodon grandiflorum (Changkil saponins, CKS) have antioxidant and hepatoprotective properties. This study investigated the effects of CKS on AMP-activated protein kinase (AMPK) activation and hepatic lipogenesis in HepG2 cells. CKS suppressed high-glucose-induced lipid accumulation and inhibited high-glucose-induced fatty acid synthase (FAS) and sterol regulatory element binding protein-1c (SREBP-1c) expression in HepG2 cells. Moreover, the use of a pharmacological AMPK inhibitor revealed that AMPK is essential for the suppression of SREBP-1c expression in CKS-treated cells. Finally, the activation of calcium/calmodulin-dependent kinase kinase β (CaMKKβ) and SIRT1 was necessary for CKS-enhanced activation of AMPK. These results indicate that CKS prevents lipid accumulation in HepG2 cells by blocking the expression of SREBP-1c and FAS through SIRT1 and CaMKKβ/AMPK activation. Using CKS to target AMPK activation may provide a promising approach for the prevention lipogenesis. PMID:23578622

  3. SREBP and MDT-15 protect C. elegans from glucose-induced accelerated aging by preventing accumulation of saturated fat

    PubMed Central

    Lee, Dongyeop; Jeong, Dae-Eun; Son, Heehwa G.; Yamaoka, Yasuyo; Kim, Hyunmin; Seo, Keunhee; Khan, Abdul Aziz; Roh, Tae-Young; Moon, Dae Won; Lee, Youngsook; Lee, Seung-Jae V.

    2015-01-01

    Glucose-rich diets shorten the life spans of various organisms. However, the metabolic processes involved in this phenomenon remain unknown. Here, we show that sterol regulatory element-binding protein (SREBP) and mediator-15 (MDT-15) prevent the life-shortening effects of a glucose-rich diet by regulating fat-converting processes in Caenorhabditis elegans. Up-regulation of the SREBP/MDT-15 transcription factor complex was necessary and sufficient for alleviating the life-shortening effect of a glucose-rich diet. Glucose feeding induced key enzymes that convert saturated fatty acids (SFAs) to unsaturated fatty acids (UFAs), which are regulated by SREBP and MDT-15. Furthermore, SREBP/MDT-15 reduced the levels of SFAs and moderated glucose toxicity on life span. Our study may help to develop strategies against elevated blood glucose and free fatty acids, which cause glucolipotoxicity in diabetic patients. PMID:26637528

  4. SREBP and MDT-15 protect C. elegans from glucose-induced accelerated aging by preventing accumulation of saturated fat.

    PubMed

    Lee, Dongyeop; Jeong, Dae-Eun; Son, Heehwa G; Yamaoka, Yasuyo; Kim, Hyunmin; Seo, Keunhee; Khan, Abdul Aziz; Roh, Tae-Young; Moon, Dae Won; Lee, Youngsook; Lee, Seung-Jae V

    2015-12-01

    Glucose-rich diets shorten the life spans of various organisms. However, the metabolic processes involved in this phenomenon remain unknown. Here, we show that sterol regulatory element-binding protein (SREBP) and mediator-15 (MDT-15) prevent the life-shortening effects of a glucose-rich diet by regulating fat-converting processes in Caenorhabditis elegans. Up-regulation of the SREBP/MDT-15 transcription factor complex was necessary and sufficient for alleviating the life-shortening effect of a glucose-rich diet. Glucose feeding induced key enzymes that convert saturated fatty acids (SFAs) to unsaturated fatty acids (UFAs), which are regulated by SREBP and MDT-15. Furthermore, SREBP/MDT-15 reduced the levels of SFAs and moderated glucose toxicity on life span. Our study may help to develop strategies against elevated blood glucose and free fatty acids, which cause glucolipotoxicity in diabetic patients. PMID:26637528

  5. 6,6'-bieckol isolated from Ecklonia cava protects oxidative stress through inhibiting expression of ROS and proinflammatory enzymes in high-glucose-induced human umbilical vein endothelial cells.

    PubMed

    Park, Mi-Hwa; Heo, Soo-Jin; Park, Pyo-Jam; Moon, Sang-Ho; Sung, Si-Heung; Jeon, Byong-Tae; Lee, Seung-Hong

    2014-09-01

    Hyperglycemia-induced oxidative stress accelerates endothelial cell dysfunctions, which cause various complications of diabetes. The protective effects of 6,6'-bieckol (BEK), one of phlorotannin compound purified from Ecklonia cava against high-glucose-induced oxidative stress was investigated using human umbilical vein endothelial cells (HUVECs), which is susceptible to oxidative stress. High glucose (30 mM) treatment induced HUVECs' cell death, but BEK, at concentration 10 or 50 μg/ml, significantly inhibited the high-glucose-induced cytotoxicity. Furthermore, treatment with BEK dose-dependently decreased thiobarbituric acid reactive substances (TBARS), intracellular reactive oxygen species (ROS) generation, and nitric oxide level increased by high glucose. In addition, high glucose levels induced the overexpressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and nuclear factor-kappa B (NF-κB) proteins in HUVECs, but BEK treatment reduced the overexpressions of these proteins. These findings indicate that BEK is a potential therapeutic agent that will prevent diabetic endothelial dysfunction and related complications. PMID:25086922

  6. 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

  7. 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. PMID:26114862

  8. A novel polysaccharide compound derived from algae extracts protects retinal pigment epithelial cells from high glucose-induced oxidative damage in vitro.

    PubMed

    Xie, Peiyu; Fujii, Isao; Zhao, Ji'en; Shinohara, Makoto; Matsukura, Makoto

    2012-01-01

    Diabetic retinopathy is a common complication of diabetes mellitus (DM). The oxidative damage inflicted on retinal pigment epithelial (RPE) cells by high glucose closely approximates the molecular basis for the loss of vision associated with this disease. We investigate a novel algae-derived polysaccharide compound for its role in protecting ARPE-19 cells from high glucose-induced oxidative damage. ARPE-19 cells were cultured for 4 d with normal concentration of D-glucose, and exposed to either normal or high concentrations of D-glucose in the presence or absence of the polysaccharide compound at variety of concentrations for another 48 h. Taurine was used as a positive control. Activity of super oxide dismutase (SOD) and concentration of glutathione (GSH) were measured as well as cytotoxicity of high glucose and the polysaccharide compound. To analyse cellular damage by high glucose, activation of Annexin V and p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) were examined. Our results showed that a significant cellular damage on ARPE-19 cells after 48 h treatment with high glucose, accompanied by a decrease in SOD activity and GSH concentration; high glucose also caused ARPE-19 cell apoptosis and activation of p38MAPK and ERK. As the non-toxic polysaccharide compound protected ARPE-19 cells from high glucose-induced cellular damage, the compound recovered SOD activity and concentration of GSH in the cells. The compound also abrogated the cell apoptosis and activation of p38MAPK and ERK. Therefore, the polysaccharide compound derived from algae extracts could be unique candidate for a new class of anti-DM and anti-oxidative damage. PMID:22975494

  9. Attenuation of high-glucose-induced inflammatory response by a novel curcumin derivative B06 contributes to its protection from diabetic pathogenic changes in rat kidney and heart.

    PubMed

    Pan, Yong; Zhu, Guanghui; Wang, Yi; Cai, Lu; Cai, Yuepiao; Hu, Jie; Li, Yilan; Yan, Yongbo; Wang, Zengshou; Li, Xiaokun; Wei, Tiemin; Liang, Guang

    2013-01-01

    There is increasing evidence indicating that inflammatory processes are involved in the development and progression of diabetic complications. However, effective anti-inflammatory treatments for patients who have diabetic complications have yet been practically identified. Curcumin is a main component of Curcuma longa with numerous pharmacological activities. Previously, we synthesized a novel curcumin analogue (B06) that exhibited an improved pharmacokinetic and enhanced anti-inflammatory activity compared to curcumin. The present study aimed to test the hypothesis that B06 may reduce high-glucose-induced inflammation and inflammation-mediated diabetic complications. In vitro, pretreatment with B06 at a concentration of 5 μM significantly reduced the high-glucose-induced overexpression of inflammatory cytokines in macrophages. This anti-inflammatory activity of B06 is associated with its inhibition of c-Jun N-terminal kinase/nuclear factor κB activation. In vivo, despite that B06 administration at 0.2 mg · kg(-1) · d(-1) for 6 weeks did not affect the blood glucose profile of diabetic rats, the B06-treated animals displayed significant decreases in inflammatory mediators in the serum, kidney, and heart and renal macrophage infiltration. This was accompanied with an attenuation of diabetes-induced structural and functional abnormalities in the kidney and heart. Taken together, these data suggest that the novel derivative B06 might be a potential therapeutic agent for diabetic complications via an anti-inflammatory mechanism and support the potential application in diabetic complication therapy via anti-inflammatory strategy. PMID:22819547

  10. 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

  11. Overexpression of uncoupling protein 2 inhibits the high glucose-induced apoptosis of human umbilical vein endothelial cells

    PubMed Central

    HE, YING; LUAN, ZHOU; FU, XUNAN; XU, XUN

    2016-01-01

    Ectopic apoptosis of vascular cells plays a critical role in the early stage development of diabetic retinopathy (DR). Uncoupling protein 2 (UCP2) is a mitochondrial modulator which protects against endothelial dysfunction. However, the role which UCP2 plays in endothelial apoptosis and its association with DR was unclear. In the present study, we investigated whether UCP2 functioned as an inhibitor of DR in endothelial cells. Firstly, we noted that in UCP2-knockout mice retinal cell death and damage in vivo was similar to that of db/db diabetic mice. Additionally, UCP2 knockdown induced caspase-3 activation and exaggerated high glucose (HG)-induced apoptosis of human umbilical vein endothelial cells (HUVECs). Conversely, adenovirus-mediated UCP2 overexpression inhibited the apoptosis of HUVECs and HG-induced caspase-3 activation. Furthermore, HG treatment resulted in the opening of the permeability transition pore (PTP) and liberation of cytochrome c from mitochondria to the cytosol in HUVECs. Notably, UCP2 overexpression inhibited these processes. Furthermore, adenovirus-mediated UCP2 overexpression led to a significant increase in intracellular nitric oxide (NO) levels and a decrease in reactive oxygen species (ROS) generation in HUVECs. Collectively, these data suggest that UCP2 plays an anti-apoptotic role in endothelial cells. Thus, we suggest that approaches which augment UCP2 expression in vascular endothelial cells aid in preventing the early stage development and progression of DR. PMID:26846204

  12. High glucose induces Smad activation via the transcriptional coregulator p300 and contributes to cardiac fibrosis and hypertrophy

    PubMed Central

    2014-01-01

    Background Despite advances in the treatment of heart failure, mortality remains high, particularly in individuals with diabetes. Activated transforming growth factor beta (TGF-β) contributes to the pathogenesis of the fibrotic interstitium observed in diabetic cardiomyopathy. We hypothesized that high glucose enhances the activity of the transcriptional co-activator p300, leading to the activation of TGF-β via acetylation of Smad2; and that by inhibiting p300, TGF-β activity will be reduced and heart failure prevented in a clinically relevant animal model of diabetic cardiomyopathy. Methods p300 activity was assessed in H9c2 cardiomyoblasts under normal glucose (5.6 mmol/L—NG) and high glucose (25 mmol/L—HG) conditions. 3H-proline incorporation in cardiac fibroblasts was also assessed as a marker of collagen synthesis. The role of p300 activity in modifying TGF-β activity was investigated with a known p300 inhibitor, curcumin or p300 siRNA in vitro, and the functional effects of p300 inhibition were assessed using curcumin in a hemodynamically validated model of diabetic cardiomyopathy – the diabetic TG m(Ren-2)27 rat. Results In vitro, H9c2 cells exposed to HG demonstrated increased p300 activity, Smad2 acetylation and increased TGF-β activity as assessed by Smad7 induction (all p < 0.05 c/w NG). Furthermore, HG induced 3H-proline incorporation as a marker of collagen synthesis (p < 0.05 c/w NG). p300 inhibition, using either siRNA or curcumin reduced p300 activity, Smad acetylation and TGF-β activity (all p < 0.05 c/w vehicle or scrambled siRNA). Furthermore, curcumin therapy reduced 3H-proline incorporation in HG and TGF-β stimulated fibroblasts (p < 0.05 c/w NG). To determine the functional significance of p300 inhibition, diabetic Ren-2 rats were randomized to receive curcumin or vehicle for 6 weeks. Curcumin treatment reduced cardiac hypertrophy, improved diastolic function and reduced extracellular matrix production, without

  13. High levels of glucose induce "metabolic memory" in cardiomyocyte via epigenetic histone H3 lysine 9 methylation.

    PubMed

    Yu, Xi-Yong; Geng, Yong-Jian; Liang, Jia-Liang; Zhang, Saidan; Lei, He-Ping; Zhong, Shi-Long; Lin, Qiu-Xiong; Shan, Zhi-Xin; Lin, Shu-Guang; Li, Yangxin

    2012-09-01

    Diabetic patients continue to develop inflammation and cardiovascular complication even after achieving glycemic control, suggesting a "metabolic memory". Metabolic memory is a major challenge in the treatment of diabetic complication, and the mechanisms underlying metabolic memory are not clear. Recent studies suggest a link between chromatin histone methylation and metabolic memory. In this study, we tested whether histone 3 lysine-9 tri-methylation (H3K9me3), a key epigenetic chromatin marker, was involved in high glucose (HG)-induced inflammation and metabolic memory. Incubating cardiomyocyte cells in HG resulted in increased levels of inflammatory cytokine IL-6 mRNA when compared with myocytes incubated in normal culture media, whereas mannitol (osmotic control) has no effect. Chromatin immunoprecipitation (ChIP) assays showed that H3K9me3 levels were significantly decreased at the promoters of IL-6. Immunoblotting demonstrated that protein levels of the H3K9me3 methyltransferase, Suv39h1, were also reduced after HG treatment. HG-induced apoptosis, mitochondrial dysfunction and cytochrome-c release were reversible. However, the effects of HG on the expression of IL-6 and the levels of H3K9me3 were irreversible after the removal of HG from the culture. These results suggest that HG-induced sustained inflammatory phenotype and epigenetic histone modification, rather than HG-induced mitochondrial dysfunction and apoptosis, are main mechanisms responsible for metabolic memory. In conclusion, our data demonstrate that HG increases expression of inflammatory cytokine and decreases the levels of histone-3 methylation at the cytokine promoter, and suggest that modulating histone 3 methylation and inflammatory cytokine expression may be a useful strategy to prevent metabolic memory and cardiomyopathy in diabetic patients. PMID:22707199

  14. High Glucose-Induced Oxidative Stress Mediates Apoptosis and Extracellular Matrix Metabolic Imbalances Possibly via p38 MAPK Activation in Rat Nucleus Pulposus Cells

    PubMed Central

    Cheng, Xiaofei; Ni, Bin; Zhang, Feng; Hu, Ying

    2016-01-01

    Objectives. To investigate whether high glucose-induced oxidative stress is implicated in apoptosis of rat nucleus pulposus cells (NPCs) and abnormal expression of critical genes involved in the metabolic balance of extracellular matrix (ECM). Methods. NPCs were cultured with various concentrations of glucose to detect cell viability and apoptosis. Cells cultured with high glucose (25 mM) were untreated or pretreated with N-acetylcysteine or a p38 MAPK inhibitor SB 202190. Reactive oxygen species (ROS) production was evaluated. Activation of p38 MAPK was measured by Western blot. The expression of ECM metabolism-related genes, including type II collagen, aggrecan, SRY-related high-mobility-group box 9 (Sox-9), matrix metalloproteinase 3 (MMP-3), and tissue inhibitor of metalloproteinase 1 (TIMP-1), was analyzed by semiquantitative RT-PCR. Results. High glucose reduced viability of NPCs and induced apoptosis. High glucose resulted in increased ROS generation and p38 MAPK activation. In addition, it negatively regulated the expression of type II collagen, aggrecan, Sox-9, and TIMP-1 and positively regulated MMP-3 expression. These results were changed by pretreatment with N-acetylcysteine or SB 202190. Conclusions. High glucose might promote apoptosis of NPCs, trigger ECM catabolic pathways, and inhibit its anabolic activities, possibly through a p38 MAPK-dependent oxidative stress mechanism.

  15. CTRP9 induces mitochondrial biogenesis and protects high glucose-induced endothelial oxidative damage via AdipoR1 -SIRT1- PGC-1α activation.

    PubMed

    Cheng, Liang; Li, Bin; Chen, Xu; Su, Jie; Wang, Hongbing; Yu, Shiqiang; Zheng, Qijun

    2016-09-01

    Vascular lesions caused by endothelial dysfunction are the most common and serious complication of diabetes. The vasoactive potency of CTRP9 has been reported in our previous study via nitric oxide (NO) production. However, the effect of CTRP9 on vascular endothelial cells remains unknown. This study aimed to investigate the protection role of CTRP9 in the primary aortic vascular endothelial cells and HAECs under high-glucose condition. We found that the aortic vascular endothelial cells isolated from mice fed with a high fat diet generated more ROS production than normal cells, along with decreased mitochondrial biogenesis, which was also found in HAECs treated with high glucose. However, the treatment of CTPR9 significantly reduced ROS production and increased the activities of endogenous antioxidant enzymes, the expression of PGC-1α, NRF1, TFAM, ATP5A1 and SIRT1, and the activity of cytochrome c oxidase, indicating an induction of mitochondrial biogenesis. Furthermore, silencing the expression of SIRT1 in HAECs impeded the effect of CTRP9 on mitochondrial biogenesis, while silencing the expression of AdipoR1 in HAECs reversed the expression of SIRT1 and PGC-1α. Based on these findings, this study showed that CTRP9 might induce mitochondrial biogenesis and protect high glucose-induced endothelial oxidative damage via AdipoR1-SIRT1-PGC-1α signaling pathway. PMID:27349872

  16. [Microdevice for the investigation of high-glucose induced lifespan and the protective effect of polydatin in C. elegans].

    PubMed

    Zhu, Guoli; Yin, Fangchao; Wang, Li; Zhang, Min; Jiang, Lei; Qin, Jianhua

    2016-02-01

    Caenorhabditis elegans (C. elegans) has been widely used as a model organism for biomedical research due to its sufficient homology with human at molecular or genomic level. In this work, we describe a microfluidic device not only to investigate the response of C. elegans including lifespan and oxidative stress, but also to evaluate the protective effect of polydatin induced by high-glucose condition. It was found that the mean lifespan of worms was significantly reduced and the oxidative stress protein GST-4 was increased in worms that are subjected to high glucose. However, a certain dose of polydatin could weaken the increased oxidative stress induced by high-glucose and extend the lifespan, indicating the protective effect of polydatin against the toxic of high-glucose. The established approach is simple to operate, easy for realtime imaging and multiparatemer evaluations in parallel, providing a potential platform for drug evaluation/screening in a high throughput format at single animal resolution. PMID:27382717

  17. 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

  18. The role of local renin-angiotensin system on high glucose-induced cell toxicity, apoptosis and reactive oxygen species production in PC12 cells

    PubMed Central

    Shahveisi, Kaveh; Mousavi, Seyed Hadi; Hosseini, Mahmoud; Rad, Abolfazl Khajavi; Jalali, Seyed Amir; Rajaei, Ziba; Sadeghnia, Hamid Reza; Hadjzadeh, Mousa-Al-Reza

    2014-01-01

    Objective(s): Hyperglycemia, oxidative stress and apoptosis have key roles in pathogenesis of diabetic neuropathy. There are local renin-angiotensin systems (RASs) in different tissues such as neural tissue. Local RASs are involved in physiological and pathophysiological processes such as inflammation, proliferation and apoptosis. This study aimed to investigate the role of local renin-angiotensin system on high glucose-induced cell toxicity, apoptosis and reactive oxygen species (ROS) production in PC12 cells, as a cell model of diabetic neuropathy. Materials and Methods: PC12 cells were exposed to a high glucose concentration (27 mg/ml), captopril (ACE inhibitor), telmisartan and losartan (AT1 antagonists), and also PD123319 (AT2 antagonist) were administered before and after induction of high glucose toxicity. Then cell viability was assessed by MTT assay and apoptotic cells and intracellular ROS production were detected by annexin V-propidium iodide and DCFDA, respectively, using flow cytometry. Results: High glucose concentration decreased cell viability, and increased apoptotic cells. Intracellular ROS production was also increased. In PC12 cells pretreatment and treatment by the drugs showed a significant improvement in cell viability and reduced apoptosis in captopril, telmisartan and PD123319 but only captopril and telmisartan were able to reduce ROS production. Losrtan significantly lowered ROS but didn't show any improvements in cell viability and apoptotic cells. Conclusion: The results of the present study showed that RAS inhibitors reduced cell toxicity and apoptosis and ROS production was induced by high glucose. It may be suggested that local RAS has a role in high glucose toxicity. PMID:25422756

  19. Biphasic Response to Luteolin in MG-63 Osteoblast-Like Cells under High Glucose-Induced Oxidative Stress

    PubMed Central

    Abbasi, Naser; Khosravi, Afra; Aidy, Ali; Shafiei, Massoumeh

    2016-01-01

    Background: Clinical evidence indicates the diabetes-induced impairment of osteogenesis caused by a decrease in osteoblast activity. Flavonoids can increase the differentiation and mineralization of osteoblasts in a high-glucose state. However, some flavonoids such as luteolin may have the potential to induce cytotoxicity in osteoblast-like cells. This study was performed to investigate whether a cytoprotective concentration range of luteolin could be separated from a cytotoxic concentration range in human MG-63 osteoblast-like cells in high-glucose condition. Methods: Cells were cultured in a normal- or high-glucose medium. Cell viability was determined with the MTT assay. The formation of intracellular reactive oxygen species (ROS) was measured using probe 2’,7’ -dichlorofluorescein diacetate, and osteogenic differentiation was evaluated with an alkaline phosphatase bioassay. Results: ROS generation, reduction in alkaline phosphatase activity, and cell death induced by high glucose were inhibited by lower concentrations of luteolin (EC50, 1.29±0.23 µM). Oxidative stress mediated by high glucose was also overcome by N-acetyl-L-cysteine. At high concentrations, luteolin caused osteoblast cell death in normal- and high-glucose states (IC50, 34±2.33 and 27±2.42 µM, respectively), as represented by increased ROS and decreased alkaline phosphatase activity. Conclusion: Our results indicated that the cytoprotective action of luteolin in glucotoxic condition was manifested in much lower concentrations, by a factor of approximately 26 and 20, than was its cytotoxic activity, which occurred under normal or glucotoxic condition, respectively. PMID:26989282

  20. Agmatine Ameliorates High Glucose-Induced Neuronal Cell Senescence by Regulating the p21 and p53 Signaling

    PubMed Central

    Song, Juhyun; Lee, Byeori; Kang, Somang; Oh, Yumi; Kim, Eosu; Kim, Chul-Hoon; Song, Ho-Taek

    2016-01-01

    Neuronal senescence caused by diabetic neuropathy is considered a common complication of diabetes mellitus. Neuronal senescence leads to the secretion of pro-inflammatory cytokines, the production of reactive oxygen species, and the alteration of cellular homeostasis. Agmatine, which is biosynthesized by arginine decarboxylation, has been reported in previous in vitro to exert a protective effect against various stresses. In present study, agmatine attenuated the cell death and the expression of pro-inflammatory cytokines such as IL-6, TNF-alpha and CCL2 in high glucose in vitro conditions. Moreover, the senescence associated-β-galatosidase's activity in high glucose exposed neuronal cells was reduced by agmatine. Increased p21 and reduced p53 in high glucose conditioned cells were changed by agmatine. Ultimately, agmatine inhibits the neuronal cell senescence through the activation of p53 and the inhibition of p21. Here, we propose that agmatine may ameliorate neuronal cell senescence in hyperglycemia. PMID:26924930

  1. Agmatine Ameliorates High Glucose-Induced Neuronal Cell Senescence by Regulating the p21 and p53 Signaling.

    PubMed

    Song, Juhyun; Lee, Byeori; Kang, Somang; Oh, Yumi; Kim, Eosu; Kim, Chul-Hoon; Song, Ho-Taek; Lee, Jong Eun

    2016-02-01

    Neuronal senescence caused by diabetic neuropathy is considered a common complication of diabetes mellitus. Neuronal senescence leads to the secretion of pro-inflammatory cytokines, the production of reactive oxygen species, and the alteration of cellular homeostasis. Agmatine, which is biosynthesized by arginine decarboxylation, has been reported in previous in vitro to exert a protective effect against various stresses. In present study, agmatine attenuated the cell death and the expression of pro-inflammatory cytokines such as IL-6, TNF-alpha and CCL2 in high glucose in vitro conditions. Moreover, the senescence associated-β-galatosidase's activity in high glucose exposed neuronal cells was reduced by agmatine. Increased p21 and reduced p53 in high glucose conditioned cells were changed by agmatine. Ultimately, agmatine inhibits the neuronal cell senescence through the activation of p53 and the inhibition of p21. Here, we propose that agmatine may ameliorate neuronal cell senescence in hyperglycemia. PMID:26924930

  2. Panax Quinquefolius Saponin of Stem and Leaf Attenuates Intermittent High Glucose-Induced Oxidative Stress Injury in Cultured Human Umbilical Vein Endothelial Cells via PI3K/Akt/GSK-3β Pathway

    PubMed Central

    Wang, Jingshang; Yin, Huijun; Guo, Chunyu; Xia, Chengdong; Liu, Qian; Zhang, Lu

    2013-01-01

    Panax quinquefolius saponin of stem and leaf (PQS), the effective parts of American ginseng, is widely used in China as a folk medicine for diabetes and cardiovascular diseases treatment. In our previous studies, we have demonstrated that PQS could improve the endothelial function of type II diabetes mellitus (T2DM) rats with high glucose fluctuation. In the present study, we investigated the protective effects of PQS against intermittent high glucose-induced oxidative damage on human umbilical vein endothelial cells (HUVECs) and the role of phosphatidylinositol 3-kinase kinase (PI3K)/Akt/GSK-3β pathway involved. Our results suggested that exposure of HUVECs to a high glucose concentration for 8 days showed a great decrease in cell viability accompanied by marked MDA content increase and SOD activity decrease. Moreover, high glucose significantly reduced the phosphorylation of Akt and GSK-3β. More importantly, these effects were even more evident in intermittent high glucose condition. PQS treatment significantly attenuated intermittent high glucose-induced oxidative damage on HUVECs and meanwhile increased cell viability and phosphorylation of Akt and GSK-3β of HUVECs. Interestingly, all these reverse effects of PQS on intermittent high glucose-cultured HUVECs were inhibited by PI3K inhibitor LY294002. These findings suggest that PQS attenuates intermittent-high-glucose-induced oxidative stress injury in HUVECs by PI3K/Akt/GSK-3β pathway. PMID:23956765

  3. Panax Quinquefolius Saponin of Stem and Leaf Attenuates Intermittent High Glucose-Induced Oxidative Stress Injury in Cultured Human Umbilical Vein Endothelial Cells via PI3K/Akt/GSK-3 β Pathway.

    PubMed

    Wang, Jingshang; Yin, Huijun; Huang, Ye; Guo, Chunyu; Xia, Chengdong; Liu, Qian; Zhang, Lu

    2013-01-01

    Panax quinquefolius saponin of stem and leaf (PQS), the effective parts of American ginseng, is widely used in China as a folk medicine for diabetes and cardiovascular diseases treatment. In our previous studies, we have demonstrated that PQS could improve the endothelial function of type II diabetes mellitus (T2DM) rats with high glucose fluctuation. In the present study, we investigated the protective effects of PQS against intermittent high glucose-induced oxidative damage on human umbilical vein endothelial cells (HUVECs) and the role of phosphatidylinositol 3-kinase kinase (PI3K)/Akt/GSK-3 β pathway involved. Our results suggested that exposure of HUVECs to a high glucose concentration for 8 days showed a great decrease in cell viability accompanied by marked MDA content increase and SOD activity decrease. Moreover, high glucose significantly reduced the phosphorylation of Akt and GSK-3 β . More importantly, these effects were even more evident in intermittent high glucose condition. PQS treatment significantly attenuated intermittent high glucose-induced oxidative damage on HUVECs and meanwhile increased cell viability and phosphorylation of Akt and GSK-3 β of HUVECs. Interestingly, all these reverse effects of PQS on intermittent high glucose-cultured HUVECs were inhibited by PI3K inhibitor LY294002. These findings suggest that PQS attenuates intermittent-high-glucose-induced oxidative stress injury in HUVECs by PI3K/Akt/GSK-3 β pathway. PMID:23956765

  4. 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. PMID:26822433

  5. Linagliptin Limits High Glucose Induced Conversion of Latent to Active TGFß through Interaction with CIM6PR and Limits Renal Tubulointerstitial Fibronectin

    PubMed Central

    Gangadharan Komala, Muralikrishna; Gross, Simon; Zaky, Amgad; Pollock, Carol; Panchapakesan, Usha

    2015-01-01

    Background In addition to lowering blood glucose in patients with type 2 diabetes mellitus, dipeptidyl peptidase 4 (DPP4) inhibitors have been shown to be antifibrotic. We have previously shown that cation independent mannose-6-phosphate receptor (CIM6PR) facilitates the conversion of latent to active transforming growth factor β1 (GFß1) in renal proximal tubular cells (PTCs) and linagliptin (a DPP4 inhibitor) reduced this conversion with downstream reduction in fibronectin transcription. Objective We wanted to demonstrate that linagliptin reduces high glucose induced interaction between membrane bound DPP4 and CIM6PR in vitro and demonstrate reduction in active TGFß mediated downstream effects in a rodent model of type 1 diabetic nephropathy independent of high glycaemic levels. Materials and Methods We used human kidney 2 (HK2) cells and endothelial nitric oxide synthase knock out mice to explore the mechanism and antifibrotic potential of linagliptin independent of glucose lowering. Using a proximity ligation assay, we show that CIM6PR and DPP4 interaction was increased by high glucose and reduced by linagliptin and excess mannose-6-phosphate (M6P) confirming that linagliptin is operating through an M6P-dependent mechanism. In vivo studies confirmed these TGFß1 pathway related changes and showed reduced fibronectin, phosphorylated smad2 and phosphorylated smad2/3 (pSmad2/3) with an associated trend towards reduction in tubular atrophy, which was independent of glucose lowering. No reduction in albuminuria, glomerulosclerotic index or cortical collagen deposition was observed. Conclusion Linagliptin inhibits activation of TGFß1 through a M6P dependent mechanism. However this in isolation is not sufficient to reverse the multifactorial nature of diabetic nephropathy. PMID:26509887

  6. Relaxin Inhibits High Glucose-Induced Matrix Accumulation in Human Mesangial Cells by Interfering with TGF-β1 Production and Mesangial Cells Phenotypic Transition.

    PubMed

    Xie, Xiangcheng; Xia, Wenkai; Fei, Xiao; Xu, Qunhong; Yang, Xiu; Qiu, Donghao; Wang, Ming

    2015-01-01

    Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). DN is characterized by glomerular extracellular matrix accumulation, mesangial expansion, basement membrane thickening, and renal interstitial fibrosis. To date, mounting evidence has shown that H2 relaxin possesses powerful antifibrosis properties; however, the mechanisms of H2 relaxin on diabetic nephropathy remain unknown. Here, we aimed to explore whether H2 relaxin can reduce production of extracellular matrix (ECM) secreted by human mesangial cells (HMC). HMC were exposed to 5.5 mM glucose (NG) or 30 mM glucose (HG) with or without H2 relaxin. Fibronectin (FN) and collagen type IV levels in the culture supernatants were examined by solid-phase enzyme-linked immunoadsorbent assay (ELISA). Western blot was used to detect the expression of α-smooth muscle actin (α-SMA) protein. Quantitative polymerase chain reaction (qPCR) method was employed to analyze transforming growth factor (TGF)-β1 mRNA expression. Compared with the normal glucose group, the levels of fibronectin and collagen type were markedly increased after being cultured in high glucose medium. Compared with the high glucose group, remarkable decreases of fibronectin, collagen type IV, α-smooth muscle actin, and TGF-β1 mRNA expression were observed in the H2 relaxin-treated group. The mechanism by which H2 relaxin reduced high glucose-induced overproduction of ECM may be associated with inhibition of TGF-β1 mRNA expression and mesangial cells' phenotypic transition. H2 relaxin is a potentially effective modality for the treatment of DN. PMID:26424011

  7. Sodium Tanshinone IIA Silate Inhibits High Glucose-Induced Vascular Smooth Muscle Cell Proliferation and Migration through Activation of AMP-Activated Protein Kinase

    PubMed Central

    Wu, Wen-yu; Yan, Hong; Wang, Xin-bo; Gui, Yu-zhou; Gao, Fei; Tang, Xi-lan; Qin, Yin-lin; Su, Mei; Chen, Tao; Wang, Yi-ping

    2014-01-01

    The proliferation of vascular smooth muscle cells may perform a crucial role in the pathogenesis of diabetic vascular disease. AMPK additionally exerts several salutary effects on vascular function and improves vascular abnormalities. The current study sought to determine whether sodium tanshinone IIA silate (STS) has an inhibitory effect on vascular smooth muscle cell (VSMC) proliferation and migration under high glucose conditions mimicking diabetes without dyslipidemia, and establish the underlying mechanism. In this study, STS promoted the phosphorylation of AMP-activated protein kinase (AMPK) at T172 in VSMCs. VSMC proliferation was enhanced under high glucose (25 mM glucose, HG) versus normal glucose conditions (5.5 mM glucose, NG), and this increase was inhibited significantly by STS treatment. We utilized western blotting analysis to evaluate the effects of STS on cell-cycle regulatory proteins and found that STS increased the expression of p53 and the Cdk inhibitor, p21, subsequent decreased the expression of cell cycle-associated protein, cyclin D1. We further observed that STS arrested cell cycle progression at the G0/G1 phase. Additionally, expression and enzymatic activity of MMP-2, translocation of NF-κB, as well as VSMC migration were suppressed in the presence of STS. Notably, Compound C (CC), a specific inhibitor of AMPK, as well as AMPK siRNA blocked STS-mediated inhibition of VSMC proliferation and migration. We further evaluated its potential for activating AMPK in aortas in animal models of type 2 diabetes and found that Oral administration of STS for 10 days resulted in activation of AMPK in aortas from ob/ob or db/db mice. In conclusion, STS inhibits high glucose-induced VSMC proliferation and migration, possibly through AMPK activation. The growth suppression effect may be attributable to activation of AMPK-p53-p21 signaling, and the inhibitory effect on migration to the AMPK/NF-κB signaling axis. PMID:24739942

  8. High Glucose-Induced PC12 Cell Death by Increasing Glutamate Production and Decreasing Methyl Group Metabolism.

    PubMed

    Chen, Minjiang; Zheng, Hong; Wei, Tingting; Wang, Dan; Xia, Huanhuan; Zhao, Liangcai; Ji, Jiansong; Gao, Hongchang

    2016-01-01

    Objective. High glucose- (HG-) induced neuronal cell death is responsible for the development of diabetic neuropathy. However, the effect of HG on metabolism in neuronal cells is still unclear. Materials and Methods. The neural-crest derived PC12 cells were cultured for 72 h in the HG (75 mM) or control (25 mM) groups. We used NMR-based metabolomics to examine both intracellular and extracellular metabolic changes in HG-treated PC12 cells. Results. We found that the reduction in intracellular lactate may be due to excreting more lactate into the extracellular medium under HG condition. HG also induced the changes of other energy-related metabolites, such as an increased succinate and creatine phosphate. Our results also reveal that the synthesis of glutamate from the branched-chain amino acids (isoleucine and valine) may be enhanced under HG. Increased levels of intracellular alanine, phenylalanine, myoinositol, and choline were observed in HG-treated PC12 cells. In addition, HG-induced decreases in intracellular dimethylamine, dimethylglycine, and 3-methylhistidine may indicate a downregulation of methyl group metabolism. Conclusions. Our metabolomic results suggest that HG-induced neuronal cell death may be attributed to a series of metabolic changes, involving energy metabolism, amino acids metabolism, osmoregulation and membrane metabolism, and methyl group metabolism. PMID:27413747

  9. The role of TGF-β-activated kinase 1 in db/db mice and high glucose-induced macrophage.

    PubMed

    Xu, Xingxin; Fan, Zhe; Qi, Xiangming; Shao, Yunxia; Wu, Yonggui

    2016-09-01

    Accumulating evidence reveals that inflammation plays a vital part in the development of diabetic nephropathy (DN), little information is available about the TGF-β-activated kinase 1 (TAK1) signal pathway activating inflammatory response in DN. We used bone marrow-derived macrophages (BMMs) and db/db mice to investigate the potential protective effects and mechanisms of TAK1 inhibitor (5Z-7-oxozeaenol) on diabetic kidney disease. The study showed that pretreatment with 5Z-7-oxozeaenol not only remarkably decreased high glucose (HG) stimulated excessive release of MCP-1 and TNF-α, but also significantly down-regulated ERK1/2, p38MAPK phosphorylation, and NF-κB activation in macrophages. In consistent, 5Z-7-oxozeaenol markedly reduced diabetes-induced albuminuria, histological changes, macrophage infiltration, and renal inflammatory cytokines expression and exerted its function through down-regulating ERK1/2, p38MAPK, NF-κB activation in the kidneys of db/db mice. Our findings may provide a novel direction to study the molecular mechanism and a perspective intervention to halt the progression of DN. PMID:27268284

  10. High Glucose-Induced PC12 Cell Death by Increasing Glutamate Production and Decreasing Methyl Group Metabolism

    PubMed Central

    Chen, Minjiang; Zheng, Hong; Wei, Tingting; Wang, Dan; Xia, Huanhuan; Zhao, Liangcai; Ji, Jiansong

    2016-01-01

    Objective. High glucose- (HG-) induced neuronal cell death is responsible for the development of diabetic neuropathy. However, the effect of HG on metabolism in neuronal cells is still unclear. Materials and Methods. The neural-crest derived PC12 cells were cultured for 72 h in the HG (75 mM) or control (25 mM) groups. We used NMR-based metabolomics to examine both intracellular and extracellular metabolic changes in HG-treated PC12 cells. Results. We found that the reduction in intracellular lactate may be due to excreting more lactate into the extracellular medium under HG condition. HG also induced the changes of other energy-related metabolites, such as an increased succinate and creatine phosphate. Our results also reveal that the synthesis of glutamate from the branched-chain amino acids (isoleucine and valine) may be enhanced under HG. Increased levels of intracellular alanine, phenylalanine, myoinositol, and choline were observed in HG-treated PC12 cells. In addition, HG-induced decreases in intracellular dimethylamine, dimethylglycine, and 3-methylhistidine may indicate a downregulation of methyl group metabolism. Conclusions. Our metabolomic results suggest that HG-induced neuronal cell death may be attributed to a series of metabolic changes, involving energy metabolism, amino acids metabolism, osmoregulation and membrane metabolism, and methyl group metabolism. PMID:27413747

  11. Ghrelin inhibits high glucose-induced 16HBE cells apoptosis by regulating Wnt/β-catenin pathway.

    PubMed

    Liu, Xiaoyan; Chen, Dilong; Wu, Zhongjun; Li, Jing; Li, Jianqiang; Zhao, Hui; Liu, Tanzhen

    2016-09-01

    Ghrelin has a protective effect on diabetes and its complications. To expound its probable molecular mechanisms, we investigated the effects of ghrelin on high glucose (HG)-induced cell apoptosis and intracellular signaling pathways in cultured human bronchial epithelial cells (16HBE). In this study, we firstly came to conclusion that HG-induced 16HBE apoptosis was significantly inhibited by co-treatment of ghrelin. The molecular mechanism of ghrelin-induced protective effects for lungs is still not understood. We reported here for the first time that ghrelin can not only eliminate apoptosis of 16HBE, but also regulate the disordered cell cycle caused by HG. We speculated here that ghrelin inhibits the apoptosis of 16HBE by regulating the abnormal cell cycle to some extent. The mechanism may be that ghrelin up-regulates the expression of cyclin D1 via regulating Wnt/β-catenin pathway, which has an intimate relationship with lung diseases. These results suggested the possible role of ghrelin in treating diabetic lung diseases, especially in view of its low toxicity in humans. PMID:27378423

  12. MicroRNA-218 promotes high glucose-induced apoptosis in podocytes by targeting heme oxygenase-1.

    PubMed

    Yang, Haibo; Wang, Qingjun; Li, Sutong

    2016-03-18

    Emerging evidence has demonstrated that microRNAs (miRNAs) play a mediatory role in the pathogenesis of diabetic nephropathy. In this study, we found that miR-218 was upregulated in high glucose (HG) treated podocytes, which are essential components of the glomerular filtration barrier and a major prognostic determinant in diabetic nephropathy. Additionally, up-regulation of miR-218 was accompanied by an increased rate of podocyte death and down-regulation in the level of nephrin, a key marker of podocytes. However, inhibition of miR-218 exerted the opposite effect. In addition, the dual-luciferase reporter assay showed that miR-218 directly targeted the 3'-untranslated region of heme oxygenase-1 (HO-1), and further study confirmed an increase of HO-1 in HG-treated podocytes transfected with anti-miR-218. Knockdown of HO-1 blocked the anti-apoptotic effect of anti-miR-218. Furthermore, inhibition of miR-218 was associated with decreased expression of the known pro-apoptotic molecule p38-mitogen-activated protein kinase (p38-MAPK) activation. Following preconditioning with SB203580, an inhibitor of p38-MAPK, the stimulatory effect of HG on podocyte apoptosis was strikingly ameliorated. These findings suggested that miR-218 accelerated HG-induced podocyte apoptosis through directly down-regulating HO-1 and facilitating p38-MAPK activation. PMID:26876575

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

    PubMed Central

    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. PMID:26191142

  14. Oxidative Stress-Activated NHE1 Is Involved in High Glucose-Induced Apoptosis in Renal Tubular Epithelial Cells

    PubMed Central

    Wu, Yiqing; Zhang, Min; Liu, Rui

    2016-01-01

    Purpose Diabetic nephropathy (DN) is a prevalent chronic microvascular complication of diabetes mellitus involving disturbances in electrolytes and the acid-base balance caused by a disorder of glucose metabolism. NHE1 is a Na+/H+ exchanger responsible for keeping intracellular pH (pHi) balance and cell growth. Our study aimed to investigate roles of NHE1 in high glucose (HG)-induced apoptosis in renal tubular epithelial cells. Materials and Methods Renal epithelial tubular cell line HK-2 was cultured in medium containing 5 mM or 30 mM glucose. Then, cell apoptosis, oxidative stress, NHE1 expression, and pHi were evaluated. NHE1 siRNA and inhibitor were used to evaluate its role in cell apoptosis. Results HG significantly increased cell apoptosis and the production of reactive oxygen species (ROS) and 8-OHdG (p<0.05). Meanwhile, we found that HG induced the expression of NHE1 and increased the pHi from 7.0 to 7.6 after 48 h of incubation. However, inhibiting NHE1 using its specific siRNA or antagonist DMA markedly reduced cell apoptosis stimulated by HG. In addition, suppressing cellular oxidative stress using antioxidants, such as glutathione and N-acetyl cysteine, significantly reduced the production of ROS, accompanied by a decrease in NHE1. We also found that activated cyclic GMP-Dependent Protein Kinase Type I (PKG) signaling promoted the production of ROS, which contributed to the regulation of NHE1 functions. Conclusion Our study indicated that HG activates PKG signaling and elevates the production of ROS, which was responsible for the induction of NHE1 expression and dysfunction, as well as subsequent cell apoptosis, in renal tubular epithelial cells. PMID:27401659

  15. Naringin inhibits ROS-activated MAPK pathway in high glucose-induced injuries in H9c2 cardiac cells.

    PubMed

    Chen, Jingfu; Guo, Runmin; Yan, Hai; Tian, Lihong; You, Qiong; Li, Shanghai; Huang, Ruina; Wu, Keng

    2014-04-01

    Naringin, an active flavonoid isolated from citrus fruit extracts, exhibits biological and pharmacological properties, such as antioxidant activity and antidiabetic effect. Mitogen-activated protein kinase (MAPK) signalling pathway has been shown to participate in hyperglycaemia-induced injury. The present study tested the hypothesis that naringin protects against high glucose (HG)-induced injuries by inhibiting MAPK pathway in H9c2 cardiac cells. To examine this, the cells were treated with 35 mM glucose (HG) for 24 hr to establish a HG-induced cardiomyocyte injury model. The cells were pre-treated with 80 μM naringin for 2 hr before exposure to HG. The findings of this study showed that exposure of H9c2 cells to HG for 24 hr markedly induced injuries, as evidenced by a decrease in cell viability, increases in apoptotic cells and reactive oxygen species (ROS) production, as well as dissipation of mitochondrial membrance potential (MMP). These injuries were significantly attenuated by the pre-treatment of cells with either naringin or SB203580 (a selective inhibitor of p38 MAPK) or U0126 (a selective inhibitor of extracellular signal regulated kinase 1/2, ERK1/2) or SP600125 (a selective inhibitor of c-jun N-termanal kinase, JNK) before exposure to HG, respectively. Furthermore, exposure of cells to HG increased the phosphorylation of p38 MAPK, ERK1/2 and JNK. The increased activation of MAPK pathway was ameliorated by pre-treatment with either naringin or N-acetyl-L-cysteine (NAC), a ROS scavenger, which also reduced HG-induced cytotoxicity and apoptosis, leading to increase in cell viability and decrease in apoptotic cells. In conclusion, our findings provide new evidence for the first time that naringin protects against HG-induced injuries by inhibiting the activation of MAPK (p38 MAPK, ERK1/2 and JNK) and oxidative stress in H9c2 cells. PMID:24118820

  16. The Inhibitory Effect of Rhein on Proliferation of High Glucose-induced Mesangial Cell Through Cell Cycle Regulation and Induction of Cell Apoptosis

    PubMed Central

    Xu, Shouzhu; Lv, Yanying; Zhao, Jing; Wang, Junping; Wang, Guangjian; Wang, Siwang

    2016-01-01

    Objectives: Increased mesangial cell proliferation and accumulation of extracellular matrix (ECM) are the major pathological features of early-stage diabetic nephropathy. This study was sought to investigate the inhibitory effects of rhein (RH) on high glucose (HG)-cultured mesangial cells. Specially, we focus on the analysis of proliferation rate, cell cycle regulation, apoptosis, and the expression of collagen IV and laminin. Materials and Methods: The established rat renal mesangial cell (RMC) line was cultured in medium with different concentrations of glucose (5.6 mM or 25 mM) and RH (40 μM, 20 μM, and 10 μM). Pro-treated cells were collected at 12 h, 24 h, and 48 h for cell proliferation analysis and after 24 h for the experiments of flow cytometry, transmission electron microscope, real-time polymerase chain reaction, and Western blotting. Results: Our data shows HG can promote the proliferation of RMCs and RH has an inhibitory effect on HG-induced RMC proliferation and expression of ECM. Based on our data, we hypothesize this inhibitory effect might be a result of cell cycle regulation and the induction of cellular apoptosis. Conclusion: RH can inhibit cellular proliferation and downregulate the expression of ECM under the circumstance of HG. The mechanism of growth suppression may be due to cell cycle arrest at G1 phase, induction of cell apoptosis, and upregulation of apoptotic mediators bax and caspase-3. SUMMARY Rhein (RH) has an inhibitory effect on high glucose.induced rat mesangial cells proliferationRH has an inhibitory effect on the expression of extracellular matrixRH has a growth.suppression effectRH can upregulate the expression of apoptotic mediators bax and caspase-3All above shows RH is one of the main active ingredient in Shenkang injection. Abbreviations used: RH: Rhein, ECM: Extracellular matrix, DN: Diabetic nephropathy, RMC: Renal mesangial cell, SKI: Shenkang injection, MTT: 3-(4,5-dimethylthiazol–2-yl)-2,5-diphenyltetrazolium

  17. 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 Central

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

    2013-01-01

    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. PMID:24076121

  18. Sinomenine alleviates high glucose-induced renal glomerular endothelial hyperpermeability by inhibiting the activation of RhoA/ROCK signaling pathway.

    PubMed

    Yin, Qingqiao; Xia, Yuanyu; Wang, Guan

    2016-09-01

    As an early sign of diabetic cardiovascular disease, endothelial dysfunction may contribute to progressive diabetic nephropathy (DN). Endothelial hyperpermeability induced by hyperglycemia (HG) is a central pathogenesis for DN. Sinomenine (SIN) has strong anti-inflammatory and renal protective effects, following an unknown protective mechanism against HG-induced hyperpermeability. We herein explored the role of SIN in vitro in an HG-induced barrier dysfunction model in human renal glomerular endothelial cells (HRGECs). The cells were exposed to SIN and/or HG for 24 h, the permeability of which was significantly increased by HG. Moreover, junction protein occludin in the cell-cell junction area and its total expression in HRGECs were significantly decreased by HG. However, the dysfunction of tight junction and hyperpermeability of HRGECs were significantly reversed by SIN. Furthermore, SIN prevented HG-increased reactive oxygen species (ROS) by activating nuclear factor-E2-related factor 2 (Nrf2). Interestingly, activation of RhoA/ROCK induced by HG was reversed by SIN or ROCK inhibitor. HG-induced hyperpermeability was prevented by SIN. High ROS level, tight junction dysfunction and RhoA/ROCK activation were significantly attenuated with knockdown of Nrf2. Mediated by activation of Nrf2, SIN managed to significantly prevent HG-disrupted renal endothelial barrier function by suppressing the RhoA/ROCK signaling pathway through reducing ROS. We successfully identified a novel pathway via which SIN exerted antioxidative and renal protective functions, and provided a molecular basis for potential SIN applications in treating DN vascular disorders. PMID:27378427

  19. 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

  20. Protective effects of Notch1 signaling activation against high glucose-induced myocardial cell injury: Analysis of its mechanisms of action.

    PubMed

    Zhang, Jian; Li, Bingong; Zheng, Zeqi; Kang, Ting; Zeng, Minghui; Liu, Yanhua; Xia, Baohua

    2015-09-01

    Notch1 plays an important role in cardiomyocyte apoptosis and cardiac fibrosis. However, the effects of Notch1 on diabetic cardiomyopathy (DCM) and its mechanisms of action remain unclear. In the present study, we sought to investigate the role of Notch1 in, and its effects on high glucose (HG)‑induced myocardial cell apoptosis and myocardial fibrosis. H9c2 cells exposed to HG were used to establish an in vitro model of myocardial injury. The H9c2 cells were cultured with normal glucose (NG; 5.5 mmol/L‑ NG), and were then epxosed to HG (33 mmol/L‑ HG), a γ‑secretase inhibitor (DAPT), and were transfected with a lentiviral vector containing the Notch1 intracellular domain (N1ICD; lentivirus‑N1ICD). At 72 h following exposure to HG, DAPT or transfection with lentivirus‑N1ICD, myocardial cell viability was assessed using a Cell Counting kit‑8 (CCK‑8) assay. Cell apoptosis was measured using Annexin V/propidium iodide (PI) double staining and flow cytometry. The mRNA expression levels of hairy/enhancer of split‑1 (Hes‑1) and hairy/enhancer-of-split related with YRPW motif‑1 (Hey‑1) were measured by quantitative PCR (qPCR), while the protein expression of N1ICD, Bax, Bcl‑2, transforming growth factor‑β1 (TGF‑β1) and connective tissue growth factor (CTGF), and the levels of phosphorylated (p-)AKT, total (t-)AKT, p‑phosphoinositide 3-kinase (PI3K) and t‑AKT were measured by western blot analysis. Our results revealed that exposure to HG induced apoptosis and upregulated TGF‑β1 and CTGF expression in the H9c2 cardiomyocytes. Furthermore, the Notch1 and PI3K/AKT signaling pathways were activated following transfection with lentivirus‑N1ICD, and this activation enhanced myocardial cell viability, prevented cardiomyocyte apoptosis and decreased TGF‑β1 and CTGF expression. On the whole, our data demonstrate that the overexpression of Notch1 prevents HG‑induced cardiomyocyte apoptosis and decreases CTGF expression in H9c2 cells

  1. 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…

  2. Fagopyrum tataricum (Buckwheat) Improved High-Glucose-Induced Insulin Resistance in Mouse Hepatocytes and Diabetes in Fructose-Rich Diet-Induced Mice

    PubMed Central

    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. PMID:22548048

  3. Exogenous spermine ameliorates high glucose-induced cardiomyocytic apoptosis via decreasing reactive oxygen species accumulation through inhibiting p38/JNK and JAK2 pathways

    PubMed Central

    He, Yuqin; Yang, Jinxia; Li, Hongzhu; Shao, Hongjiang; Wei, Can; Wang, Yuehong; Li, Meixiu; Xu, Changqing

    2015-01-01

    Reactive oxygen species (ROS) generation has been suggested to play a vital role in the initiation and progression of diabetic cardiomyopathy, a major complication of diabetes mellitus. Recent studies reveal that spermine possesses proliferative, antiaging and antioxidative properties. Thus, we hypothesized that spermine could decrease apoptosis via suppressing ROS accumulation induced by high glucose (HG) in cardiomyocytes. Cultured neonatal rat ventricle cardiomyocytes were treated with normal glucose (NG) (5 mM) or HG (25 mM) in the presence or absence of spermine for 48 h. The cell activity, apoptosis, ROS production, T-SOD and GSH activities, MDA content and GSSG level were assessed. The results showed that HG induced lipid peroxidation and the increase of intracellular ROS formation and apoptosis in primary cardiomyocytes. Spermine could obviously improve the above-mentioned changes. Western blot analysis revealed that spermine markedly inhibited HG-induced the phosphorylation of p38/JNK MAPKs and JAK2. Moreover, spermine had better antioxidative and anti-apoptotic effects than N-acetyl-L-cysteine (NAC). Taken together, the present data suggested that spermine could suppress ROS accumulation to decrease cardiomyocytes apoptosis in HG condition, which may be attributed to the inhibition of p38/JNK and JAK2 activation and its natural antioxidative property. Our findings may highlight a new therapeutic intervention for the prevention of diabetic cardiomyopathy. PMID:26884823

  4. Thioredoxin-interacting protein mediates high glucose-induced reactive oxygen species generation by mitochondria and the NADPH oxidase, Nox4, in mesangial cells.

    PubMed

    Shah, Anu; Xia, Ling; Goldberg, Howard; Lee, Ken W; Quaggin, Susan E; Fantus, I George

    2013-03-01

    Thioredoxin-interacting protein (TxNIP) is up-regulated by high glucose and is associated with oxidative stress. It has been implicated in hyperglycemia-induced β-cell dysfunction and apoptosis. As high glucose and oxidative stress mediate diabetic nephropathy (DN), the contribution of TxNIP was investigated in renal mesangial cell reactive oxygen species (ROS) generation and collagen synthesis. To determine the role of TxNIP, mouse mesangial cells (MC) cultured from wild-type C3H and TxNIP-deficient Hcb-19 mice were incubated in HG. Confocal microscopy was used to measure total and mitochondrial ROS production (DCF and MitoSOX) and collagen IV. Trx and NADPH oxidase activities were assayed and NADPH oxidase isoforms, Nox2 and Nox4, and antioxidant enzymes were determined by immunoblotting. C3H MC exposed to HG elicited a significant increase in cellular and mitochondrial ROS as well as Nox4 protein expression and NADPH oxidase activation, whereas Hcb-19 MC showed no response. Trx activity was attenuated by HG only in C3H MC. These defects in Hcb-19 MC were not due to increased antioxidant enzymes or scavenging of ROS, but associated with decreased ROS generation. Adenovirus-mediated overexpression of TxNIP in Hcb-19 MC and TxNIP knockdown with siRNA in C3H confirmed the specific role of TxNIP. Collagen IV accumulation in HG was markedly reduced in Hcb-19 cells. TxNIP is a critical component of the HG-ROS signaling pathway, required for the induction of mitochondrial and total cell ROS and the NADPH oxidase isoform, Nox4. TxNIP is a potential target to prevent DN. PMID:23329835

  5. Thioredoxin-interacting Protein Mediates High Glucose-induced Reactive Oxygen Species Generation by Mitochondria and the NADPH Oxidase, Nox4, in Mesangial Cells*

    PubMed Central

    Shah, Anu; Xia, Ling; Goldberg, Howard; Lee, Ken W.; Quaggin, Susan E.; Fantus, I. George

    2013-01-01

    Thioredoxin-interacting protein (TxNIP) is up-regulated by high glucose and is associated with oxidative stress. It has been implicated in hyperglycemia-induced β-cell dysfunction and apoptosis. As high glucose and oxidative stress mediate diabetic nephropathy (DN), the contribution of TxNIP was investigated in renal mesangial cell reactive oxygen species (ROS) generation and collagen synthesis. To determine the role of TxNIP, mouse mesangial cells (MC) cultured from wild-type C3H and TxNIP-deficient Hcb-19 mice were incubated in HG. Confocal microscopy was used to measure total and mitochondrial ROS production (DCF and MitoSOX) and collagen IV. Trx and NADPH oxidase activities were assayed and NADPH oxidase isoforms, Nox2 and Nox4, and antioxidant enzymes were determined by immunoblotting. C3H MC exposed to HG elicited a significant increase in cellular and mitochondrial ROS as well as Nox4 protein expression and NADPH oxidase activation, whereas Hcb-19 MC showed no response. Trx activity was attenuated by HG only in C3H MC. These defects in Hcb-19 MC were not due to increased antioxidant enzymes or scavenging of ROS, but associated with decreased ROS generation. Adenovirus-mediated overexpression of TxNIP in Hcb-19 MC and TxNIP knockdown with siRNA in C3H confirmed the specific role of TxNIP. Collagen IV accumulation in HG was markedly reduced in Hcb-19 cells. TxNIP is a critical component of the HG-ROS signaling pathway, required for the induction of mitochondrial and total cell ROS and the NADPH oxidase isoform, Nox4. TxNIP is a potential target to prevent DN. PMID:23329835

  6. Prevention of High Blood Pressure

    MedlinePlus

    ... page from the NHLBI on Twitter. Prevention of High Blood Pressure Healthy lifestyle habits, proper use of medicines, and ... prevent high blood pressure or its complications. Preventing High Blood Pressure Onset Healthy lifestyle habits can help prevent high ...

  7. Berberine attenuates high glucose-induced fibrosis by activating the G protein-coupled bile acid receptor TGR5 and repressing the S1P2/MAPK signaling pathway in glomerular mesangial cells.

    PubMed

    Yang, Zhiying; Li, Jie; Xiong, Fengxiao; Huang, Junying; Chen, Cheng; Liu, Peiqing; Huang, Heqing

    2016-08-15

    Berberine (BBR) exerts powerful renoprotective effects on diabetic nephropathy (DN), but the underlying mechanisms remain unclear. We previously demonstrated that activation of the G protein-coupled bile acid receptor TGR5 ameliorates diabetic nephropathy by inhibiting the activation of the sphingosine 1-phosphate (S1P)/sphingosine 1-phosphate receptor 2 (S1P2) signaling pathway. In this study, we explored the role of TGR5 in the BBR-induced downregulation of sphingosine 1-phosphate receptor 2 (S1P2)/mitogen-activated protein kinase (MAPK)-mediated fibrosis in glomerular mesangial cells (GMCs). Results showed that, BBR suppressed the expression of FN, ICAM-1, and TGF-β1 in high-glucose cultures of GMCs, and the phosphorylation level of c-Jun/c-Fos was downregulated. The high glucose lowered TGR5 expression in a time-dependent manner; this effect was reversed by BBR in a dose-dependent manner. The TGR5 agonist INT-777 decreased the high glucose-induced FN, ICAM-1, and TGF-β1 protein contents. In addition, TGR5 siRNA blocked S1P2 degradation by BBR. And MAPK signaling, which plays important regulatory roles in the pathological progression of DN, was activated by TGR5 siRNA. Apart from this, MAPK signaling as well as FN, ICAM-1, and TGF-β1 suppressed by BBR under high glucose conditions were limited by TGR5 depletion. Thus, BBR decreases FN, ICAM-1, and TGF-β1 levels under high glucose conditions in GMCs possibly by activating TGR5 and inhibiting S1P2/MAPK signaling. PMID:27292312

  8. 1,25-Dihydroxyvitamin D3 Promotes High Glucose-Induced M1 Macrophage Switching to M2 via the VDR-PPARγ Signaling Pathway

    PubMed Central

    Zhang, Xiaoliang; Zhou, Min; Guo, Yinfeng; Song, Zhixia; Liu, Bicheng

    2015-01-01

    Macrophages, especially their activation state, are closely related to the progression of diabetic nephropathy. Classically activated macrophages (M1) are proinflammatory effectors, while alternatively activated macrophages (M2) exhibit anti-inflammatory properties. 1,25-Dihydroxyvitamin D3 has renoprotective roles that extend beyond the regulation of mineral metabolism, and PPARγ, a nuclear receptor, is essential for macrophage polarization. The present study investigates the effect of 1,25-dihydroxyvitamin D3 on macrophage activation state and its underlying mechanism in RAW264.7 cells. We find that, under high glucose conditions, RAW264.7 macrophages tend to switch to the M1 phenotype, expressing higher iNOS and proinflammatory cytokines, including TNFα and IL-12. While 1,25-dihydroxyvitamin D3 significantly inhibited M1 activation, it enhanced M2 macrophage activation; namely, it upregulated the expression of MR, Arg-1, and the anti-inflammatory cytokine IL-10 but downregulated the M1 markers. However, the above effects of 1,25-dihydroxyvitamin D3 were abolished when the expression of VDR and PPARγ was inhibited by VDR siRNA and a PPARγ antagonist. In addition, PPARγ was also decreased upon treatment with VDR siRNA. The above results demonstrate that active vitamin D promoted M1 phenotype switching to M2 via the VDR-PPARγ pathway. PMID:25961000

  9. 1,25(OH)2D3 inhibits high glucose-induced apoptosis and ROS production in human peritoneal mesothelial cells via the MAPK/P38 pathway.

    PubMed

    Yang, Lina; Wu, Lan; Du, Shuyan; Hu, Ye; Fan, Yi; Ma, Jianfei

    2016-07-01

    The regulation of cell proliferation, differentiation and immunomodulation are affected by 1,25(OH)2D3. However, its function during apoptosis and oxidative stress in human peritoneal mesothelial cells (HPMCs) remains unknown. The aim of the present study was to investigate whether the regulation of apoptosis and oxidative stress have therapeutic relevance in peritoneal dialysis (PD) therapy. The present study investigated the effects of 1,25(OH)2D3 on high glucose (HG)-induced apoptosis and reactive oxygen species (ROS) production in HPMCs, and examined the underlying molecular mechanisms. Flow cytometry and western blotting were performed to detect cell apoptosis, 2,7-dichlorofluorescein diacetate was used to measure reactive oxygen species production and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide was used to measure cell viability. The results of the present study demonstrated that exposure to HG increased apoptosis and ROS production in HPMCs, whereas pretreatment with 1,25(OH)2D3 significantly inhibited HG‑induced apoptosis and ROS production. Further analysis revealed that 1,25(OH)2D3 facilitated cell survival via the MAPK/P38 pathway. The results of the present study indicate that 1,25(OH)2D3 inhibits apoptosis and ROS production in HG‑induced HPMCs via inhibition of the MAPK/P38 pathway. PMID:27220355

  10. High glucose induces mitochondrial dysfunction and apoptosis in human retinal pigment epithelium cells via promoting SOCS1 and Fas/FasL signaling.

    PubMed

    Chen, Min; Wang, Wei; Ma, Jian; Ye, Panpan; Wang, Kaijun

    2016-02-01

    Diabetic retinopathy (DR) is one of the most serious complications of diabetes mellitus (DM), however, the contribution of high glucose (HG) or hyperglycemia to DR is far from fully understanding. In the present study, we examined the expression of Fas/FasL signaling and suppressors of cytokine signaling (SOCS)1 and 3 in HG-induced human retinal pigment epithelium cells (ARPE-19 cells). And then we investigated the regulatory role of both Fas and SOCS1 in HG-induced mitochondrial dysfunction and apoptosis. Results demonstrated that HG with more than 40mM induced mitochondrial dysfunction via reducing mitochondrial membrane potential (MMP) and via inhibiting the Bcl-2 level, which is the upstream signaling of mitochondria in ARPE-19 cells. HG also upreuglated the Fas signaling and SOCS levels probably via promoting JAK/STAT signaling in ARPE-19 cells. Moreover, the exogenous Fas or entogenous overexpressed SOCS1 accentuated the HG-induced mitochondrial dysfunction and apoptosis, whereas the knockdown of either Fas or SOCS1 reduced the HG-induced mitochondria dysfunction and apoptosis. Thus, the present study confirmed that both Fas/FasL signaling and SOCS1 promoted the HG-induced mitochondrial dysfunction and apoptosis. These results implies the key regulatory role of Fas signaling and SOCS in DR. PMID:26700587

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

    PubMed Central

    Kim, Daehoon; Seong, Ki Moon; Park, Sungkyun; Kim, Wanyeon; Youn, BuHyun

    2016-01-01

    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. PMID:26769850

  12. P38 MAPK/miR-1 are involved in the protective effect of EGCG in high glucose-induced Cx43 downregulation in neonatal rat cardiomyocytes.

    PubMed

    Yu, Lu; Yu, Hongmei; Li, Xiaoting; Jin, Chongying; Zhao, Yanbo; Xu, Shengjie; Sheng, Xia

    2016-08-01

    The remodeling of cardiac gap junctions contributes to various arrhythmias in a diabetic heart. We previously reported that Epigallocatechin-3-gallate (EGCG) attenuated connexin43 (Cx43) protein downregulation induced by high glucose (HG) in neonatal rat cardiomyocytes, but Cx43 mRNA expression was not affected. It indicated the possible mechanisms of post-transcriptional regulation, which still remains unclear. As microRNAs (miRNAs) regulate gene expression widely at post-transcriptional level, we measured miR-1/206 in cardiomyocytes treated with HG and EGCG by quantitative RT-PCR and investigated their relationship with signal transduction pathways. The results showed that HG induced miR-1/206 elevation by PKC MAPK pathway. Moreover, we tested the negative regulation effect of miR-1/206 on Cx43 protein by miRNAs transfection. EGCG, however, nearly abolished the HG-induced miR-1 augmentation via P38 MAPK pathway. Therefore, our study suggested that PKC-activated miR-1/206 expression might contribute to Cx43 downregulation in HG-treated cardiomyocytes, and EGCG conferred protective effect by inhibiting miR-1 elevation via P38 MAPK pathway. PMID:27306406

  13. CKIP-1 ameliorates high glucose-induced expression of fibronectin and intercellular cell adhesion molecule-1 by activating the Nrf2/ARE pathway in glomerular mesangial cells.

    PubMed

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

    2016-09-15

    Glucose and lipid metabolism disorders as well as oxidative stress (OSS) play important roles in diabetic nephropathy (DN). Glucose and lipid metabolic dysfunctions are the basic pathological changes of chronic microvascular complications of diabetes mellitus, such as DN. OSS can lead to the accumulation of extracellular matrix and inflammatory factors which will accelerate the progress of DN. Casein kinase 2 interacting protein-1 (CKIP-1) mediates adipogenesis, cell proliferation and inflammation under many circumstances. However, whether CKIP-1 is involved in the development of DN remains unknown. Here, we show that CKIP-1 is a novel regulator of resisting the development of DN and the underlying molecular mechanism is related to activating the nuclear factor E2-related factor 2 (Nrf2)/antioxidant response element (ARE) antioxidative stress pathway. The following findings were obtained: (1) The treatment of glomerular mesangial cells (GMCs) with high glucose (HG) decreased CKIP-1 levels in a time-dependent manner; (2) CKIP-1 overexpression dramatically reduced fibronectin (FN) and intercellular adhesionmolecule-1 (ICAM-1) expression. Depletion of CKIP-1 further induced the production of FN and ICAM-1; (3) CKIP-1 promoted the nuclear accumulation, DNA binding, and transcriptional activity of Nrf2. Moreover, CKIP-1 upregulated the expression of Nrf2 downstream genes, heme oxygenase (HO-1) and superoxide dismutase 1 (SOD1); and ultimately decreased the levels of reactive oxygen species (ROS). The molecular mechanisms clarify that the advantageous effect of CKIP-1 on DN are well connected with the activation of the Nrf2/ARE antioxidative stress pathway. PMID:27481061

  14. Retinoic Acid Protects Cardiomyocytes from High Glucose-Induced Apoptosis via Inhibition of Sustained Activation of NF-κB Signaling

    PubMed Central

    Nizamutdinova, Irina T.; Guleria, Rakeshwar S.; Singh, Amar B.; Kendall, Jonathan A.; Baker, Kenneth M.; Pan, Jing

    2012-01-01

    We have previously shown that retinoic acid (RA) has protective effects on high glucose (HG)-induced cardiomyocyte apoptosis. To further elucidate the molecular mechanisms of RA effects, we determined the interaction between nuclear factor (NF)-κB and RA signaling. HG induced a sustained phosphorylation of IKK/IκBα and transcriptional activation of NF-κB in cardiomyocytes. Activated NF-κB signaling has an important role in HG-induced cardiomyocyte apoptosis and gene expression of interleukin-6 (IL-6), tumor necrosis factor (TNF)-α and monocyte chemoattractant protein-1 (MCP-1). All-trans RA (ATRA) and LGD1069, through activation of RAR/RXR-mediated signaling, inhibited the HG-mediated effects in cardiomyocytes. The inhibitory effect of RA on NF-κB activation was mediated through inhibition of IKK/IκBα phosphorylation. ATRA and LGD1069 treatment promoted protein phosphatase 2A (PP2A) activity, which was significantly suppressed by HG stimulation. The RA effects on IKK and IκBα were blocked by okadaic acid or silencing the expression of PP2Ac-subunit, indicating that the inhibitory effect of RA on NF-κB is regulated through activation of PP2A and subsequent dephosphorylation of IKK/IκBα. Moreover, ATRA and LGD1069 reversed the decreased PP2A activity and inhibited the activation of IKK/IκBα and gene expression of MCP-1, IL-6 and TNF-α in the hearts of Zucker diabetic fatty rats. In summary, our findings suggest that the suppressed activation of PP2A contributed to sustained activation of NF-κB in HG-stimulated cardiomyocytes; and that the protective effect of RA on hyperglycemia-induced cardiomyocyte apoptosis and inflammatory responses is partially regulated through activation of PP2A and suppression of NF-κB-mediated signaling and downstream targets. PMID:22718360

  15. High Glucose Induces Down-Regulated GRIM-19 Expression to Activate STAT3 Signaling and Promote Cell Proliferation in Cell Culture

    PubMed Central

    Li, Yong-Guang; Han, Bei-Bei; Li, Feng; Yu, Jian-Wu; Dong, Zhi-Feng; Niu, Geng-Ming; Qing, Yan-Wei; Li, Jing-Bo; Wei, Meng; Zhu, Wei

    2016-01-01

    Recent studies indicated that Gene Associated with Retinoid-IFN-Induced Mortality 19 (GRIM-19), a newly discovered mitochondria-related protein, can regulate mitochondrial function and modulate cell viability possibly via interacting with STAT3 signal. In the present study we sought to test: 1) whether GRIM-19 is involved in high glucose (HG) induced altered cell metabolism in both cancer and cardiac cells, 2) whether GRIM-19/STAT3 signaling pathway plays a role in HG induced biological effects, especially whether AMPK activity could be involved. Our data showed that HG enhanced cell proliferation of both HeLa and H9C2 cells, which was closely associated with down-regulated GRIM-19 expression and increased phosphorylated STAT3 level. We showed that GRIM-19 knock-down alone in normal glucose cultured cells can also result in an increase in phosphorylated STAT3 level and enhanced proliferation capability, whereas GRIM-19 over-expression can abolished HG induced STAT3 activation and enhanced cell proliferation. Importantly, both down-regulated or over-expression of GRIM-19 increased lactate production in both HeLa and H9C2 cells. The activated STAT3 was responsible for increased cell proliferation as either AG-490, an inhibitor of JAK2, or siRNA targeting STAT3 can attenuate cell proliferation increased by HG. In addition, HG increased lactate acid levels in HeLa cells, which was also observed when GRIM-19 was genetically manipulated. However, HG did not affect the lactate levels in H9C2 cells. Of note, over-expression of GRIM-19 and silencing of STAT3 both increased lactate production in H9C2 cells. As expected, HG resulted in significant decreases in phosphorylated AMPKα levels in H9C2 cells, but not in HeLa cells. Interestingy, activation of AMPKα by metformin was associated with a reversal of the suppressed GRIM-19 expression in H9C2 cells, the fold of changes in GRIM-19 expression by metformin were much less in HeLa cells. Metformin did not affect the

  16. 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

  17. Preventing High Blood Pressure

    MedlinePlus

    ... this? Submit What's this? Submit Button Related CDC Web Sites Division for Heart Disease and Stroke Prevention ... this? Submit What's this? Submit Button Related CDC Web Sites Division for Heart Disease and Stroke Prevention ...

  18. High Blood Cholesterol Prevention

    MedlinePlus

    ... this? Submit What's this? Submit Button Related CDC Web Sites Division for Heart Disease and Stroke Prevention ... this? Submit What's this? Submit Button Related CDC Web Sites Division for Heart Disease and Stroke Prevention ...

  19. GYY4137, a novel hydrogen sulfide-releasing molecule, likely protects against high glucose-induced cytotoxicity by activation of the AMPK/mTOR signal pathway in H9c2 cells.

    PubMed

    Wei, Wen-Bin; Hu, Xun; Zhuang, Xiao-Dong; Liao, Li-Zhen; Li, Wei-Dong

    2014-04-01

    Diabetic cardiomyopathy (DCM) has become a major cause of diabetes-related morbidity and mortality. Increasing evidences have proved that hydrogen sulfide (H2S) fulfills a positive role in regulating diabetic myocardial injury. The present study was designed to determine whether GYY4137, a novel H2S-releasing molecule, protected H9c2 cells against high glucose (HG)-induced cytotoxicity by activation of the AMPK/mTOR signal pathway. H9c2 cells were incubated in normal glucose (5.5 mM), 22, 33, and 44 mM glucose for 24 h to mimic the hyperglycemia in DCM in vitro. Then we added 50, 100, and 200 μM GYY4137, and measured the cell viability, lactate dehydrogenase (LDH) enzyme activity, and mitochondrial membrane potential (MMP). 0.5 mM 5-amino-4-imidazole-carboxamide riboside (AICAR, an AMPK activator) and 1 mM adenine 9-β-D-arabinofuranoside (Ara-A, an AMPK inhibitor) were used to identity whether the AMPK/mTOR signal pathway was involved in GYY4137-mediated cardioprotection. We demonstrated that HG decreased cell viability and increased LDH enzyme activity in a concentration-dependent manner. 33 mM HG treatment for 24 h was chosen as our model group for further study. Both 100 and 200 μM GYY4137 treatments significantly attenuated HG-induced cell viability decrement, LDH enzyme activity increase, and MMP collapse. AICAR had similar effects to GYY4137 treatment while Ara-A attenuated GYY4137-mediated cardioprotection. Importantly, both GYY4137 and AICAR increased AMPK phosphorylation and decreased mTOR phosphorylation compared with the HG model group while Ara-A attenuated GYY4137-mediated AMPK phosphorylation increase and mTOR phosphorylation decrement. In conclusion, we propose that GYY4137 likely protects against HG-induced cytotoxicity by activation of the AMPK/mTOR signal pathway in H9c2 cells. PMID:24374752

  20. Eicosapentaenoic acid inhibits glucose-induced membrane cholesterol crystalline domain formation through a potent antioxidant mechanism.

    PubMed

    Mason, R Preston; Jacob, Robert F

    2015-02-01

    Lipid oxidation leads to endothelial dysfunction, inflammation, and foam cell formation during atherogenesis. Glucose also contributes to lipid oxidation and promotes pathologic changes in membrane structural organization, including the development of cholesterol crystalline domains. In this study, we tested the comparative effects of eicosapentaenoic acid (EPA), an omega-3 fatty acid indicated for the treatment of very high triglyceride (TG) levels, and other TG-lowering agents (fenofibrate, niacin, and gemfibrozil) on lipid oxidation in human low-density lipoprotein (LDL) as well as membrane lipid vesicles prepared in the presence of glucose (200 mg/dL). We also examined the antioxidant effects of EPA in combination with atorvastatin o-hydroxy (active) metabolite (ATM). Glucose-induced changes in membrane structural organization were measured using small angle x-ray scattering approaches and correlated with changes in lipid hydroperoxide (LOOH) levels. EPA was found to inhibit LDL oxidation in a dose-dependent manner (1.0-10.0 µM) and was distinguished from the other TG-lowering agents, which had no significant effect as compared to vehicle treatment alone. Similar effects were observed in membrane lipid vesicles exposed to hyperglycemic conditions. The antioxidant activity of EPA, as observed in glucose-treated vesicles, was significantly enhanced in combination with ATM. Glucose treatment produced highly-ordered, membrane-restricted, cholesterol crystalline domains, which correlated with increased LOOH levels. Of the agents tested in this study, only EPA inhibited glucose-induced cholesterol domain formation. These data demonstrate that EPA, at pharmacologic levels, inhibits hyperglycemia-induced changes in membrane lipid structural organization through a potent antioxidant mechanism associated with its distinct, physicochemical interactions with the membrane bilayer. PMID:25449996

  1. Mediation of glucose-induced anorexia by central nervous system interleukin 1 signaling.

    PubMed

    Mizuno, Tooru M; Lew, Pei San; Spirkina, Alexandra; Xu, Yang

    2013-11-01

    Hypothalamic glucose sensing plays a critical role in the regulation of food intake and metabolism. Glucose injection, either centrally or peripherally suppresses food intake. However, the mechanism of glucose-induced feeding suppression is not fully understood. It has been demonstrated that hypothalamic interleukin 1 beta (IL-1β) mRNA levels are altered by metabolic states and IL-1 signaling participates in the regulation of food intake. Therefore, we hypothesized that hypothalamic IL-1 gene expression is regulated by glucose and glucose-induced feeding suppression is mediated via hypothalamic IL-1 signaling. To address this hypothesis, we examined the effect of glucose on IL-1α and IL-1β mRNA expression in the hypothalamus. We also examined the effect of intraperitoneal injection of glucose on food intake in wild-type and type I IL-1 receptor (IL-1RI)-deficient mice. Levels of IL-1α and IL-1β mRNA in the hypothalamus were increased in response to feeding and intraperitoneal injection of glucose, and were positively correlated with blood glucose levels in mice. Exposure of hypothalamic explants to high glucose (10 mM) media increased IL-1α and IL-1β mRNA levels compared to low glucose (1 mM) media. Intraperitoneal glucose administration reduced food intake in wild-type mice, while the feeding-suppressing effect of glucose was attenuated in IL-1RI-deficient mice. These findings support the role for hypothalamic IL-1 signaling in the mediation of the anorectic effect of glucose. PMID:24013028

  2. 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.

  3. [Role of the NADH shuttle system in glucose-induced insulin secretion].

    PubMed

    Eto, K; Kadowaki, T

    1999-03-01

    To determine the role of the NADH shuttle system composed of the glycerol phosphate shuttle and malate-aspartate shuttle in glucose-induced insulin secretion from pancreatic beta cells, we have generated mice which lack mitochondrial glycerol-3 phosphate dehydrogenase (mGPDH), a rate-limiting enzyme of the glycerol phosphate shuttle. When both shuttles were halted in mGPDH-deficient islets treated with aminooxyacetate, an inhibitor of the malate-aspartate shuttle, glucose-induced insulin secretion was almost completely abrogated. Under these conditions, although the flux of glycolysis and supply of glucose-derived pyruvate into mitochondria were unaffected, glucose-induced increases in NAD(P)H autofluorescence, mitochondrial membrane potential, Ca2+ entry into mitochondria, and ATP content were severely attenuated. This study provides the first direct evidence that the NADH shuttle system is essential for coupling glycolysis with the activation of mitochondrial energy metabolism to trigger glucose-induced insulin secretion and thus revises the classical model for the metabolic signals of glucose-induced insulin secretion. PMID:10199125

  4. 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.

  5. Ascorbate Reverses High Glucose- and RAGE-induced Leak of the Endothelial Permeability Barrier

    PubMed Central

    Meredith, M. Elizabeth; Qu, Zhi-chao; May, James M.

    2014-01-01

    High glucose concentrations due to diabetes increase leakage of plasma constituents across the endothelial permeability barrier. We sought to determine whether vitamin C, or ascorbic acid (ascorbate), could reverse such high glucose-induced increases in endothelial barrier permeability. Human umbilical vein endothelial cells and two brain endothelial cell lines cultured at 25 mM glucose showed increases in endothelial barrier permeability to radiolabeled inulin compared to cells cultured at 5 mM glucose. Acute loading of the cells for 30–60 min with ascorbate before the permeability assay prevented the high glucose-induced increase in permeability and decreased basal permeability at 5 mM glucose. High glucose-induced barrier leakage was mediated largely by activation of the receptor for advanced glycation end products (RAGE), since it was prevented by RAGE blockade and mimicked by RAGE ligands. Intracellular ascorbate completely prevented RAGE ligand-induced increases in barrier permeability. The high glucose-induced increase in endothelial barrier permeability was also acutely decreased by several cell-penetrant antioxidants, suggesting that at least part of the ascorbate effect could be due to its ability to act as an antioxidant. PMID:24472555

  6. Glucose induces rapid changes in the secretome of Saccharomyces cerevisiae

    PubMed Central

    2014-01-01

    Background Protein secretion is a fundamental process in all living cells. Proteins can either be secreted via the classical or non-classical pathways. In Saccharomyces cerevisiae, gluconeogenic enzymes are in the extracellular fraction/periplasm when cells are grown in media containing low glucose. Following a transfer of cells to high glucose media, their levels in the extracellular fraction are reduced rapidly. We hypothesized that changes in the secretome were not restricted to gluconeogenic enzymes. The goal of the current study was to use a proteomic approach to identify extracellular proteins whose levels changed when cells were transferred from low to high glucose media. Results We performed two iTRAQ experiments and identified 347 proteins that were present in the extracellular fraction including metabolic enzymes, proteins involved in oxidative stress, protein folding, and proteins with unknown functions. Most of these proteins did not contain typical ER-Golgi signal sequences. Moreover, levels of many of these proteins decreased upon a transfer of cells from media containing low to high glucose media. Using an extraction procedure and Western blotting, we confirmed that the metabolic enzymes (glyceraldehyde-3-phosphate dehydrogenase, 3-phosphoglycerate kinase, glucose-6-phosphate dehydrogenase, pyruvate decarboxylase), proteins involved in oxidative stress (superoxide dismutase and thioredoxin), and heat shock proteins (Ssa1p, Hsc82p, and Hsp104p) were in the extracellular fraction during growth in low glucose and that the levels of these extracellular proteins were reduced when cells were transferred to media containing high glucose. These proteins were associated with membranes in vesicle-enriched fraction. We also showed that small vesicles were present in the extracellular fraction in cells grown in low glucose. Following a transfer from low to high glucose media for 30 minutes, 98% of these vesicles disappeared from the extracellular fraction

  7. Fructose impairs glucose-induced hepatic triglyceride synthesis

    PubMed Central

    2011-01-01

    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. PMID:21261970

  8. Regulation of brain water during acute glucose-induced hyperosmolality in ovine fetuses, lambs, and adults.

    PubMed

    Stonestreet, Barbara S; Petersson, Katherine H; Sadowska, Grazyna B; Patlak, Clifford S

    2004-02-01

    We tested the hypothesis that, during acute glucose-induced hyperosmolality, the brain shrinks less than predicted on the basis of an ideal osmometer and that brain volume regulation is present in fetuses, premature and newborn lambs. Brain water responses to glucose-induced hyperosmolality were measured in the cerebral cortex, cerebellum, and medulla of fetuses at 60% of gestation, premature ventilated lambs at 90% of gestation, newborn lambs, and adult sheep. After exposure of the sheep to increases in osmolality with glucose plus NaCl, brain water and electrolytes were measured. The ideal osmometer is a system in which impermeable solutes do not enter or leave in response to an osmotic stress. In the absence of volume regulation, brain solute remains constant as osmolality changes. The osmotically active solute demonstrated direct linear correlations with plasma osmolality in the cerebral cortex of the fetuses at 60% of gestation (r = 0.72, n = 24, P = 0.0001), premature lambs (r = 0.58, n = 22, P = 0.005), newborn lambs (r = 0.57, n = 24, P = 0.004), and adult sheep (r = 0.70, n = 18, P = 0.001). Similar findings were observed in the cerebellum and medulla. Increases in the quantity of osmotically active solute over the range of plasma osmolalities indicate that volume regulation was present in the brain regions of the fetuses, premature lambs, newborn lambs, and adult sheep during glucose-induced hyperosmolality. We conclude that, during glucose-induced hyperosmolality, the brain shrinks less than predicted on the basis of an ideal osmometer and exhibits volume regulation in fetuses at 60% of gestation, premature lambs, newborn lambs, and adult sheep. PMID:14578364

  9. Glucose-induced conformational change in yeast hexokinase.

    PubMed Central

    Bennett, W S; Steitz, T A

    1978-01-01

    The A isozyme of yeast hexokinase (ATP:D-hexose 6-phosphotransferase, EC 2.7.1.1) crystallized as a complex with glucose has a conformation that is dramatically different from the conformation of the B isozyme crystallized in the absence of glucose. Comparison of the high-resolution structures shows that one lobe of the molecule is rotated by 12 degrees relative to the other lobe, resulting in movements of as much as 8 A in the polypeptide backbone and closing the cleft between the lobes into which glucose is bound. The conformational change is produced by the binding of glucose (R.C. McDonald, T.A. Steitz, and D.M. Engelman, unpublished data) and is essential for catalysis [Anderson, C.M., Stenkamp, R.E., McDonald, R.C. & Steitz, T.A. (1978) J. Mol. Biol. 123, 207-219] and thus provides an example of induced fit. The surface area of the hexokinase A-glucose complex exposed to solvent is smaller than that of native hexokinase B. By using the change in exposed surface area to estimate the hydrophobic contribution to the free energy changes upon glucose binding, we find that the hydrophobic effect alone favors the active conformation of hexokinase in the presence and absence of sugar. The observed stability of the inactive conformation of the enzyme in the absence of substrates may result from a deficiency of complementary interactions within the cavity that forms when the two lobes close together. PMID:283394

  10. Working with Youth in High-Risk Environments: Experiences in Prevention. OSAP Prevention Monograph-12.

    ERIC Educational Resources Information Center

    Marcus, Carol E., Ed.; Swisher, John D., Ed.

    This report focuses on prevention programs developed with support from the Office for Substance Abuse Prevention's (OSAP) High-Risk Youth Demonstration Grant Program. Included are an Introduction (Eric Goplerud and others) and the following reports: (1) "Athletes Coaching Teens for Substance Abuse Prevention: Alcohol and Other Drug Use and Risk…

  11. Glucose-Induced Down Regulation of Thiamine Transporters in the Kidney Proximal Tubular Epithelium Produces Thiamine Insufficiency in Diabetes

    PubMed Central

    Larkin, James R.; Zhang, Fang; Godfrey, Lisa; Molostvov, Guerman; Zehnder, Daniel; Rabbani, Naila; Thornalley, Paul J.

    2012-01-01

    Increased renal clearance of thiamine (vitamin B1) occurs in experimental and clinical diabetes producing thiamine insufficiency mediated by impaired tubular re-uptake and linked to the development of diabetic nephropathy. We studied the mechanism of impaired renal re-uptake of thiamine in diabetes. Expression of thiamine transporter proteins THTR-1 and THTR-2 in normal human kidney sections examined by immunohistochemistry showed intense polarised staining of the apical, luminal membranes in proximal tubules for THTR-1 and THTR-2 of the cortex and uniform, diffuse staining throughout cells of the collecting duct for THTR-1 and THTR-2 of the medulla. Human primary proximal tubule epithelial cells were incubated with low and high glucose concentration, 5 and 26 mmol/l, respectively. In high glucose concentration there was decreased expression of THTR-1 and THTR-2 (transporter mRNA: −76% and −53% respectively, p<0.001; transporter protein −77% and −83% respectively, p<0.05), concomitant with decreased expression of transcription factor specificity protein-1. High glucose concentration also produced a 37% decrease in apical to basolateral transport of thiamine transport across cell monolayers. Intensification of glycemic control corrected increased fractional excretion of thiamine in experimental diabetes. We conclude that glucose-induced decreased expression of thiamine transporters in the tubular epithelium may mediate renal mishandling of thiamine in diabetes. This is a novel mechanism of thiamine insufficiency linked to diabetic nephropathy. PMID:23285265

  12. Dropout Prevention: A Study of Prevention Programs Used by High Schools to Increase Graduation Rate

    ERIC Educational Resources Information Center

    Simmons, Christopher L.

    2013-01-01

    This mixed methods study focused on the relationship between dropout prevention programs and graduation rates in one school district in Florida during the 2010-2011 school year. The dropout prevention program data analyzed included high school principals' perceptions in regard to perceived effectiveness, fidelity of implementation, cost efficacy,…

  13. High School Teachers' Perceptions of Cyberbullying Prevention and Intervention Strategies

    ERIC Educational Resources Information Center

    Stauffer, Sterling; Heath, Melissa Allen; Coyne, Sarah Marie; Ferrin, Scott

    2012-01-01

    Recent meta-analyses indicate that bully prevention programs produce minimal change in student behavior. This study examined 66 high school teachers' perceptions regarding the effect of cyberbullying on students, which intervening strategies teachers would use when dealing with cyberbullying, and which prevention strategies would assist in…

  14. Skeletal Muscle TRIB3 Mediates Glucose Toxicity in Diabetes and High- Fat Diet-Induced Insulin Resistance.

    PubMed

    Zhang, Wei; Wu, Mengrui; Kim, Teayoun; Jariwala, Ravi H; Garvey, W John; Luo, Nanlan; Kang, Minsung; Ma, Elizabeth; Tian, Ling; Steverson, Dennis; Yang, Qinglin; Fu, Yuchang; Garvey, W Timothy

    2016-08-01

    In the current study, we used muscle-specific TRIB3 overexpressing (MOE) and knockout (MKO) mice to determine whether TRIB3 mediates glucose-induced insulin resistance in diabetes and whether alterations in TRIB3 expression as a function of nutrient availability have a regulatory role in metabolism. In streptozotocin diabetic mice, TRIB3 MOE exacerbated, whereas MKO prevented, glucose-induced insulin resistance and impaired glucose oxidation and defects in insulin signal transduction compared with wild-type (WT) mice, indicating that glucose-induced insulin resistance was dependent on TRIB3. In response to a high-fat diet, TRIB3 MOE mice exhibited greater weight gain and worse insulin resistance in vivo compared with WT mice, coupled with decreased AKT phosphorylation, increased inflammation and oxidative stress, and upregulation of lipid metabolic genes coupled with downregulation of glucose metabolic genes in skeletal muscle. These effects were prevented in the TRIB3 MKO mice relative to WT mice. In conclusion, TRIB3 has a pathophysiological role in diabetes and a physiological role in metabolism. Glucose-induced insulin resistance and insulin resistance due to diet-induced obesity both depend on muscle TRIB3. Under physiological conditions, muscle TRIB3 also influences energy expenditure and substrate metabolism, indicating that the decrease and increase in muscle TRIB3 under fasting and nutrient excess, respectively, are critical for metabolic homeostasis. PMID:27207527

  15. Administrative Plan to Prevent High School Dropouts.

    ERIC Educational Resources Information Center

    Carnes, Ernest B.

    Recommendations for developing educational programs for high school dropout-prone students are presented in this publication. Data compiled on dropouts by the South Carolina State Department of Education indicate that approximately one out of every two first graders in South Carolina public schools drops out of school before completing the…

  16. Preventing cavitation in high energy centrifugal pumps

    SciTech Connect

    Garbers, A.W.F.; Wasfi, A.K. Ltd. )

    1990-07-01

    Large-eye impellers for high energy centrifugal pumps were developed to meet the specification of reduced NPSH{sub r} at rated flow conditions. Unfortunately, this improved NPSH performance was not without adverse tradeoffs because an abnormal increase in noise, vibration and cavitation erosion were experienced at low flows. Centrifugal pumps are often used under widely varying and adverse conditions, and in the case of high energy and large-eye impeller pumps, these conditions should be evaluated very carefully. At petrochemical complexes in Secunda in the Republic of South Africa, a centrifugal pump application for lean carbonate solution experienced frequent failures. An investigation and literature survey indicated the cause was low flow cavitation. The purpose of this article is but to give design guidelines as obtained from literature and experience.

  17. Obesity prevention in defined (high school) populations

    PubMed Central

    Taylor, C B; Taylor, K; Jones, M; Shorter, A; Yee, M; Genkin, B; Burrows, A; Kass, A E; Rizk, M; Redman, M; Romer, P; Williams, J; Wilfley, D E

    2012-01-01

    Background: A challenge for the widespread dissemination of Internet-based programs designed to produce weight maintenance/loss in defined (high school) populations is to adapt them to local needs and interests, whereas demonstrating effectiveness and salience for both universal and targeted populations. Objective: The objective of this study is to examine the feasibility of providing an inexpensive, Internet-based universal (healthy weight regulation) and targeted (weight maintenance/loss) health program to all ninth-grade students in a high school serving a lower socioecnomic status, diverse population. Design: A total of 118 normal-weight and 64 overweight/obese students in the same ninth-grade class completed a baseline screen and were allocated to a healthy weight regulation program or a weight-loss maintenance program. Both groups simultaneously received a 10-week Internet-based intervention. Program implementation required minimal teacher time. Measurement included self-reported fruit, vegetable and high-fat/-calorie food consumption, self-reported change in body mass index (BMI), weight and shape concerns, as well as program engagement. Results: The program was successfully implemented in nine classes, with minimal help from the investigators. There was a significant increase in self-reported consumption of fruits and vegetables (P=0.001). There was a significant reduction in self-reported BMI in the overweight/obese group (P=0.001). Students found the program helpful and engaging. There was a significant reduction in weight and shape concerns in the high-risk female students, consistent with a reduced risk for the development of an eating disorder. Providing a universal and targeted online healthy weight regulation program to ninth-grade students is feasible and inexpensive. The results suggest the program can serve as ‘core' for future studies using adaptive, continuous quality-improvement designs. PMID:24567839

  18. Peroxiredoxin 4 improves insulin biosynthesis and glucose-induced insulin secretion in insulin-secreting INS-1E cells.

    PubMed

    Mehmeti, Ilir; Lortz, Stephan; Elsner, Matthias; Lenzen, Sigurd

    2014-09-26

    Oxidative folding of (pro)insulin is crucial for its assembly and biological function. This process takes place in the endoplasmic reticulum (ER) and is accomplished by protein disulfide isomerase and ER oxidoreductin 1β, generating stoichiometric amounts of hydrogen peroxide (H2O2) as byproduct. During insulin resistance in the prediabetic state, increased insulin biosynthesis can overwhelm the ER antioxidative and folding capacity, causing an imbalance in the ER redox homeostasis and oxidative stress. Peroxiredoxin 4 (Prdx4), an ER-specific antioxidative peroxidase can utilize luminal H2O2 as driving force for reoxidizing protein disulfide isomerase family members, thus efficiently contributing to disulfide bond formation. Here, we examined the functional significance of Prdx4 on β-cell function with emphasis on insulin content and secretion during stimulation with nutrient secretagogues. Overexpression of Prdx4 in glucose-responsive insulin-secreting INS-1E cells significantly metabolized luminal H2O2 and improved the glucose-induced insulin secretion, which was accompanied by the enhanced proinsulin mRNA transcription and insulin content. This β-cell beneficial effect was also observed upon stimulation with the nutrient insulin secretagogue combination of leucine plus glutamine, indicating that the effect is not restricted to glucose. However, knockdown of Prdx4 had no impact on H2O2 metabolism or β-cell function due to the fact that Prdx4 expression is negligibly low in pancreatic β-cells. Moreover, we provide evidence that the constitutively low expression of Prdx4 is highly susceptible to hyperoxidation in the presence of high glucose. Overall, these data suggest an important role of Prdx4 in maintaining insulin levels and improving the ER folding capacity also under conditions of a high insulin requirement. PMID:25122762

  19. Long-term exposure of proximal tubular epithelial cells to glucose induces transforming growth factor-beta 1 synthesis via an autocrine PDGF loop.

    PubMed

    Fraser, Donald; Brunskill, Nigel; Ito, Takafumi; Phillips, Aled

    2003-12-01

    We have recently reported increased transforming growth factor (TGF)-beta1 gene transcription in proximal tubular cells within 12 hours of exposure to 25 mmol/L D-glucose, with a requirement for a second stimulus such as platelet-derived growth factor (PDGF) to increase its translation in short-term experiments. In the current study we investigated the effect on TGF-beta 1 production of prolonged exposure of proximal tubular cells to high glucose concentrations. Enzyme-linked immunosorbent assay of cell culture supernatant showed significant increase in latent TGF-beta 1 only after 7 days exposure to high glucose. Radiolabeling of glucose-stimulated cells with (3)H amino acids and subsequent immunoprecipitation of TGF-beta 1 demonstrated de novo synthesis from day 5 of high glucose exposure onwards. Similarly, polysome analysis showed enhanced translation of TGF-beta mRNA after 4 or more days of high glucose exposure. TGF-beta 1 synthesis, following addition of glucose, was inhibited by blockade of the PDGF-alpha receptor subunit. Glucose did not alter PDGF expression, nor expression of PDGF alpha-receptors. Activation of the receptor following addition of 25 mm D-glucose could be demonstrated suggesting increased sensitivity to endogenous PDGF. Exposure to glucose activated p38MAP kinase, and inhibition of this activation abrogated both glucose induced TGF-beta 1 transcriptional activation and TGF-beta 1 synthesis. Inhibition of p38MAP kinase did not influence the effect of exogenous PDGF when cells were stimulated sequentially by glucose and PDGF. We postulate that glucose induces an early increase in TGF-beta 1 transcription via activation of p38MAP kinase. In addition, glucose causes a late increase in PDGF-dependent TGF-beta 1 translation by enhancing cellular sensitivity to PDGF. This provides a potential explanation for the clinical observation that prolonged poor glycemic control may contribute to progression of diabetic nephropathy. PMID:14633628

  20. Over-expression of miR375 reduces glucose-induced insulin secretion in Nit-1 cells.

    PubMed

    Xia, Hua-Qiang; Pan, Yi; Peng, Ju; Lu, Guang-Xiu

    2011-06-01

    MicroRNAs (miRNAs) are 19- to 25-nt fragments cleaved from 70- to 100-nt hairpin precursors. These molecules participate in essential biological processes. It was estimated that 30% of all protein-coding genes are miRNA targets. Thousands of miRNAs have already been identified in plants and animals, but little is known about their biological roles. MicroRNA375 (miR375) is highly expressed in pancreatic islets of humans and mice and regulates insulin secretion in isolated pancreatic cells. To improve our understanding of the biological roles of miR375, we constructed the plasmid pAAV-miR375 and transfected it into mouse Nit-1 cells. Real-time PCR and Northern blot analysis showed that the Nit-1 cells transfected with pAAV-miR375 over-expressed the mature miR375 compared with Nit-1 cells transfected with control plasmid or untransfected cells. The expression of myotrophin (Mtpn) decreased and insulin secretion was reduced in Nit-1 cells transfected with pAAV-miR375. In this study, we successfully established an over-expression system for miR375 and a technique to study the biological function of miRNAs by over-expression. We verified that miR375 reduced glucose-induced insulin secretion by down-regulating the expression of Mtpn in Nit-1 cells in vitro, suggesting that miR375 has potential therapeutic applications in type II diabetes. PMID:20221699

  1. A Mixed Methods Study of High School Dropout Prevention Programs

    ERIC Educational Resources Information Center

    Hibler, Derrick, Sr.

    2013-01-01

    In the United States in 2011, 6,000 students between the ages of 16 and 24 dropped out of high school on a daily basis. Educators have developed numerous dropout prevention programs to address this problem. However, little research exists examining how high school principals and counselors engage students in these programs. The purpose of this…

  2. Adapter assembly prevents damage to tubing during high pressure tests

    NASA Technical Reports Server (NTRS)

    Stinett, L. L.

    1965-01-01

    Portable adapter assembly prevents damage to tubing and injury to personnel when pressurizing a system or during high pressure tests. The assembly is capable of withstanding high pressure. It is securely attached to the tubing stub end and may be removed without brazing, cutting or cleaning the tube.

  3. Tetrahydropteridines possess antioxidant roles to guard against glucose-induced oxidative stress in Dictyostelium discoideum

    PubMed Central

    Park, Seon-Ok; Kim, Hye-Lim; Lee, Soo-Woong; Park, Young Shik

    2013-01-01

    Glucose effects on the vegetative growth of Dictyostelium discoideum Ax2 were studied by examining oxidative stress and tetrahydropteridine synthesis in cells cultured with different concentrations (0.5X, 7.7 g L-1; 1X, 15.4 g L-1; 2X, 30.8 g L-1) of glucose. The growth rate was optimal in 1X cells (cells grown in 1X glucose) but was impaired drastically in 2X cells, below the level of 0.5X cells. There were glucose-dependent increases in reactive oxygen species (ROS) levels and mitochondrial dysfunction in parallel with the mRNA copy numbers of the enzymes catalyzing tetrahydropteridine synthesis and regeneration. On the other hand, both the specific activities of the enzymes and tetrahydropteridine levels in 2X cells were lower than those in 1X cells, but were higher than those in 0.5X cells. Given the antioxidant function of tetrahydropteridines and both the beneficial and harmful effects of ROS, the results suggest glucose-induced oxidative stress in Dictyostelium, a process that might originate from aerobic glycolysis, as well as a protective role of tetrahydropteridines against this stress. [BMB Reports 2013; 46(2): 86-91] PMID:23433110

  4. High-altitude pulmonary edema: diagnosis, prevention, and treatment.

    PubMed

    Pennardt, Andre

    2013-01-01

    High-altitude pulmonary edema (HAPE) is a lethal, noncardiogenic form of pulmonary edema that afflicts susceptible individuals after rapid ascent to high altitude above 2,500 m. Prevention of HAPE is achieved most effectively by gradual ascent allowing time for proper acclimatization. Certain prophylactic medications may further reduce the risk of ascending to high altitude in individuals with a prior history of HAPE. The most effective and reliable treatment of HAPE is immediate descent and administration of supplemental oxygen. PMID:23478563

  5. HIGH GLUCOSE INDUCES TOLL-LIKE RECEPTOR EXPRESSION IN HUMAN MONOCYTES: MECHANISM OF ACTIVATION

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Objective: Hyperglycemia induced inflammation is central in diabetes complications and monocytes are important in orchestrating these effects. Toll-like receptors (TLRs) play a key role in innate immune responses as well as inflammation. However, there is a paucity of data examining the expression a...

  6. Angiotensin-converting enzyme inhibition increases glucose-induced insulin secretion in response to acute restraint.

    PubMed

    Schweizer, Júnia R O L; Miranda, Paulo A C; Fóscolo, Rodrigo B; Lemos, Joao P M; Paula, Luciano F; Silveira, Warley C; Santos, Robson A S; Pinheiro, Sérgio V B; Coimbra, Candido C; Ribeiro-Oliveira, Antônio

    2012-12-01

    There is increasing evidence suggesting involvement of the renin-angiotensin system (RAS) in carbohydrate metabolism and its response to stress. Thus, the aim of the present study was to evaluate the effects of chronic inhibition of the RAS on glucose and insulin levels during acute restraint stress. Male Holtzman rats were treated with 10 mg/kg per day enalapril solution or vehicle for 14 days. After 14 days, rats were divided into three experimental groups: enalapril + restraint (ER), vehicle + restraint (VR) and enalapril + saline (ES). Rats in the restraint groups were subjected to 30 min restraint stress, whereas rats in the ES groups were given saline infusion instead. Blood samples were collected at baseline and after 5, 10, 20 and 30 min restraint stress or saline infusion. After restraint, a hyperglycaemic response was observed in the ER and VR groups that peaked at 20 and 10 min, respectively (P < 0.05 compared with baseline). The area under the glucose curve was markedly increased in the ER and VR groups compared with that in the ES group (P < 0.05 for both). Importantly, restraint induced a marked increase in insulin secretion in the ER group compared with only a mild elevation in the VR group; insulin secretion in both groups peaked at 20 min (P < 0.05 compared with baseline). Analysis of the area under the insulin curve confirmed an increase in insulin secretion in the ER compared with the VR and ES groups (P < 0.05 for both). The results of the present study reinforce that the RAS is involved in modulating responses to stress and suggest that RAS inhibition with enalapril may increase glucose-induced insulin secretion in response to acute restraint. PMID:23734984

  7. Effects of Comprehensive, Multiple High-Risk Behaviors Prevention Program on High School Students

    ERIC Educational Resources Information Center

    Collier, Crystal

    2013-01-01

    The purpose of this mixed methods study was to examine the effect of a multiple high-risk behaviors prevention program applied comprehensively throughout an entire school-system involving universal, selective, and indicated levels of students at a local private high school during a 4-year period. The prevention program was created based upon the…

  8. Can migraine prophylaxis prevent acute mountain sickness at high altitude?

    PubMed

    Kim, M W; Kim, M

    2011-11-01

    Acute mountain sickness (AMS) develops in people trekking at high altitude. The underlying mechanism is vasodilation due to low pressure of oxygen. However, individual susceptibility for AMS is unknown, thus, one cannot predict when or to whom it happens. Because AMS usually begins with headache, and because migraineurs are more vulnerable to AMS, we studied by the literatures review on the mechanism and clinical features in common, and assessed the treatment modalities for both disorders. This led to us the following hypothesis that, migraine prophylaxis may prevent or delay the onset of AMS at high altitude. Clinical features of AMS include nausea or vomiting when it progresses. Hypobaric hypoxia, dehydration or increased physical exertion trigger or aggravate both disorders. In migraine, cerebral vasodilation can happen following alteration of neuronal activity, whereas the AMS is associated with peripheral vessel dilation. Medications that dilate the vessels worsen both conditions. Acute treatment strategies for migraine overlap with to those of AMS, including drugs such as vasoconstrictors, or other analgesics. To prevent AMS, adaptation to high altitude or pharmacological prophylaxis, i.e., acetazolamide has been recommended. This carbonic anhydrase inhibitor lowers serum potassium level, and thus stabilizes membrane excitability. Acetazolamide is also effective on specific forms of migraine. Taken together, these evidences implicate that migraine prophylaxis may prevent or delay the onset of AMS by elevating the threshold for high altitude. PMID:21856088

  9. Prevention

    MedlinePlus

    ... our e-newsletter! Aging & Health A to Z Prevention Basic Facts & Information Some factors that affect your ... control of the things that you can change. Preventive Recommendations for Adults Aged 65 and Older The ...

  10. Preventing ash agglomeration during gasification of high-sodium lignite

    SciTech Connect

    Robert S. Dahlin; Johnny R. Dorminey; WanWang Peng; Roxann F. Leonard; Pannalal Vimalchand

    2009-01-15

    Various additives were evaluated to assess their ability to prevent ash agglomeration during the gasification of high-sodium lignite. Additives that showed promise in simple muffle furnace tests included meta-kaolin, vermiculite, two types of silica fume, and one type of bauxite. Additives that were tested and rejected included dolomite, calcite, sand flour, kaolinite, fine kaolin, and calcined bauxite. Based on the muffle furnace test results, the meta-kaolin was selected for a follow-on demonstration in a pilot-scale coal gasifier. Pilot-scale testing showed that the addition of coarse (minus 14-mesh, 920-{mu}m mean size) meta-kaolin at a feed rate roughly equivalent to the ash content of the lignite (10 wt %) successfully prevented agglomeration and deposition problems during gasification of high-sodium lignite at a maximum operating temperature of 927{sup o}C (1700{sup o}F). 13 refs., 24 figs., 1 tab.

  11. High-density lipoprotein prevents organ damage in endotoxemia.

    PubMed

    Lee, Ru-Ping; Lin, Nien-Tsung; Chao, Yann-Fen Chiou; Lin, Chia-Chin; Harn, Horng-Jyh; Chen, Hsing-I

    2007-06-01

    High-density lipoprotein (HDL) may decrease organ injury in sepsis. This study was designed using an animal model to mimic people who had a high HDL level and to test HDL effects on preventing organ damage in endotoxemia. Endotoxemia was induced by an infusion of lipopolysac-charide (LPS) after HDL or LDL administration. Levels of blood biochemical substances, nitrate/nitrite, and TNF-alpha in sera were measured. Pathological examinations were performed 72 hours after LPS infusion. HDL decreased the endotoxin-induced elevation of AST, ALT, BUN, creatinine, LDH, CPK, nitrate/nitrite, and TNF-alpha. On histological examination, neutrophil infiltration was lower in the HDL group. HDL had a significant effect in preventing endotoxin-induced organ damage. PMID:17514720

  12. Highly active antiretroviral treatment for the prevention of HIV transmission

    PubMed Central

    2010-01-01

    In 2007 an estimated 33 million people were living with HIV; 67% resided in sub-Saharan Africa, with 35% in eight countries alone. In 2007, there were about 1.4 million HIV-positive tuberculosis cases. Globally, approximately 4 million people had been given highly active antiretroviral therapy (HAART) by the end of 2008, but in 2007, an estimated 6.7 million were still in need of HAART and 2.7 million more became infected with HIV. Although there has been unprecedented investment in confronting HIV/AIDS - the Joint United Nations Programme on HIV/AIDS estimates $13.8 billion was spent in 2008 - a key challenge is how to address the HIV/AIDS epidemic given limited and potentially shrinking resources. Economic disparities may further exacerbate human rights issues and widen the increasingly divergent approaches to HIV prevention, care and treatment. HIV transmission only occurs from people with HIV, and viral load is the single greatest risk factor for all modes of transmission. HAART can lower viral load to nearly undetectable levels. Prevention of mother to child transmission offers proof of the concept of HAART interrupting transmission, and observational studies and previous modelling work support using HAART for prevention. Although knowing one's HIV status is key for prevention efforts, it is not known with certainty when to start HAART. Building on previous modelling work, we used an HIV/AIDS epidemic of South African intensity to explore the impact of testing all adults annually and starting persons on HAART immediately after they are diagnosed as HIV positive. This theoretical strategy would reduce annual HIV incidence and mortality to less than one case per 1000 people within 10 years and it would reduce the prevalence of HIV to less than 1% within 50 years. To explore HAART as a prevention strategy, we recommend further discussions to explore human rights and ethical considerations, clarify research priorities and review feasibility and acceptability

  13. Evaluation of preventive programs in high caries active preschool children.

    PubMed

    Sundell, Anna Lena; Ullbro, Christer; Koch, Göran

    2013-01-01

    Although caries prevalence in preschool children has dramatically decreased during the last decades it is still a large problem for a minor group of these children. Great efforts have been invested in finding effective preventive programs for the high caries active preschool children. However, few studies have evaluated and discussed which approach will give the best effect. The aim of the present study was to compare the effect of a "standard" preventive program with a series of programs with more extensive measures during a two-year period. At start one hundred and sixty high caries active preschool children (mean age 4 years) were included in the study. The children were randomly distributed to four groups. All groups were exposed to the basic program composed of dietary counselling, oral hygiene instructions and fluoride varnish application. Three groups were exposed to one additional preventive measure e.g. 1% chlorhexidine gel in trays, 0.2% NaF gel in trays or daily tooth brushing with 1% chlorhexidine gel. The programs were repeated seven times during the two-year study period and were executed by trained dental hygienists. Caries examination and saliva sampling for Streptococcus mutans measurements were performed at start of the study and after two years. The mean defs at start was between 10.8 and 12.6 for the four groups (NS). After two years the caries increment was 1.9 ds in the basic preventive group and between 1.9 and 2.6 (NS) in the other groups. Numerically there were more children in the chlorhexidine groups that showed reduction of Streptococcus mutans counts compared to the other groups, but the differences were small. The mean caries increment of about 1.9 ds per year in all groups indicate that all programs were effective taken into account that the children had about 11 defs at start. There were no differences in caries increment between the basic preventive group and the other groups. The conclusion was that addition of preventive measures

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

    PubMed Central

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

    2015-01-01

    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. PMID:25713368

  15. Rosuvastatin Treatment Affects Both Basal and Glucose-Induced Insulin Secretion in INS-1 832/13 Cells.

    PubMed

    Salunkhe, Vishal A; Elvstam, Olof; Eliasson, Lena; Wendt, Anna

    2016-01-01

    Rosuvastatin is a member of the statin family. Like the other statins it is prescribed to lower cholesterol levels and thereby reduce the risk of cardiovascular events. Rosuvastatin lowers the cholesterol levels by inhibiting the key enzyme 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase) in the cholesterol producing mevalonate pathway. It has been recognized that apart from their beneficial lipid lowering effects, statins also exhibit diabetogenic properties. The molecular mechanisms behind these remain unresolved. To investigate the effects of rosuvastatin on insulin secretion, we treated INS-1 832/13 cells with varying doses (20 nM to 20 μM) of rosuvastatin for 48 h. At concentrations of 2 μM and above basal insulin secretion was significantly increased. Using diazoxide we could determine that rosuvastatin did not increase basal insulin secretion by corrupting the KATP channels. Glucose-induced insulin secretion on the other hand seemed to be affected differently at different rosuvastatin concentrations. Rosuvastatin treatment (20 μM) for 24-48 h inhibited voltage-gated Ca(2+) channels, which lead to reduced depolarization-induced exocytosis of insulin-containing granules. At lower concentrations of rosuvastatin (≤ 2 μM) the stimulus-secretion coupling pathway was intact downstream of the KATP channels as assessed by the patch clamp technique. However, a reduction in glucose-induced insulin secretion could be observed with rosuvastatin concentrations as low as 200 nM. The inhibitory effects of rosuvastatin on glucose-induced insulin secretion could be reversed with mevalonate, but not squalene, indicating that rosuvastatin affects insulin secretion through its effects on the mevalonate pathway, but not through the reduction of cholesterol biosynthesis. Taken together, these data suggest that rosuvastatin has the potential to increase basal insulin secretion and reduce glucose-induced insulin secretion. The latter is possibly an unavoidable

  16. Rosuvastatin Treatment Affects Both Basal and Glucose-Induced Insulin Secretion in INS-1 832/13 Cells

    PubMed Central

    Salunkhe, Vishal A.; Elvstam, Olof; Eliasson, Lena; Wendt, Anna

    2016-01-01

    Rosuvastatin is a member of the statin family. Like the other statins it is prescribed to lower cholesterol levels and thereby reduce the risk of cardiovascular events. Rosuvastatin lowers the cholesterol levels by inhibiting the key enzyme 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase) in the cholesterol producing mevalonate pathway. It has been recognized that apart from their beneficial lipid lowering effects, statins also exhibit diabetogenic properties. The molecular mechanisms behind these remain unresolved. To investigate the effects of rosuvastatin on insulin secretion, we treated INS-1 832/13 cells with varying doses (20 nM to 20 μM) of rosuvastatin for 48 h. At concentrations of 2 μM and above basal insulin secretion was significantly increased. Using diazoxide we could determine that rosuvastatin did not increase basal insulin secretion by corrupting the KATP channels. Glucose-induced insulin secretion on the other hand seemed to be affected differently at different rosuvastatin concentrations. Rosuvastatin treatment (20 μM) for 24–48 h inhibited voltage-gated Ca2+ channels, which lead to reduced depolarization-induced exocytosis of insulin-containing granules. At lower concentrations of rosuvastatin (≤ 2 μM) the stimulus-secretion coupling pathway was intact downstream of the KATP channels as assessed by the patch clamp technique. However, a reduction in glucose-induced insulin secretion could be observed with rosuvastatin concentrations as low as 200 nM. The inhibitory effects of rosuvastatin on glucose-induced insulin secretion could be reversed with mevalonate, but not squalene, indicating that rosuvastatin affects insulin secretion through its effects on the mevalonate pathway, but not through the reduction of cholesterol biosynthesis. Taken together, these data suggest that rosuvastatin has the potential to increase basal insulin secretion and reduce glucose-induced insulin secretion. The latter is possibly an unavoidable

  17. Pituitary adenylate cyclase-activating polypeptide (PACAP) is an islet substance serving as an intra-islet amplifier of glucose-induced insulin secretion in rats.

    PubMed Central

    Yada, T; Sakurada, M; Ishihara, H; Nakata, M; Shioda, S; Yaekura, K; Hamakawa, N; Yanagida, K; Kikuchi, M; Oka, Y

    1997-01-01

    1. We examined whether pituitary adenylate cyclase-activating polypeptide with 38 or 27 residues (PACAP-38 or PACAP-27) serves as an intra-islet regulator of glucose-induced insulin secretion in rats. PACAP antiserum specific for PACAP-38 and PACAP-27 was used to neutralize the effect of endogenous PACAP in islets. PACAP release from islets was bioassayed using the response of cytosolic Ca2+ concentration ([Ca2+]i) in single beta-cells, monitored by dual-wavelength fura-2 microfluorometry. Expression of PACAP mRNA was studied by reverse transcription-polymerase chain reaction (RT-PCR), while expression of PACAP was studied by metabolic labelling and immunoblotting. Localization of PACAP receptors was studied immunohistochemically. 2. High glucose-stimulated insulin release from isolated islets was attenuated by PACAP antiserum but not by non-immune sera. 3. The islet incubation medium with high glucose (Med) possessed a capacity, which was neutralized by PACAP antiserum, to increase [Ca2+]i in beta-cells. PACAP antiserum also neutralized the [Ca2+]i-increasing action of synthetic PACAP-38 and PACAP-27, but not that of vasoactive intestinal polypeptide (VIP) and glucagon. 4. Both Med and synthetic PACAP increased [Ca2+]i in beta-cells only in the presence of stimulatory, but not basal, glucose concentrations. In contrast, ATP, a substance that is known to be released from beta-cells, increased [Ca2+]i in beta-cells at both and stimulatory glucose concentrations. 5. Expression of PACAP mRNA and biosynthesis of PACAP-38 were detected in islets and a beta-cell line, MIN6. 6. Immunoreactivity for PACAP-selective type-I receptor was observed in islets. 7. [Ca2+]i measurements combined with immunocytochemistry with insulin antiserum revealed a substantial population of glucose-unresponsive beta-cells, many of which were recruited by PACAP-38 into [Ca2+]i responses. 8. These results indicate that PACAP-38 is a novel islet substance that is synthesized and released by islet

  18. Optimization of extraction and purification of arctiin from Fructus arctii and its protection against glucose-induced rat aortic endothelial cell injury.

    PubMed

    Lu, Lai-chun; Zhang, Rong; Song, Ming-bao; Zhou, Shi-wen; Qian, Gui-sheng

    2014-05-01

    To develop an efficient method for extracting and purifying the active ingredient, arctiin, from Fructus arctii and to investigate the protective effect of arctiin against glucose-induced rat aortic endothelial cell (RAEC) injury was investigated. Using a L9 (34) orthogonal array and two-step column chromatography (with AB-8 macroporous resin) arctiin extraction was optimized using a reflux method with 70% ethanol. The RAECs were then treated with different concentrations of arctiin (1, 10, or 100 μg/ml). The effects of arctiin on cell viability in a high glucose medium, malondialdehyde (MDA) levels, and lactate dehydrogenase were measured using commercially available assays. After extraction, the purity of arctiin reached 95.7%. In rats, arctiin was shown to stimulate the proliferation of RAECs in a high glucose medium in a dose-dependent manner. Exposure of RAECs to high glucose resulted in a significant increase in MDA and release of lactate dehydrogenase. This was accompanied by significant increase in nitric oxide release and expression of antiendothelial nitric oxide synthase. This technique resulted in relatively pure arctiin extraction. Furthermore, the results from this study suggest that arctiin could potentially function as a protector against vascular endothelial cell injury and further investigation is warranted. PMID:24163109

  19. High-Altitude Illnesses: Physiology, Risk Factors, Prevention, and Treatment

    PubMed Central

    Taylor, Andrew T.

    2011-01-01

    High-altitude illnesses encompass the pulmonary and cerebral syndromes that occur in non-acclimatized individuals after rapid ascent to high altitude. The most common syndrome is acute mountain sickness (AMS) which usually begins within a few hours of ascent and typically consists of headache variably accompanied by loss of appetite, nausea, vomiting, disturbed sleep, fatigue, and dizziness. With millions of travelers journeying to high altitudes every year and sleeping above 2,500 m, acute mountain sickness is a wide-spread clinical condition. Risk factors include home elevation, maximum altitude, sleeping altitude, rate of ascent, latitude, age, gender, physical condition, intensity of exercise, pre-acclimatization, genetic make-up, and pre-existing diseases. At higher altitudes, sleep disturbances may become more profound, mental performance is impaired, and weight loss may occur. If ascent is rapid, acetazolamide can reduce the risk of developing AMS, although a number of high-altitude travelers taking acetazolamide will still develop symptoms. Ibuprofen can be effective for headache. Symptoms can be rapidly relieved by descent, and descent is mandatory, if at all possible, for the management of the potentially fatal syndromes of high-altitude pulmonary and cerebral edema. The purpose of this review is to combine a discussion of specific risk factors, prevention, and treatment options with a summary of the basic physiologic responses to the hypoxia of altitude to provide a context for managing high-altitude illnesses and advising the non-acclimatized high-altitude traveler. PMID:23908794

  20. 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. PMID:25951323

  1. Preventing Raman Lasing in High-Q WGM Resonators

    NASA Technical Reports Server (NTRS)

    Savchenkov, Anatoliy; Matsko, Andrey; Strekalov, Dmitry; Maleki, Lute

    2007-01-01

    A generic design has been conceived to suppress the Raman effect in whispering- gallery-mode (WGM) optical resonators that have high values of the resonance quality factor (Q). Although it is possible to exploit the Raman effect (even striving to maximize the Raman gain to obtain Raman lasing), the present innovation is intended to satisfy a need that arises in applications in which the Raman effect inhibits the realization of the full potential of WGM resonators as frequency-selection components. Heretofore, in such applications, it has been necessary to operate high-Q WGM resonators at unattractively low power levels to prevent Raman lasing. (The Raman-lasing thresholds of WGM optical resonators are very low and are approximately proportional to Q(sup -2)). Heretofore, two ways of preventing Raman lasting at high power levels have been known, but both entail significant disadvantages: A resonator can be designed so that the optical field is spread over a relatively large mode volume to bring the power density below the threshold. For any given combination of Q and power level, there is certain mode volume wherein Raman lasing does not start. Unfortunately, a resonator that has a large mode volume also has a high spectral density, which is undesirable in a typical photonic application. A resonator can be cooled to the temperature of liquid helium, where the Raman spectrum is narrower and, therefore, the Raman gain is lower. However, liquid-helium cooling is inconvenient. The present design overcomes these disadvantages, making it possible to operate a low-spectral-density (even a single-mode) WGM resonator at a relatively high power level at room temperature, without risk of Raman lasing.

  2. Prevention

    MedlinePlus

    ... Prevention Treatment 2003 U.S. Outbreak African Rodent Importation Ban For Clinicians Clinical Recognition Specimen Collection Treatment Smallpox ... Examining Animals with Suspected Monkeypox African Rodent Importation Ban Resources Related Links Poxvirus Molluscum Contagiosum Orf Virus ( ...

  3. Protection against glucose-induced neuronal death by NAAG and GCP II inhibition is regulated by mGluR3.

    PubMed

    Berent-Spillson, Alison; Robinson, Amanda M; Golovoy, David; Slusher, Barbara; Rojas, Camilo; Russell, James W

    2004-04-01

    Glutamate carboxypeptidase II (GCP II) inhibition has previously been shown to be protective against long-term neuropathy in diabetic animals. In the current study, we have determined that the GCP II inhibitor 2-(phosphonomethyl) pentanedioic acid (2-PMPA) is protective against glucose-induced programmed cell death (PCD) and neurite degeneration in dorsal root ganglion (DRG) neurons in a cell culture model of diabetic neuropathy. In this model, inhibition of caspase activation is mediated through the group II metabotropic glutamate receptor, mGluR3. 2-PMPA neuroprotection is completely reversed by the mGluR3 antagonist (S)-alpha-ethylglutamic acid (EGLU). In contrast, group I and III mGluR inhibitors have no effect on 2-PMPA neuroprotection. Furthermore, we show that two mGluR3 agonists, the direct agonist (2R,4R)-4-aminopyrrolidine-2, 4-dicarboxylate (APDC) and N-acetyl-aspartyl-glutamate (NAAG) provide protection to neurons exposed to high glucose conditions, consistent with the concept that 2-PMPA neuroprotection is mediated by increased NAAG activity. Inhibition of GCP II or mGluR3 may represent a novel mechanism to treat neuronal degeneration under high-glucose conditions. PMID:15030392

  4. Central and peripheral contributions to dynamic changes in nucleus accumbens glucose induced by intravenous cocaine

    PubMed Central

    Wakabayashi, Ken T.; Kiyatkin, Eugene A.

    2015-01-01

    The pattern of neural, physiological and behavioral effects induced by cocaine is consistent with metabolic neural activation, yet direct attempts to evaluate central metabolic effects of this drug have produced controversial results. Here, we used enzyme-based glucose sensors coupled with high-speed amperometry in freely moving rats to examine how intravenous cocaine at a behaviorally active dose affects extracellular glucose levels in the nucleus accumbens (NAc), a critical structure within the motivation-reinforcement circuit. In drug-naive rats, cocaine induced a bimodal increase in glucose, with the first, ultra-fast phasic rise appearing during the injection (latency 6–8 s; ~50 μM or ~5% of baseline) followed by a larger, more prolonged tonic elevation (~100 μM or 10% of baseline, peak ~15 min). While the rapid, phasic component of the glucose response remained stable following subsequent cocaine injections, the tonic component progressively decreased. Cocaine-methiodide, cocaine's peripherally acting analog, induced an equally rapid and strong initial glucose rise, indicating cocaine's action on peripheral neural substrates as its cause. However, this analog did not induce increases in either locomotion or tonic glucose, suggesting direct central mediation of these cocaine effects. Under systemic pharmacological blockade of dopamine transmission, both phasic and tonic components of the cocaine-induced glucose response were only slightly reduced, suggesting a significant role of non-dopamine mechanisms in cocaine-induced accumbal glucose influx. Hence, intravenous cocaine induces rapid, strong inflow of glucose into NAc extracellular space by involving both peripheral and central, non-dopamine drug actions, thus preventing a possible deficit resulting from enhanced glucose use by brain cells. PMID:25729349

  5. Do high concentrations of microcystin prevent Daphnia control of phytoplankton?

    PubMed

    Chislock, Michael F; Sarnelle, Orlando; Jernigan, Lauren M; Wilson, Alan E

    2013-04-15

    Toxin-producing cyanobacteria have frequently been hypothesized to limit the ability of herbivorous zooplankton (such as Daphnia) to control phytoplankton biomass by inhibiting feeding, and in extreme cases, causing zooplankton mortality. Using limnocorral experiments in hyper-eutrophic ponds located in Alabama and Michigan (U.S.A.), we tested the hypothesis that high levels of cyanobacteria and microcystin, a class of hepatotoxins produced by several cyanobacterial genera, prevent Daphnia from strongly reducing phytoplankton abundance. At the start of the first experiment (Michigan), phytoplankton communities were dominated by toxic Microcystis and Anabaena (∼96% of total phytoplankton biomass), and concentrations of microcystin were ∼3 μg L⁻¹. Two weeks after adding Daphnia pulicaria from a nearby eutrophic lake, microcystin levels increased to ∼6.5 μg L⁻¹, yet Daphnia populations increased exponentially (r = 0.24 day⁻¹). By the third week, Daphnia had suppressed phytoplankton biomass by ∼74% relative to the no Daphnia controls and maintained reduced phytoplankton biomass until the conclusion of the five-week experiment. In the second experiment (Alabama), microcystin concentrations were greater than 100 μg L⁻¹, yet a mixture of three D. pulicaria clones from eutrophic lakes in southern MI increased and again reduced phytoplankton biomass, in this case by over 80%. The ability of Daphnia to increase in abundance and suppress phytoplankton biomass, despite high initial levels of cyanobacteria and microcystin, indicates that the latter does not prevent strong control of phytoplankton biomass by Daphnia genotypes that are adapted to environments with abundant cyanobacteria and associated cyanotoxins. PMID:23395484

  6. "Cancer--Educate to Prevent"--high-school teachers, the new promoters of cancer prevention education campaigns.

    PubMed

    Barros, Ana; Moreira, Luís; Santos, Helena; Ribeiro, Nuno; Carvalho, Luís; Santos-Silva, Filipe

    2014-01-01

    Cancer is one of the leading causes of death worldwide, and thus represents a priority for national public health programs. Prevention has been assumed as the best strategy to reduce cancer burden, however most cancer prevention programs are implemented by healthcare professionals, which constrain range and educational impacts. We developed an innovative approach for cancer prevention education focused on high-school biology teachers, considered privileged mediators in the socialization processes. A training program, "Cancer, Educate to Prevent" was applied, so that the teachers were able to independently develop and implement prevention campaigns focused on students and school-related communities. The program encompassed different educational modules, ranging from cancer biology to prevention campaigns design. Fifty-four teachers were empowered to develop and implement their own cancer prevention campaigns in a population up to five thousands students. The success of the training program was assessed through quantitative evaluation--questionnaires focused on teachers' cancer knowledge and perceptions, before the intervention (pre-test) and immediately after (post-test). The projects developed and implemented by teachers were also evaluated regarding the intervention design, educational contents and impact on the students' knowledge about cancer. This study presents and discusses the results concerning the training program "Cancer, Educate to Prevent" and clearly shows a significant increase in teacher's cancer literacy (knowledge and perceptions) and teachers' acquired proficiency to develop and deliver cancer prevention campaigns with direct impact on students' knowledge about cancer. This pilot study reinforces the potential of high-school teachers and schools as cancer prevention promoters and opens a new perspective for the development and validation of cancer prevention education strategies, based upon focused interventions in restricted targets (students

  7. Glucose-induced thermogenesis in patients with small cell lung carcinoma. Before and after inhibition of tumour growth by chemotherapy.

    PubMed

    Simonsen, L; Bülow, J; Sengeløv, H; Madsen, J; Ovesen, L

    1993-07-01

    Seven weight-losing patients with histologically verified small cell lung carcinoma were given an oral glucose load of 75 g before and at least 3 weeks after the end of chemotherapy to examine the effect of glucose on whole body and skeletal muscle thermogenesis before and after reduction of tumour. Whole body energy expenditure was measured by the open circuit ventilated hood system. Forearm blood flow was measured by venous-occlusion strain-gauge plethysmography. The uptake of oxygen in skeletal muscle was calculated as the product of the forearm blood flow and the difference in a-v oxygen concentration. Whole body resting energy expenditure (REE) did not increase, it was 4.4 +/- 0.3 kJ min-1 (mean +/- SE) before chemotherapy and 4.4 +/- 0.2 kJ min-1 after chemotherapy. The glucose-induced thermogenesis in the 180 min following the glucose load was 93.6 +/- 9.9 kJ 180 min-1 before chemotherapy. This is significantly increased compared to that found in a healthy control group (74.7 +/- 4.8 kJ 180 min-1, P < 0.02). The glucose-induced thermogenesis was significantly reduced to 47.7 +/- 10.2 kJ 180 min-1 (P < 0.05) after chemotherapy. The oxygen uptake in resting skeletal muscles was 6.9 +/- 0.3 mumol 100 g-1 min-1 before chemotherapy and 7.0 +/- 0.7 mumol 100 g-1 min-1 after chemotherapy. This did not increase during the first 90 min following the glucose load in either investigations. In the period 90-180 min following the glucose load, the oxygen uptake was significantly increased before chemotherapy as compared to after chemotherapy, which suggests that the reduced whole body thermogenesis after chemotherapy in part was due to reduced skeletal muscle thermogenesis. PMID:8396523

  8. High dynamic range image display with halo and clipping prevention.

    PubMed

    Guarnieri, Gabriele; Marsi, Stefano; Ramponi, Giovanni

    2011-05-01

    The dynamic range of an image is defined as the ratio between the highest and the lowest luminance level. In a high dynamic range (HDR) image, this value exceeds the capabilities of conventional display devices; as a consequence, dedicated visualization techniques are required. In particular, it is possible to process an HDR image in order to reduce its dynamic range without producing a significant change in the visual sensation experienced by the observer. In this paper, we propose a dynamic range reduction algorithm that produces high-quality results with a low computational cost and a limited number of parameters. The algorithm belongs to the category of methods based upon the Retinex theory of vision and was specifically designed in order to prevent the formation of common artifacts, such as halos around the sharp edges and clipping of the highlights, that often affect methods of this kind. After a detailed analysis of the state of the art, we shall describe the method and compare the results and performance with those of two techniques recently proposed in the literature and one commercial software. PMID:21078576

  9. Bioactive fraction of Saraca indica prevents diabetes induced cataractogenesis: An aldose reductase inhibitory activity

    PubMed Central

    Somani, Gauresh; Sathaye, Sadhana

    2015-01-01

    Background: The present study was designed to investigate the effect of Saraca indica (SI) flowers extract and different bioactive fraction on in vitro aldose reductase (AR) inhibitory activity, high glucose-induced cataract in goat lens and in vivo streptozotocin (STZ; 45 mg/kg, i.p) induced cataract in rats. Methods: Extract of flowers of SI tested for inhibition against rat lens AR. Furthermore, bioactive fraction was investigated against high glucose-induced opacification of the lens in vitro lens culture and STZ induced diabetic cataract in rats. Identification of the bioactive component was attempted through high-performance thin-layer chromatography, high-performance liquid chromatography and liquid chromatography-mass spectrometry analysis. Results: Ethyl acetate fraction of S. indica (EASI) produced maximum inhibition that may be due to high phenolic content. Goat lenses in media containing glucose developed a distinctly opaque ring in 72 h and treatment with EASI fraction lowered lens opacity in 72 h. Prolonged treatment with EASI to STZ-induced diabetic rats inhibited the AR activity and delayed cataract progression in a dose dependent manner. Conclusion: Ethyl acetate fraction of S. indica fraction has potential to inhibit rat lens AR enzyme and prevent cataractogenesis not only in goat lens model (in vitro), but also in STZ induced diabetic rats (in vivo). This study is suggestive of the anticataract activity of EASI fraction that could be attributed to the phytoconstituents present in the same. PMID:25709218

  10. Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells

    PubMed Central

    Yuneva, Mariia; Zamboni, Nicola; Oefner, Peter; Sachidanandam, Ravi; Lazebnik, Yuri

    2007-01-01

    The idea that conversion of glucose to ATP is an attractive target for cancer therapy has been supported in part by the observation that glucose deprivation induces apoptosis in rodent cells transduced with the proto-oncogene MYC, but not in the parental line. Here, we found that depletion of glucose killed normal human cells irrespective of induced MYC activity and by a mechanism different from apoptosis. However, depletion of glutamine, another major nutrient consumed by cancer cells, induced apoptosis depending on MYC activity. This apoptosis was preceded by depletion of the Krebs cycle intermediates, was prevented by two Krebs cycle substrates, but was unrelated to ATP synthesis or several other reported consequences of glutamine starvation. Our results suggest that the fate of normal human cells should be considered in evaluating nutrient deprivation as a strategy for cancer therapy, and that understanding how glutamine metabolism is linked to cell viability might provide new approaches for treatment of cancer. PMID:17606868

  11. Glucose-induced alterations of cytosolic free calcium in cultured rat tail artery vascular smooth muscle cells.

    PubMed Central

    Barbagallo, M; Shan, J; Pang, P K; Resnick, L M

    1995-01-01

    We have previously suggested that hyperglycemia per se may contribute to diabetic hypertensive and vascular disease by altering cellular ion content. To more directly investigate the potential role of glucose in this process, we measured cytosolic free calcium in primary cultures of vascular smooth muscle cells isolated from Sprague-Dawley rat tail artery before and after incubation with 5 (basal), 10, 15, and 20 mM glucose. Glucose significantly elevated cytosolic free calcium in a dose- and time-dependent manner, from 110.0 +/- 5.4 to 124.5 +/- 9.0, 192.7 +/- 20.4, and 228.4 +/- 21.9 nM at 5, 10, 15, and 20 mM glucose concentrations, respectively. This glucose-induced cytosolic free calcium elevation was also specific, no change being observed after incubation with equivalent concentrations of L-glucose or mannitol. This glucose effect was also dependent on extracellular calcium and pH, since these calcium changes were inhibited in an acidotic or a calcium-free medium, or by the competitive calcium antagonist lanthanum. We conclude that ambient glucose concentrations within clinically observed limits may alter cellular calcium ion homeostasis in vascular smooth muscle cells. We suggest that these cellular ionic effects of hyperglycemia may underlie the predisposition to hypertension and vascular diseases among diabetic subjects and/or those with impaired glucose tolerance. PMID:7860758

  12. Glucose-induced regulation of protein import receptor Tom22 by cytosolic and mitochondria-bound kinases.

    PubMed

    Gerbeth, Carolin; Schmidt, Oliver; Rao, Sanjana; Harbauer, Angelika B; Mikropoulou, Despina; Opalińska, Magdalena; Guiard, Bernard; Pfanner, Nikolaus; Meisinger, Chris

    2013-10-01

    Most mitochondrial proteins are imported by the translocase of the outer mitochondrial membrane (TOM). Tom22 functions as central receptor and transfers preproteins to the import pore. Casein kinase 2 (CK2) constitutively phosphorylates the cytosolic precursor of Tom22 at Ser44 and Ser46 and, thus, promotes its import. It is unknown whether Tom22 is regulated under different metabolic conditions. We report that CK1, which is involved in glucose-induced signal transduction, is bound to mitochondria. CK1 phosphorylates Tom22 at Thr57 and stimulates the assembly of Tom22 and Tom20. In contrast, protein kinase A (PKA), which is also activated by the addition of glucose, phosphorylates the precursor of Tom22 at Thr76 and impairs its import. Thus, PKA functions in an opposite manner to CK1 and CK2. Our results reveal that three kinases regulate the import and assembly of Tom22, demonstrating that the central receptor is a major target for the posttranslational regulation of mitochondrial protein import. PMID:24093680

  13. Effect of Aegle marmelos and Hibiscus rosa sinensis leaf extract on glucose tolerance in glucose induced hyperglycemic rats (Charles foster).

    PubMed

    Sachdewa, A; Raina, D; Srivastava, A K; Khemani, L D

    2001-01-01

    In an effort to test the hypoglycemic activity of Aegle marmelos and Hibiscus rosa sinensis in glucose induced hyperglycemic rats, their alcoholic leaf extracts were studied. Both the groups of animals receiving either. A. marmelos or H. rosa sinensis leaf extract for seven consecutive days, at an oral dose equivalent to 250 mg kg-1 showed significant improvements in their ability to utilize the external glucose load. Average blood glucose lowering caused by A. marmelos and H. rosa sinensis was 67% and 39% respectively, which shows that former significantly (p < 0.001) improves the glucose tolerance curve. The magnitude of this effect showed time related variation with both the plants. Efficacy of A. marmelos and H. rosa sinensis was 71% and 41% of glybenclamide, respectively. These data throw some light on the possible mechanism of hypoglycemic activity of both the plants. The mechanism of action could be speculated partly to increased utilization of glucose, either by direct stimulation of glucose uptake or via the mediation of enhanced insulin secretion. PMID:11480352

  14. Detection and prevention of highly pathogenic avian influenza in communities with high poultry disease burdens.

    PubMed

    Cardona, Carol J; Byarugaba, Denis; Mbuthia, Paul; Aning, George; Sourou, Sabi; Bunn, David A; Msoffe, Peter L

    2010-03-01

    The implementation of strategies to detect, prevent, and control highly pathogenic avian influenza (HPAI) in developing countries presents several challenges, one of which is the presence of other diseases in poultry populations. Training workshops in developing countries using the Avian Flu School have revealed that in areas with heavy Newcastle disease burdens, smallholder poultry keepers do not recognize HPAI as an immediate threat. We have developed a strategy to address the more proximal needs and priorities of communities with free-ranging poultry flocks as a means to create value in poultry, and thus to improve disease detection and prevention overall. To this end, we have created the Poultry Health and Well-Being for Development project, which trains graduate veterinarians and paraprofessionals in poultry disease diagnosis, control, and treatment. These trainees then serve their local communities to improve poultry health and to implement disease detection and management programs. PMID:20521727

  15. Emerging technologies for the prevention of dental caries. Are current methods of prevention sufficient for the high risk patient?

    PubMed Central

    Bretz, Walter A; Rosa, Odila P S

    2011-01-01

    Fluorides and chlorhexidine are technologies that are 65 and 40 yeas old, respectively. This overview argues that current methods of caries prevention are not effective for the high caries risk patient. In this review examples, arguments and recommendations are provided to address the high caries risk patient that include: failure of comprehensive chemical modalities treatments to address the high caries risk patient; ecological alteration - would this be an effective approach?; and biomaterials and oral microbiome research to address the high caries risk patient. PMID:21726223

  16. Emerging technologies for the prevention of dental caries. Are current methods of prevention sufficient for the high risk patient?

    PubMed

    Bretz, Walter A; Rosa, Odila P S

    2011-08-01

    Fluorides and chlorhexidine are technologies that are 65 and 40 years old, respectively. This overview argues that current methods of caries prevention are not effective for the high caries risk patient. In this review examples, arguments and recommendations are provided to address the high caries risk patient that include: failure of comprehensive chemical modalities treatments to address the high caries risk patient; ecological alteration - would this be an effective approach?; and biomaterials and oral microbiome research to address the high caries risk patient. PMID:21726223

  17. Glucose induced activation of canonical Wnt signaling pathway in hepatocellular carcinoma is regulated by DKK4.

    PubMed

    Chouhan, Surbhi; Singh, Snahlata; Athavale, Dipti; Ramteke, Pranay; Pandey, Vimal; Joseph, Jomon; Mohan, Rajashekar; Shetty, Praveen Kumar; Bhat, Manoj Kumar

    2016-01-01

    Elevated glycemic index, an important feature of diabetes is implicated in an increased risk of hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms of this association are relatively less explored. Present study investigates the effect of hyperglycemia over HCC proliferation. We observed that high glucose culture condition (HG) specifically activates canonical Wnt signaling in HCC cells, which is mediated by suppression of DKK4 (a Wnt antagonist) expression and enhanced β-catenin level. Functional assays demonstrated that a normoglycemic culture condition (NG) maintains constitutive expression of DKK4, which controls HCC proliferation rate by suppressing canonical Wnt signaling pathway. HG diminishes DKK4 expression leading to loss of check at G0/G1/S phases of the cell cycle thereby enhancing HCC proliferation, in a β-catenin dependent manner. Interestingly, in NOD/SCID mice supplemented with high glucose, HepG2 xenografted tumors grew rapidly in which elevated levels of β-catenin, c-Myc and decreased levels of DKK4 were detected. Knockdown of DKK4 by shRNA promotes proliferation of HCC cells in NG, which is suppressed by treating cells exogenously with recombinant DKK4 protein. Our in vitro and in vivo results indicate an important functional role of DKK4 in glucose facilitated HCC proliferation. PMID:27272409

  18. Glucose induced activation of canonical Wnt signaling pathway in hepatocellular carcinoma is regulated by DKK4

    PubMed Central

    Chouhan, Surbhi; Singh, Snahlata; Athavale, Dipti; Ramteke, Pranay; Pandey, Vimal; Joseph, Jomon; Mohan, Rajashekar; Shetty, Praveen Kumar; Bhat, Manoj Kumar

    2016-01-01

    Elevated glycemic index, an important feature of diabetes is implicated in an increased risk of hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms of this association are relatively less explored. Present study investigates the effect of hyperglycemia over HCC proliferation. We observed that high glucose culture condition (HG) specifically activates canonical Wnt signaling in HCC cells, which is mediated by suppression of DKK4 (a Wnt antagonist) expression and enhanced β-catenin level. Functional assays demonstrated that a normoglycemic culture condition (NG) maintains constitutive expression of DKK4, which controls HCC proliferation rate by suppressing canonical Wnt signaling pathway. HG diminishes DKK4 expression leading to loss of check at G0/G1/S phases of the cell cycle thereby enhancing HCC proliferation, in a β-catenin dependent manner. Interestingly, in NOD/SCID mice supplemented with high glucose, HepG2 xenografted tumors grew rapidly in which elevated levels of β-catenin, c-Myc and decreased levels of DKK4 were detected. Knockdown of DKK4 by shRNA promotes proliferation of HCC cells in NG, which is suppressed by treating cells exogenously with recombinant DKK4 protein. Our in vitro and in vivo results indicate an important functional role of DKK4 in glucose facilitated HCC proliferation. PMID:27272409

  19. 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. PMID:26236960

  20. 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

  1. Initial Indicators of Effectiveness for a High School Drug Prevention Program

    ERIC Educational Resources Information Center

    Fearnow-Kenney, Melodie D.; Wyrick, David L.; Jackson-Newsom, Julia; Wyrick, Cheryl H.; Hansen, William B.

    2003-01-01

    All Stars, Sr. is a comprehensive high school health education supplement designed to prevent high-risk behaviors among adolescents. The program includes topics such as personal health, nutrition, interpersonal relationships, and stress, with a special emphasis on drug prevention. Effective research-based programs that target late onset prevention…

  2. Effect of (-)-epigallocatechin-3-gallate on glucose-induced human serum albumin glycation.

    PubMed

    Li, M; Hagerman, A E

    2015-01-01

    (-)-Epigallocatechin-3-gallate (EGCg) is a naturally occurring polyphenol found in plant-based foods and beverages such as green tea. Although EGCg can eliminate carbonyl species produced by glucose autoxidation and thus can inhibit protein glycation, it is also reported to be a pro-oxidant that stimulates protein glycation in vitro. To better understand the balance between antioxidant and pro-oxidant features of EGCg, we evaluated EGCg-mediated bioactivities in a human serum albumin (HSA)/glucose model by varying three different parameters (glucose level, EGCg concentration, and time of exposure to EGCg). Measurements of glycation-induced fluorescence, protein carbonyls, and electrophoretic mobility showed that the level of HSA glycation was positively related to the glucose level over the range 10-100 mM during a 21-day incubation at 37°C and pH: 7.4. Under mild glycemic pressure (10 mM), long exposure to EGCg enhanced HSA glycation, while brief exposure to low concentrations of EGCg did not. Under high glycemic pressure (100 mM glucose), long exposure to EGCg inhibited glycation. For the first time we showed that brief exposure to EGCg reversed glycation-induced fluorescence, indicating a restorative effect. In conclusion, our research identified glucose level, EGCg concentration, and time of exposure as critical factors dictating EGCg bioactivities in HSA glycation. EGCg did not affect HSA glycation under normal physiological conditions but had a potential therapeutic effect on HSA severely damaged by glycation. PMID:25794449

  3. Effect of (−)-Epigallocatechin-3-Gallate on Glucose-Induced Human Serum Albumin Glycation

    PubMed Central

    Li, Min; Hagerman, Ann E.

    2016-01-01

    (−)-Epigallocatechin-3-gallate (EGCg) is a naturally occurring polyphenol found in plant-based foods and beverages such as green tea. Although EGCg can eliminate carbonyl species produced by glucose autoxidation and thus can inhibit protein glycation, it is also reported to be a pro-oxidant that stimulates protein glycation in vitro. To better understand the balance between antioxidant and pro-oxidant features of EGCg, we evaluated EGCg-mediated bioactivities in a human serum albumin (HSA)/glucose model by varying three different parameters (glucose level, EGCg concentration, and time of exposure to EGCg). Measurements of glycation-induced fluorescence, protein carbonyls, and electrophoretic mobility showed that the level of HSA glycation was positively related to the glucose level over the range 10 to 100 mM during a 21-day incubation at 37 °C and pH 7.4. Under mild glycemic pressure (10 mM), long exposure to EGCg enhanced HSA glycation, while brief exposure to low concentrations of EGCg did not. Under high glycemic pressure (100 mM glucose), long exposure to EGCg inhibited glycation. For the first time we showed that brief exposure to EGCg reversed glycation-induced fluorescence, indicating a restorative effect. In conclusion, our research identified glucose level, EGCg concentration, and time of exposure as critical factors dictating EGCg bioactivities in HSA glycation. EGCg did not affect HSA glycation under normal physiological conditions but had a potential therapeutic effect on HSA severely damaged by glycation. PMID:25794449

  4. 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.

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

    PubMed Central

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

    2009-01-01

    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. PMID:20026095

  6. [Secondary prevention of osteoporosis and identification of high risk patients].

    PubMed

    Lehmann, R; Pfeifer, M; Minne, H; Allolio, B

    2000-08-01

    Low bone mass is a major determinant of bone fragility. With respect to hip fracture risk however, there is limited contribution of BMD to the exponential age-related increase in hip fracture incidence. Large prospective studies have identified a number of additional risk factors for hip fractures independent of bone density. These can be classified as skeletal factors and fall-related factors. Body height and hip axis length are positively correlated with fracture risk. Neuromuscular impairment with low gait speed, difficulty in doing a tandem walk, lower limb dysfunction, body sway or inability to rise from a chair without using one's arms predict future fracture risk. According to the concept of evidence-based medicine (EBM) preventive strategies are now available. Supplementation with calcium and vitamin D restores bone quality through suppression of secondary hyperparathyroidism and decreases the risk of falling through improvement of neuromuscular co-ordination and body sway. Treatment with the bisphosphonates alendronate and risedronate increase bone strength and result in a significant reduction of vertebral as well as non-vertebral fractures. Hip protectors absorb energy during a fall and reduce hip fracture risk by 56%. Risk factor based patient selection may improve the cost-effectiveness of therapy. PMID:10996933

  7. A Birth Defects Prevention Curriculum for Inner-City Junior High School Students.

    ERIC Educational Resources Information Center

    Cohen, Ellen J.; Cohen, Carl I.

    1981-01-01

    Educators have begun to recognize that the public school system is an ideal setting in which to introduce the topic of birth defects prevention. A highly structured two week curriculum was developed using March of Dimes materials to teach inner-city school children about birth defects prevention. (JN)

  8. Suicide Prevention: An Analysis and Replication of a Curriculum-Based High School Program

    ERIC Educational Resources Information Center

    Ciffone, Jerry

    2007-01-01

    This article highlights some of the concerns about and benefits of curriculum-based suicide prevention programs delivered to students in a high school setting. In addition, it presents information about a specific curriculum-based prevention program and provides evidence that the program changed unwanted attitudes about suicide in all the areas…

  9. Sources of HIV-Prevention Information for Individuals at High Risk.

    ERIC Educational Resources Information Center

    Sagrestano, Lynda M.; Heiss-Wendt, Renate M.; Mizan, Ainon N.; Kittleson, Mark J.; Sarvela, Paul D.

    2001-01-01

    Identified the best methods of reaching people at high risk with HIV-prevention messages. Data from men who had sex with men, injection drug users, sex workers, HIV-positive people, heterosexuals, migrant workers, and perinatal women indicated that over 70 percent were exposed to HIV-prevention messages, though sources of exposure varied by risk…

  10. Phlorotannins from Brown Algae: inhibition of advanced glycation end products formation in high glucose induced Caenorhabditis elegans.

    PubMed

    Shakambari, Ganeshan; Ashokkumar, Balasubramaniem; Varalakshmi, Perumal

    2015-06-01

    Advanced Glycation End products (AGE) generated in a non enzymatic protein glycation process are frequently associated with diabetes, aging and other chronic diseases. Here, we explored the protective effect of phlorotannins from brown algae Padina pavonica, Sargassum polycystum and Turbinaria ornata against AGEs formation. Phlorotannins were extracted from brown algae with methanol and its purity was analyzed by TLC and RP-HPLC-DAD. Twenty five grams of P. pavonica, S. polycystum, T. ornata yielded 27.6 ± 0.8 μg/ml, 37.7 μg/ml and 37.1 ± 0.74 μg/ml of phloroglucinol equivalent of phlorotannins, respectively. Antioxidant potentials were examined through DPPH assay and their IC50 values were P. pavonica (30.12 ± 0.99 μg), S. polycystum (40.9 ± 1.2 μg) and T. ornata (22.9 ± 1.3 μg), which was comparatively lesser than the control ascorbic acid (46 ± 0.2 μg). Further, anti-AGE activity was examined in vitro by BSA-glucose assay with the extracted phlorotannins of brown algae (P. pavonica, 15.16 ± 0.26 μg/ml; S. polycystum, 35.245 ± 2.3 μg/ml; T. ornata, 22.7 ± 0.3 μg/ml), which revealed the required concentration to inhibit 50% of albumin glycation (IC50) were lower for extracts than controls (phloroglucinol, 222.33 ± 4.9 μg/ml; thiamine, 263 μg/ml). Furthermore, brown algal extracts containing phlorotannins (100 μl) exhibited protective effects against AGE formation in vivo in C. elegans with induced hyperglycemia. PMID:26155677

  11. Tobacco Education Curriculum. Senior High. Health Education: Substance Abuse Prevention.

    ERIC Educational Resources Information Center

    New York State Education Dept., Albany. Bureau of Drug Education.

    This tobacco education curriculum for senior high contains a sampling of teaching methods, concepts and objectives for the course, and instructional units. Each unit, designed to reinforce a particular concept in regard to smoking, lists suggested learning activities as well as instructional materials to be used and resources available to the…

  12. Tobacco Education Curriculum. Junior High. Health Education: Substance Abuse Prevention.

    ERIC Educational Resources Information Center

    New York State Education Dept., Albany. Bureau of Drug Education.

    This tobacco education curriculum for junior high contains a sampling of teaching methods, concepts and objectives for the course, and instructional units. Each unit, designed to reinforce a major concept in regard to smoking, lists suggested learning activities as well as instructional materials to be used and resources available to the teacher.…

  13. Suicide Prevention for High-Risk Persons Who Refuse Treatment

    ERIC Educational Resources Information Center

    Motto, Jerome A.

    1976-01-01

    Patients (N=3,006) admitted to a psychiatric in-patient service because of a suicidal state were contacted to determine if post-discharge plans were followed. Half of those who refused treatment were contacted by telephone or letter on a set schedule. Evidence is that a high-risk population for suicide can be identified. (Author)

  14. Participation in Counseling Programs: High-Risk Participants Are Reluctant to Accept HIV-Prevention Counseling

    PubMed Central

    Earl, Allison; Albarracín, Dolores; Durantini, Marta R.; Gunnoe, Joann B.; Leeper, Josh; Levitt, Justin H.

    2013-01-01

    HIV-prevention intervention effectiveness depends on understanding whether clients with highest need for HIV-prevention counseling accept it. With this objective, a field study with a high-risk community sample from the southeastern United States (N = 350) investigated whether initial knowledge about HIV, motivation to use condoms, condom-use-relevant behavioral skills, and prior condom use correlate with subsequent acceptance of an HIV-prevention counseling session. Ironically, participants with high (vs. low) motivation to use condoms, high (vs. low) condom-use-relevant behavioral skills, and high (vs. low) prior condom use were more likely to accept the HIV-prevention counseling. Moreover, the influence of motivation to use condoms, condom-use-relevant behavioral skills, and prior condom use on acceptance of the counseling was mediated by expectations that the counseling session would be useful. Methods to reduce barriers to recruitment of clients for counseling programs are discussed. PMID:19634960

  15. The challenge of HIV prevention among high-risk adolescents.

    PubMed

    Sullivan, T R

    1996-02-01

    This article reports findings from an exploratory study of HIV knowledge and risk behaviors among 60 teenagers and young men engaged in the street life of Hollywood, California. The sample was composed largely of youths of homosexual or bisexual orientation who were substance abusers, prostitutes, or both. The data suggest that although community-based education efforts may be associated with lower-risk behavior among this population, the overall risk profiles of these socially marginalized youths remained high. Inferences are drawn about the cofactors of risk that must be addressed and the education needed to enhance the health prospects of these youths. PMID:8626159

  16. Mitigation of starch and glucose-induced postprandial glycemic excursion in rats by antioxidant-rich green-leafy vegetables’ juice

    PubMed Central

    Tiwari, Ashok Kumar; Jyothi, Atmakuri Lakshmana; Tejeswini, Vasantharao Brahma; Madhusudana, Kuncha; Kumar, Domati Anand; Zehra, Amtul; Agawane, Sachin Bharat

    2013-01-01

    Objective: Consumption of green-leafy vegetables is being advocated beneficial for type 2 diabetes mellitus individuals possibly because they are cost effective source of potent biological antioxidants. This research analyzed various phytochemicals, free radicals scavenging antioxidant potentials and starch digesting enzymes inhibitory activities in fresh juice of nine green-leafy vegetables. Furthermore, this study also investigated influence of these vegetables juice on starch and glucose induced postprandial glycemic load. Materials and Methods: Phytochemical constituents, in vitro free radicals scavenging antioxidant and enzymes inhibitory activities were evaluated applying various reported methods. Post-prandial glycemic excursion was induced in rats pretreated with vegetables juice by oral administration of starch and glucose. Results: All the leafy vegetables juice displayed potent free radicals scavenging activities. Juice of amaranthus, rumex, palak and raphanus displayed potential anti-oxidative property by reducing H2O2 induced hemolysis in rats red blood cells RBCs. Ajwain and rumex juice showed pancreatic α-amylase inhibitory activity. Alternanthera, ajwain, methi, amaranthus and sowa leaves juice displayed intestinal α-glucosidase inhibitory activity. Juice of raphanus, ajwain and sowa significantly mitigated starch-induced postprandial glycemic load. Amaranthus leaves juice potently mitigated glucose-induced postprandial glycemic load and also reduced hemoglobin glycation induced by glucose in vitro. Conclusions: This investigation finds that juice of leafy vegetables is potent source of biological antioxidants. In addition, juice of raphanus, ajwain and sowa leaves possess capacity to mitigate starch induced postprandial glycemic burden and amaranthus leaves’ juice can reduce glucose induced postprandial glycemic excursion. PMID:24143048

  17. Gly-46 and His-50 of yeast maltose transporter Mal21p are essential for its resistance against glucose-induced degradation.

    PubMed

    Hatanaka, Haruyo; Omura, Fumihiko; Kodama, Yukiko; Ashikari, Toshihiko

    2009-06-01

    The maltose transporter gene is situated at the MAL locus, which consists of genes for a transporter, maltase, and transcriptional activator. Five unlinked MAL loci (MAL1, MAL2, MAL3, MAL4, and MAL6) constitute a gene family in Saccharomyces cerevisiae. The expression of the maltose transporter is induced by maltose and repressed by glucose. The activity of the maltose transporter is also regulated post-translationally; Mal61p is rapidly internalized from the plasma membrane and degraded by ubiquitin-mediated proteolysis in the presence of glucose. We found that S. cerevisiae strain ATCC20598 harboring MAL21 could grow in maltose supplemented with a non- assimilable glucose analogue, 2-deoxyglucose, whereas strain ATCC96955 harboring MAL61 and strain CB11 with MAL31 and AGT1 could not. These observations implied a Mal21p-specific resistance against glucose-induced degradation. Mal21p found in ATCC20598 has 10 amino acids, including Gly-46 and His-50, that are inconsistent with the corresponding residues in Mal61p. The half-life of Mal21p for glucose-induced degradation was 118 min when expressed using the constitutive TPI1 promoter, which was significantly longer than that of Mal61p (25 min). Studies with mutant cells that are defective in endocytosis or the ubiquitination process indicated that Mal21p was less ubiquitinated than Mal61p, suggesting that Mal21p remains on the plasma membrane because of poor susceptibility to ubiquitination. Mutational studies revealed that both residues Gly-46 and His-50 in Mal21p are essential for the full resistance of maltose transporters against glucose-induced degradation. PMID:19359240

  18. Gly-46 and His-50 of Yeast Maltose Transporter Mal21p Are Essential for Its Resistance against Glucose-induced Degradation

    PubMed Central

    Hatanaka, Haruyo; Omura, Fumihiko; Kodama, Yukiko; Ashikari, Toshihiko

    2009-01-01

    The maltose transporter gene is situated at the MAL locus, which consists of genes for a transporter, maltase, and transcriptional activator. Five unlinked MAL loci (MAL1, MAL2, MAL3, MAL4, and MAL6) constitute a gene family in Saccharomyces cerevisiae. The expression of the maltose transporter is induced by maltose and repressed by glucose. The activity of the maltose transporter is also regulated post-translationally; Mal61p is rapidly internalized from the plasma membrane and degraded by ubiquitin-mediated proteolysis in the presence of glucose. We found that S. cerevisiae strain ATCC20598 harboring MAL21 could grow in maltose supplemented with a non- assimilable glucose analogue, 2-deoxyglucose, whereas strain ATCC96955 harboring MAL61 and strain CB11 with MAL31 and AGT1 could not. These observations implied a Mal21p-specific resistance against glucose-induced degradation. Mal21p found in ATCC20598 has 10 amino acids, including Gly-46 and His-50, that are inconsistent with the corresponding residues in Mal61p. The half-life of Mal21p for glucose-induced degradation was 118 min when expressed using the constitutive TPI1 promoter, which was significantly longer than that of Mal61p (25 min). Studies with mutant cells that are defective in endocytosis or the ubiquitination process indicated that Mal21p was less ubiquitinated than Mal61p, suggesting that Mal21p remains on the plasma membrane because of poor susceptibility to ubiquitination. Mutational studies revealed that both residues Gly-46 and His-50 in Mal21p are essential for the full resistance of maltose transporters against glucose-induced degradation. PMID:19359240

  19. Transdermal deferoxamine prevents pressure-induced diabetic ulcers

    PubMed Central

    Duscher, Dominik; Neofytou, Evgenios; Wong, Victor W.; Maan, Zeshaan N.; Rennert, Robert C.; Januszyk, Michael; Rodrigues, Melanie; Malkovskiy, Andrey V.; Whitmore, Arnetha J.; Galvez, Michael G.; Whittam, Alexander J.; Brownlee, Michael; Rajadas, Jayakumar; Gurtner, Geoffrey C.

    2015-01-01

    There is a high mortality in patients with diabetes and severe pressure ulcers. For example, chronic pressure sores of the heels often lead to limb loss in diabetic patients. A major factor underlying this is reduced neovascularization caused by impaired activity of the transcription factor hypoxia inducible factor-1 alpha (HIF-1α). In diabetes, HIF-1α function is compromised by a high glucose-induced and reactive oxygen species-mediated modification of its coactivator p300, leading to impaired HIF-1α transactivation. We examined whether local enhancement of HIF-1α activity would improve diabetic wound healing and minimize the severity of diabetic ulcers. To improve HIF-1α activity we designed a transdermal drug delivery system (TDDS) containing the FDA-approved small molecule deferoxamine (DFO), an iron chelator that increases HIF-1α transactivation in diabetes by preventing iron-catalyzed reactive oxygen stress. Applying this TDDS to a pressure-induced ulcer model in diabetic mice, we found that transdermal delivery of DFO significantly improved wound healing. Unexpectedly, prophylactic application of this transdermal delivery system also prevented diabetic ulcer formation. DFO-treated wounds demonstrated increased collagen density, improved neovascularization, and reduction of free radical formation, leading to decreased cell death. These findings suggest that transdermal delivery of DFO provides a targeted means to both prevent ulcer formation and accelerate diabetic wound healing with the potential for rapid clinical translation. PMID:25535360

  20. Violence Prevention after Columbine: A Survey of High School Mental Health Professionals

    ERIC Educational Resources Information Center

    Crepeau-Hobson, M. Franci; Filaccio, Marylynne; Gottfried, Linda

    2005-01-01

    The authors examined changes in mental health services and violence prevention strategies in public high schools since the shootings at Columbine High School. Surveys were mailed to school mental health professionals at public high schools in Colorado. Respondents included school counselors, school psychologists, school social workers, principals,…

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

    PubMed

    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 Ca(2+) entry through L-type voltage-dependent Ca(2+) channels. Thus, CEACAM2 regulates insulin secretion, at least in part, by a GLP-1-mediated mechanism, independent of confounding metabolic factors. PMID:26586918

  2. Volatile anesthetics suppress glucose-stimulated insulin secretion in MIN6 cells by inhibiting glucose-induced activation of hypoxia-inducible factor 1

    PubMed Central

    Suzuki, Kengo; Sato, Yoshifumi; Kai, Shinichi; Nishi, Kenichiro; Adachi, Takehiko; Matsuo, Yoshiyuki

    2015-01-01

    Proper glycemic control is one of the most important goals in perioperative patient management. Insulin secretion from pancreatic β-cells in response to an increased blood glucose concentration plays the most critical role in glycemic control. Several animal and human studies have indicated that volatile anesthetics impair glucose-stimulated insulin secretion (GSIS). A convincing GSIS model has been established, in which the activity of ATP-dependent potassium channels (KATP) under the control of intracellular ATP plays a critical role. We previously reported that pimonidazole adduct formation and stabilization of hypoxia-inducible factor-1α (HIF-1α) were detected in response to glucose stimulation and that MIN6 cells overexpressing HIF-1α were resistant to glucose-induced hypoxia. Genetic ablation of HIF-1α or HIF-1β significantly inhibited GSIS in mice. Moreover, we previously reported that volatile anesthetics suppressed hypoxia-induced HIF activation in vitro and in vivo.To examine the direct effect of volatile anesthetics on GSIS, we used the MIN6 cell line, derived from mouse pancreatic β-cells. We performed a series of experiments to examine the effects of volatile anesthetics (sevoflurane and isoflurane) on GSIS and demonstrated that these compounds inhibited the glucose-induced ATP increase, which is dependent on intracellular hypoxia-induced HIF-1 activity, and suppressed GSIS at a clinically relevant dose in these cells. PMID:26713247

  3. School-Based Drug Abuse Prevention Programs in High School Students

    ERIC Educational Resources Information Center

    Sharma, Manoj; Branscum, Paul

    2013-01-01

    Drug abuse, or substance abuse, is a substantial public health problem in the United States, particularly among high school students. The purpose of this article was to review school-based programs implemented in high schools for substance abuse prevention and to suggest recommendations for future interventions. Included were English language…

  4. Antiemetic Therapy With or Without Olanzapine in Preventing Chemotherapy-Induced Nausea and Vomiting in Patients With Cancer Receiving Highly Emetogenic Chemotherapy | Division of Cancer Prevention

    Cancer.gov

    This randomized phase III trial studies antiemetic therapy with olanzapine to see how well they work compared to antiemetic therapy alone in preventing chemotherapy-induced nausea and vomiting in patients with cancer receiving highly emetogenic (causes vomiting) chemotherapy. Antiemetic drugs, such as palonosetron hydrochloride, ondansetron, and granisetron hydrochloride, may help lessen or prevent nausea and vomiting in patients treated with chemotherapy. |

  5. Harm Reduction for the Prevention of Youth Gambling Problems: Lessons Learned From Adolescent High-Risk Behavior Prevention Programs

    ERIC Educational Resources Information Center

    Dickson, Laurie M.; Derevensky, Jeffrey L.; Gupta, Rina

    2004-01-01

    Despite the growing popularity of the harm reduction approach in the field of adolescent alcohol and substance abuse, a harm reduction approach to prevention and treatment of youth problem gambling remains largely unexplored. This article poses the question of whether the harm reduction paradigm is a promising approach to the prevention of…

  6. Dropout Prevention in Middle and High Schools: From Research to Practice

    ERIC Educational Resources Information Center

    Wilkins, Julia; Bost, Loujeania Williams

    2016-01-01

    Based on work with state and local education agencies in dropout prevention for students with disabilities, successful research-based interventions are described along with details of how these interventions have been implemented in middle and high schools across the country. The interventions that have helped students with disabilities graduate…

  7. High School Health-Education Teachers' Perceptions and Practices Related to Teaching HIV Prevention

    ERIC Educational Resources Information Center

    Herr, Scott W.; Telljohann, Susan K.; Price, James H.; Dake, Joseph A.; Stone, Gregory E.

    2012-01-01

    Background: HIV/AIDS is one of the leading causes of illness and death in the United States with individuals between the ages of 13 and 19 years being especially vulnerable for infection. The purpose of this study was to examine the attitudes, perceptions, and instructional practices of high school health teachers toward teaching HIV prevention.…

  8. Violence Prevention at Thurgood Marshall Academy Public Charter High School. Summary Brief

    ERIC Educational Resources Information Center

    Fontaine, Jocelyn; Debus-Sherrill, Sara; Downey, P. Mitchell; Lowry, Samantha S.

    2010-01-01

    This summary brief is based on research conducted by the Urban Institute's Justice Policy Center on the violence prevention activities taking place at the Thurgood Marshall Academy Public Charter High School during the 2008-2009 school year. Researchers from the Justice Policy Center conducted an assessment of the school's violence prevention…

  9. High School Success: An Effective Intervention for Achievement and Dropout Prevention

    ERIC Educational Resources Information Center

    Lowder, Christopher Michael

    2012-01-01

    The purpose of this mixed-design study was to use quantitative and qualitative research to explore the effects of High School Success (a course for at-risk ninth graders) and its effectiveness on student achievement, attendance, and dropout prevention. The research questions address whether there is a significant difference between at-risk ninth…

  10. The Effectiveness of an Alcohol Abuse Prevention Program among High School Students in Rural Missouri.

    ERIC Educational Resources Information Center

    Dixon, David J.; McLearen, Alix M.

    2002-01-01

    A three-pronged program to prevent underage drinking delivered alcohol education and anti-drinking messages to high school students and their parents and distributed pertinent information to local alcohol retailers in a rural community. Compared to a control community, students in the intervention community were less likely to develop risky…

  11. Core Competencies and the Prevention of High-Risk Sexual Behavior

    ERIC Educational Resources Information Center

    Charles, Vignetta Eugenia; Blum, Robert Wm.

    2008-01-01

    Adolescent sexual risk-taking behavior has numerous individual, family, community, and societal consequences. In an effort to contribute to the research and propose new directions, this chapter applies the core competencies framework to the prevention of high-risk sexual behavior. It describes the magnitude of the problem, summarizes explanatory…

  12. Randomized Controlled Trial of a Preventive Intervention for Perinatal Depression in High-Risk Latinas

    ERIC Educational Resources Information Center

    Le, Huynh-Nhu; Perry, Deborah F.; Stuart, Elizabeth A.

    2011-01-01

    Objective: A randomized controlled trial was conducted to evaluate the efficacy of a cognitive-behavioral (CBT) intervention to prevent perinatal depression in high-risk Latinas. Method: A sample of 217 participants, predominantly low-income Central American immigrants who met demographic and depression risk criteria, were randomized into usual…

  13. Interdisciplinary Coleadership of High School Groups for Dropout Prevention: Practice Issues.

    ERIC Educational Resources Information Center

    Arons, RoseMarie D.; Schwartz, Florence S.

    1993-01-01

    Describes dropout prevention model of teamwork between teacher and graduate social work intern at inner-city alternative public high school. Notes that model provides framework for programmatic responses to problems of school dropouts among inner-city minority youths and also furnishes new opportunities for intern training in school social work.…

  14. The Effectiveness of Peer-Led FAS/FAE Prevention Presentations in Middle and High Schools

    ERIC Educational Resources Information Center

    Boulter, Lyn

    2007-01-01

    Pregnant women and women who might become pregnant, including middle school- and high school-age adolescents, continue to consume alcohol, placing themselves at risk of having a child with the effects of prenatal alcohol exposure. However, most prevention programs that attempt to increase public awareness and knowledge of FAS and related disorders…

  15. A High School Depression and Suicide Prevention Program: A Collaboration between Health Education and Psychological Services.

    ERIC Educational Resources Information Center

    Moilanen, Donna L.; Bradbury, Susan

    2002-01-01

    Examined a collaboration between health education and psychological services in generating a high school depression and suicide prevention program. The five-component program raised awareness of teen depression and suicide, increased communication about these issues within the school and community, and provided information about available…

  16. The Role of the Fine and Performing Arts in High School Dropout Prevention.

    ERIC Educational Resources Information Center

    Florida State Univ., Tallahassee. Center for Music Research.

    A 1-year research project was undertaken to discover how the arts could help keep at-risk high school students in school. The project was conducted in three phases. In phase 1, recent literature was reviewed to define criteria for the at-risk student and to identify implications for the arts in dropout prevention programs. Phase 2 consisted of…

  17. Going the Distance: Delivery of High School Drug Prevention via Distance Education

    ERIC Educational Resources Information Center

    Wyrick, David L.; Fearnow-Kenney, Melodie; Wyrick, Cheryl Haworth; Orsini, Muhsin Michael; Strack, Robert W.; Milroy, Jeffrey J.

    2010-01-01

    The purpose of this project was to develop a technology that can be used in schools where there are insufficient resources to implement a quality drug prevention program. The specific technology--distance education via teleconferencing--allows a highly qualified teacher to deliver programs in such settings with increased quality. A promising high…

  18. Acupressure in Controlling Nausea in Young Patients Receiving Highly Emetogenic Chemotherapy | Division of Cancer Prevention

    Cancer.gov

    RATIONALE: Acupressure wristbands may prevent or reduce nausea and caused by chemotherapy. It is not yet known whether standard care is more effective with or without acupressure wristbands in controlling acute and delayed nausea. PURPOSE: This randomized phase III trial is studying how well acupressure wristbands work with or without standard care in controlling nausea in young patients receiving highly emetogenic chemotherapy. |

  19. Comparative study of preventive protocols in children at high cariogenic risk.

    PubMed

    Martínez, María C; Tolcachir, Betina; Lescano de Ferrer, Alfonsina; Bojanich, María A; Barembaum, Silvina R; Calamari, Silvia E; Azcurra, Ana I

    2012-01-01

    The aim of this study was to compare the efficacy of two preventive protocols -fluoride gel (F) alone or combined with chlorhexidine varnishes (CHX) - on sialochemical, clinical and microbiological parameters in a group of children at high cariogenic risk Two therapeutic-preventive protocols were applied in 73 children at high cariogenic risk (average age 6.2 +/- 1.4 years old) and clinical parameters (simplified oral hygiene index: OHI-S; decayed, missing and filled teeth: dmf index; sugar intake and exposure to fluoride), as well as sialochemical parameters (salivary pH and flow, buffer capacity) and microbiological parameters (CFU/mg of dental biofilm of Streptococcus mutans group) were recorded and correlated before and after the protocols. Association was found between parameters that cause deficient control of dental biofilm: high values of OHIS index, CFU/mg dental biofilm, sugar intake and the d component of dmft index, and lower values of salivary flow rate and buffer capacity. After the protocols, a significant decrease was found in OHI-S and CFU/mg dental biofilm. No significant difference was found with children's gender and age. The association observed between OHI-S and cariogenic bacteria emphasizes the importance of prevention, especially regarding the oral health of the most vulnerable children. The early inclusion of F associated with CHX in the initial step of preventive and therapeutic protocols would provide benefits regarding oral microbe control while children acquire new habits of oral hygiene. PMID:23230645

  20. Evaluation of a Public Awareness Campaign to Prevent High School Dropout.

    PubMed

    Babinski, Leslie M; Corra, Ashley J; Gifford, Elizabeth J

    2016-08-01

    Many advocacy organizations devote time and resources to increasing community awareness and educating the public in an effort to gain support for their issue. One such effort, the Dropout Prevention Campaign by America's Promise Alliance, aimed to increase the visibility of the high school dropout problem and mobilize the community to take action. The objective of this paper is to evaluate the framing of the Dropout Prevention Campaign in television news media. To evaluate this campaign, television news coverage about high school dropout in 12 U.S. communities (N = 982) was examined. A content analysis of news transcripts was conducted and coded to determine the definition of the problem, the reasons for dropout and the possible solutions. Findings indicated that the high school dropout problem was most often framed (30 % of news segments) in terms of the economic and societal implications for the community. Individual student factors as well as broader societal influences were frequently discussed as possible reasons for dropout. The most commonly mentioned solutions were school-based interventions. News segments that mentioned America's Promise Alliance were more likely to frame the issue as a crisis and to use statistics to illustrate that point. Solutions that were more likely to appear in America's Promise segments promoted community and cross-sector involvement, consistent with the messages promoted by the Dropout Prevention Campaign. The findings suggest that a media content analysis can be an effective framework for analyzing a prevention campaign. PMID:27357504

  1. The efficacy of a high school rape prevention program in Israel.

    PubMed

    Moor, Avigail

    2011-01-01

    Sexual violence against women and girls in Israel is rather prevalent. To address this problem, the Association of Rape Crisis Centers in Israel (ARCCI) provides rape prevention programs for middle to high school teens. These programs have been in place for several decades, but their effectiveness has not been evaluated empirically to date. This study seeks to fill this gap by performing an evaluation of one such preventive program. Three hundred and ninety-four 11th graders completed a preintervention and postintervention questionnaire, assessing their rape-related attitudes and behaviors. Results indicate a significant improvement following the workshop in the understanding of what distinguishes rape from mutually consensual relations, along with a substantial shift in many rape-supportive attitudes. At the same time, some victim blaming still remained. Likewise, self-reported behavioral changes were minimal, possibly because of a ceiling effect. Implications for future rape prevention programs in Israel are discussed. PMID:21846018

  2. Endocrine therapy for breast cancer prevention in high-risk women: clinical and economic considerations.

    PubMed

    Groom, Amy G; Younis, Tallal

    2016-04-01

    The global burden of breast cancer highlights the need for primary prevention strategies that demonstrate both favorable clinical benefit/risk profile and good value for money. Endocrine therapy with selective estrogen-receptor modulators (SERMs) or aromatase inhibitors (AIs) has been associated with a favorable clinical benefit/risk profile in the prevention of breast cancer in women at high risk of developing the disease. The available endocrine therapy strategies differ in terms of their relative reductions of breast cancer risk, potential side effects, and upfront drug acquisition costs, among others. This review highlights the clinical trials of SERMs and AIs for the primary prevention of breast cancer, and the cost-effectiveness /cost-utility studies that have examined their "value for money" in various health care jurisdictions. PMID:26923683

  3. 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

  4. Bardoxolone Methyl Prevents High-Fat Diet-Induced Colon Inflammation in Mice.

    PubMed

    Dinh, Chi H L; Yu, Yinghua; Szabo, Alexander; Zhang, Qingsheng; Zhang, Peng; Huang, Xu-Feng

    2016-04-01

    Obesity induces chronic, low-grade inflammation, which increases the risk of colon cancer. We investigated the preventive effects of Bardoxolone methyl (BARD) on high-fat diet (HFD)-induced inflammation in a mouse colon. Male C57BL/6J mice (n=7) were fed a HFD (HFD group), HFD plus BARD (10 mg/kg) in drinking water (HFD/BARD group), or normal laboratory chow diet (LFD group) for 21 weeks. In HFD mice, BARD reduced colon thickness and decreased colon weight per length. This was associated with an increase in colon crypt depth and the number of goblet cells per crypt. BARD reduced the expression of F4/80 and CD11c but increased CD206 and IL-10, indicating an anti-inflammatory effect. BARD prevented an increase of the intracellular pro-inflammatory biomarkers (NF-қB, p NF-қB, IL-6, TNF-α) and cell proliferation markers (Cox2 and Ki67). BARD prevented fat deposition in the colon wall and prevented microbial population changes. Overall, we report the preventive effects of BARD on colon inflammation in HFD-fed mice through its regulation of macrophages, NF-қB, cytokines, Cox2 and Ki67, fat deposition and microflora. PMID:26920068

  5. “The Internet is a Mask”: High School Students' Suggestions for Preventing Cyberbullying

    PubMed Central

    Parris, Leandra N.; Varjas, Kris; Meyers, Joel

    2014-01-01

    Introduction: Interactions through technology have an important impact on today's youth. While some of these interactions are positive, there are concerns regarding students engaging in negative interactions like cyberbullying behaviors and the negative impact these behaviors have on others. The purpose of the current study was to explore participant suggestions for both students and adults for preventing cyberbullying incidents. Methods: Forty high school students participated in individual, semi-structured interviews. Participant experiences and perceptions were coded using constant comparative methods to illustrate ways in which students and adults may prevent cyberbullying from occurring within their school and community. Results: Students reported that peers would benefit from increasing online security, as well as becoming more aware of their cyber-surroundings. Regarding adult-provided prevention services, participants often discussed that there is little adults can do to reduce cyberbullying. Reasons included the difficulties in restricting online behaviors or providing effective consequences. However, some students did discuss the use of in-school curricula while suggesting that adults blame people rather than technology as potential ways to prevent cyberbullying. Conclusion: Findings from the current study indicate some potential ways to improve adult efforts to prevent cyberbullying. These strategies include parent/teacher training in technology and cyberbullying, interventions focused more on student behavior than technology restriction, and helping students increase their online safety and awareness. PMID:25157306

  6. Alcohol, Tobacco, and Other Drug Misuse Prevention and Cessation Programming for Alternative High School Youth: A Review

    ERIC Educational Resources Information Center

    Sussman, Steve; Arriaza, Bridget; Grigsby, Timothy J.

    2014-01-01

    Background: Relative to youth in regular high schools, alternative high school (AHS) youth are at high risk for alcohol, tobacco, and other drug (ATOD) misuse. Prevention and cessation efforts are needed for this population. Methods: A systematic, exhaustive literature search was completed to identify ATOD misuse prevention and cessation research…

  7. Preventing dyslipidemia by Chlorella pyrenoidosa in rats and hamsters after chronic high fat diet treatment.

    PubMed

    Cherng, Jong-Yuh; Shih, Mei-Fen

    2005-05-13

    The effects of Chlorella pyrenoidosa on serum lipid profiles, after concomitant long-term treatment of high-fat diet (HFD) in rats and hamsters was studied. Wistar rats and Syrian hamsters were fed with or without various concentrations of Chlorella pyrenoidosa contained high-fat diet (CHFD) for 2, 4 and 8 weeks prior to assay of serum lipids. Fasting triglycerides, total cholesterol, and LDL cholesterol as well as HDL cholesterol levels in high-fat diet treated rats and hamster were determined. Results showed that triglycerides, total cholesterol and LDL cholesterol levels in HFD treated rats and hamsters were increased from the normal rodent diet (NRD) treated controls after 2, 4, and 8-week treatments. However, the presence of Chlorella pyrenoidosa in high-fat diets significantly decreased the levels of triglycerides, total cholesterol and LDL cholesterol with comparison to HFD group in rats and hamsters. The total cholesterol/HDL ratios, an indication of occurrence of coronary heart disease, were decreased in all CHFD treated grouped rats and hamsters which suggests administration of Chlorella pyrenoidosa could lower the occurring risk of heart diseases. In conclusion, Chlorella pyrenoidosa has the ability to prevent dyslipidemia in chronic high-fat fed animals and could be potential in use to prevent intestinal absorption of redundant lipid from our daily intake and subsequently to prevent hyperlipidemia as well as atherosclerosis. PMID:15850594

  8. Activation of corticotropin-releasing factor receptors in the rostral ventrolateral medulla is required for glucose-induced sympathoexcitation.

    PubMed

    Bardgett, Megan E; Sharpe, Amanda L; Toney, Glenn M

    2014-11-15

    Energy expenditure is determined by metabolic rate and diet-induced thermogenesis. Normally, energy expenditure increases due to neural mechanisms that sense plasma levels of ingested nutrients/hormones and reflexively increase sympathetic nerve activity (SNA). Here, we investigated neural mechanisms of glucose-driven sympathetic activation by determining contributions of neuronal activity in the hypothalamic paraventricular nucleus (PVN) and activation of corticotropin-releasing factor (CRF) receptors in the rostral ventrolateral medulla (RVLM). Glucose was infused intravenously (150 mg/kg, 10 min) in male rats to raise plasma glucose concentration to a physiological postprandial level. In conscious rats, glucose infusion activated CRF-containing PVN neurons and TH-containing RVLM neurons, as indexed by c-Fos immunofluorescence. In α-chloralose/urethane-anesthetized rats, glucose infusion increased lumbar and splanchnic SNA, which was nearly prevented by prior RVLM injection of the CRF receptor antagonist astressin (10 pmol/50 nl). This cannot be attributed to a nonspecific effect, as sciatic afferent stimulation increased SNA and ABP equivalently in astressin- and aCSF-injected rats. Glucose-stimulated sympathoexcitation was largely reversed during inhibition of PVN neuronal activity with the GABA-A receptor agonist muscimol (100 pmol/50 nl). The effects of astressin to prevent glucose-stimulated sympathetic activation appear to be specific to interruption of PVN drive to RVLM because RVLM injection of astressin prior to glucose infusion effectively prevented SNA from rising and prevented any fall of SNA in response to acute PVN inhibition with muscimol. These findings suggest that activation of SNA, and thus energy expenditure, by glucose is initiated by activation of CRF receptors in RVLM by descending inputs from PVN. PMID:25269482

  9. An intravenous medication safety system: preventing high-risk medication errors at the point of care.

    PubMed

    Hatcher, Irene; Sullivan, Mark; Hutchinson, James; Thurman, Susan; Gaffney, F Andrew

    2004-10-01

    Improving medication safety at the point of care--particularly for high-risk drugs--is a major concern of nursing administrators. The medication errors most likely to cause harm are administration errors related to infusion of high-risk medications. An intravenous medication safety system is designed to prevent high-risk infusion medication errors and to capture continuous quality improvement data for best practice improvement. Initial testing with 50 systems in 2 units at Vanderbilt University Medical Center revealed that, even in the presence of a fully mature computerized prescriber order-entry system, the new safety system averted 99 potential infusion errors in 8 months. PMID:15577664

  10. Des-acyl ghrelin prevents heatstroke-like symptoms in rats exposed to high temperature and high humidity.

    PubMed

    Inoue, Yoshiyuki; Hayashi, Yujiro; Kangawa, Kenji; Suzuki, Yoshihiro; Murakami, Noboru; Nakahara, Keiko

    2016-02-26

    We have shown previously that des-acyl ghrelin decreases body temperature in rats through activation of the parasympathetic nervous system. Here we investigated whether des-acyl ghrelin ameliorates heatstroke in rats exposed to high temperature. Peripheral administration of des-acyl ghrelin significantly attenuated hyperthermia induced by exposure to high-temperature (35°C) together with high humidity (70-80%). Although biochemical analysis revealed that exposure to high temperature significantly increased hematocrit and the serum levels of aspartate amino transferase (AST), alanine transaminase (ALT), blood urea nitrogen (BUN), creatinine and electrolytes (Na(+), K(+), Cl(-)), most of these heatstroke-associated reactions were significantly reduced by treatment with des-acyl ghrelin. The level of des-acyl ghrelin in plasma was also found to be significantly increased under high-temperature conditions. These results suggest that des-acyl ghrelin could be useful for preventing heatstroke under high temperature condition. PMID:26773867