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Sample records for prevents high glucose-induced

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

    PubMed

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

    2007-07-02

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

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

    PubMed

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

    2015-08-07

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

  3. 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

  4. Conjugated linoleic acid prevents high glucose-induced hypertrophy and contractile dysfunction in adult rat cardiomyocytes.

    PubMed

    Aloud, Basma Milad; Raj, Pema; O'Hara, Kimberley; Shao, Zongjun; Yu, Liping; Anderson, Hope D; Netticadan, Thomas

    2016-02-01

    Diabetes mellitus is associated with increased risk and incidence of cardiovascular morbidity and mortality, independently of other risk factors typically associated with diabetes such as coronary artery disease and hypertension. This promotes the development of a distinct condition of the heart muscle known as diabetic cardiomyopathy. We have previously shown that conjugated linoleic acid (CLA) prevents endothelin-1-induced cardiomyocyte hypertrophy. However, the effects of CLA in preventing alterations in cardiomyocyte structure and function due to high glucose are unknown. We therefore hypothesized that CLA will have protective effects in an in vitro model of diabetic cardiomyopathy using adult rat cardiomyocytes exposed to high glucose. Our results demonstrate that subjecting adult rat cardiomyocytes to high glucose (25 mmol/L) for 24 hours significantly impaired the contractile function as evidenced by decreases in maximal velocity of shortening, peak shortening, and maximal velocity of relengthening. High glucose-induced contractile dysfunction was inhibited by pretreatment with CLA (30 μmol/L; 1 hour). In addition to contractile aberrations, exposing adult rat cardiomyocytes to high glucose for 48 hours induced cardiomyocyte hypertrophy. High glucose-induced cardiomyocyte hypertrophy was likewise prevented by CLA. The antihypertrophic effects of CLA were abolished when cardiomyocytes were pretreated with the pharmacologic inhibitor of peroxisome proliferator-activated receptor γ, GW9662 (1 μmol/L). In conclusion, our findings show that exposing cardiomyocytes to high glucose results in cardiomyocyte functional and structural abnormalities, and these abnormalities are prevented by pretreatment with CLA and mediated, in part, by peroxisome proliferator-activated receptor γ activation. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

  5. 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.

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

    PubMed

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

    2017-01-25

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

  8. Rutin Prevents High Glucose-Induced Renal Glomerular Endothelial Hyperpermeability by Inhibiting the ROS/Rhoa/ROCK Signaling Pathway.

    PubMed

    Wang, Xiaoming; Zhao, Xiaohong; Feng, Ting; Jin, Gang; Li, Zhenjiang

    2016-09-01

    Diabetic nephropathy is a progressive kidney disease caused by damage to the capillaries in the glomeruli. Endothelial dysfunction is an early sign of diabetic cardiovascular disease and may contribute to progressive diabetic nephropathy. Hyperglycemia-induced endothelial hyperpermeability is crucial to diabetic nephropathy. Rutin has beneficial effects on diabetic nephropathy, but the exact mechanisms of its protective effect remain elusive. The aim of this study was to assess the role of pretreatment with rutin in an in vitro model of hyperglycemia-induced barrier dysfunction in human renal glomerular endothelial cells. Human renal glomerular endothelial cells were exposed to rutin and/or hyperglycemia for 24 h. Hyperglycemia increased permeability and decreased the junction protein occludin in the cell-cell junction area and the total expression in human renal glomerular endothelial cells, whereas rutin treatment significantly corrected these abnormalities. Furthermore, hyperglycemia-induced activation of RhoA/ROCK was reversed by treatment with rutin or the knockdown of ROCK2. Interestingly, rutin prevented hyperglycemia-induced hyperpermeability, and dysfunction of the tight junction, a high level of reactive oxygen species, and activation of RhoA/ROCK were significantly abolished with the knockdown of Nrf2. In conclusion, rutin significantly prevented hyperglycemia-disrupted renal endothelial barrier function by inhibiting the RhoA/ROCK signaling pathway through decreasing reactive oxygen species, which was mediated by the activation of Nrf2. Our results may explain, at least in part, some beneficial effects of rutin that may be applicable to the treatment of vascular disorders in diabetic nephropathy.

  9. Mechanisms of action of troglitazone in the prevention of high glucose-induced migration and proliferation of cultured coronary smooth muscle cells.

    PubMed

    Yasunari, K; Kohno, M; Kano, H; Yokokawa, K; Minami, M; Yoshikawa, J

    1997-12-01

    Recent findings suggest that high glucose levels may promote atherosclerosis in coronary vascular smooth muscle cells (VSMCs). To explore the intracellular mechanisms of action by which troglitazone affects this process, we examined the effect of troglitazone on the migration and growth characteristics of cultured rabbit coronary VSMCs. Treatment with chronic high glucose medium (22.2 mmol/L) for 5 days increased VSMC migration by 92%, [3H]thymidine incorporation by 135%, and cell number by 32% compared with VSMCs treated with normal glucose (5.5 mmol/L glucose + 16.6 mmol/L mannose) medium. Trolitazone at 100 nmol/L and 1 mumol/L significantly suppressed high glucose-induced VSMC migration by 34% and 42%, respectively, the proliferative effect (as measured by cell number) by 17% and 27%, and [3H]thymidine incorporation by 45% and 60% (n = 6, P < .05). The high glucose-induced impairment of insulin-mediated [3H]deoxyglucose uptake was blocked by a protein kinase C (PKC) inhibitor (calphostin C, 1 mumol/L) and was also improved by troglitazone without any change in insulin receptor number and affinity. The high glucose-induced insulin-mediated increase in cell number and in [3H]thymidine incorporation was suppressed by troglitazone. Troglitazone (1 mumol/L) also suppressed high glucose-induced phospholipase D activation, elevation of the cytosolic NADH/NAD+ ratio (as measured by the cytosolic ratio of lactate/pyruvate), and membrane-bound PKC activation. Flow cytometric DNA histogram analysis of cell cycle stage showed that high glucose-induced increase in the percentage of cells in the S phase was suppressed by 1 mumol/L troglitazone. These findings suggest that PKC may be a link between impairment of insulin-mediated glucose uptake and the increase in migration and proliferation induced by high glucose levels and that troglitazone may be clinically useful for the treatment of high glucose-induced coronary atherosclerosis.

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

    PubMed Central

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

    2013-01-01

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

  11. 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. Copyright © 2015 Elsevier Inc. All rights reserved.

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

    PubMed Central

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

    2015-01-01

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

  13. SIRT1 is required for the effects of rapamycin on high glucose-inducing mesangial cells senescence.

    PubMed

    Zhang, Sifang; Cai, Guangyan; Fu, Bo; Feng, Zhe; Ding, Rui; Bai, Xueyuan; Liu, Weiping; Zhuo, Li; Sun, Lin; Liu, Fuyou; Chen, Xiangmei

    2012-06-01

    The mTOR deregulation has a role in chronic kidney disease including diabetic nephropathy. SIRT1 is an important participant in renal cytoprotective responses to aging and stress. However, whether both mTOR and SIRT1 are involved in high glucose-inducing mesangial cells (MCs) senescence still remains to be explored. Hence we investigate the potential functional interrelationship between these two proteins in high glucose-inducing MCs senescence. High glucose increased mTOR expression and activity, but decreased SIRT1 expression and activity. The level of mTOR was increased significantly, while the SIRT1 expression and activity was declined significantly with serial cell culture passage. The siRNA-SIRT1 and nicotinamide promoted MCs senescence. NAD or resveratrol arrested high glucose-inducing MCs senescence. Meanwhile, the effects of NAD or resveratrol on high glucose-inducing MCs senescence were also completely blocked by SiRNA-SIRT1. Rapamycin arrested MCs senescence induced by high glucose and prevented MCs senescence with serial cell culture passage, and meanwhile increased the SIRT1 expression and activity. Moreover, the effects of rapamycin on MCs senescence induced by high glucose were also completely blocked by treating cells with niacinamide or siRNA-SIRT1. These findings provide support for the hypothesis that SIRT1 is required for the effects of rapamycin on high glucose-inducing MCs senescence. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  14. Astragaloside IV, a Novel Antioxidant, Prevents Glucose-Induced Podocyte Apoptosis In Vitro and In Vivo

    PubMed Central

    Liu, Wei; Chen, Jianguo; Chen, Yifang; Huang, Jianhua; Wang, Niansong

    2012-01-01

    Glucose-induced reactive oxygen species (ROS) production initiates podocyte apoptosis, which represents a novel early mechanism leading to diabetic nephropathy (DN). Here, we tested the hypothesis that Astragaloside IV(AS-IV) exerts antioxidant and antiapoptotic effects on podocytes under diabetic conditions. Apoptosis, albuminuria, ROS generation, caspase-3 activity and cleavage, as well as Bax and Bcl-2 mRNA and protein expression were measured in vitro and in vivo. Cultured podocytes were exposed to high glucose (HG) with 50, 100 and 200 µg/ml of AS-IV for 24 h. AS-IV significantly attenuated HG-induced podocyte apoptosis and ROS production. This antiapoptotic effect was associated with restoration of Bax and Bcl-2 expression, as well as inhibition of caspase-3 activation and overexpression. In streptozotocin (STZ)-induced diabetic rats, severe hyperglycemia and albuminuria were developed. Increased apoptosis, Bax expression, caspase-3 activity and cleavage while decreased Bcl-2 expression were detected in diabetic rats. However, pretreatment with AS-IV (2.5, 5, 10 mg·kg−1·d−1) for 14 weeks ameliorated podocyte apoptosis, caspase-3 activation, renal histopathology, podocyte foot process effacement, albuminuria and oxidative stress. Expression of Bax and Bcl-2 mRNA and protein in kidney cortex was partially restored by AS-IV pretreatment. These findings suggested AS-IV, a novel antioxidant, to prevent Glucose-Induced podocyte apoptosis partly through restoring the balance of Bax and Bcl-2 expression and inhibiting caspase-3 activation. PMID:22745830

  15. 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

  16. 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

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

    PubMed

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

    2014-02-01

    The aim of current work was to evaluate in vitro anticataract potential of Moringa oliefera extract. 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. 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 (FNx01 P < 0.05) reduction in MDA and increased level of catalase, glutathione, total and soluble protein. Results of present findings suggest protective effect of Moringa oliefera in prevention of in vitro glucose induced cataract.

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-10-01

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

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

    PubMed

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

    2015-03-01

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

  1. Propofol inhibits high glucose-induced PP2A expression in human umbilical vein endothelial cells.

    PubMed

    Wu, Qichao; Zhao, Yanjun; Duan, Wenming; Liu, Yi; Chen, Xiangyuan; Zhu, Minmin

    2017-04-01

    Perioperative hyperglycemia is a common clinical metabolic disorder. Hyperglycemia could induce endothelial apoptosis, dysfunction and inflammation, resulting in endothelial injury. Propofol is a widely used anesthetic drug in clinical settings. Our previous studies indicated that propofol, via inhibiting high glucose-induced phosphatase A2 (PP2A) expression, attenuated high glucose-induced reactive oxygen species (ROS) accumulation, thus improving endothelial apoptosis, dysfunction and inflammation. However, the mechanisms by which propofol attenuated high glucose-induced PP2A expression is still obscure. In the present study, we examined how propofol attenuates high glucose-induced endothelial PP2A expression. Compared with 5mM glucose treatment, 15mM glucose up-regulated expression and activity of PP2A, increased cAMP response element binding protein (CREB), Ca(2+)-calmodulin dependent kinase II (CaMK II) phosphorylation and Ca(2+) accumulation. More importantly, propofol decreased PP2A expression and activity, attenuated CREB, CaMK II phosphorylation and Ca(2+) accumulation in a concentration-dependent manner. Moreover, we demonstrated that the effect of propofol was similar to that of MK801, an inhibitor of NMDA receptor. In contrast, rapastinel, an activator of NMDA receptor, antagonized the effect of propofol. Also, the effect of KN93, an inhibitor of CaMK II, was similar to that of propofol, except KN93 had no effect on 15mM glucose-mediated Ca(2+) accumulation. Our data indicated that propofol, via inhibiting NMDA receptor, attenuated 15mM glucose-induced Ca(2+) accumulation, CaMK II and CREB phosphorylation, thus inhibiting PP2A expression and improving 15mM glucose-induced endothelial dysfunction and inflammation. Copyright © 2017 Elsevier Inc. All rights reserved.

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

    PubMed Central

    Zhang, Xiaotian; Dai, Jiezhi; Li, Li

    2017-01-01

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

  3. 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

  4. Propofol attenuates high glucose-induced superoxide anion accumulation in human umbilical vein endothelial cells.

    PubMed

    Wang, Jiaqiang; Jiang, Hui; Wang, Jing; Zhao, Yanjun; Zhu, Yun; Zhu, Minmin

    2016-12-01

    Perioperative hyperglycemia is a common clinical metabolic disorder. Hyperglycemia could induce endothelial apoptosis, dysfunction, and inflammation, resulting in endothelial injury. Propofol is a widely used anesthetic drug in clinical settings. Our previous studies indicated that propofol attenuated high glucose-induced endothelial apoptosis, dysfunction, and inflammation via inhibiting reactive oxygen species (ROS) accumulation. However, the mechanisms by which propofol reduces high glucose-induced endothelial ROS accumulation are still obscure. In this study, we examined how propofol attenuates high glucose-induced endothelial ROS accumulation. Compared with 5 mm glucose treatment, 15 mm glucose upregulated the expression of pin-1, phosphatase A2 (PP2A), p66(shc) and mitochondrial p66(shc) expression, increased p66(shc) -Ser(36) phosphorylation, and O2·- accumulation. More importantly, although propofol had no effect on 15 mm glucose-induced p66(shc) -Ser(36) phosphorylation and pin-1 expression, propofol could downregulated PP2A expression and p66(shc) expression in whole-cell and mitochondrion, resulting in the reduction of O2·- accumulation. Moreover, we demonstrated that the antioxidative effect of propofol was similar to that of calyculin A, an inhibitor of PP2A. In contrast, FTY720, an activator of PP2A, antagonized the effect of propofol. Our data indicated that the antioxidative effect of propofol was achieved by downregulating PP2A expression, resulting in the inhibition of p66(shc) -Ser(36) dephosphorylation and mitochondrial p66(shc) expression.

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

    PubMed

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

    1988-06-01

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

  6. High glucose induces DNA damage in cultured human endothelial cells.

    PubMed Central

    Lorenzi, M; Montisano, D F; Toledo, S; Barrieux, A

    1986-01-01

    Morphologic and functional abnormalities of vascular endothelium are well recognized in diabetes. In view of our previous finding that high glucose concentrations accelerate death and hamper replication of cultured human endothelial cells, we have investigated in the same model the possibility that exposure to high glucose may result in DNA damage. DNA from human endothelial cells--but not from fibroblasts--exposed to 30 mM glucose for 9-14 d manifested an accelerated rate of unwinding in alkali indicative of an increased number of single strand breaks (P less than 0.001 vs. control). Endothelial cells exposed to high glucose also manifested an increased amount of hydroxy-urea-resistant thymidine incorporation (333 +/- 153 cpm/10(5) cells vs. 88 +/- 42 in control cells, mean +/- SD, P = 0.04), which is indicative of increased DNA repair synthesis. Neither DNA damage nor repair synthesis were increased by medium hypertonicity achieved with 30 mM mannitol. These findings suggest the possibility that, under conditions of high ambient glucose, excess glucose entry in cells that are insulin independent for glucose transport may, directly or indirectly, perturb DNA function. Further, they suggest the possibility that different individual capabilities to repair DNA damage--a process that is under genetic control--may represent a mechanism for different individual susceptibilities to development of diabetic vascular complication. PMID:3944257

  7. Somatostatin protects photoreceptor cells against high glucose-induced apoptosis.

    PubMed

    Arroba, Ana I; Mazzeo, Aurora; Cazzoni, Daniele; Beltramo, Elena; Hernández, Cristina; Porta, Massimo; Simó, Rafael; Valverde, Ángela M

    2016-01-01

    Many cellular and molecular studies in experimental animals and early retinal function tests in patients with diabetic retinopathy (DR) have shown that retinal neurodegeneration is an early event in the pathogenesis of the disease. Somatostatin (SST) is one of the most important neuroprotective factors synthesized by the retina: SST levels are decreased in parallel to retinal neurodegeneration in early stages of DR. In this study, we characterized the induction of apoptosis (programmed cell death) in a 661W photoreceptor-like cell line cultured under high glucose (HG) conditions and the effect of SST. A 661W photoreceptor-like cell line and retinal explants from 10-week-old male C57BL/6 mice were cultured under HG conditions and treated with SST. Hyperglycemia significantly reduced the cellular viability by increasing the percentage of apoptotic cells, and this effect was ameliorated by SST (p˂0.05). Activation of caspase-8 by hyperglycemia was found in the 661W cells and retinal explants and decreased in the presence of SST (p˂0.05). Moreover, we detected activation of calpain-2 associated with hyperglycemia-induced cell death, as well as increased protein tyrosine phosphatase 1B (PTP1B) protein levels; both had a pattern of cleavage that was absent in the presence of SST (p˂0.05). Treatment of the 661W cells and retinal explants with SST for 24 h increased the phosphorylation of type 1 insulin-like growth factor receptor (IGF-IR; tyrosine 1165/1166) and protein kinase B (Akt; serine 473), suggesting this survival signaling is activated in the neuroretina by SST (p˂0.05). This study has provided new mechanistic insights first into the involvement of calpain-2 and PTP1B in the loss of cell survival and increased caspase-8-dependent apoptosis induced by hyperglycemia in photoreceptor cells and second, on the protective effect of SST against apoptosis by the enhancement of IGF-IR-mediated Akt phosphorylation.

  8. High glucose induced endothelial to mesenchymal transition in human umbilical vein endothelial cell.

    PubMed

    Yu, Chun-Hong; Suriguga; Gong, Meng; Liu, Wen-Juan; Cui, Ning-Xuan; Wang, Ying; Du, Xin; Yi, Zong-Chun

    2017-06-01

    Studies have shown that endothelial-to-mesenchymal transition (EndMT) could contribute to the progression of diabetic nephropathy, diabetic renal fibrosis, and cardiac fibrosis. The aim of this study was to investigate the influence of high glucose and related mechanism of MAPK inhibitor or specific antioxidant on the EndMT. In vitro human umbilical vein endothelial cells (HUVEC) were cultured with 11mM, 30mM, 60mM and 120mM glucose for 0, 24, 48, 72 and 168h. Endothelial cell morphology was observed with microscope, and RT-PCR was used to detect mRNA expression of endothelial markers VE-cadherin and CD31, mesenchymal markers α-SMA and collagen I, and transforming growth factor TGF-β1. Immunofluorescence staining was performed to detect the expression of CD31 and α-SMA. The concentration of TGF-β1 in the supernatant was detected by ELISA. ERK1/2 phosphorylation level was detected by Western blot analysis. High glucose induced EndMT and increased the TGF-β1 level in HUVEC cells. Cells in high glucose for 7 days showed a significant decrease in mRNA expression of CD31 and VE-cadherin, and a significant increase in that of α-SMA and collagen I, while lost CD31 staining and acquired α-SMA staining. ERK signaling pathway blocker PD98059 significantly attenuated the high glucose-induced increase in the ERK1/2 phosphorylation level. PD98059 and NAC both inhibited high glucose-induced TGF-β1 expression and attenuated EndMT marker protein synthesis. High glucose could induce HUVEC cells to undergo EndMT. NAC and ERK signaling pathway may play important role in the regulation of the TGF-β1 biosynthesis during high glucose-induced EndMT. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Nifedipine Protects INS-1 β-Cell from High Glucose-Induced ER Stress and Apoptosis

    PubMed Central

    Wang, Yao; Gao, Lu; Li, Yuan; Chen, Hong; Sun, Zilin

    2011-01-01

    Sustained high concentration of glucose has been verified toxic to β-cells. Glucose augments Ca2+-stimulated insulin release in pancreatic β-cells, but chronic high concentration of glucose could induce a sustained level of Ca2+ in β-cells, which leads to cell apoptosis. However, the mechanism of high glucose-induced β-cell apoptosis remains unclear. In this study, we use a calcium channel blocker, nifedipine, to investigate whether the inhibition of intracellular Ca2+ concentration could protect β-cells from chronic high glucose-induced apoptosis. It was found that in a concentration of 33.3 mM, chronic stimulation of glucose could induce INS-1 β-cells apoptosis at least through the endoplasmic reticulum stress pathway and 10 μM nifedipine inhibited Ca2+ release to protect β-cells from high glucose-induced endoplasmic reticulum stress and apoptosis. These results indicated that inhibition of Ca2+ over-accumulation might provide benefit to attenuate islet β-cell decompensation in a high glucose environment. PMID:22174617

  10. 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.

  11. SIRT3 protects endothelial cells from high glucose-induced cytotoxicity

    PubMed Central

    Liu, Guodong; Cao, Mingming; Xu, Ying; Li, Yanbo

    2015-01-01

    Diabetes is a frequent and increasing public health problem with a large economic burden in modern society. Endothelial cells dysfunction was involved in the development of diabetes-associated diseases. Sirtuins are a conserved family of NAD-dependent deacetylases. However, the role of sirtuins in diabetes-associated endothelial cell dysfunction was relatively unknown. In this study, we focus on the intrinsic link between SIRT3, a mitochondrial sirtuin, and high glucose-induced endothelial cells dysfunction. We showed that loss of SIRT3 expression was associated with decreased viability in endothelial cells from diabetes patients. Knockdown of SIRT3 decreased viability of endothelia cells exposed to high glucose condition. Further, mechanistic study showed that SIRT3 repression results in SOD2 acetylation, leading to SOD2 inactivation, which enhanced high glucose-induced oxidative stress in endothelial cells. Our data suggested that SIRT3 protects endothelial cells from high glucose-induced cytotoxicity. Our findings are considered a significant step toward a better understanding of diabetes-associated vascular diseases. PMID:25755722

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

    PubMed Central

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

    2015-01-01

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

  13. 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.

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

    PubMed

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

    2009-01-01

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

  15. Resveratrol attenuates high glucose-induced oxidative stress and cardiomyocyte apoptosis through AMPK.

    PubMed

    Guo, Shuang; Yao, Qing; Ke, Zhiqiang; Chen, Hongguang; Wu, Jiliang; Liu, Chao

    2015-09-05

    Diabetic cardiomyopathy (DCM) suggests a direct cellular insult to myocardium. Hyperglycemia-induced oxidative stress and apoptosis have been implicated in the pathogenesis of DCM. NADPH oxidase is a major source of reactive oxygen species (ROS) generation in cardiomyocytes. Resveratrol, a naturally occurring polyphenol, has shown beneficial effects on some cardiovascular complications associated with diabetes. We aimed to examine the role of resveratrol on high glucose-induced NADPH oxidase-derived ROS production and cardiac apoptosis, together with modulation of protein signaling pathways in cardiomyocytes. Primary cultures of neonatal rat cardiomyocytes were exposed to 30 mmol/L high glucose with or without resveratrol. Cell viability, apoptosis, superoxide formation, NADPH oxidase activity and its subunits expression, antioxidant enzymes activities, as well as the potential regulatory molecules AMPK, Akt and GSK-3β were assessed in cardiac cells. Elevated ROS production induced by 30 mmol/L high glucose was inhibited with the addition of resveratrol in primary cultured neonatal rat cardiomyocytes. Consistently, resveratrol markedly suppressed the increased activity of NADPH oxidase and Rac1, as well as the enhanced expression of p67(phox), p47(phox), and gp91(phox) induced by high glucose. Lipid peroxidation, SOD, catalase, GSH-px activity and GSH content was reversed in the presence of resveratrol. Moreover, the expression of pro-apoptotic protein Bax was down regulated while anti-apoptotic protein Bcl-2 was up regulated. And cardiac cell injury and apoptosis were markedly rescued by resveratrol. In addition, resveratrol significantly increased phosphorylation of AMP-activated protein kinase (AMPK) at Thr172 in cardiomyocytes exposed to high glucose. Compound C, the pharmacologic inhibitor of AMPK, could mostly abrogate roles of resveratrol on cardiomyocytes in high glucose. In contrast, Akt and GSK-3β were little influenced by resveratrol. Our data

  16. High glucose-induced transforming growth factor beta1 production is mediated by the hexosamine pathway in porcine glomerular mesangial cells.

    PubMed Central

    Kolm-Litty, V; Sauer, U; Nerlich, A; Lehmann, R; Schleicher, E D

    1998-01-01

    Previous studies revealed that exposure of mesangial cells to high glucose concentration induces the production of matrix proteins mediated by TGF-beta1. We tested if structural analogues of D-glucose may mimic the high glucose effect and found that D-glucosamine was strikingly more potent than D-glucose itself in enhancing the production of TGF-beta protein and subsequent production of the matrix components heparan sulfate proteoglycan and fibronectin in a time- and dose-dependent manner. D-Glucosamine also promoted conversion of latent TGF-beta to the active form. Therefore, we suggested that the hexosamine biosynthetic pathway (the key enzyme of which is glutamine:fructose-6-phosphate amidotransferase [GFAT]) contributes to the high glucose-induced TGF-beta1 production. Inhibition of GFAT by the substrate analogue azaserine or by inhibition of GFAT protein synthesis with antisense oligonucleotide prevented the high glucose-induced increase in cellular glucosamine metabolites and TGF-beta1 expression and bioactivity and subsequent effects on mesangial cell proliferation and matrix production. Overall, our study indicates that the flux of glucose metabolism through the GFAT catalyzed hexosamine biosynthetic pathway is involved in the glucose-induced mesangial production of TGF-beta leading to increased matrix production. PMID:9421478

  17. 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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2015-01-01

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

  20. Three pentacyclic triterpenes protect H9c2 cardiomyoblast cells against high-glucose-induced injury.

    PubMed

    Chan, C Y; Mong, M C; Liu, W H; Huang, C Y; Yin, M C

    2014-04-01

    H9c2 cardiomyoblast cell line was used to examine the protection of three triterpenes, asiatic acid, boswellic acid, and oleanolic acid, at 5 or 10 μM against high-glucose-induced injury. High glucose stimulated reactive oxygen species (ROS), oxidized glutathione (GSSG), interleukin-6, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1 production, as well as decreased glutathione peroxidase (GPX), glutathione reductase (GR) and catalase activities, and protein expression. However, pre-treatments of three triterpenes reserved glutathione, maintained activity and expression of GPX, GR, and catalase, as well as lowered ROS, GSSG, and inflammatory cytokines generation. High glucose reduced Na(+)-K(+)-ATPase activity, raised nuclear factor kappa (NF-κ) B and caspase-3 activities, up-regulated protein expression of NF-κB, mitogen-activated protein kinase, Bax, and cleaved caspase-3, as well as down-regulated Bcl-2 expression. Pre-treatments of three triterpenes retained Na(+)-K(+)-ATPase activity, declined NF-κB and caspase-3 activities, reserved Bcl-2 expression, as well as suppressed protein expression of NF-κB, p-p38, Bax, and cleaved caspase-3. These findings suggest that these triterpenes are potent cardiac-protective agents.

  1. 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

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

    PubMed

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

    2003-02-01

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

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

    PubMed

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

    2015-11-20

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

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

    PubMed Central

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

    2014-01-01

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

  5. 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. © 2016 S. Karger AG, Basel.

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

    PubMed

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

    2015-04-01

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

  7. 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

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

    PubMed

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

    2017-01-05

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

  9. 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.

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

    PubMed Central

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

    2016-01-01

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

  11. Neuroprotective Effects of Ginsenoside Rb1 on High Glucose-Induced Neurotoxicity in Primary Cultured Rat Hippocampal Neurons

    PubMed Central

    Liu, Di; Zhang, Hong; Gu, Wenjuan; Liu, Yuqin; Zhang, Mengren

    2013-01-01

    Ginsenoside Rb1 is one of the main active principles in traditional herb ginseng and has been reported to have a wide variety of neuroprotective effects. Endoplasmic reticulum (ER) stress has been implicated in neurodegenerative diseases, so the present study aimed to observe the effects of ginsenoside Rb1 on ER stress signaling pathways in high glucose-treated hippocampal neurons. The results from MTT, TUNEL labeling and Annexin V-FITC/PI/Hoechst assays showed that incubating neurons with 50 mM high glucose for 72h decreased cell viability and increased the number of apoptotic cells whereas treating neurons with 1 μM Rb1 for 72h protected the neurons against high glucose-induced cell damage. Further molecular mechanism study demonstrated that Rb1 suppressed the activation of ER stress-associated proteins including protein kinase RNA (PKR)-like ER kinase (PERK) and C/EBP homology protein (CHOP) and downregulation of Bcl-2 induced by high glucose. Moreover, Rb1 inhibited both the elevation of intracellular reactive oxygen species (ROS) and the disruption of mitochondrial membrane potential induced by high glucose. In addition, the high glucose-induced cell apoptosis, activation of ER stress, ROS accumulation and mitochondrial dysfunction can also be attenuated by the inhibitor of ER stress 4-phenylbutyric acid (4-PBA) and anti-oxidant N-acetylcysteine(NAC). In conclusion, these results suggest that Rb1 may protect neurons against high glucose-induced cell injury through inhibiting CHOP signaling pathway as well as oxidative stress and mitochondrial dysfunction. PMID:24223941

  12. 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.

  13. ROCK inhibitor fasudil attenuated high glucose-induced MCP-1 and VCAM-1 expression and monocyte-endothelial cell adhesion.

    PubMed

    Li, Hailing; Peng, Wenhui; Jian, Weixia; Li, Yuanmin; Li, Qi; Li, Weiming; Xu, Yawei

    2012-06-13

    Previous studies suggested that the RhoA/ROCK pathway may contribute to vascular complications in diabetes. The present study was designed to investigate whether ROCK inhibitor fasudil could prevent high glucose-induced monocyte-endothelial cells adhesion, and whether this was related to fasudil effects on vascular endothelial cell expression of chemotactic factors, vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1). HUVECs were stimulated with high glucose (HG) or HG + fasudil in different concentration or different time. Monocyte-endothelial cell adhesion was determined using fluorescence-labeled monocytes. The mRNA and protein expression of VCAM-1 and MCP-1 were measured using real-time PCR and western blot. The protein levels of RhoA, ROCKI and p-MYPT were determined using western blot analysis. ELISA was employed to measure the expression of soluble VCAM-1 and MCP-1 in cell supernatants and human serum samples. Fasudil significantly suppressed HG-induced adhesion of THP-1 to HUVECs. Fasudil reduced Rho/ROCK activity (as indicated by lower p-MYPT/MYPT ratio), and prevented HG induced increases in VCAM-1 and MCP-1 mRNA and protein levels. Fasudil also decreased MCP-1 concentration in HUVEC supernatants, but increased sVCAM-1 shedding into the media. In human diabetic subjects, 2 weeks of fasudil treatment significantly decreased serum MCP-1 level from 27.9 ± 10.6 pg/ml to 13.8 ± 7.0 pg/ml (P < 0.05), while sVCAM-1 increased from 23.2 ± 7.5 ng/ml to 39.7 ± 5.6 ng/ml after fasudil treatment (P < 0.05). Treatment with the Rho/ROCK pathway inhibitor fasudil attenuated HG-induced monocyte-endothelial cell adhesion, possibly by reducing endothelial expression of VCAM-1 and MCP-1. These results suggest inhibition of Rho/ROCK signaling may have therapeutic potential in preventing diabetes associated vascular inflammation and atherogenesis.

  14. 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.

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

    PubMed

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

    2013-12-01

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

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

    PubMed

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

    2004-02-01

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

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

    PubMed Central

    Eid, Ali Hussein

    2017-01-01

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

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

    PubMed

    Pavan, Barbara; Capuzzo, Antonio; Forlani, Giuseppe

    2014-03-01

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

  19. PKC?-dependent activation of the ubiquitin proteasome system is responsible for high glucose-induced human breast cancer MCF-7 cell proliferation, migration and invasion.

    PubMed

    Zhu, Shan; Yao, Feng; Li, Wen-Huan; Wan, Jin-Nan; Zhang, Yi-Min; Tang, Zhao; Khan, Shahzad; Wang, Chang-Hua; Sun, Sheng-Rong

    2013-01-01

    Type 2 diabetes mellitus (T2DM) has contributed to advanced breast cancer development over the past decades. However, the mechanism underlying this contribution is poorly understood. In this study, we determined that high glucose enhanced proteasome activity was accompanied by enhanced proliferation, migration and invasion, as well as suppressed apoptosis, in human breast cancer MCF-7 cells. Proteasome inhibitor bortezomib (BZM) pretreatment mitigated high glucose-induced MCF-7 cell growth and invasion. Furthermore, high glucose increased protein kinase C delta (PKC?)-phosphorylation. Administration of the specific PKC? inhibitor rottlerin attenuated high glucose-stimulated cancer cell growth and invasion. In addition, PKC? inhibition by both rottlerin and PKC? shRNA significantly suppressed high glucose-induced proteasome activity. Our results suggest that PKC?-dependent ubiquitin proteasome system activation plays an important role in high glucose- induced breast cancer cell growth and metastasis.

  20. Zinc supplementation attenuates high glucose-induced epithelial-to-mesenchymal transition of peritoneal mesothelial cells.

    PubMed

    Zhang, Xiuli; Wang, Jun; Fan, Yi; Yang, Lina; Wang, Lining; Ma, Jianfei

    2012-12-01

    Zinc (Zn) plays an important role in preventing many types of epithelial-to-mesenchymal transition (EMT)-driven fibrosis in vivo. But its function in the EMT of the peritoneal mesothelial cells (PMCs) remains unknown. Here, we studied the Zn effect on the high glucose (HG)-induced EMT in the rat PMCs (RPMCs) and the underlying molecular mechanisms. We found that Zn supplementation significantly inhibited TGF-β1 and ROS production, and attenuated the HG-induced EMT in the RPMCs, likely through inhibition of MAPK, NF-κB, and TGF-β/Smad pathways.

  1. PRAS40 ACTS AS A NODAL REGULATOR OF HIGH GLUCOSE-INDUCED TORC1 ACTIVATION IN GLOMERULAR MESANGIAL CELL HYPERTROPHY

    PubMed Central

    Dey, Nirmalya; Ghosh-Choudhury, Nandini; Das, Falguni; Li, Xiaonan; Venkatesan, Balachandar; Barnes, Jeffrey L.; Kasinath, Balakuntalam S.; Choudhury, Goutam Ghosh

    2010-01-01

    Diabetic nephropathy manifests aberrant activation of TORC1, which senses key signals to modulate protein synthesis and renal hypertrophy. PRAS40 has recently been identified as a raptor-interacting protein and is a component and a constitutive inhibitor of TORC1. The mechanism by which high glucose stimulates TORC1 activity is not known. PRAS40 was identified in the mesangial cells in renal glomeruli and in tubulointerstitium of rat kidney. Streptozotocin-induced diabetic renal hypertrophy was associated with phosphorylation of PRAS40 in the cortex and glomeruli. In vitro, high glucose concentration increased PRAS40 phosphorylation in a PI 3 kinase- and Akt-dependent manner, resulting in dissociation of raptor-PRAS40 complex in mesangial cells. High glucose augmented the inactivating and activating phosphorylation of 4EBP-1 and S6 kinase, respectively with concomitant induction of protein synthesis and hypertrophy. Expression of TORC1-nonphosphorylatable mutant of 4EBP-1 and dominant negative S6 kinase significantly inhibited high glucose-induced protein synthesis and hypertrophy. PRAS40 knockdown mimicked the effect of high glucose on phosphorylation of 4EBP-1 and S6 kinase, protein synthesis and hypertrophy. To elucidate the role of PRAS40 phosphorylation, we used phosphorylation-deficient mutant of PRAS40, which in contrast to PRAS40 knockdown inhibited phosphorylation of 4EBP-1 and S6 kinase, leading to reduced mesangial cell hypertrophy. Thus our data identify high glucose-induced phosphorylation and inactivation of PRAS40 as a central node for mesangial cell hypertrophy in diabetic nephropathy. PMID:20629086

  2. 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.

  3. Enhancement of high glucose-induced PINK1 expression by melatonin stimulates neuronal cell survival: Involvement of MT2 /Akt/NF-κB pathway.

    PubMed

    Onphachanh, Xaykham; Lee, Hyun Jik; Lim, Jae Ryong; Jung, Young Hyun; Kim, Jun Sung; Chae, Chang Woo; Lee, Sei-Jung; Gabr, Amr Ahmed; Han, Ho Jae

    2017-09-01

    Hyperglycemia is a representative hallmark and risk factor for diabetes mellitus (DM) and is closely linked to DM-associated neuronal cell death. Previous investigators reported on a genome-wide association study and showed relationships between DM and melatonin receptor (MT), highlighting the role of MT signaling by assessing melatonin in DM. However, the role of MT signaling in DM pathogenesis is unclear. Therefore, we investigated the role of mitophagy regulators in high glucose-induced neuronal cell death and the effect of melatonin against high glucose-induced mitophagy regulators in neuronal cells. In our results, high glucose significantly increased PTEN-induced putative kinase 1 (PINK1) and LC-3B expressions; as well it decreased cytochrome c oxidase subunit 4 expression and Mitotracker™ fluorescence intensity. Silencing of PINK1 induced mitochondrial reactive oxygen species (ROS) accumulation and mitochondrial membrane potential impairment, increased expressions of cleaved caspases, and increased the number of annexin V-positive cells. In addition, high glucose-stimulated melatonin receptor 1B (MTNR1B) mRNA and PINK1 expressions were reversed by ROS scavenger N-acetyl cysteine pretreatment. Upregulation of PINK1 expression in neuronal cells is suppressed by pretreatment with MT2 receptor-specific inhibitor 4-P-PDOT. We further showed melatonin stimulated Akt phosphorylation, which was followed by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) phosphorylation and nuclear translocation. Silencing of PINK1 expression abolished melatonin-regulated mitochondrial ROS production, cleaved caspase-3 and caspase-9 expressions, and the number of annexin V-positive cells. In conclusion, we have demonstrated the melatonin stimulates PINK1 expression via an MT2 /Akt/NF-κB pathway, and such stimulation is important for the prevention of neuronal cell apoptosis under high glucose conditions. © 2017 The Authors. Journal of Pineal Research

  4. High glucose induces bone marrow-derived mesenchymal stem cell senescence by upregulating autophagy.

    PubMed

    Chang, Tzu-Ching; Hsu, Min-Fen; Wu, Kenneth K

    2015-01-01

    Hyperglycemia was reported to cause bone marrow hematopoietic niche dysfunction, and high glucose (HG) in the cultured medium induces MSC senescence. The underlying mechanism is unclear. Here, we investigated the role of HG-induced autophagy in bone-marrow-derived mesenchymal stem cell (BMSC) senescence. HG (25 mM) increased expression of Beclin-1, Atg 5, 7 and 12, generation of LC3-II and autophagosome formation which was correlated with development of cell senescence. Pretreatment of HG-MSC with 3-methyladenine (3-MA) prevented senescence but increased apoptosis. N-acetylcysteine (NAC) was effective in abrogating HG-induced autophagy accompanied by prevention of senescence. Diphenyleneiodonium (DPI), an inhibitor of NADPH oxidase, blocked autophagy and senescence in a manner comparable to NAC. 3-MA, NAC and DPI inhibited HG-induced interleukin-6 production in BMSCs. These results suggest that hyperglycemia induces MSC senescence and local inflammation via a novel oxidant-mediated autophagy which contributes to bone marrow niche dysfunction and hematopoietic impairment.

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

    PubMed Central

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

    2017-01-01

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

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

    PubMed

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

    2017-04-01

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

  7. High glucose induces apoptosis via upregulation of Bim expression in proximal tubule epithelial cells.

    PubMed

    Zhang, Xiao-Qian; Dong, Jian-Jun; Cai, Tian; Shen, Xue; Zhou, Xiao-Jun; Liao, Lin

    2017-04-11

    Diabetic nephropathy is the primary cause of end-stage renal disease. Apoptosis of tubule epithelial cells is a major feature of diabetic nephropathy. The mechanisms of high glucose (HG) induced apoptosis are not fully understood. Here we demonstrated that, HG induced apoptosis via upregulating the expression of proapoptotic Bcl-2 homology domain 3 (BH3)-only protein Bim protein, but not bring a significant change in the baseline level of autophagy in HK2 cells. The increase of Bim expression was caused by the ugregulation of transcription factors, FOXO1 and FOXO3a. Bim expression initiates BAX/BAK-mediated mitochondria-dependent apoptosis. Silence of Bim by siRNA in HK2 cells prevented HG-induced apoptosis and also sensitized HK2 cells to autophagy during HG treatment. The autophagy inhibitor 3-MA increased the injury in Bim knockdown HK2 cells by retriggering apoptosis. The above results suggest a Bim-independent apoptosis pathway in HK2 cells, which normally could be inhibited by autophagy. Overall, our results indicate that HG induces apoptosis via up-regulation of Bim expression in proximal tubule epithelial cells.

  8. High glucose induces apoptosis via upregulation of Bim expression in proximal tubule epithelial cells

    PubMed Central

    Zhang, Xiao-Qian; Dong, Jian-Jun; Cai, Tian; Shen, Xue; Zhou, Xiao-Jun; Liao, Lin

    2017-01-01

    Diabetic nephropathy is the primary cause of end-stage renal disease. Apoptosis of tubule epithelial cells is a major feature of diabetic nephropathy. The mechanisms of high glucose (HG) induced apoptosis are not fully understood. Here we demonstrated that, HG induced apoptosis via upregulating the expression of proapoptotic Bcl-2 homology domain 3 (BH3)-only protein Bim protein, but not bring a significant change in the baseline level of autophagy in HK2 cells. The increase of Bim expression was caused by the ugregulation of transcription factors, FOXO1 and FOXO3a. Bim expression initiates BAX/BAK-mediated mitochondria-dependent apoptosis. Silence of Bim by siRNA in HK2 cells prevented HG-induced apoptosis and also sensitized HK2 cells to autophagy during HG treatment. The autophagy inhibitor 3-MA increased the injury in Bim knockdown HK2 cells by retriggering apoptosis. The above results suggest a Bim-independent apoptosis pathway in HK2 cells, which normally could be inhibited by autophagy. Overall, our results indicate that HG induces apoptosis via up-regulation of Bim expression in proximal tubule epithelial cells. PMID:28445931

  9. Possible roles of tumor necrosis factor-α and angiotensin II type 1 receptor on high glucose-induced damage in renal proximal tubular cells.

    PubMed

    Takao, Toshihiro; Horino, Taro; Matsumoto, Reiko; Shimamura, Yoshiko; Ogata, Koji; Inoue, Kousuke; Taniguchi, Yoshinori; Taguchi, Takafumi; Terada, Yoshio

    2015-02-01

    Recent studies have identified that high glucose-induced renal tubular cell damage. We previously demonstrated that high glucose treatment induced oxidative stress in human renal proximal tubular epithelial cells (RPTECs), and angiotensin II type 1 (AT1) receptor blockers reduce high glucose-induced oxidative stress in RPTEC possibly via blockade of intracellular as well as extracellular AT1 receptor. However, exact roles of tumor necrosis factor (TNF)-α and AT1 receptor on high glucose-induced renal tubular function remain unclear. N-acetyl-beta-glucosaminidase (NAG), concentrations of TNF-α/angiotensin II and p22(phox) protein levels after high glucose treatment with or without AT1 receptor blocker or thalidomide, an inhibitor of TNF-α protein synthesis, were measured in immortalized human renal proximal tubular epithelial cells (HK2 cells). AT1 receptor knockdown was performed with AT1 receptor small interfering RNA (siRNA). High glucose treatment (30 mM) significantly increased NAG release, TNF-α/angiotensin II concentrations in cell media and p22(phox) protein levels compared with those in regular glucose medium (5.6 mM). Candesartan, an AT1R blocker, showed a significant reduction on high glucose-induced NAG release, TNF-α concentrations and p22(phox) protein levels in HK2 cells. In addition, significant decreases of NAG release, TNF-α concentrations and p22(phox) protein levels in HK2 cells were observed in high glucose-treated group with thalidomide. AT1R knockdown with siRNA markedly reversed high glucose, angiotensin II or TNF-α-induced p22(phox) protein levels in HK2 cells. TNF-α may be involved in high glucose-induced renal tubular damage in HK2 cells possibly via AT1 receptor signaling.

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

    PubMed Central

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

    2017-01-01

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

  11. 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

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

    PubMed

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

    2017-03-16

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

  13. Adiponectin attenuates high glucose-induced apoptosis through the AMPK/p38 MAPK signaling pathway in NRK-52E cells

    PubMed Central

    Wang, Yuanyuan; Zhang, Juan; Zhang, Lian; Gao, Ping

    2017-01-01

    Excessive apoptosis of proximal tubule cell is closely related to the development of diabetes. Recent evidence suggests that adiponectin (ADPN) protects cells from high glucose induced apoptosis. However, the precise mechanisms remain poorly understood. We sought to investigate the role of p38 mitogen-activated protein kinase (p38 MAPK) and AMP activated protein kinase (AMPK) in anti-apoptotic of adiponectin under high glucose condition in rat tubular NRK-52E cells. Cells were cultured in constant and oscillating high glucose media with or without recombinant rat adiponectin for 48 h. Cell counting kit-8 (CCK-8) was used to detect cell viability, flow cytometry and Hoechst Staining were applied to investigate cell apoptosis, and western blotting was used to examine protein expression, such as phospho-AMPK and phospho-p38MAPK. Exposure to oscillating high glucose exerted lower cell viability and higher early apoptosis than constant high glucose, which were both partially prevented by adiponectin. Further studies revealed that adiponectin suppressed p38MAPK phosphorylation, but led to an increase in AMPK α phosphorylation. Compared to stable high glucose group, blockage of p38MAPK cascade with SB203580 attenuated apoptosis significantly, but failed to affect the phosphorylation level of AMPK. While AMPK inhibitor, Compound C, increased apoptosis and remarkably inhibited the p38MAPK phosphorylation. Adiponectin exert a crucial protective role against apoptosis induced by high glucose via AMPK/p38MAPK pathway. PMID:28542560

  14. Adiponectin attenuates high glucose-induced apoptosis through the AMPK/p38 MAPK signaling pathway in NRK-52E cells.

    PubMed

    Wang, Yuanyuan; Zhang, Juan; Zhang, Lian; Gao, Ping; Wu, Xiaoyan

    2017-01-01

    Excessive apoptosis of proximal tubule cell is closely related to the development of diabetes. Recent evidence suggests that adiponectin (ADPN) protects cells from high glucose induced apoptosis. However, the precise mechanisms remain poorly understood. We sought to investigate the role of p38 mitogen-activated protein kinase (p38 MAPK) and AMP activated protein kinase (AMPK) in anti-apoptotic of adiponectin under high glucose condition in rat tubular NRK-52E cells. Cells were cultured in constant and oscillating high glucose media with or without recombinant rat adiponectin for 48 h. Cell counting kit-8 (CCK-8) was used to detect cell viability, flow cytometry and Hoechst Staining were applied to investigate cell apoptosis, and western blotting was used to examine protein expression, such as phospho-AMPK and phospho-p38MAPK. Exposure to oscillating high glucose exerted lower cell viability and higher early apoptosis than constant high glucose, which were both partially prevented by adiponectin. Further studies revealed that adiponectin suppressed p38MAPK phosphorylation, but led to an increase in AMPK α phosphorylation. Compared to stable high glucose group, blockage of p38MAPK cascade with SB203580 attenuated apoptosis significantly, but failed to affect the phosphorylation level of AMPK. While AMPK inhibitor, Compound C, increased apoptosis and remarkably inhibited the p38MAPK phosphorylation. Adiponectin exert a crucial protective role against apoptosis induced by high glucose via AMPK/p38MAPK pathway.

  15. The carboxyl terminus of heat shock protein 70-interacting protein (CHIP) participates in high glucose-induced cardiac injury.

    PubMed

    Xiong, Wenjun; Liu, Shiwen; Cai, Wenyao; Wen, Jinhua; Fu, Yongnan; Peng, Jingtian; Zheng, Zeqi

    2017-05-01

    The carboxyl terminus of heat shock protein 70-interacting protein (CHIP) is confirmed to have a protective effect on the myocardium, but its effect on diabetic cardiomyopathy is unclear. Small interfering RNA (siRNA) was used for knockdown experiments in neonatal rat cardiomyocytes to examine the function of CHIP in high glucose-induced injury. High glucose stimulated the production of reactive oxygen species (ROS), nicotinamide adenine dinucleotide phosphate oxidase (NOX), interleukin-1β (IL-1β), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1) production. However, cardiomyocytes lacking CHIP suffered from increased oxidative stress and inflammatory responses. High glucose increased the expression of Bax and caspase-3 mRNAs, decreased the expression of Bcl-2 mRNA, and up-regulated the expression of the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) proteins. However, upon CHIP knockdown, the expression of Bax and caspase-3 mRNAs increased even further, and the expression of Bcl-2 mRNA was further suppressed. The expression of the phosphorylated p65 and p38 proteins (p-p65 and p-p38) was also further enhanced. Thus, CHIP is a potent cardioprotective molecule. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. 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

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

    PubMed

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

    2015-01-01

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

  18. 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.

  19. Amelioration of insulin resistance by scopoletin in high-glucose-induced, insulin-resistant HepG2 cells.

    PubMed

    Zhang, W Y; Lee, J-J; Kim, Y; Kim, I-S; Park, J-S; Myung, C-S

    2010-12-01

    Insulin resistance plays an important role in the development of type 2 diabetes mellitus. Scopoletin, a phenolic coumarin, is reported to regulate hyperglycemia and diabetes. To examine its effect on insulin resistance, we treated high-glucose-induced, insulin-resistant HepG2 cells with scopoletin and measured phosphatidylinositol 3-kinase (PI3 K)-linked protein kinase B (Akt/PKB) phosphorylation. Scopoletin significantly stimulated the reactivation of insulin-mediated Akt/PKB phosphorylation. This effect was blocked by LY294002, a specific PI3 K inhibitor. The ability of scopoletin to activate insulin-mediated Akt/PKB was greater than that of rosiglitazone, a thiazolidinedione, and scopoletin was less adipogenic than rosiglitazone, as shown by the extent of lipid accumulation in differentiated adipocytes. Scopoletin increased the gene expression of both peroxisome proliferator-activated receptor γ2 (PPARγ2), a target receptor for rosiglitazone, and adipocyte-specific fatty acid binding protein, but not to the level induced by rosiglitazone. However, the PPARγ2 protein level was increased equally by rosiglitazone and scopoletin in differentiated adipocytes. Our results suggest that scopoletin can ameliorate insulin resistance in part by upregulating PPARγ2 expression. With its lower adipogenic property, scopoletin may be a useful candidate for managing metabolic disorders, including type 2 diabetes mellitus. © Georg Thieme Verlag KG Stuttgart · New York.

  20. Inhibitory effect of serotonin derivatives on high glucose-induced adhesion and migration of monocytes on human aortic endothelial cells.

    PubMed

    Piga, Rosaria; Naito, Yuji; Kokura, Satoshi; Handa, Osamu; Yoshikawa, Toshikazu

    2009-07-01

    Previous reports have shown that safflower-seed extract and its major antioxidant constituents, serotonin hydroxycinnamic amides, attenuated atherosclerotic lesion formation in apoE-deficient mice, as well as inflammation and aortic stiffness in human subjects. In the present report, we examined a still unknown cell-based mechanism of serotonin derivatives against the development of atherosclerosis, focusing our attention on their action against the increase of adhesion molecules and the release of chemotactic factors on human aortic endothelial cells, phenomena that represent the key events in the early stages of atherosclerogenesis. Serotonin derivatives N-(p-coumaroyl)serotonin and N-feruloylserotonin exerted an inhibitory effect on short-term high glucose-induced up-regulation of mRNA and protein of adhesion and migration factors, and the consequent adhesion and migration of monocytes to endothelial cells; they inhibited the activation of transcription factors such as NF-kappaB, and the overproduction of the mitochondrial superoxide by acting as scavengers of the superoxide radical. In addition, serotonin derivative concentration inside the cells and inside the mitochondria was increased in a time-dependent manner. These results identify a mechanism of action of serotonin derivatives against endothelial damage at a cellular level, and underline their benefits against the disorders and complications related to reactive oxygen species.

  1. 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.

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

    SciTech Connect

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

    2012-10-26

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

  3. 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.

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

    PubMed

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

    2014-12-01

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

  5. 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.

  6. (-)-Epicatechin attenuates high-glucose-induced inflammation by epigenetic modulation in human monocytes.

    PubMed

    Cordero-Herrera, Isabel; Chen, Xinpu; Ramos, Sonia; Devaraj, Sridevi

    2017-04-01

    Diabetes is a pro-inflammatory state associated with increased monocyte activity. NF-κB is the master switch of inflammation and is activated during diabetes. (-)-Epicatechin (EC), the main cocoa flavonol, displays anti-inflammatory and anti-diabetic effects under high glucose conditions. Recently, it has been suggested that dietary polyphenols might modulate chromatin remodelling by epigenetic changes and regulate monocyte NF-κB activation and cytokine expression under diabetic conditions. The aim of the study was to test the potential anti-inflammatory role of EC via inducing posttranslational histone changes in the presence of a high glucose (HG) concentrations. Human monocytic cells (THP-1 cells) were pre-treated with EC (5 μM) and 4 h later exposed to 25 mM glucose (HG) for a total of 24 h. Control cells were grown under normoglycemic conditions (NG, 5.5 mM glucose). Acetyl CBP/p300, HDAC4, total histone 3 (HH3), H3K9ac, H3K4me2 and H3K9me2, and phosphorylated and total levels of p65-NF-κB were analysed by Western blot. Histone acetyltransferase (HAT) activity was measured in nuclear lysates, and TNF-α release was evaluated in culture media. EC incubation restored to control levels (NG) the changes induced by HG in p-p65/p65-NF-ĸB ratio, acetyl CBP/p300 values and HAT activity. Moreover, EC pre-treatment counteracted the increased acetylation of H3K9 and H3K4 dimethylation and attenuated the diminished H3K9 dimethylation triggered by HG. EC also significantly decreased HG-enhanced HDAC4 levels and TNF-α release, respectively. EC induces epigenetic changes and decreased NF-κB and TNF-α levels in human monocytes cultured in HG conditions such as in diabetes.

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

    PubMed

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

    2007-07-01

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

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

    PubMed

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

    2010-04-15

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

  9. Zinc inhibits high glucose-induced NLRP3 inflammasome activation in human peritoneal mesothelial cells.

    PubMed

    Fan, Yi; Zhang, Xiuli; Yang, Lina; Wang, Jun; Hu, Ye; Bian, Aishu; Liu, Jin; Ma, Jianfei

    2017-10-01

    Zinc (Zn) deficiency is important for inducing nucleotide-binding domain and leucine‑rich repeat‑containing family, pyrin domain-containing-3 (NLRP3) inflammasome activation in macrophages. However, its function in the NLRP3 inflammasome activation of peritoneal mesothelial cells (PMCs) remains to be elucidated. In the present study, the human PMC (HPMC) line HMrSV5 was co‑treated with high glucose and either ZnSO4 or a Zn chelator. The activity of the NLRP3/caspase‑1 inflammasome was assessed via western blot analysis, immunofluorescence, reverse transcription‑quantitative polymerase chain reaction and ELISA. In addition, the activity of the nuclear factor erythroid 2‑related factor 2 (Nrf2) pathway was detected using western blotting, and the level of reactive oxygen species (ROS) was assessed by 2,7‑dichlorofluorescein fluorescence and flow cytometry. It was found that Zn supplementation inhibited HG‑induced NLRP3 inflammasome activation in the HPMCs by attenuating ROS production. Further experiments revealed that Zn supplementation inhibited the HG‑induced production of ROS through activation of the Nrf2 antioxidant pathway. These results indicated that Zn inhibited NLRP3 inflammasome activation in the HG‑treated HPMCs by activating the Nrf2 antioxidant pathway and reducing the production of ROS.

  10. 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.

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

    PubMed

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

    2013-01-01

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

  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.

  13. 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.

  14. Role of salt inducible kinase 1 in high glucose-induced lipid accumulation in HepG2 cells and metformin intervention.

    PubMed

    Zhang, Yue; Takemori, Hiroshi; Wang, Chang; Fu, JiaHui; Xu, MingWang; Xiong, Liang; Li, NingXu; Wen, XiuYing

    2017-03-15

    To investigate the roles of salt inducible kinase (SIK1) in high glucose-induced triglyceride accumulation in human hepatoma HepG2 cells as well as in the molecular mechanism by which metformin, a drug to treat diabetes, suppresses high glucose-induced lipogenesis. A cell model for high glucose-induced hepatic steatosis was prepared by exposing HepG2 cells to high glucose (25mmol) in the absence or presence of metformin (0.5mmol). Intracellular triglycerides were visualized by Oil Red O and measured using a triglyceride assay kit. Cell viability was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. SIK1 overexpression in HepG2 cells was achieved by transient transfection, and the mRNA and protein levels of SIK1 and lipogenic factors were measured using a reverse transcription-polymerase chain reaction and western blotting, respectively. Lipid accumulation in HepG2 cells was obvious after treatment with high glucose for 24h. In response to high glucose, SIK1 expression was negatively correlated with that of lipogenic factors and lipid accumulation in HepG2 cells. We observed that overexpression of SIK1, or treatment with metformin, suppressed lipogenesis, even in high glucose conditions. Furthermore, treatment with metformin upregulated SIK1 mRNA and protein levels, as well as the active form of SIK1. SIK1 plays a vital role in high glucose-induced lipid accumulation, and metformin suppresses lipogenesis via the induction and activation of SIK1. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Salvianolic acid B inhibits intermittent high glucose-induced INS-1 cell apoptosis through regulation of Bcl-2 proteins and mitochondrial membrane potential.

    PubMed

    Tao, Shanjun; Ren, Younan; Zheng, Haowen; Zhao, Mengqiu; Zhang, Xu; Zhu, Yuanmei; Yang, Jieren; Zheng, Shuguo

    2017-08-08

    Blood glucose fluctuations, also referred to as intermittent high glucose, have been validated to be more harmful than sustained high glucose in exacerbating pancreatic dysfunction by inducing β cell apoptosis. Salvianolic acid B (Sal B), an aqueous component of Salvia miltiorrhiza, has been proved beneficial to pancreatic islet function in diabetes, but the underlying mechanisms remain to be elucidated. The present study investigated the protective effect of Sal B on INS-1 cells exposed to intermittent high glucose and the possible mechanisms implicated. The results indicated that Sal B was able to restore cell viability and suppress INS-1 cell apoptosis induced by intermittent high glucose. Preincubation with Sal B led to a significant decrease of caspase-9 and caspase-3 activity and poly ADP-ribose polymerase (PARP) cleavage. Exposure to intermittent high glucose induced significant up-regulation of proapoptotic proteins, down-regulation of antiapoptotic protein and depolarization of mitochondrial membrane potential (MMP) in INS-1 cells, while these changes were reversed effectively in Sal B treated groups. In addition, Sal B markedly attenuated intermittent high glucose-induced oxidative stress as manifested by notably decreased levels of intracellular reactive oxygen species and malondialdehyde (MDA). Taken together, these results indicate that Sal B is able to suppress intermittent high glucose-induced INS-1 cell apoptosis, which might be ascribed to regulation of Bcl-2 family protein expression and preservation of mitochondrial membrane potential. Copyright © 2017. Published by Elsevier B.V.

  16. S1PR2 antagonist protects endothelial cells against high glucose-induced mitochondrial apoptosis through the Akt/GSK-3β signaling pathway.

    PubMed

    Liu, Hengdao; Peng, Hui; Chen, Shuhua; Liu, Yanwei; Xiang, Hong; Chen, Ruifang; Chen, Wei; Zhao, Shaoli; Chen, Pan; Lu, Hongwei

    2017-08-26

    Vascular complications are the main cause of morbidity and mortality associated with type 2 diabetes mellitus. An early hallmark of the onset of vascular complications is endothelial dysfunction and apoptosis. We aimed to explore the role of sphingosine-1-phosphatereceptor 2 (S1PR2) in high glucose-induced endothelial cells apoptosis and to elaborate the underlying mechanism. Human umbilical vein endothelial cells (HUVECs) were cultured in a high glucose with or without S1PR2 antagonist. The apoptosis of the cells was measured by flow cytometry and mitochondrial membrane permeability was detected by the fluorescent probe JC-1. The expression of the related protein was determined by western blot. Cell apoptosis and the loss of mitochondrial membrane permeability were induced under high glucose conditions in HUVECs. The expression of mitochondrial apoptosis related protein bax increased and bcl-2 decreased in high glucose-induced HUVECs. The level of cytochrome c released into the cytoplasm increased when cells were exposed to high glucose. In addition, the expression of p-AKT and p-GSK3β was reduced when HUVECs were treated with high glucose. However, these effects were reversed in HUVECs when cells treated with S1PR2 antagonist. In conclusion, S1PR2 antagonist protects endothelial cells against high glucose-induced mitochondrial apoptosis through the Akt/GSK-3β signaling pathway. Copyright © 2017 Elsevier Inc. All rights reserved.

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

    PubMed

    Yang, Xiuqin; Wang, Yangang; Gao, Guanqi

    2016-01-01

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

  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. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

  19. Emodin ameliorates high glucose induced-podocyte epithelial-mesenchymal transition in-vitro and in-vivo.

    PubMed

    Chen, Tingfang; Zheng, Li Yang; Xiao, Wenzhen; Gui, Dingkun; Wang, Xiaoxia; Wang, Niansong

    2015-01-01

    Epithelial-to-mesenchymal transition (EMT) is a potential pathway leading to podocyte depletion and proteinuria in diabetic kidney disease (DKD). Here, we investigated the protective effects of Emodin (EMO) on high glucose (HG) induced-podocyte EMT in-vitro and in-vivo. Conditionally immortalized mouse podocytes were exposed to HG with 30 μg /ml of EMO and 1 μmol/ml of integrin-linked kinase (ILK) inhibitor QLT0267 for 24 h. Streptozotocin (STZ)-induced diabetic rats were treated with EMO at 20 mg· kg(-1)· d(-1) and QLT0267 at 10 mg· kg(-1)· w(-1) p.o., for 12 weeks. Albuminuria and blood glucose level were measured. Immunohistochemistry, immunofluorescence, western blotting and real-time PCR were used to detect expression of ILK, the epithelial marker of nephrin and the mesenchymal marker of desmin in-vitro and in-vivo. HG increased podocyte ILK and desmin expression while decreased nephrin expression. However, EMO significantly inhibited ILK and desmin expression and partially restored nephrin expression in HG-stimulated podocytes. These in-vitro observations were further confirmed in-vivo. Treatment with EMO for 12 weeks attenuated albuminuria, renal histopathology and podocyte foot process effacement in diabetic rats. EMO also repressed renal ILK and desmin expression, preserved nephrin expression, as well as ameliorated albuminuria in STZ-induced diabetic rats. EMO ameliorated glucose-induced EMT and subsequent podocyte dysfunction partly through ILK and desmin inhibition as well as nephrin upregulatiotion, which might provide a potential novel therapeutic option for DKD. © 2015 S. Karger AG, Basel.

  20. 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

  1. Dynamin-related protein inhibitor downregulates reactive oxygen species levels to indirectly suppress high glucose-induced hyperproliferation of vascular smooth muscle cells

    SciTech Connect

    Maimaitijiang, Alimujiang; Zhuang, Xinyu; Jiang, Xiaofei; Li, Yong

    2016-03-18

    Hyperproliferation of vascular smooth muscle cells is a pathogenic mechanism common in diabetic vascular complications and is a putatively important therapeutic target. This study investigated multiple levels of biology, including cellular and organellar changes, as well as perturbations in protein synthesis and morphology. Quantitative and qualitative analysis was utilized to assess the effect of mitochondrial dynamic changes and reactive oxygen species(ROS) levels on high-glucose-induced hyperproliferation of vascular smooth muscle cells. The data demonstrated that the mitochondrial fission inhibitor Mdivi-1 and downregulation of ROS levels both effectively inhibited the high-glucose-induced hyperproliferation of vascular smooth muscle cells. Downregulation of ROS levels played a more direct role and ROS levels were also regulated by mitochondrial dynamics. Increased ROS levels induced excessive mitochondrial fission through dynamin-related protein (Drp 1), while Mdivi-1 suppressed the sensitivity of Drp1 to ROS levels, thus inhibiting excessive mitochondrial fission under high-glucose conditions. This study is the first to propose that mitochondrial dynamic changes and ROS levels interact with each other and regulate high-glucose-induced hyperproliferation of vascular smooth muscle cells. This finding provides novel ideas in understanding the pathogenesis of diabetic vascular remodeling and intervention. - Highlights: • Mdivi-1 inhibits VSMC proliferation by lowering ROS level in high-glucose condition. • ROS may be able to induce mitochondrial fission through Drp1 regulation. • Mdivi-1 can suppress the sensitivity of Drp1 to ROS.

  2. Dynamin-related protein inhibitor downregulates reactive oxygen species levels to indirectly suppress high glucose-induced hyperproliferation of vascular smooth muscle cells.

    PubMed

    Maimaitijiang, Alimujiang; Zhuang, Xinyu; Jiang, Xiaofei; Li, Yong

    2016-03-18

    Hyperproliferation of vascular smooth muscle cells is a pathogenic mechanism common in diabetic vascular complications and is a putatively important therapeutic target. This study investigated multiple levels of biology, including cellular and organellar changes, as well as perturbations in protein synthesis and morphology. Quantitative and qualitative analysis was utilized to assess the effect of mitochondrial dynamic changes and reactive oxygen species(ROS) levels on high-glucose-induced hyperproliferation of vascular smooth muscle cells. The data demonstrated that the mitochondrial fission inhibitor Mdivi-1 and downregulation of ROS levels both effectively inhibited the high-glucose-induced hyperproliferation of vascular smooth muscle cells. Downregulation of ROS levels played a more direct role and ROS levels were also regulated by mitochondrial dynamics. Increased ROS levels induced excessive mitochondrial fission through dynamin-related protein (Drp 1), while Mdivi-1 suppressed the sensitivity of Drp1 to ROS levels, thus inhibiting excessive mitochondrial fission under high-glucose conditions. This study is the first to propose that mitochondrial dynamic changes and ROS levels interact with each other and regulate high-glucose-induced hyperproliferation of vascular smooth muscle cells. This finding provides novel ideas in understanding the pathogenesis of diabetic vascular remodeling and intervention. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. 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.

  4. Protective effects of marein on high glucose-induced glucose metabolic disorder in HepG2 cells.

    PubMed

    Jiang, Baoping; Le, Liang; Zhai, Wei; Wan, Wenting; Hu, Keping; Yong, Peng; He, Chunnian; Xu, Lijia; Xiao, Peigen

    2016-08-15

    Our previous study has shown that Coreopsis tinctoria increases insulin sensitivity and regulates hepatic metabolism in high-fat diet (HFD)-induced insulin resistance rats. However, it is unclear whether or not marein, a major compound of C. tinctoria, could improve insulin resistance. Here we investigate the effect and mechanism of action of marein on improving insulin resistance in HepG2 cells. We investigated the protective effects of marein in high glucose-induced human liver carcinoma cell HepG2. In kinase inhibitor studies, genistein, LY294002, STO-609 and compound C were added to HepG2 cells 1h before the addition of marein. Transfection with siRNA was used to knock down LKB1, and 2-(N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl) amino)-2-deoxyglucose (2-NBDG), an effective tracer, was used to detect glucose uptake. The results showed for the first time that marein significantly stimulates the phosphorylation of AMP-activated protein kinase (AMPK) and the Akt substrate of 160kDa (AS160) and enhanced the translocation of glucose transporter 1 (GLUT1) to the plasma membrane. Further study indicated that genistein (an insulin receptor tyrosine kinase inhibitor) altered the effect of marein on glucose uptake, and both LY294002 (a phosphatidylinositol 3-kinase inhibitor) and compound C (an AMP-activated protein kinase inhibitor) significantly decreased marein-stimulated 2-NBDG uptake. Additionally, marein-stimulated glucose uptake was blocked in the presence of STO-609, a CaMKK inhibitor; however, marein-stimulated AMPK phosphorylation was not blocked by LKB1 siRNA in HepG2 cells. Marein also inhibited the phosphorylation of insulin receptor substrate (IRS-1) at Ser 612, but inhibited GSK-3β phosphorylation and increased glycogen synthesis. Moreover, marein significantly decreased the expression levels of FoxO1, G6Pase and PEPCK. Consequently, marein improved insulin resistance induced by high glucose in HepG2 cells through CaMKK/AMPK/GLUT1 to promote glucose uptake

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

    PubMed Central

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

    2016-01-01

    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

  6. 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.

  7. Interferon regulatory factor-1 together with reactive oxygen species promotes the acceleration of cell cycle progression by up-regulating the cyclin E and CDK2 genes during high glucose-induced proliferation of vascular smooth muscle cells.

    PubMed

    Zhang, Xi; Liu, Long; Chen, Chao; Chi, Ya-Li; Yang, Xiang-Qun; Xu, Yan; Li, Xiao-Tong; Guo, Shi-Lei; Xiong, Shao-Hu; Shen, Man-Ru; Sun, Yu; Zhang, Chuan-Sen; Hu, Kai-Meng

    2013-10-14

    The high glucose-induced proliferation of vascular smooth muscle cells (VSMCs) plays an important role in the development of diabetic vascular diseases. In a previous study, we confirmed that Interferon regulatory factor-1 (Irf-1) is a positive regulator of the high glucose-induced proliferation of VSMCs. However, the mechanisms remain to be determined. The levels of cyclin/CDK expression in two cell models involving Irf-1 knockdown and overexpression were quantified to explore the relationship between Irf-1 and its downstream effectors under normal or high glucose conditions. Subsequently, cells were treated with high glucose/NAC, normal glucose/H₂O₂, high glucose/U0126 or normal glucose/H₂O₂/U0126 during an incubation period. Then proliferation, cyclin/CDK expression and cell cycle distribution assays were performed to determine whether ROS/Erk1/2 signaling pathway was involved in the Irf-1-induced regulation of VSMC growth under high glucose conditions. We found that Irf-1 overexpression led to down-regulation of cyclin D1/CDK4 and inhibited cell cycle progression in VSMCs under normal glucose conditions. In high glucose conditions, Irf-1 overexpression led to an up-regulation of cyclin E/CDK2 and an acceleration of cell cycle progression, whereas silencing of Irf-1 suppressed the expression of both proteins and inhibited the cell cycle during the high glucose-induced proliferation of VSMCs. Treatment of VSMCs with antioxidants prevented the Irf-1 overexpression-induced proliferation of VSMCs, the up-regulation of cyclin E/CDK2 and the acceleration of cell cycle progression in high glucose conditions. In contrast, under normal glucose conditions, H₂O₂ stimulation and Irf-1 overexpression induced cell proliferation, up-regulated cyclin E/CDK2 expression and promoted cell cycle acceleration. In addition, overexpression of Irf-1 promoted the activation of Erk1/2 and when VSMCs overexpressing Irf-1 were treated with U0126, the specific Erk1/2 inhibitor

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

    PubMed

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

    2015-01-01

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

  9. 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

  10. Grape seed procyanidin B2 protects podocytes from high glucose-induced mitochondrial dysfunction and apoptosis via the AMPK-SIRT1-PGC-1α axis in vitro.

    PubMed

    Cai, Xiaxia; Bao, Lei; Ren, Jinwei; Li, Yong; Zhang, Zhaofeng

    2016-02-01

    Grape seed procyanidin B2 (GSPB2) was reported to have protective effects on diabetic nephropathy (DN) as a strong antioxidant. Our previous studies demonstrated that GSPB2 was effective in ameliorating podocyte injury in rats with DN. However, little is known about the benefits of GSPB2 in protecting against podocyte apoptosis and its molecular mechanisms in vitro. In the present study, we investigated whether GSPB2 could protect podocytes from high glucose-induced apoptosis and explored the possible mechanism. Cell viability and apoptosis were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry, respectively. The intracellular reactive oxygen species (ROS) level was measured using a dichlorofluorescein diacetate (DCFH-DA) fluorescent probe. Real-time reverse transcription-PCR was used to determine the gene expression of nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (TFAM), and quantitative real-time PCR was used to detect mitochondrial DNA (mtDNA) copy number. Western blots were carried out for the related protein expression in podocytes. Our results showed that GSPB2 significantly inhibited high glucose-induced podocyte apoptosis and increased the expression of nephrin and podocalyxin. GSPB2 treatment also suppressed intracellular ROS production and oxidative stress. The mRNA expressions of NRF-1, TFAM and mtDNA copy number were markedly increased, and mitochondrial swelling was effectively reduced in podocytes cultured under high glucose after GSPB2 treatment. The AMPK-SIRT1-PGC-1α axis was also activated by GSPB2 intervention. In conclusion, GSPB2 protected podocytes from high glucose-induced mitochondrial dysfunction and apoptosis via the AMPK-SIRT1-PGC-1α axis in vitro, suggesting a potential role of GSPB2 in the treatment of DN.

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

    PubMed

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

    2017-02-01

    Asiaticoside (AC) has been known to have anti-oxidative activity, however, the effect of AC on the progression of high glucose-induced hearing loss has not been studied. This study aims to analyze the effect of AC on cochlear hair cells under the treatment of high glucose in vitro and the hearing function in vivo. The results of MTT showed that high glucose decreased the activity of HEI-OC1 cells, but AC increased the activity of HEI-OC1 cells compared with high glucose group. The results of flow cytometry showed that AC decreased the degree of apoptosis induced by high levels of glucose. The results of DCFH-DA staining showed that AC inhibited the ROS production induced by high glucose levels. The results of JC-1 staining showed that AC inhibited the mitochondrial depolarization induced by high glucose levels. Furthermore, AC decreased the threshold, and protected inner and outer hair cells from damage in rats with hearing loss induced by diabetes mellitus. Moreover, AC decreased the activity of MDA, but, increased the activity of SOD, CAT and GSH-Px in vivo. AC also decreased the expression of AGEs, RAGE and NF-κB p65. Collectively, these results suggest that AC protects cochlear hair cells from high glucose-induced injury by increasing anti-oxidative activity and suppressing the AGEs/RAGE/NF-κB pathway. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

    Zhang, Yu; Yang, Jian-Hong

    2013-11-01

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

  14. 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

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  17. The Role of the p38 MAPK Signaling Pathway in High Glucose-Induced Epithelial-Mesenchymal Transition of Cultured Human Renal Tubular Epithelial Cells

    PubMed Central

    Lv, Zhi-Mei; Wang, Qun; Wan, Qiang; Lin, Jian-Gong; Hu, Meng-Si; Liu, You-Xia; Wang, Rong

    2011-01-01

    Background Epithelial-mesenchymal transition of tubular epithelial cells, which is characterized by a loss of epithelial cell characteristics and a gain of ECM-producing myofibroblast characteristics, is an essential mechanism that is involved in tubulointerstitial fibrosis, an important component of the renal injury that is associated with diabetic nephropathy. Under diabetic conditions, p38 MAPK activation has been reported in glomeruli and mesangial cells; however, studies on p38 MAPK in TECs are lacking. In this study, the role of p38 MAPK in AP-1 activation and in the EMT in the human proximal tubular epithelial cell line (HK-2) under high glucose concentration conditions is investigated. Methodology/Principal Findings A vector for small interfering RNA that targets p38 MAPK was constructed; the cells were then either transfected with p38 siRNA or pretreated with a chemical inhibitor of AP-1 and incubated with low glucose plus TGF-β1 or high glucose for 48 h. Cells that were not transfected or pretreated and were exposed to low glucose with or without TGF-β1 or high glucose for 48 h were considered to be the controls. We found that high glucose induced an increase in TGF-β1. And high glucose-induced p38 MAPK activation was inhibited by p38 siRNA (P<0.05). A significant decline in E-cadherin and CK expression and a notable increase in vimentin and α-SMA were detected when exposed to low glucose with TGF-β1 or high glucose, and a significant raise of secreted fibronectin were detected when exposed to high glucose; whereas these changes were reversed when the cells were treated with p38 siRNA or AP-1 inhibitor (P<0.05). AP-1 activity levels and Snail expression were up-regulated under high glucose conditions but were markedly down-regulated through knockdown of p38 MAPK with p38 siRNA or pretreatment with AP-1 inhibitor (P<0.05). Conclusion This study suggests that p38 MAPK may play an important role in the high glucose-induced EMT by activating AP-1 in

  18. [Salidroside attenuates high glucose-induced apoptosis in human umbilical vein endothelial cells via activating the Ca(2)+/CaM/CAMKIIδ/eNOS pathway].

    PubMed

    Chen, Ziwei; Wu, Xiang

    2014-04-01

    Endothelial oxidative stress plays an important role in the pathogenesis of cardiovascular disease. Salidroside, a phenylpropanoid glycoside isolated from Rhodiola rosea L, could exert potent antioxidant properties. In this study, we investigated the protective effects, and related mechanism of salidroside against high glucose (33 mmol/L)-induced cell damage in human umbilical vein endothelial cells (HUVECs). HUVECs were cultured in normal glucose (5.5 mmol/L), high glucose (33 mmol/L), high salidroside (10 µg/ml+33 mmol/L glucose), moderate salidroside (4 µg/ml+33 mmol/L glucose), low salidroside (1 µg/ml+33 mmol/L glucose) and very low salidroside (0.1 µg/ml+33 mmol/L glucose) for 48 h. Cell viability, the level of malondialdehyde (MDA) , reactive oxygen species (ROS) , nitric oxide (NO) , [Ca(2)+]i, calmodulin (CaM) , calmodulin-dependent kinase (CaMK) IIδ, endothelial nitric oxide synthase (eNOS) , active caspase-3 protein expression and eNOS ser 1177 phosphorylation of HUVECs post various treatments were measured. The cell viability was assessed with MTT assay, and the level of ROS, and [Ca(2)+]i was analyzed using flow cytometry. Nitric oxide and MDA was detected by Nitric Oxide Assay Kit and MDA Assay Kit. Western blot was performed to detect the protein expressions of eNOS, active caspase-3 and eNOS ser 1177 phosphorylation. Comparing to the normal glucose group, high glucose treatment increased the cell damage, the level of NO and [Ca(2)+]i (P < 0.05) , downregulated CAMKIIδ, eNOS expression and eNOS ser 1177 phosphorylation (P < 0.05), elevated the concentration of MDA and ROS (P < 0.05) in HUVECs. Salidroside treatment significantly attenuated high glucose-induce cell damage on cultured HUVECs in a dose-dependent manner. Comparing to the high glucose group, 10 µg/ml Salidroside significantly increased cell viability (P < 0.05) , inhibited high glucose-induced release of MDA , generation of ROS, active caspase 3 protein expression (P < 0

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

    PubMed

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

    2016-11-01

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

  20. Autophagy Inhibition Contributes to ROS-Producing NLRP3-Dependent Inflammasome Activation and Cytokine Secretion in High Glucose-Induced Macrophages.

    PubMed

    Dai, Jiezhi; Zhang, Xiaotian; Li, Li; Chen, Hua; Chai, Yimin

    2017-08-30

    Type 2 diabetes is a persistent inflammatory response that impairs the healing process. We hypothesized that stimulation with high glucose following a pro-inflammatory signal would lead to autophagy inhibition, reactive oxygen species (ROS) production and eventually to the activation of the Nod-like receptor protein (NLRP) -3. Macrophages were isolated from human diabetic wound. We measured the expression of NLRP3, caspase1 and interleukin-1 beta (IL-1β) by western blot and real-time PCR, and the surface markers on cells by flow cytometry. THP-1-derived macrophages exposed to high glucose were applied to study the link between autophagy, ROS and NLRP3 activation. LC3-II, P62, NLRP3 inflammation and IL-1β expression were measured by western blot and real-time PCR. ROS production was measured with a Cellular Reactive Oxygen Species Detection Assay Kit. Macrophages isolated from diabetic wounds exhibited a pro-inflammatory phenotype, including sustained NLRP3 inflammasome activity associated with IL-1β secretion. Our data showed that high glucose inhibited autophagy, induced ROS production, and activated NLRP3 inflammasome and cytokine secretion in THP-1-derived macrophages. To study high glucose-induced NLRP3 inflammasome signalling, we performed studies using an autophagy inducer, a ROS inhibitor and a NLRP3 inhibitor and found that all reduced the NLRP3 inflammasome activation and cytokine secretion. Sustained NLRP3 inflammasome activity in wound-derived macrophages contributes to the hyper-inflammation in human diabetic wounds. Autophagy inhibition and ROS generation play an essential role in high glucose-induced NLRP3 inflammasome activation and cytokine secretion in macrophages. © 2017 The Author(s). Published by S. Karger AG, Basel.

  1. 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

  2. Sanguis draconis, a dragon's blood resin, attenuates high glucose-induced oxidative stress and endothelial dysfunction in human umbilical vein endothelial cells.

    PubMed

    Chang, Yi; Chang, Ting-Chen; Lee, Jie-Jen; Chang, Nen-Chung; Huang, Yung-Kai; Choy, Cheuk-Sing; Jayakumar, Thanasekaran

    2014-01-01

    Hyperglycaemia, a characteristic feature of diabetes mellitus, induces endothelial dysfunction and vascular complications by limiting the proliferative potential of these cells. Here we aimed to investigate the effect of an ethanolic extract of Sanguis draconis (SD), a kind of dragon's blood resin that is obtained from Daemonorops draco (Palmae), on human umbilical vein endothelial cells (HUVEC) under high-glucose (HG) stimulation and its underlying mechanism. Concentration-dependent (0-50 μg/mL) assessment of cell viability showed that SD does not affect cell viability with a similar trend up to 48 h. Remarkably, SD (10-50 μg/mL) significantly attenuated the high-glucose (25 and 50 mM) induced cell toxicity in a concentration-dependent manner. SD inhibited high glucose-induced nitrite (NO) and lipid peroxidation (MDA) production and reactive oxygen species (ROS) formation in HUVEC. Western blot analysis revealed that SD treatments abolished HG-induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK 1/2), nuclear transcription factor, κB (NF-κB), VCAM-1, and E-selectin, and it also blocked the breakdown of PARP-116 kDa protein in a dose-dependent manner. Furthermore, we found that SD increased the expression of Bcl-2 and decreased Bax protein expression in HG-stimulated HUVEC. Thus, these results of this study demonstrate for the first time that SD inhibits glucose induced oxidative stress and vascular inflammation in HUVEC by inhibiting the ERK/NF-κB/PARP-1/Bax signaling cascade followed by suppressing the activation of VCAM-1 and E-selectin. These data suggest that SD may have a therapeutic potential in vascular inflammation due to the decreased levels of oxidative stress, apoptosis, and PARP-1 activation.

  3. Sanguis draconis, a Dragon's Blood Resin, Attenuates High Glucose-Induced Oxidative Stress and Endothelial Dysfunction in Human Umbilical Vein Endothelial Cells

    PubMed Central

    Chang, Yi; Chang, Ting-Chen; Lee, Jie-Jen; Chang, Nen-Chung; Choy, Cheuk-Sing; Jayakumar, Thanasekaran

    2014-01-01

    Hyperglycaemia, a characteristic feature of diabetes mellitus, induces endothelial dysfunction and vascular complications by limiting the proliferative potential of these cells. Here we aimed to investigate the effect of an ethanolic extract of Sanguis draconis (SD), a kind of dragon's blood resin that is obtained from Daemonorops draco (Palmae), on human umbilical vein endothelial cells (HUVEC) under high-glucose (HG) stimulation and its underlying mechanism. Concentration-dependent (0–50 μg/mL) assessment of cell viability showed that SD does not affect cell viability with a similar trend up to 48 h. Remarkably, SD (10–50 μg/mL) significantly attenuated the high-glucose (25 and 50 mM) induced cell toxicity in a concentration-dependent manner. SD inhibited high glucose-induced nitrite (NO) and lipid peroxidation (MDA) production and reactive oxygen species (ROS) formation in HUVEC. Western blot analysis revealed that SD treatments abolished HG-induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK 1/2), nuclear transcription factor, κB (NF-κB), VCAM-1, and E-selectin, and it also blocked the breakdown of PARP-116 kDa protein in a dose-dependent manner. Furthermore, we found that SD increased the expression of Bcl-2 and decreased Bax protein expression in HG-stimulated HUVEC. Thus, these results of this study demonstrate for the first time that SD inhibits glucose induced oxidative stress and vascular inflammation in HUVEC by inhibiting the ERK/NF-κB/PARP-1/Bax signaling cascade followed by suppressing the activation of VCAM-1 and E-selectin. These data suggest that SD may have a therapeutic potential in vascular inflammation due to the decreased levels of oxidative stress, apoptosis, and PARP-1 activation. PMID:24987732

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

    PubMed

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

    2016-03-01

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

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

    PubMed

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

    2015-02-05

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

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

    PubMed

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

    2016-11-01

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

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

    PubMed

    Yu, Jingwen; Wu, Yanqing; Yang, Peixin

    2016-05-01

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

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

    PubMed

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

    2012-06-01

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

  9. Essential role of TGF-beta signaling in glucose-induced cell hypertrophy.

    PubMed

    Wu, Liyu; Derynck, Rik

    2009-07-01

    In multicellular organisms, cell size is tightly controlled by nutrients and growth factors. Increasing ambient glucose induces enhanced protein synthesis and cell size. Continued exposure of cells to high glucose in vivo, as apparent under pathological conditions, results in cell hypertrophy and tissue damage. We demonstrate that activation of TGF-beta signaling has a central role in glucose-induced cell hypertrophy in fibroblasts and epithelial cells. Blocking the kinase activity of the TbetaRI receptor or loss of its expression prevented the effects of high glucose on protein synthesis and cell size. Exposure of cells to high glucose induced a rapid increase in cell surface levels of the TbetaRI and TbetaRII receptors and a rapid activation of TGF-beta ligand by matrix metalloproteinases, including MMP-2 and MMP-9. The consequent autocrine TGF-beta signaling in response to glucose led to Akt-TOR pathway activation. Accordingly, preventing MMP-2/MMP-9 or TGF-beta-induced TOR activation inhibited high glucose-induced cell hypertrophy.

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

    PubMed

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

    2014-03-25

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

  11. Tyrosines-740/751 of PDGFRβ contribute to the activation of Akt/Hif1α/TGFβ nexus to drive high glucose-induced glomerular mesangial cell hypertrophy.

    PubMed

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

    2017-09-23

    Glomerular mesangial cell hypertrophy contributes to the complications of diabetic nephropathy. The mechanism by which high glucose induces mesangial cell hypertrophy is poorly understood. Here we explored the role of the platelet-derived growth factor receptor-β (PDGFRβ) tyrosine kinase in driving the high glucose-induced mesangial cell hypertrophy. We show that high glucose stimulates the association of the PDGFRβ with PI 3 kinase leading to tyrosine phosphorylation of the latter. High glucose-induced Akt kinase activation was also dependent upon PDGFRβ and its tyrosine phosphorylation at 740/751 residues. Inhibition of PDGFRβ activity, its downregulation and expression of its phospho-deficient (Y740/751F) mutant inhibited mesangial cell hypertrophy by high glucose. Interestingly, expression of constitutively active Akt reversed this inhibition, indicating a role of Akt kinase downstream of PDGFRβ phosphorylation in this process. The transcription factor Hif1α is a target of Akt kinase. siRNAs against Hif1α inhibited the high glucose-induced mesangial cell hypertrophy. In contrast, increased expression of Hif1α induced hypertrophy similar to high glucose. We found that inhibition of PDGFRβ and expression of PDGFRβ Y740/751F mutant significantly inhibited the high glucose-induced expression of Hif1α. Importantly, expression of Hif1α countered the inhibition of mesangial cell hypertrophy induced by siPDGFRβ or PDGFRβ Y740/751F mutant. Finally, we show that high glucose-stimulated PDGFRβ tyrosine phosphorylation at 740/751 residues and the tyrosine kinase activity of the receptor regulate the transforming growth factor-β (TGFβ) expression by Hif1α. Thus we define the cell surface PDGFRβ as a major link between high glucose and its effectors Hif1α and TGFβ for induction of diabetic mesangial cell hypertrophy. Copyright © 2017. Published by Elsevier Inc.

  12. Neuro-protective effects of cerium and yttrium oxide nanoparticles on high glucose-induced oxidative stress and apoptosis in undifferentiated PC12 cells.

    PubMed

    Ghaznavi, Habib; Najafi, Rezvan; Mehrzadi, Saeed; Hosseini, Asieh; Tekyemaroof, Neda; Shakeri-Zadeh, Ali; Rezayat, Mehdi; Sharifi, Ali M

    2015-07-01

    Oxidative stress has been recognized as the major factor for the development of diabetes and its complications. Cerium oxide and Yttrium oxide nanoparticles are known as free radicals scavengers. The aim of this study was to investigate the protective effect of CeO2 and Y2O3 on oxidative stress induced by high glucose in undifferentiated rat pheochromocytoma (PC12) cells. In this study, undifferentiated PC12 cells were exposed to high glucose (25 mg/ml, 24 hours) and the protective effects of CeO2 and Y2O3 nanoparticles were evaluated. The viability of undifferentiated PC12 cells was determined by MTT assay. The levels of reactive oxygen species (ROS) were measured using 2,7-dichlorodihydrofluorescein diacetate (DCF). The expression levels of pro-apoptotic Bax, anti-apoptotic Bcl-2 and caspase3 proteins were also detected by western blotting. Total antioxidant power (TAP), total thiol molecules (TTM) and lipid peroxidation (LPO) were also evaluated. CeO2 and Y2O3 increased survival of undifferentiated PC12 cells exposed to high glucose-induced oxidative stress. CeO2 and Y2O3 pre-treatment decreased ROS production, LPO, Bax and caspase-3 proteins expression. Both nanoparticles have also increased the TTM and Bcl-2 protein expression. These findings suggest that CeO2 and Y2O3 protect the undifferentiated PC12 cells against the oxidative stress and apoptosis induced by high glucose.

  13. Reactive oxygen species and nuclear factor-kappa B pathway mediate high glucose-induced Pax-2 gene expression in mouse embryonic mesenchymal epithelial cells and kidney explants.

    PubMed

    Chen, Y-W; Liu, F; Tran, S; Zhu, Y; Hébert, M-J; Ingelfinger, J R; Zhang, S-L

    2006-11-01

    Diabetic mellitus confers a major risk of congenital malformations, and is associated with diabetic embryopathy, affecting multiple organs including the kidney. The DNA paired box-2 (Pax-2) gene is essential in nephrogenesis. We investigated whether high glucose alters Pax-2 gene expression and aimed to delineate its underlying mechanism(s) of action using both in vitro (mouse embryonic mesenchymal epithelial cells (MK4) and ex vivo (kidney explant from Hoxb7-green florescent protein (GFP) mice) approaches. Pax-2 gene expression was determined by reverse transcriptase-polymerase chain reaction, Western blotting, and immunofluorescent staining. A fusion gene containing the full-length 5'-flanking region of the human Pax-2 promoter linked to a luciferase reporter gene, pGL-2/hPax-2, was transfected into MK4 cells with or without dominant negative IkappaBalpha (DN IkappaBalpha) cotransfection. Fusion gene expression level was quantified by cellular luciferase activity. Reactive oxygen species (ROS) generation was measured by lucigenin assay. Embryonic kidneys from Hoxb7-GFP mice were cultured ex vivo. High D(+) glucose (25 mM), compared to normal glucose (5 mM), specifically induced Pax-2 gene expression in MK4 cells and kidney explants. High glucose-induced Pax-2 gene expression is mediated, at least in part, via ROS generation and activation of the nuclear factor kappa B signaling pathway, but not via protein kinase C, p38 mitogen-activated protein kinase (MAPK), and p44/42 MAPK signaling.

  14. Hydrogen Sulfide Inhibits High Glucose-Induced sFlt-1 Production via Decreasing ADAM17 Expression in 3T3-L1 Adipocytes

    PubMed Central

    Wang, Gang; Wu, Wei; Gao, Lu; Tan, Qing-ying

    2017-01-01

    Hydrogen sulfide (H2S) has recently been identified as an endogenous gaseous signaling molecule. The aim of the present study was to investigate the effect of H2S on high glucose- (HG-) induced ADAM17 expression and sFlt-1 production in 3T3-L1 adipocytes. Firstly, we found that HG DMEM upregulated the expression of ADAM17 and production of sFlt-1 in 3T3-L1 adipocytes. Knocking down ADAM17 attenuated the effect of high glucose on sFlt-1 production in adipocytes. HG decreased the expression of CSE and 3-MST, as well as the endogenous H2S production. Furthermore, knocking down CSE and 3-MST significantly increased ADAM17 expression and sFlt-1 production. The addition of exogenous H2S through the administration of sodium hydrosulfide (NaHS) inhibited HG-induced upregulation of ADAM17 expression and sFlt-1 production. In conclusion, decreased expression of CSE and 3-MST and the subsequent decrease in H2S production contribute to high glucose-induced sFlt-1 production via activating ADAM17 in adipocytes. Exogenous H2S donor NaHS has a potential therapeutic value for diabetic vascular complications. PMID:28740508

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

    PubMed Central

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

    2001-01-01

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

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

    PubMed

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

    2016-11-11

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

  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. T-type Ca2+ channels are involved in high glucose-induced rat neonatal cardiomyocyte proliferation.

    PubMed

    Li, Ming; Zhang, Min; Huang, Luping; Zhou, Jianxin; Zhuang, Hean; Taylor, James T; Keyser, Brian M; Whitehurst, Richard M

    2005-04-01

    Infants develop hypertrophic cardiomyopathy in approximately 30% of diabetic pregnancies. We have characterized the effects of glucose on voltage-gated T-type Ca2+ channels and intracellular free calcium concentration, [Ca2+]i in neonatal rat cardiomyocytes. We found that T-type Ca2+ channel current density increased significantly in primary culture neonatal cardiac myocytes that were treated with 25 mM glucose for 48 h when compared with those that were treated with 5 mM glucose. High-glucose treatment also caused a higher Ca2+ influx elicited by 50 mM KCl in the myocytes. KCl-induced Ca2+ influx was attenuated when nickel was present. Real-time PCR studies demonstrated that mRNA levels of both alpha1G (Ca(v)3.1) and alpha1H (Ca(v)3.2) T-type Ca2+ channels were elevated after high-glucose treatment. High-glucose also significantly increased ventricular cell proliferation as well as the proportion of cells in the S-phase of the cell cycle; both effects were reversed by nickel or mibefradil. These results indicate that high glucose causes a rise in [Ca2+]i in neonatal cardiac myocytes by a mechanism that is associated with the regulation of the T-type Ca2+ channel activity.

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

    PubMed

    Lin, Chih-Li; Lin, Jen-Kun

    2008-08-01

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

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

    PubMed

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

    2014-03-01

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

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

    PubMed Central

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

    2017-01-01

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

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

    PubMed

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

    2017-03-01

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

  3. Purinergic regulation of high-glucose-induced caspase-1 activation in the rat retinal Müller cell line rMC-1

    PubMed Central

    Trueblood, Katherine E.; Mohr, Susanne

    2011-01-01

    Chronic activation of proinflammatory caspase-1 in the retinas of diabetic animals and patients in vivo and retinal Müller cells in vitro is well documented. In this study we characterized how elevated glucose and extracellular purines contribute to the activation of caspase-1 in a cultured rat Müller cell (rMC-1) model. The ability of high glucose (25 mM, 24 h) to activate caspase-1 was attenuated by either apyrase, which metabolizes extracellular ATP to AMP, or adenosine deaminase (ADA), which metabolizes extracellular adenosine to inosine. This suggested that autocrine stimulation of ATP-sensing P2 receptors and adenosine-sensing P1 receptors may in part mediate the response to high glucose. Exogenous ATP, 5′-N-ethylcarboxamido-adenosine (NECA), a nonselective P1 receptor agonist, or forskolin (FSK) increased caspase-1 activity in rMC-1 cells cultured in control glucose (5 mM) medium. Accumulation of active caspase-1 was also increased by dipyridamole, which suppresses adenosine reuptake. High-glucose stimulation of caspase-1 was attenuated by suramin, a nonselective P2 antagonist, or A2 adenosine receptor antagonists, but not by antagonism of P2X7 ATP-gated ion channel receptors. Although high glucose increased P2X7 mRNA, neither P2X7 protein nor function was detected in rMC-1 cells. The increased caspase-1 activity stimulated by high glucose, FSK, NECA, or ATP was correlated with increased gene expression of caspase-1 and thioredoxin-interacting-protein (TXNIP). These findings support a novel role for autocrine P1 and P2 purinergic receptors coupled to cAMP signaling cascades and transcriptional induction of caspase-1 in mediating the high-glucose-induced activation of caspase-1 and secretion of IL-1β in a cell culture model of nonhematopoietic retinal Müller cells. PMID:21832250

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

    PubMed

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

    1998-05-01

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

  5. 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.

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

    PubMed

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

    2015-02-01

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

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

    PubMed Central

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

    2016-01-01

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

  8. 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

  9. Salidroside Reduces High-Glucose-Induced Podocyte Apoptosis and Oxidative Stress via Upregulating Heme Oxygenase-1 (HO-1) Expression.

    PubMed

    Lu, Hua; Li, Ying; Zhang, Tao; Liu, Maodong; Chi, Yanqing; Liu, Shuxia; Shi, Yonghong

    2017-08-23

    BACKGROUND Hyperglycemia is one of the most dangerous factors causing diabetic nephropathy. Salidroside is considered to have the effects of reducing oxidative stress damage and improving cell viability. This study was performed to investigate whether and how salidroside reduces high-glucose (HG)-induced apoptosis in mouse podocytes. MATERIAL AND METHODS We examined whether salidroside could decrease HG-induced podocyte oxidative stress and podocyte apoptosis in vitro. The potential signaling pathways were also investigated. Podocytes (immortalized mouse epithelial cells) were treated with normal glucose (5.5 mM) as control or HG (30 mM), and then exposed to salidroside treatment. RESULTS HG enhanced the generation of intracellular reactive oxygen species (ROS) and apoptosis in podocytes. Salidroside reduced HG-induced apoptosis-related consequences via promoting HO-1 expression. Salidroside increased the expression level of phosphorylated Akt (p-Akt) and phosphorylated ILK (p-ILK), p-JNK, and p-ERK and localization of Nrf-2. JNK inhibitor and ILK inhibitor decreased HO-1 expression to different degrees. Moreover, specific siRNAs of ILK, Nrf-2, and HO-1, and inhibitors of HO-1 and ILK significantly increased ROS generation and Caspase9/3 expression in the presence of salidroside and HG. CONCLUSIONS The results suggest that salidroside reduces HG-induced ROS generation and apoptosis and improves podocytes viability by upregulating HO-1 expression. ILK/Akt, JNK, ERK1/2, p38 MAPK, and Nrf-2 are involved in salidroside-decreased podocyte apoptosis in HG condition.

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

    PubMed

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

    2015-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

  13. Resveratrol protects vascular smooth muscle cells against high glucose-induced oxidative stress and cell proliferation in vitro

    PubMed Central

    Guo, Rong; Li, Weiming; Liu, Baoxin; Li, Shuang; Zhang, Buchun; Xu, Yawei

    2014-01-01

    Background Resveratrol exhibits beneficial effects against numerous degenerative diseases at different stages of pathogenesis. This study investigated potential mechanisms and resveratrol effects on high glucose (HG)-induced oxidative stress (30 mM d-glucose, 30 min) and cell proliferation (30 mM d-glucose, 24 h) in vascular smooth muscle cells (VSMCs). Material/Methods Intracellular reactive oxygen species (ROS) generation was detected by 2′,7′-dichlorofluorescein diacetate (DCFH-DA). Total antioxidant capacity (TAC), malonyldialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) were measured to evaluate oxidative stress. VSMC proliferation was measured by CCK-8 assays and through propidium iodide-based cell cycle analysis. Expression of NAD(P)H oxidase, proliferation proteins, and cell signalling were assessed by immunoblot analysis. Results Co-treatment of primary cultures of VSMCs with 1–100 μM resveratrol decreased HG-induced ROS overproduction (P<0.05). Resveratrol also abolished HG-induced phosphorylation of oxidase subunit p47 phox and reduced HG-induced cyclin D1, cyclin E, and PCNA expression in a concentration-dependent manner. Furthermore, resveratrol (10 μM) attenuated HG-induced phosphorylation of Akt, p38 mitogen-activated protein kinase (MAPK), ERK 1/2, and JNK1/2 without affecting total levels. HG stimulation enhanced downstream IκB-α phosphorylation and NF-κB activity, and resveratrol repressed these effects. Conclusions Resveratrol inhibits HG-induced oxidative stress and VSMC proliferation by suppressing ROS generation, NADPH oxidase, Akt phosphorylation, p38 MAPK/JNK/ERK phosphorylation, and IκB-α and NF-κB activities. PMID:24971582

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

    PubMed

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

    2015-09-01

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

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

    PubMed Central

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

    2016-01-01

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

  16. The protective effects and genetic pathways of thorn grape seeds oil against high glucose-induced apoptosis in pancreatic β-cells.

    PubMed

    Lai, Xihu; Kang, Xincong; Zeng, Luman; Li, Jian; Yang, Yan; Liu, Dongbo

    2014-01-09

    Excessive apoptosis of β-cell is closely related to diabetes mellitus. Chronic exposure to high glucose causes β-cell dysfunction and apoptosis in diabetes. Thorn grape (Vitis davidii Foex.) has been used to treat diabetes in Traditional Chinese medicine for many years. In our previous research, thorn grape seeds oil (TGSO) showed promising anti-diabetic effects in animal models. However, it is unknown whether TGSO played an anti-apoptotic role in the anti-diabetic effects and the mechanism regarding signal transduction pathway is unclear either. The rattus pancreatic β-cell line RIN-m5F was treated with/without TGSO which was extracted by supercritical carbon dioxide (CO2) fluid extraction and analyzed by Gas Chromatography/Mass Spectrometry (GC/MS). Cell apoptosis was detected by fluorescence activated cell sorting (FACS), insulin secretion was assayed by Enzyme-Linked Immunosorbent Assay (ELISA), and the apoptosis-related genes expressions were evaluated by quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR). TGSO, containing 87.02% unsaturated fatty acids (UFAs), significantly reduced pancreatic β-cell apoptosis and protected the insulin secretion impaired by high glucose. The expressions of pro-apoptotic genes such as iNOS, Caspase-3, ATF-3, JNK, p38 and Fas were down-regulated while the anti-apoptotic genes Akt and Bcl-2/Bax were up-regulated. The results indicated that TGSO protected β-cells from high glucose-induced apoptosis and its protective activity may be linked to mitochondrial pathway, endoplasmic reticulum (ER) stress pathway and Fas signal pathway, which implied that TGSO might be an effective complementary or alternative medicine to reduce β-cell apoptosis and dysfunction.

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

    PubMed

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

    2016-04-01

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

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

    PubMed

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

    2017-03-01

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

  19. Inhibition of high glucose-induced VEGF release in retinal ganglion cells by RNA interference targeting G protein-coupled receptor 91.

    PubMed

    Hu, Jianyan; Wu, Qiang; Li, Tingting; Chen, Yongdong; Wang, Shuai

    2013-04-01

    from RGC-5 cells treated with high glucose (F = 57.43, P = 0.000) or succinate (F = 241.91, P = 0.000) was also downregulated when transduced with GPR91 shRNA. The siRNA-mediated knockdown of GPR91 was also found to inhibit the proliferation of RF/6A cells in high glucose-stimulated (t = 8.21, P = 0.001) or succinate-stimulated (t = 3.36, P = 0.028) conditioned media. However, the siRNA-mediated knockdown of GPR91 suppressed the migration of RF/6A cells incubated with moderate levels of glucose (t = 2.97, P = 0.018). The exposure of RGC-5 cells to high glucose activated ERK1/2 and JNK MAPK signaling blocking by GPR91 shRNA (P < 0.01). These results indicate that GPR91 modulates the high glucose-induced VEGF release of RGC-5 cells, possibly by inhibiting ERK1/2 and JNK MAPK signaling. Copyright © 2013 Elsevier Ltd. All rights reserved.

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

    PubMed

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

    2008-11-21

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

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

    PubMed

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

    2014-02-01

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

  2. The quinic acid derivative KZ-41 prevents glucose-induced caspase-3 activation in retinal endothelial cells through an IGF-1 receptor dependent mechanism

    PubMed Central

    He, Hui; Weir, Rebecca L.; Toutounchian, Jordan J.; Pagadala, Jayaprakash; Steinle, Jena J.; Baudry, Jerome; Miller, Duane D.

    2017-01-01

    Retinal microaneurysms, an early disease manifestation of diabetic retinopathy, are associated with retinal endothelial cell (REC) death and macular edema. We previously demonstrated that a quinic acid (QA) analog, KZ-41, promoted REC survival by blunting stress-induced p38 MAPK activation. Herein, we sought to expand our understanding of the pro-survival signal transduction pathways actuated by KZ-41. Using human RECs exposed to high glucose (25 mM, 72 hours), we demonstrated that KZ-41 blocks caspase-3 activation by triggering phosphorylation of the PI3K regulatory subunit (p85; Tyr458) and its downstream target Akt (Ser473). Akt signal transduction was accompanied by autophosphorylation of the receptor tyrosine kinase, insulin growth factor-1 receptor (IGF-1R). IGF-1R knockdown using either the tyrosine kinase inhibitor AG1024 or silencing RNA abolished KZ-41’s pro-survival effect. Under high glucose stress, caspase-3 activation correlated with elevated ERK1/2 phosphorylation and decreased insulin receptor substrate-1 (IRS-1) levels. KZ-41 decreased ERK1/2 phosphorylation and reversed the glucose-dependent reduction in IRS-1. To gain insight into the mechanistic basis for IGF-1R activation by KZ-41, we used molecular modeling and docking simulations to explore a possible protein:ligand interaction between the IGF-1R kinase domain and KZ-41. Computational investigations suggest two possible KZ-41 binding sites within the kinase domain: a region with high homology to the insulin receptor contains one potential allosteric binding site, and another potential site on the other side of the kinase domain, near the hinge domain. These data, together with previous proof-of-concept efficacy studies demonstrating KZ-41 mitigates pathologic retinal neovascularization in the murine oxygen-induced retinopathy model, suggests that QA derivatives may offer therapeutic benefit in ischemic retinopathies. PMID:28796787

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

    PubMed

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

    2013-10-18

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

  4. 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

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

    SciTech Connect

    Yin, Qingqiao; Xia, Yuanyu; Wang, Guan

    2016-09-02

    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.

  6. High Blood Pressure Prevention

    MedlinePlus

    ... version of this page please turn Javascript on. High Blood Pressure Prevention Steps You Can Take You can take steps to prevent high blood pressure by adopting these healthy lifestyle habits. Follow a ...

  7. 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

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

    PubMed

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

    2012-01-01

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

  9. 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

  10. Resveratrol protects vascular endothelial cells from high glucose-induced apoptosis through inhibition of NADPH oxidase activation-driven oxidative stress.

    PubMed

    Chen, Feng; Qian, Li-Hua; Deng, Bo; Liu, Zhi-Min; Zhao, Ying; Le, Ying-Ying

    2013-09-01

    Hyperglycemia-induced oxidative stress has been implicated in diabetic vascular complications in which NADPH oxidase is a major source of reactive oxygen species (ROS) generation. Resveratrol is a naturally occurring polyphenol, which has vasoprotective effects in diabetic animal models and inhibits high glucose (HG)-induced oxidative stress in endothelial cells. We aimed to examine whether HG-induced NADPH oxidase activation and ROS production contribute to glucotoxicity to endothelial cells and the effect of resveratrol on glucotoxicity. Using a murine brain microvascular endothelial cell line bEnd3, we found that NADPH oxidase inhibitor (apocynin) and resveratrol both inhibited HG-induced endothelial cell apoptosis. HG-induced elevation of NADPH oxidase activity and production of ROS were inhibited by apocynin, suggesting that HG induces endothelial cell apoptosis through NADPH oxidase-mediated ROS production. Mechanistic studies revealed that HG upregulated NADPH oxidase subunit Nox1 but not Nox2, Nox4, and p22(phox) expression through NF-κB activation, which resulted in elevation of NADPH oxidase activity and consequent ROS production. Resveratrol prevented HG-induced endothelial cell apoptosis through inhibiting HG-induced NF-κB activation, NADPH oxidase activity elevation, and ROS production. HG induces endothelial cell apoptosis through NF-κB/NADPH oxidase/ROS pathway, which was inhibited by resveratrol. Our findings provide new potential therapeutic targets against brain vascular complications of diabetes. © 2013 John Wiley & Sons Ltd.

  11. Glucose-Induced Acidification in Yeast Cultures

    ERIC Educational Resources Information Center

    Myers, Alan; Bourn, Julia; Pool, Brynne

    2005-01-01

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

  12. 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…

  13. 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 ...

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

    PubMed

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

    2012-02-10

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

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

    PubMed

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

    2017-01-01

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

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

    PubMed

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

    2016-03-01

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

  17. Serotonin potentiates high-glucose-induced endothelial injury: the role of serotonin and 5-HT(2A) receptors in promoting thrombosis in diabetes.

    PubMed

    Yamada, Kumi; Niki, Hisae; Nagai, Hitoshi; Nishikawa, Masakuni; Nakagawa, Haruto

    2012-01-01

    To clarify the involvement of 5-hydroxytryptamine (5-HT) in promotion of thrombogenesis in diabetes, we examined the inhibitory effect of sarpogrelate, a 5-HT(2A) receptor antagonist, on thrombus formation in diabetic rats. In streptozotocin-induced diabetic rats, polyethylene tube-induced thrombus formation was enhanced compared with that in normal rats. The thrombogenesis was inhibited by sarpogrelate; cilostazol, a PDE3 inhibitor; and aspirin, a COX inhibitor, by 75.8%, 42.3%, and 34.3%, respectively. The inhibition by sarpogrelate was more pronounced in diabetic rats than normal ones. High glucose and 5-HT increased the expression of vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vein endothelial cells (HUVECs) and combination of both high glucose and 5-HT further potentiated the effect. Sarpogrelate but not aspirin inhibited the increase in VCAM-1 expression induced by high glucose and 5-HT. These findings suggest that 5-HT mediates the enhanced thrombogenesis in diabetes and suggests that a 5-HT(2A) receptor antagonist may have novel therapeutic potential for the treatment of diabetic complications.

  18. Comparative evaluation of in vitro and in vivo high glucose-induced alterations in voltage-gated tetrodotoxin-resistant sodium channel: Effects attenuated by sodium channel blockers.

    PubMed

    Kharatmal, S B; Singh, J N; Sharma, S S

    2015-10-01

    Glucose uptake in neurons depends on their cellular/physiological activity and the extracellular concentration of glucose around the cell. High concentration of extra-cellular glucose, as under hyperglycemic conditions or pathological condition in diabetes, may persist for extended periods of time in neurons and trigger cellular damage by altering voltage-gated sodium channels (VGSCs), the exact mechanism of which remains unclear. Therefore, we hypothesized that high glucose may directly affect kinetics of the VGSCs in the dorsal root ganglion (DRG) neurons. DRG neurons were exposed to normal glucose (NG: 5.5 mM) and high glucose (HG: 30 mM) for 24 h. In another set of experiments, diabetic DRG neurons were also isolated from streptozotocin-induced diabetic rats. Effects of sodium channel blockers on nociceptive parameters and tetrodotoxin-resistant (TTX-R) Na(+) channel kinetics were elucidated by whole-cell patch-clamp in HG exposure and diabetes-induced rat DRG neurons. HG exposure and diabetes-induced DRG neurons demonstrated significant increase in TTX-R Na(+) current (INa) densities in comparison to the control. Both HG-exposed and diabetic DRG neurons demonstrated similar biophysical characteristics of INa. Lidocaine and tetracaine significantly decreased TTX-R INa density in a concentration- and voltage-dependent manner. Steady-state fast inactivation of INa was shifted in the hyperpolarizing direction whereas voltage-dependent activation was shifted in the rightward direction. Diabetic rats treated with lidocaine and tetracaine (3 mg/kg, i.p.) significantly improved thermal hyperalgesia, mechanical allodynia and motor nerve conduction velocity with a significant inhibition of TTX-R INa density as compared to the diabetic control. These results suggest that HG exposure increases the TTX-R Na(+) channel activity sensitive to Na(+) channel blockers, lidocaine and tetracaine. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

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

    PubMed

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

    2011-11-01

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

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

    PubMed

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

    2016-02-09

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

  1. Regulation of Na(+)-K(+)-ATPase effected high glucose-induced myocardial cell injury through c-Src dependent NADPH oxidase/ROS pathway.

    PubMed

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

    2017-08-15

    Depressed Na(+)/K(+)-ATPase activity has long been reported to be involved in diabetic-related cardiomyocyte death and cardiac dysfunction. However, the nature of directly regulating Na(+)-K(+)-ATPase in diabetic-related myocardial diseases remains unknown. Hyperglycemia is believed as one of major factors responsible for diabetic-related myocardial apoptosis and dysfunction. In this study, whether inhibiting Na(+)-K(+)-ATPase by ouabain or activating Na(+)-K(+)-ATPase by DRm217 has functions on high glucose (HG) -induced myocardial injury was investigated. Here we found that addition of DRm217 or ouabain to HG-treated cells had opposite effects. DRm217 decreased but ouabain increased HG-induced cell injury and apoptosis. This was mediated by changing Na(+)-K(+)-ATPase activity and Na(+)-K(+)-ATPase cell surface expression. The inhibition of Na(+)-K(+)-ATPase endocytosis alleviated HG-induced ROS accumulation. Na(+)-K(+)-ATPase·c-Src dependent NADPH oxidase/ROS pathway was also involved in the effects of ouabain and DRm217 on HG-induced cell injury. These novel results may help us to understand the important role of the Na(+)-K(+)-ATPase in diabetic cardiovascular diseases. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Longevity is associated with increased vascular resistance to high glucose-induced oxidative stress and inflammatory gene expression in Peromyscus leucopus.

    PubMed

    Labinskyy, Nazar; Mukhopadhyay, Partha; Toth, Janos; Szalai, Gabor; Veres, Monika; Losonczy, Gyorgy; Pinto, John T; Pacher, Pal; Ballabh, Praveen; Podlutsky, Andrej; Austad, Steven N; Csiszar, Anna; Ungvari, Zoltan

    2009-04-01

    Vascular aging is characterized by increased oxidative stress and proinflammatory phenotypic alterations. Metabolic stress, such as hyperglycemia in diabetes, is known to increase the production of ROS and promote inflammatory gene expression, accelerating vascular aging. The oxidative stress hypothesis of aging predicts that vascular cells of long-lived species exhibit lower steady-state production of ROS and/or superior resistance to the prooxidant effects of metabolic stress. We tested this hypothesis using two taxonomically related rodents, the white-footed mouse (Peromyscus leucopus) and the house mouse (Mus musculus), which show a more than twofold difference in maximum lifespan potential (8.2 and 3.5 yr, respectively). We compared interspecies differences in steady-state and high glucose (HG; 30 mmol/l)-induced production of O(2)(*-) and H(2)O(2), endothelial function, mitochondrial ROS generation, and inflammatory gene expression in cultured aortic segments. In P. leucopus aortas, steady-state endothelial O(2)(*-) and H(2)O(2) production and ROS generation by mitochondria were less than in M. musculus vessels. Furthermore, vessels of P. leucopus were more resistant to the prooxidant effects of HG. Primary fibroblasts from P. leucopus also exhibited less steady-state and HG-induced ROS production than M. musculus cells. In M. musculus arteries, HG elicited significant upregulation of inflammatory markers (TNF-alpha, IL-6, ICAM-1, VCAM, and monocyte chemoattractant protein-1). In contrast, the proinflammatory effects of HG were blunted in P. leucopus vessels. Thus, increased life span potential in P. leucopus is associated with decreased cellular ROS generation and increased resistance to prooxidant and proinflammatory effects of metabolic stress, which accord with predictions of the oxidative stress hypothesis of aging.

  3. Longevity is associated with increased vascular resistance to high glucose-induced oxidative stress and inflammatory gene expression in Peromyscus leucopus

    PubMed Central

    Labinskyy, Nazar; Mukhopadhyay, Partha; Toth, Janos; Szalai, Gabor; Veres, Monika; Losonczy, Gyorgy; Pinto, John T.; Pacher, Pal; Ballabh, Praveen; Podlutsky, Andrej; Austad, Steven N.; Csiszar, Anna; Ungvari, Zoltan

    2009-01-01

    Vascular aging is characterized by increased oxidative stress and proinflammatory phenotypic alterations. Metabolic stress, such as hyperglycemia in diabetes, is known to increase the production of ROS and promote inflammatory gene expression, accelerating vascular aging. The oxidative stress hypothesis of aging predicts that vascular cells of long-lived species exhibit lower steady-state production of ROS and/or superior resistance to the prooxidant effects of metabolic stress. We tested this hypothesis using two taxonomically related rodents, the white-footed mouse (Peromyscus leucopus) and the house mouse (Mus musculus), which show a more than twofold difference in maximum lifespan potential (8.2 and 3.5 yr, respectively). We compared interspecies differences in steady-state and high glucose (HG; 30 mmol/l)-induced production of O2•− and H2O2, endothelial function, mitochondrial ROS generation, and inflammatory gene expression in cultured aortic segments. In P. leucopus aortas, steady-state endothelial O2•− and H2O2 production and ROS generation by mitochondria were less than in M. musculus vessels. Furthermore, vessels of P. leucopus were more resistant to the prooxidant effects of HG. Primary fibroblasts from P. leucopus also exhibited less steady-state and HG-induced ROS production than M. musculus cells. In M. musculus arteries, HG elicited significant upregulation of inflammatory markers (TNF-α, IL-6, ICAM-1, VCAM, and monocyte chemoattractant protein-1). In contrast, the proinflammatory effects of HG were blunted in P. leucopus vessels. Thus, increased life span potential in P. leucopus is associated with decreased cellular ROS generation and increased resistance to prooxidant and proinflammatory effects of metabolic stress, which accord with predictions of the oxidative stress hypothesis of aging. PMID:19181967

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  6. The Opening of ATP-Sensitive K+ Channels Protects H9c2 Cardiac Cells Against the High Glucose-Induced Injury and Inflammation by Inhibiting the ROS-TLR4-Necroptosis Pathway.

    PubMed

    Liang, Weijie; Chen, Meiji; Zheng, Dongdan; Li, Jianhao; Song, Mingcai; Zhang, Wenzhu; Feng, Jianqiang; Lan, Jun

    2017-01-01

    Hyperglycemia activates multiple signaling molecules, including reactive oxygen species (ROS), toll-like receptor 4 (TLR4), receptor-interacting protein 3 (RIP3, a kinase promoting necroptosis), which mediate hyperglycemia-induced cardiac injury. This study explored whether inhibition of ROS-TLR4-necroptosis pathway contributed to the protection of ATP-sensitive K+ (KATP) channel opening against high glucose-induced cardiac injury and inflammation. H9c2 cardiac cells were treated with 35 mM glucose (HG) to establish a model of HG-induced insults. The expression of RIP3 and TLR4 were tested by western blot. Generation of ROS, cell viability, mitochondrial membrane potential (MMP) and secretion of inflammatory cytokines were measured as injury indexes. HG increased the expression of TLR4 and RIP3. Necrostatin-1 (Nec-1, an inhibitor of necroptosis) or TAK-242 (an inhibitor of TLR4) co-treatment attenuated HG-induced up-regulation of RIP3. Diazoxide (DZ, a mitochondrial KATP channel opener) or pinacidil (Pin, a non-selective KATP channel opener) or N-acetyl-L-cysteine (NAC, a ROS scavenger) pre-treatment blocked the up-regulation of TLR4 and RIP3. Furthermore, pre-treatment with DZ or Pin or NAC, or co-treatment with TAK-242 or Nec-1 attenuated HG-induced a decrease in cell viability, and increases in ROS generation, MMP loss and inflammatory cytokines secretion. However, 5-hydroxy decanoic acid (5-HD, a mitochondrial KATP channel blocker) or glibenclamide (Gli, a non-selective KATP channel blocker) pre-treatment did not aggravate HG-induced injury and inflammation. KATP channel opening protects H9c2 cells against HG-induced injury and inflammation by inhibiting ROS-TLR4-necroptosis pathway. © 2017 The Author(s)Published by S. Karger AG, Basel.

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

    PubMed

    Braun, Katherine A; Dombek, Kenneth M; Young, Elton T

    2015-12-14

    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. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  8. 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

  9. TRIB3 Mediates Glucose-Induced Insulin Resistance via a Mechanism That Requires the Hexosamine Biosynthetic Pathway

    PubMed Central

    Zhang, Wei; Liu, Jiarong; Tian, Ling; Liu, Qinglan; Fu, Yuchang; Garvey, W. Timothy

    2013-01-01

    In the current study, we investigated the role of tribbles homolog 3 (TRIB3) in glucose-induced insulin resistance and whether the induction of TRIB3 by glucose is dependent on the nutrient-sensing hexosamine biosynthetic pathway (HBP) known to mediate glucose toxicity in diabetes. In diabetic rats, TRIB3 expression in skeletal muscle was increased after 10 days of hyperglycemia, and glycemia and muscle TRIB3 were both restored toward normal by insulin therapy. In L6 myocytes, the induction of TRIB3 by high glucose or glucosamine was reversible upon removal of these substrates. To assess the role of HBP in the induction of TRIB3, we demonstrated that the ability of high glucose to augment TRIB3 expression was prevented by azaserine, an inhibitor of glutamine: fructose-6-phosphate amidotransferase (GFAT), which is the rate-limiting enzyme in the HBP pathway. TRIB3 expression was also substantially stimulated by glucosamine, which bypasses GFAT, accompanied by a decrease in the insulin-stimulated glucose transport rate, and neither response was affected by azaserine. Further, knockdown of TRIB3 inhibited, and TRIB3 overexpression enhanced, the ability of both high glucose and glucosamine to induce insulin resistance. These data provide the mechanistic link between the HBP flux and insulin resistance and point to TRIB3 as a novel target for treatment of glucose-induced insulin resistance. PMID:23990361

  10. High Blood Cholesterol Prevention

    MedlinePlus

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  11. Preventing High Blood Pressure

    MedlinePlus

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

    PubMed

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

    1975-11-01

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

  13. Aldose Reductase Regulates High Glucose-Induced Ectodomain Shedding of Tumor Necrosis Factor (TNF)-α via Protein Kinase C-δ and TNF-α Converting Enzyme in Vascular Smooth Muscle Cells

    PubMed Central

    Reddy, Aramati B. M.; Ramana, Kota V.; Srivastava, Sanjay; Bhatnagar, Aruni; Srivastava, Satish K.

    2009-01-01

    Chronic low-grade inflammation has emerged as a key contributor to the cardiovascular complications of diabetes, however, the mechanisms by which diabetes increases inflammation remain poorly understood. Here, we report that exposure to high glucose (HG) stimulates ectodomain shedding of TNF-α from rat aortic smooth muscle cells in culture. Our results show that exposure to HG decreases membrane-associated TNF-α. This decrease in unprocessed TNF-α was prevented by the aldose reductase (AR) inhibitor sorbinil and AR small interference RNA. Treatment with HG, but not equimolar mannitol or 3-O-methyl glucose, resulted in phosphorylation and activation of TNF-α converting enzyme (TACE) (ADAM17), which were attenuated by sorbinil or AR-specific small interference RNA. HG-induced TACE phosphorylation and TNF-α processing were also prevented by TNF-α protease inhibitor-1, an inhibitor of TACE. Inhibition of protein kinase C (PKC)-δ by rottlerin prevented HG-induced TACE activation and the accumulation of unprocessed TNF-α. Treatment with sorbinil decreased elevated levels of circulating TNF-α in streptozotocin-treated diabetic rats. Sorbinil treatment also decreased the expression of TNF-α, matrix metalloproteinase-2, matrix metalloproteinase-9, and increased tissue inhibitor of metalloproteinase-3 in vascular smooth muscle cells treated with HG and in balloon-injured carotid arteries of diabetic rats. These results indicate that HG-induced TNF-α shedding could be attributed to TACE activation, which is regulated, in part, by PKC-δ and AR. Therefore, inhibition of TACE by TNF-α protease inhibitor-1, or pharmacological inhibition of PKC-δ or AR may represent useful strategies for treating vascular inflammation associated with diabetes. PMID:18772236

  14. Inhibitory Effect of Bunium Persicum Hydroalcoholic Extract on Glucose-Induced Albumin Glycation, Oxidation, and Aggregation In Vitro

    PubMed Central

    Seri, Arman; Khorsand, Marjan; Rezaei, Zahra; Hamedi, Azadeh; Takhshid, Mohammad Ali

    2017-01-01

    Background: Glucose-induced protein glycation has been implicated in the progression of diabetic complications and age-related diseases. The anti-glycation potential of polyphenol-rich plant extracts has been shown previously. Bunium Persicum has been demonstrated to possess a high level of polyphenols. The aim of current in vitro study was to determine the possible inhibitory effect of Bunium Persicum hydroalcoholic extract (BPE) on glucose-induced bovine serum albumin (BSA) glycation, oxidation, and aggregation. Methods: Folin-Ciocalteu assay was used to measure the content of total phenolic compounds of BPE. To test the in vitro effect of BPE on the formation of glycated BSA, thiol group oxidation, and protein aggregation of BSA, various concentrations of BPE were incubated with BSA and glucose at 37 °C for 72 hr. Glycation, thiol group oxidation, and aggregation of BSA were then measured using thiobarbituric acid, 2, 4-dinitrophenylhydrazine, and Congo red colorimetric methods, respectively. Data were analyzed using the SPSS software (version 16.0). One-way ANOVA followed by Tukey’s post hoc test was used to compare group means. P<0.05 was accepted as the statistically significant difference between groups. Results: The results demonstrated that the content of total phenolics of BPE was 122.41 mg gallic acid equivalents per gram dried extract. BPE (10, 15, and 30 μg/ml) significantly inhibited the formation of GA in a concentration-dependent manner. BPE also significantly decreased the levels of thiol group oxidation and BSA aggregation. Conclusion: The results showed that BPE has anti-glycation and antioxidant properties and might have therapeutic potentials in the prevention of glycation-mediated diabetic complications. PMID:28761203

  15. Glucose-induced inhibition: how many ionic mechanisms?

    PubMed

    Burdakov, D; Lesage, F

    2010-03-01

    Sensing of sugar by specialized 'glucose-inhibited' cells helps organisms to counteract swings in their internal energy levels. Evidence from several cell types in both vertebrates and invertebrates suggests that this process involves sugar-induced stimulation of plasma membrane K(+) currents. However, the molecular composition and the mechanism of activation of the underlying channel(s) remain controversial. In mouse hypothalamic neurones and neurosecretory cells of the crab Cancer borealis, glucose stimulates K(+) currents displaying leak-like properties. Yet knockout of some of the candidate 'leak' channel subunits encoded by the KCNK gene family so far failed to abolish glucose inhibition of hypothalamic cells. Moreover, in other tissues, such as the carotid body, glucose-stimulated K(+) channels appear to be not leak-like but voltage-gated, suggesting that glucose-induced inhibition may engage multiple types of K(+) channels. Other mechanisms of glucose-induced inhibition, such as hyperpolarization mediated by opening of Cl(-) channels and depolarization block caused by closure of K(ATP) channels have also been proposed. Here we review known ionic and pharmacological features of glucose-induced inhibition in different cell types, which may help to identify its molecular correlates.

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

    PubMed

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

    2011-01-25

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

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

    PubMed

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

    2013-09-01

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

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

    PubMed

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

    2013-09-01

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

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

    PubMed

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

    2016-12-01

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

  20. Combination of quercetin, cinnamaldehyde and hirudin protects rat dorsal root ganglion neurons against high glucose-induced injury through Nrf-2/HO-1 activation and NF-κB inhibition.

    PubMed

    Shi, Yue; Liang, Xiao-Chun; Zhang, Hong; Sun, Qing; Wu, Qun-Li; Qu, Ling

    2017-09-01

    To examine the effects of the combination of quercetin (Q), cinnamaldehyde (C) and hirudin (H), a Chinese medicine formula on high glucose (HG)-induced apoptosis of cultured dorsal root ganglion (DRG) neurons. DRG neurons exposed to HG (45 mmol/L) for 24 h were employed as an in vitro model of diabetic neuropathy. Cell viability, reactive oxygen species (ROS) level and apoptosis were determined. The expression of nuclear factor of Kappa B (NF-κB), inhibitory kappa Bα(IκBα), phosphorylated IκBα and Nf-E2 related factor 2 (Nrf2) were examined using reverse transcription-polymerase chain reaction (RT-PCR) and Western blot assay. The expression of hemeoxygenase-1 (HO-1), interleukin-6 (IL-6), tumor necrosis factor (TNF-α) and caspase-3 were also examined by RT-PCR and Western blot assay. HG treatment markedly increased DRG neuron apoptosis via increasing intracellular ROS level and activating the NF-κB signaling pathway (P<0.05). Co-treatment with Q, C, H and their combination decreased HG-induced caspase-3 activation and apoptosis (P<0.05 or P<0.01). The expressions of NF-κB, IL-6 and TNF-α were down-regulated, and Nrf2/HO-1 expression was up-regulated (P<0.05 or P<0.01). QCH has better effect in scavenging ROS, activating Nrf-2/HO-1, and down-regulating the NF-κB pathway than other treatment group. DRG neurons' apoptosis was increased in diabetic conditions, which was reduced by QCH formula treatment. The possible reason could be activating Nrf-2/HO-1 pathway, scavenging ROS, and inhibition of NF-κB activation. The effect of QCH combination was better than each monomer or the combination of the two monomers.

  1. Microassay for glucose-induced preproinsulin mRNA expression to assess islet functional potency for islet transplantation

    PubMed Central

    Omori, Keiko; Mitsuhashi, Masato; Todorov, Ivan; Rawson, Jeffrey; Shiang, Keh-Dong; Kandeel, Fouad; Mullen, Yoko

    2009-01-01

    Background The capacity for insulin synthesis in islets is important for islet transplantation to succeed. We developed a micro assay that evaluates the potency of human islets by measuring changes in glucose induced insulin gene (INS) expression using a single islet in octuplicate samples. Methods Poly (A)+ mRNA was purified from a set of single handpicked human islets. Glucose induced mature (post-spliced) and premature (pre-spliced) insulin mRNA were quantified by RT-PCR using several insulin mRNA primers designed at different locations including, intron, exon, and an exon-intron junction. Results The synthesis of premature INS mRNA was significantly increased in islets exposed to high glucose for 16 hours (vs. 4-hour, p<0.01), whereas mature INS mRNA showed no difference. Glucose-induced premature INS mRNA synthesis was attenuated in heat-damaged islets. Stimulation index (SI) calculated by normalizing premature by mature INS mRNA (SI_INS mRNA) positively correlated with SI of insulin release (SI_16h-insulin) from the same set of islets during 16-hour incubation in high or low glucose media, as well as SI of glucose-mediated insulin release obtained from the same islet lot in a perifusion system (N=12). Furthermore, linear multiple regression analysis using SI_INS mRNA and SI_16h-insulin predicted islet transplantation outcome in NODscid mice (N=8). Conclusion The measurement of glucose induced premature INS mRNA normalized by mature INS mRNA can be used to assess the functional quality of human islets and may predict islet function after transplantation in type 1 diabetic patients. PMID:20098276

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

    PubMed

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

    2013-06-24

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

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

    PubMed Central

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

    2002-01-01

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

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

    SciTech Connect

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

    1986-12-01

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

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

    PubMed Central

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

    2013-01-01

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

  6. Effects of plant extracts on the reversal of glucose-induced impairment of stress-resistance in Caenorhabditis elegans.

    PubMed

    Fitzenberger, Elena; Deusing, Dorothé Jenni; Wittkop, Anette; Kler, Adolf; Kriesl, Erwin; Bonnländer, Bernd; Wenzel, Uwe

    2014-03-01

    Enhanced blood glucose levels are a hallmark of diabetes and are associated with diabetic complications and a reduction of lifespan. In order to search for plant extracts that display preventive activities in such a scenario, we tested 16 extracts used in human nutrition for their survival enhancing activities in the nematode Caenorhabditis elegans. Nematodes were exposed for 48 h to 10 mM glucose in the absence or presence of 0.1% extract. Thereafter, survival was measured at 37 °C. Extracts made from coffee, kola, rooibos and cinnamon, did not influence the glucose-induced reduction of survival. Those made from ginseng, camomile, lime blossom, paraguay tea, balm, rhodiola, black tea, or knotgrass all extended the lifespan of the glucose-treated nematodes significantly but did not rescue survival completely. Extracts from the leaves of blackberries, from hibiscus, elderberries, or jiaogulan completely countered the glucose-induced survival reduction. A potent activation of the proteasome was shown for the most preventive extracts suggesting a more efficient degradation of proteins impaired by glucose. In conclusion, we present a simple animal model to screen for plant extracts with potency to reverse glucose toxicity. Extracts from blackberry leaves, hibiscus, elderberries, and jiaogulan were identified as very potent in this regard whose exact mechanisms of action appear worthwile to investigate at the molecular level.

  7. The protective effects of beta-casomorphin-7 against glucose -induced renal oxidative stress in vivo and vitro.

    PubMed

    Zhang, Wei; Miao, Jinfeng; Wang, Shanshan; Zhang, Yuanshu

    2013-01-01

    Oxidative stress is implicated in the pathogenesis of diabetic nephropathy. The present study aimed to investigate the effect of β-casomorphin-7 (BCM7) on the oxidative stress occurring in kidney tissue in streptozotocin (STZ)-induced diabetic rats and proximal tubular epithelial cells (NRK-52E) exposure to high glucose (HG) by using biochemical methods. There is a significant decrease in plasma insulin and a significant increase in plasma glucagon in the rats of diabetic group. Oral administration of BCM7 for 30 days to rats with STZ-induced diabetes resulted in a significant increase in serum level of insulin, and a decrease in the level of glucagon. Moreover, rats with STZ-induced diabetes had lower levels of superoxide dismutase (SOD), glutathione peroxidase (GPx) and total antioxidative capacity (T-AOC), higher levels of malondialdehyde (MDA) and hydrogen peroxide (H2O2) in the kidney than that in the control rats. The administration of BCM7 altered the changes of SOD, GPx, T-AOC, MDA and H2O2 in the kidney of diabetic rats. Furthermore, BCM7 alleviated high glucose-induced decreasement in SOD and GPx activity, increasement in MDA contents in the NRK-52E cells. BCM7 ameliorated the changes of angiotensin converting enzyme (ACE) and ACE2 levels in the kidney of diabetic rats and BCM7 lowered the levels of angiotensin (Ang)II in the kidney of diabetic rats and culture medium for cells. Moreover losartan (antagonist of angiotensin II type I receptor) lowered the high glucose-induced oxidative stress in the NRK-52E cells. Our results suggest that administration of BCM7 would alleviate high glucose-induced renal oxidative stress in vivo and in vitro, which may be associated with down regulation of the concentration of Ang II partly.

  8. 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.

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

    PubMed Central

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

    2015-01-01

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

  10. Preventative effects of Ginkgo biloba extract (EGb761) on high glucose-cultured opacity of rat lens.

    PubMed

    Lu, Qian; Yang, Tingting; Zhang, Mingzhu; Du, Lei; Liu, Ling; Zhang, Nan; Guo, Hao; Zhang, Fan; Hu, Gang; Yin, Xiaoxing

    2014-05-01

    Diabetic cataract is one of the earliest secondary complications of diabetes, and it is characterized by opacification of the eye lens. In this study, we examined the protective effects of Ginkgo biloba extract (EGb761) on rat lenses cultured in high-glucose conditions. The cultured rat lenses were divided into six groups: normal group, high-glucose group, high glucose plus low, medium, and high concentrations of EGb761 groups, and a high glucose plus bendazac lysine group. The activities of antioxidases, aldose reductase, advanced glycosylation end products, transforming growth factor-β2, Smad2/3, E-cadherin, and α-smooth muscle actin were assessed by different methods. Compared with the levels in the high glucose group, EGb761 decreased the intensity of oxidative stress, decreased aldose reductase activation and the level of advanced glycosylation end products, and suppress the transforming growth factor-β2 or Smad pathway activation, further increase the expression of E-cadherin and decrease α-smooth muscle actin, and therefore, prevents the pathological changes of high glucose-induced lens epithelial cells and ameliorated lens opacity. These results suggest that EGb761 has protective effects on several pharmacological targets in the progress of diabetic cataract and is a potential drug for the prevention of diabetic cataract.

  11. Protective effect of serotonin derivatives on glucose-induced damage in PC12 rat pheochromocytoma cells.

    PubMed

    Piga, Rosaria; Naito, Yuji; Kokura, Satoshi; Handa, Osamu; Yoshikawa, Toshikazu

    2010-01-01

    Oxidative damage is believed to be associated with ageing, cancer and several degenerative diseases. Previous reports have shown that safflower-seed extract and its major antioxidant constituents, serotonin hydroxycinnamic amides, possess a powerful free radical-scavenging and antioxidative activity, paying particular attention to atherosclerotic reactive oxygen species (ROS)-related dysfunctions. In the present report, we examined a still unknown cell-based mechanism of serotonin derivatives against ROS-related neuronal damage, phenomena that represent a crucial event in neurodegenerative diseases. Serotonin derivatives N-(p-coumaroyl)serotonin and N-feruloylserotonin exerted a protective effect on high glucose-induced cell death, inhibited the activation of caspase-3 which represents the last and crucial step within the cascade of events leading to apoptosis, and inhibited the overproduction of the mitochondrial superoxide, which represents the most dangerous radical produced by hyperglycaemia, by acting as scavengers of the superoxide radical. In addition, serotonin derivative concentration inside the cells and inside the mitochondria was increased in a time-dependent manner. Since recent studies support the assertion that mitochondrial dysfunctions related to oxidative damage are the major contributors to neurodegenerative diseases, these preliminary cell-based results identify a mitochondria-targeted antioxidant property of serotonin derivatives that could represent a novel therapeutic approach against the neuronal disorders and complications related to ROS.

  12. Glucose Induces Protein Targeting to Glycogen in Hepatocytes by Fructose 2,6-Bisphosphate-Mediated Recruitment of MondoA to the Promoter

    PubMed Central

    Petrie, John L.; Al-Oanzi, Ziad H.; Arden, Catherine; Tudhope, Susan J.; Mann, Jelena; Kieswich, Julius; Yaqoob, Muhammad M.; Towle, Howard C.

    2013-01-01

    In the liver, a high glucose concentration activates transcription of genes encoding glucose 6-phosphatase and enzymes for glycolysis and lipogenesis by elevation in phosphorylated intermediates and recruitment of the transcription factor ChREBP (carbohydrate response element binding protein) and its partner, Mlx, to gene promoters. A proposed function for this mechanism is intracellular phosphate homeostasis. In extrahepatic tissues, MondoA, the paralog of ChREBP, partners with Mlx in transcriptional induction by glucose. We tested for glucose induction of regulatory proteins of the glycogenic pathway in hepatocytes and identified the glycogen-targeting proteins, GL and PTG (protein targeting to glycogen), as being encoded by Mlx-dependent glucose-inducible genes. PTG induction by glucose was MondoA dependent but ChREBP independent and was enhanced by forced elevation of fructose 2,6-bisphosphate and by additional xylitol-derived metabolites. It was counteracted by selective depletion of fructose 2,6-bisphosphate with a bisphosphatase-active kinase-deficient variant of phosphofructokinase 2/fructosebisphosphatase 2, which prevented translocation of MondoA to the nucleus and recruitment to the PTG promoter. We identify a novel role for MondoA in the liver and demonstrate that elevated fructose 2,6-bisphosphate is essential for recruitment of MondoA to the PTG promoter. Phosphometabolite activation of MondoA and ChREBP and their recruitment to target genes is consistent with a mechanism for gene regulation to maintain intracellular phosphate homeostasis. PMID:23207906

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

    SciTech Connect

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

    2015-05-08

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

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

    PubMed

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

    2002-08-01

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

  15. Antioxidants improve impaired insulin-mediated glucose uptake and prevent migration and proliferation of cultured rabbit coronary smooth muscle cells induced by high glucose.

    PubMed

    Yasunari, K; Kohno, M; Kano, H; Yokokawa, K; Minami, M; Yoshikawa, J

    1999-03-16

    To explore the role of intracellular oxidative stress in high glucose-induced atherogenesis, we examined the effect of probucol and/or alpha-tocopherol on the migration and growth characteristics of cultured rabbit coronary vascular smooth muscle cells (VSMCs). Chronic high-glucose-medium (22. 2 mmol/L) treatment increased platelet-derived growth factor (PDGF)-BB-mediated VSMC migration, [3H]thymidine incorporation, and cell number compared with VSMCs treated with normal-glucose medium (5.6 mmol/L+16.6 mmol/L mannose). Probucol and alpha-tocopherol significantly suppressed high glucose-induced increase in VSMC migration, cell number, and [3H]thymidine incorporation. Probucol and alpha-tocopherol suppressed high glucose-induced elevation of the cytosolic ratio of NADH/NAD+, phospholipase D, and membrane-bound protein kinase C activation. Probucol, alpha-tocopherol, and calphostin C improved the high glucose-induced suppression of insulin-mediated [3H]deoxyglucose uptake. Chronic high-glucose treatment increased the oxidative stress, which was significantly suppressed by probucol, alpha-tocopherol, suramin, and calphostin C. These findings suggest that probucol and alpha-tocopherol may suppress high glucose-induced VSMC migration and proliferation via suppression of increases in the cytosolic ratio of free NADH/NAD+, phospholipase D, and protein kinase C activation induced by high glucose, which result in reduction in intracellular oxidative stress.

  16. 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

  17. Fructose impairs glucose-induced hepatic triglyceride synthesis.

    PubMed

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

    2011-01-24

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

  18. Glibenclamide prevents increased extracellular matrix formation induced by high glucose concentration in mesangial cells.

    PubMed

    Giannico, Giovanna; Cortes, Pedro; Baccora, Mohammed H; Hassett, Clare; Taube, David W; Yee, Jerry

    2007-01-01

    Other than stimulation of cell contractility, little is known about the potential metabolic effects induced by sulfonylureas, independently of insulin action. Previous studies from our laboratory demonstrated complete abrogation of glomerulosclerosis in an experimental model of type 1 diabetes chronically (9 mo) treated with low-dose sulfonylureas (Biederman JI, Vera E, Pankhaniya R, Hassett C, Giannico G, Yee J, Cortes P. Kidney Int 67: 554-565, 2005). Therefore, the effects of glibenclamide (Glib) on net collagen I, collagen IV, and fibronectin medium net secretion and cell layer collagen I deposition were investigated in mesangial cells continuously exposed to 25 mM glucose for 8 wk and treated with predetermined increasing concentrations of Glib for the same period. Clinically relevant concentrations (0.01 microM) of Glib fully suppressed the high glucose-enhanced accumulation of collagen I, collagen IV, and fibronectin in the medium and inhibited collagen I deposition in the cell layer. These effects occurred while transforming growth factor (TGF)-beta1 medium concentration remained elevated and glucose uptake was increased to levels above those in 25 mM glucose-incubated cultures. The decreased collagen I accumulation occurred simultaneously with enhanced collagen I mRNA expression in concert with marked suppression of plasminogen inhibitor type-1 (PAI-1) mRNA and protein expression. This strongly suggests an accelerated matrix turnover favoring breakdown. Glib-induced effects demonstrated a biphasic pattern, being absent or reversed in cells treated with higher Glib concentrations (0.1 or 1 microM). Therefore, chronic Glib treatment at low concentrations markedly diminishes the high glucose-induced enhanced accumulation of extracellular matrix components by suppression of steady-state PAI-1 transcriptional activity. These results and those previously reported in vivo suggest that long-term Glib treatment may prevent glomerulosclerosis in insulin

  19. Glucose-induced inhibition of in vitro bone mineralization.

    PubMed

    Balint, E; Szabo, P; Marshall, C F; Sprague, S M

    2001-01-01

    Patients with diabetes tend to have an increased incidence of osteopenia that may be related to hyperglycemia. However, little is known about how glucose may alter bone formation and osteoblast maturation. To determine whether glucose affects osteoblastic calcium deposition, MC3T3-E1 cells were incubated in media containing either a normal (5.5 mmol/L) or high glucose concentration (15 mmol/L) or mannitol (15 mmol/L), and bone nodule formation was examined. Net calcium flux was measured thrice weekly and cumulative calcium uptake was determined. Compared with control incubations, glucose significantly inhibited daily and cumulative calcium uptake into the nodules. At the time of matrix maturation, cultures undergo a rapid phase of increased calcium deposition; this was significantly inhibited by the presence of glucose. Total calcium uptake, determined by acid digestion, was also significantly inhibited by glucose. Area and number of nodules were quantitated at the end of the incubation period (day 30) by staining with Alizarin Red S calcium stain. Compared with both control and mannitol-treated cultures, the number of nodules was increased by incubation with glucose. Furthermore, both the average total nodular area and calcified nodular area of large nodules were increased by glucose. Cellular proliferation as well as the release of markers of osteoblast activity (osteocalcin and alkaline phosphatase) were determined at the end of the experimental period (day 30). Cellular proliferation and alkaline phosphatase activity was significantly increased in the presence of glucose, however, the release of osteocalcin into culture media was similar in all three groups. In conclusion, the present study shows that elevated glucose concentration present throughout the development of murine osteoblasts stimulates cellular proliferation while inhibiting calcium uptake. The result of glucose inhibition of calcium uptake suggests that bone could be structurally altered in

  20. Converting enzyme inhibitor temocaprilat prevents high glucose-mediated suppression of human aortic endothelial cell proliferation.

    PubMed

    Yasunari, Kenichi; Maeda, Kensaku; Watanabe, Takanori; Nakamura, Munehiro; Asada, Akira; Yoshikawa, Junichi

    2003-12-01

    We examined the involvement of the oxidative stress in high glucose-induced suppression of human aortic endothelial cell proliferation. Chronic glucose treatment for 72 h concentration-dependently (5.6-22.2 mol/l) inhibited human coronary endothelial cell proliferation. Temocaprilat, an angiotensin-converting enzyme inhibitor, at 10 nmol/l to 1 micromol/l inhibited high glucose (22.2 mmol/l)-mediated suppression of human aortic endothelial cell proliferation. Temocaprilat at 1 micromol/l inhibited high glucose-induced membrane-bound protein kinase C activity in human aortic endothelial cells. The protein kinase C inhibitors calphostin C 100 nmol/l or chelerythrine 1 micromol/l inhibited high glucose-mediated suppression of human aortic endothelial cell proliferation. Chronic high glucose treatment for 72 h increased intracellular oxidative stress, directly measured by flow cytometry using carboxydichlorofluorescein diacetate bis-acetoxymethyl ester, and this increase was significantly suppressed by temocaprilat 10 nmol/l to 1 micromol/l. Bradykinin B2 receptor antagonist icatibant 100 nmol/l significantly reduced the action of temocaprilat; whereas bradykinin B1 receptor antagonist des-Arg9-Leu8-bradykinin 100 nmol/l had no effect. These findings suggest that high glucose inhibits human aortic endothelial cell proliferation and that the angiotensin-converting enzyme inhibitor temocaprilat inhibits high glucose-mediated suppression of human aortic endothelial cell proliferation, possibly through suppression of protein kinase C, bradykinin B2 receptors and oxidative stress.

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

    PubMed

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

    1995-03-01

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

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

    PubMed

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

    2013-01-01

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

  3. Aldose reductase inhibitor prevents hyperproliferation and hypertrophy of cultured rat vascular smooth muscle cells induced by high glucose.

    PubMed

    Yasunari, K; Kohno, M; Kano, H; Yokokawa, K; Horio, T; Yoshikawa, J

    1995-12-01

    Vascular remodeling is a key process in the pathophysiology of atherosclerosis. Recent evidence suggests that high glucose levels may function as a vascular smooth muscle growth and proliferation-promoting substance. To explore the role of the polyol pathway in this process, we examined the effect of an aldose reductase inhibitor (ARI), epalrestat, on the growth characteristics of cultured rat vascular smooth muscle cells (VSMCs). Epalrestat (10 nmol/L, 1 mumol/L) significantly suppressed the high glucose-induced proliferative effect as measured by [3H]thymidine incorporation by 67% and 82% in cell number, suggesting ARI as an antimitogenic factor. In VSMCs, epalrestat (10 nmol/L, 1 mumol/L) significantly suppressed the high glucose-induced incorporation of [3H]leucine by 45% and 58% with the concomitant reduction of the cell size estimated by flowcytometry. Epalrestat (1 mumol/L) also suppressed high glucose-induced intracellular NADH/NAD+ increase and membrane-bound protein kinase C activation. These results indicate that this ARI possesses an antiproliferative and antihypertrophic action on VSMCs induced by high glucose possibly through protein kinase C suppression.

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

    PubMed

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

    2013-12-01

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

  5. Charybdotoxin-sensitive K(Ca) channel is not involved in glucose-induced electrical activity in pancreatic beta-cells.

    PubMed

    Kukuljan, M; Goncalves, A A; Atwater, I

    1991-01-01

    The effects of charybdotoxin (CTX) on single [Ca2+]-activated potassium channel (K(Ca)) activity and whole-cell K+ currents were examined in rat and mouse pancreatic beta-cells in culture using the patch-clamp method. The effects of CTX on glucose-induced electrical activity from both cultured beta-cells and beta-cells in intact islets were compared. K(Ca) activity was very infrequent at negative patch potentials (-70 less than Vm less than 0 mV), channel activity appearing at highly depolarized Vm. K(Ca) open probability at these depolarized Vm values was insensitive to glucose (10 and 20 mM) and the metabolic uncoupler 2,4 dinitrophenol (DNP). However, DNP blocked glucose-evoked action potential firing and reversed glucose-induced inhibition of the activity of K+ channels of smaller conductance. The venom from Leiurus quinquestriatus hebreus (LQV) and highly purified CTX inhibited K(Ca) channel activity when applied to the outer aspect of the excised membrane patch. CTX (5.8 and 18 nM) inhibited channel activity by 50 and 100%, respectively. Whole-cell outward K+ currents exhibited an early transient component which was blocked by CTX, and a delayed component which was insensitive to the toxin. The individual spikes evoked by glucose, recorded in the perforated-patch modality, were not affected by CTX (20 nM). Moreover, the frequency of slow oscillations in membrane potential, the frequency of action potentials and the rate of repolarization of the action potentials recorded from pancreatic islet beta-cells in the presence of glucose were not affected by CTX. We conclude that the K(Ca) does not participate in the steady-state glucose-induced electrical activity in rodent pancreatic islets.

  6. 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…

  7. Adenylosuccinate Is an Insulin Secretagogue Derived from Glucose-Induced Purine Metabolism.

    PubMed

    Gooding, Jessica R; Jensen, Mette V; Dai, Xiaoqing; Wenner, Brett R; Lu, Danhong; Arumugam, Ramamani; Ferdaoussi, Mourad; MacDonald, Patrick E; Newgard, Christopher B

    2015-10-06

    Pancreatic islet failure, involving loss of glucose-stimulated insulin secretion (GSIS) from islet β cells, heralds the onset of type 2 diabetes (T2D). To search for mediators of GSIS, we performed metabolomics profiling of the insulinoma cell line 832/13 and uncovered significant glucose-induced changes in purine pathway intermediates, including a decrease in inosine monophosphate (IMP) and an increase in adenylosuccinate (S-AMP), suggesting a regulatory role for the enzyme that links the two metabolites, adenylosuccinate synthase (ADSS). Inhibition of ADSS or a more proximal enzyme in the S-AMP biosynthesis pathway, adenylosuccinate lyase, lowers S-AMP levels and impairs GSIS. Addition of S-AMP to the interior of patch-clamped human β cells amplifies exocytosis, an effect dependent upon expression of sentrin/SUMO-specific protease 1 (SENP1). S-AMP also overcomes the defect in glucose-induced exocytosis in β cells from a human donor with T2D. S-AMP is, thus, an insulin secretagogue capable of reversing β cell dysfunction in T2D. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

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

    PubMed

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

    2012-04-01

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

  9. 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

  10. Glucose Induces Mouse β-Cell Proliferation via IRS2, MTOR, and Cyclin D2 but Not the Insulin Receptor

    PubMed Central

    Stamateris, Rachel E.; Sharma, Rohit B.; Kong, Yahui; Ebrahimpour, Pantea; Panday, Deepika; Ranganath, Pavana; Zou, Baobo; Levitt, Helena; Parambil, Nisha Abraham; O’Donnell, Christopher P.; García-Ocaña, Adolfo

    2016-01-01

    An important goal in diabetes research is to understand the processes that trigger endogenous β-cell proliferation. Hyperglycemia induces β-cell replication, but the mechanism remains debated. A prime candidate is insulin, which acts locally through the insulin receptor. Having previously developed an in vivo mouse hyperglycemia model, we tested whether glucose induces β-cell proliferation through insulin signaling. By using mice lacking insulin signaling intermediate insulin receptor substrate 2 (IRS2), we confirmed that hyperglycemia-induced β-cell proliferation requires IRS2 both in vivo and ex vivo. Of note, insulin receptor activation was not required for glucose-induced proliferation, and insulin itself was not sufficient to drive replication. Glucose and insulin caused similar acute signaling in mouse islets, but chronic signaling differed markedly, with mammalian target of rapamycin (MTOR) and extracellular signal–related kinase (ERK) activation by glucose and AKT activation by insulin. MTOR but not ERK activation was required for glucose-induced proliferation. Cyclin D2 was necessary for glucose-induced β-cell proliferation. Cyclin D2 expression was reduced when either IRS2 or MTOR signaling was lost, and restoring cyclin D2 expression rescued the proliferation defect. Human islets shared many of these regulatory pathways. Taken together, these results support a model in which IRS2, MTOR, and cyclin D2, but not the insulin receptor, mediate glucose-induced proliferation. PMID:26740601

  11. A Prevention Program for Middle-School High Risk Youth.

    ERIC Educational Resources Information Center

    Gittman, Elizabeth; Cassata, Marian

    A 5-year federally funded substance abuse prevention program targeted 426 high risk middle-school youth from 4 school districts in Nassau County, New York. Combining a child-centered model with a systemic approach, the program's goal was to prevent or delay the onset of alcohol and other drug use. High-risk youth were identified by school…

  12. Ganglioside GM3 Mediates Glucose-Induced Suppression of IGF-1 Receptor-Rac1 Activation to Inhibit Keratinocyte Motility.

    PubMed

    Dam, Duncan Hieu M; Wang, Xiao-Qi; Sheu, Sarah; Vijay, Mahima; Shipp, Desmond; Miller, Luke; Paller, Amy S

    2017-02-01

    Activation of insulin-like growth factor-1 (IGF-1) receptor (IGF1R) signaling induces keratinocyte migration, but little is known about its regulation, including in diabetic wounds. GM3, a lipid raft ganglioside synthesized by GM3 synthase (GM3S), regulates receptor signaling. In diabetic mice, knockout or topically applied nanoconstruct-mediated knockdown of GM3S promotes wound edge IGF1R phosphorylation and re-epithelialization. Through modulating GM3 expression, we explored the role of GM3 in regulating human keratinocyte IGF1R signaling. Increases in GM3 and GM3S expression, including by exposure to high glucose, inhibit keratinocyte migration and IGF-1-induced chemotaxis in association with inhibition of IGF1R phosphorylation, suppression of Rac1 signaling, and activation of RhoA signaling. In contrast, GM3 depletion accelerates cell migration; increases cell velocity, displacement, and persistence; and activates IGF1R-Rac1 signaling. These data implicate GM3 in mediating glucose-induced suppression of IGF1R-Rac1 signaling. Furthermore, our findings provide evidence of a pivotal role for GM3-induced insulin resistance in impairing keratinocyte migration and reinforce the previously published studies in diabetic mice supporting GM3-depleting strategies as an approach for accelerating the healing of human diabetic wounds. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  13. Cancer Prevention Fellowship Program Aims for High Marks | Division of Cancer Prevention

    Cancer.gov

    For nearly 30 years, the NCI Cancer Prevention Fellowship Program (CPFP) has provided funding support for post-doctoral Fellows with a goal to train the future generation of researchers and leaders in the field. Infographic Highlight Cancer Prevention Fellowship Program Aims for High Marks |

  14. 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…

  15. 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…

  16. Evaluation of high myopia complications prevention program in university freshmen

    PubMed Central

    Tseng, Gow-Lieng; Chen, Cheng-Yu

    2016-01-01

    Abstract High myopia is a global eye health problem because of its high incidence of sight-threatening complications. Due to the role of awareness, self-examination, and preventive behavior in prevention of morbidity of high myopia complications, promoting knowledge, capabilities, and attitude of high myopic personnel are required in this regard. In this quasi-experiment study, 31 freshmen with high myopia in a national university were enrolled in 2014. The data were collected by validated and reliable questionnaire based on health belief model (HBM) and self-efficacy theory. The intervention program consisted of 1 educational session lasting 150 minutes by lecturing of high myopia complications, virtual reality experiencing, similarity modeling, and quibbling a film made on high myopia complications preventive concepts. Implementing the educational program showed immediate effect in knowledge, perceived susceptibility, perceived severity, self-efficacy, and preventive behavior intention. While 6 weeks after the educational program, significant increases were observed in cues to action, self-efficacy, and preventive behavior intention. This article provided that, after a single session, there was positive improvement in high myopia complication prevention behavior intention among participants. These positive effects confirmed the efficacy of the education program and will probably induce behavior change. PMID:27749586

  17. Evaluation of high myopia complications prevention program in university freshmen.

    PubMed

    Tseng, Gow-Lieng; Chen, Cheng-Yu

    2016-10-01

    High myopia is a global eye health problem because of its high incidence of sight-threatening complications. Due to the role of awareness, self-examination, and preventive behavior in prevention of morbidity of high myopia complications, promoting knowledge, capabilities, and attitude of high myopic personnel are required in this regard.In this quasi-experiment study, 31 freshmen with high myopia in a national university were enrolled in 2014. The data were collected by validated and reliable questionnaire based on health belief model (HBM) and self-efficacy theory. The intervention program consisted of 1 educational session lasting 150 minutes by lecturing of high myopia complications, virtual reality experiencing, similarity modeling, and quibbling a film made on high myopia complications preventive concepts.Implementing the educational program showed immediate effect in knowledge, perceived susceptibility, perceived severity, self-efficacy, and preventive behavior intention. While 6 weeks after the educational program, significant increases were observed in cues to action, self-efficacy, and preventive behavior intention.This article provided that, after a single session, there was positive improvement in high myopia complication prevention behavior intention among participants. These positive effects confirmed the efficacy of the education program and will probably induce behavior change.

  18. Peroxiredoxin 4 Improves Insulin Biosynthesis and Glucose-induced Insulin Secretion in Insulin-secreting INS-1E Cells*

    PubMed Central

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

    2014-01-01

    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. Dating violence prevention in middle school and high school youth.

    PubMed

    Close, Sharron M

    2005-01-01

    Dating violence and interpersonal abuse among middle school and high school students. To review the current literature and evaluate the need of conducting further study in order to create early interventions for the prevention of relationship abuse. Case report and review of the literature. Dating violence among middle school and high school youth must be addressed by screening risk and offering anticipatory guidance during each health maintenance visit in order to prevent victimization of youth in dating and attraction relationships.

  20. Leucine regulation of glucokinase and ATP synthase sensitizes glucose-induced insulin secretion in pancreatic beta-cells.

    PubMed

    Yang, Jichun; Wong, Ryan K; Park, MieJung; Wu, Jianmei; Cook, Joshua R; York, David A; Deng, Shaoping; Markmann, James; Naji, Ali; Wolf, Bryan A; Gao, Zhiyong

    2006-01-01

    We have recently shown that leucine culture upregulates ATP synthase beta-subunit (ATPSbeta) and increases ATP level, cytosolic Ca(2+), and glucose-induced insulin secretion in rat islets. The aim is to test whether glucokinase expression is also affected in rat islets and its role in glucose sensitization during leucine culture. Leucine culture increased glucose-induced NAD(P)H level at 1 and 2 days but not at 1 week. The half-maximal effective concentration of the glucose response curve for NAD(P)H was left-shifted from 5-7 to 2-3 mmol/l. The effect was dose dependent and rapamycin insensitive. Leucine culture did not affect glyceraldehyde effects on NAD(P)H. Leucine pretreatment for 30 min had no effects on NAD(P)H levels. Leucine culture for 2 days also increased glucose-induced cytosolic Ca(2+) elevation, ATP level, and insulin secretion. Leucine increase of glucokinase mRNA levels occurred as early as day 1 and lasted through 1 week. That of ATPSbeta did not occur until day 2 and lasted through 1 week. Leucine effects on both mRNAs were dose dependent. The upregulation of both genes was confirmed by Western blotting. Leucine culture also increased glucose-induced insulin secretion, ATP level, glucokinase, and ATPSbeta levels of type 2 diabetic human islets. In conclusion, leucine culture upregulates glucokinase, which increases NAD(P)H level, and ATPSbeta, which increases oxidation of NADH and production of ATP. The combined upregulation of both genes increases glucose-induced cytosolic Ca(2+) and insulin secretion.

  1. Endogenous hydrogen sulfide protects pancreatic beta-cells from a high-fat diet-induced glucotoxicity and prevents the development of type 2 diabetes.

    PubMed

    Okamoto, Mitsuhiro; Yamaoka, Mami; Takei, Masahiro; Ando, Tomomi; Taniguchi, Shigeki; Ishii, Isao; Tohya, Kazuo; Ishizaki, Toshimasa; Niki, Ichiro; Kimura, Toshihide

    2013-12-13

    Chronic exposure to high glucose induces the expression of cystathionine gamma-lyase (CSE), a hydrogen sulfide-producing enzyme, in pancreatic beta-cells, thereby suppressing apoptosis. The aim of this study was to examine the effects of hydrogen sulfide on the onset and development of type 2 diabetes. Middle-aged (6-month-old) wild-type (WT) and CSE knockout (CSE-KO) mice were fed a high-fat diet (HFD) for 8weeks. We determined the effects of CSE knockout on beta-cell function and mass in islets from these mice. We also analyzed changes in gene expression in the islets. After 8weeks of HFD, blood glucose levels were markedly increased in middle-aged CSE-KO mice, insulin responses were significantly reduced, and DNA fragmentation of the islet cells was increased. Moreover, expression of thioredoxin binding protein-2 (TBP-2, also known as Txnip) was increased. Administration of NaHS, a hydrogen sulfide donor, reduced TBP-2 gene levels in isolated islets from CSE-KO mice. Gene levels were elevated when islets were treated with the CSE inhibitor dl-propargylglycine (PPG). These results provide evidence that CSE-produced hydrogen sulfide protects beta-cells from glucotoxicity via regulation of TBP-2 expression levels and thus prevents the onset/development of type 2 diabetes. Copyright © 2013 Elsevier Inc. All rights reserved.

  2. Two glucose sensing/signaling pathways stimulate glucose-induced inactivation of maltose permease in Saccharomyces.

    PubMed Central

    Jiang, H; Medintz, I; Michels, C A

    1997-01-01

    Glucose is a global metabolic regulator in Saccharomyces. It controls the expression of many genes involved in carbohydrate utilization at the level of transcription, and it induces the inactivation of several enzymes by a posttranslational mechanism. SNF3, RGT2, GRR1 and RGT1 are known to be involved in glucose regulation of transcription. We tested the roles of these genes in glucose-induced inactivation of maltose permease. Our results suggest that at least two signaling pathways are used to monitor glucose levels. One pathway requires glucose sensor transcript and the second pathway is independent of glucose transport. Rgt2p, which along with Snf3p monitors extracellular glucose levels, appears to be the glucose sensor for the glucose-transport-independent pathway. Transmission of the Rgt2p-dependent signal requires Grr1p. RGT2 and GRR1 also play a role in regulating the expression of the HXT genes, which appear to be the upstream components of the glucose-transport-dependent pathway regulating maltose permease inactivation. RGT2-1, which was identified as a dominant mutation causing constitutive expression of several HXT genes, causes constitutive proteolysis of maltose permease, that is, in the absence of glucose. A model of these glucose sensing/signaling pathways is presented. Images PMID:9243508

  3. Palmitate potentiation of glucose-induced insulin release: a study using 2-bromopalmitate.

    PubMed

    Parker, S M; Moore, P C; Johnson, L M; Poitout, V

    2003-10-01

    The mechanisms whereby fatty acids (FA) potentiate glucose-induced insulin secretion from the pancreatic beta cell are incompletely understood. In this study, the effects of palmitate on insulin secretion were investigated in isolated rat islets. Palmitate did not initiate insulin secretion at nonstimulatory glucose concentrations, but markedly stimulated insulin release at concentrations of glucose > or = 5.6 mmol/L. At concentrations of palmitate > or =0.5 mmol/L, the important determinant of the potency of the FA was its unbound concentration. At total concentrations < or = 0.5 mmol/L, both the total and unbound concentrations appeared important. Surprisingly, 2-bromopalmitate did not affect palmitate oxidation, but significantly diminished palmitate esterification into cellular lipids. Neither methyl palmitate, which is not activated into a long-chain acyl-CoA ester, nor 2-bromopalmitate affected glucose-stimulated insulin release. Further, 2-bromopalmitate partly inhibited the potentiating effect of palmitate. These results support the concept that FA potentiation of insulin release is mediated by FA-derived signals generated in the esterification pathway.

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

    PubMed

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

    2004-10-01

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

  5. Aldose reductase inhibitor improves insulin-mediated glucose uptake and prevents migration of human coronary artery smooth muscle cells induced by high glucose.

    PubMed

    Yasunari, K; Kohno, M; Kano, H; Minami, M; Yoshikawa, J

    2000-05-01

    We examined involvement of the polyol pathway in high glucose-induced human coronary artery smooth muscle cell (SMC) migration using Boyden's chamber method. Chronic glucose treatment for 72 hours potentiated, in a concentration-dependent manner (5.6 to 22.2 mol/L), platelet-derived growth factor (PDGF) BB-mediated SMC migration. This potentiation was accompanied by an increase in PDGF BB binding, because of an increased number of PDGF-beta receptors, and this potentiation was blocked by the aldose reductase inhibitor epalrestat. Epalrestat at concentrations of 10 and 100 nmol/L inhibited high glucose-potentiated (22.2 mmol/L), PDGF BB-mediated migration. Epalrestat at 100 nmol/L inhibited a high glucose-induced increase in the reduced/oxidized nicotinamide adenine dinucleotide ratio and membrane-bound protein kinase C (PKC) activity in SMCs. PKC inhibitors calphostin C (100 nmol/L) and chelerythrine (1 micromol/L) each inhibited high glucose-induced, PDGF BB-mediated SMC migration. High glucose-induced suppression of insulin-mediated [(3)H]-deoxyglucose uptake, which was blocked by both calphostin C (100 nmol/L) and chelerythrine (1 micromol/L), was decreased by epalrestat (100 nmol/L). Chronic high glucose treatment for 72 hours increased intracellular oxidative stress, which was directly measured by flow cytometry using carboxydichlorofluorescein diacetate bis-acetoxymethyl ester, and this increase was significantly suppressed by epalrestat (100 nmol/L). Antisense oligonucleotide to PKC-beta isoform inhibited high glucose-mediated changes in SMC migration, insulin-mediated [(3)H]-deoxyglucose uptake, and oxidative stress. These findings suggest that high glucose concentrations potentiate SMC migration in coronary artery and that the aldose reductase inhibitor epalrestat inhibits high glucose-potentiated, PDGF BB-induced SMC migration, possibly through suppression of PKC (PKC-beta), impaired insulin-mediated glucose uptake, and oxidative stress.

  6. 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…

  7. 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…

  8. Glucose Induces Slow-Wave Sleep by Exciting the Sleep-Promoting Neurons in the Ventrolateral Preoptic Nucleus: A New Link between Sleep and Metabolism.

    PubMed

    Varin, Christophe; Rancillac, Armelle; Geoffroy, Hélène; Arthaud, Sébastien; Fort, Patrice; Gallopin, Thierry

    2015-07-08

    Sleep-active neurons located in the ventrolateral preoptic nucleus (VLPO) play a crucial role in the induction and maintenance of slow-wave sleep (SWS). However, the cellular and molecular mechanisms responsible for their activation at sleep onset remain poorly understood. Here, we test the hypothesis that a rise in extracellular glucose concentration in the VLPO can promote sleep by increasing the activity of sleep-promoting VLPO neurons. We find that infusion of a glucose concentration into the VLPO of mice promotes SWS and increases the density of c-Fos-labeled neurons selectively in the VLPO. Moreover, we show in patch-clamp recordings from brain slices that VLPO neurons exhibiting properties of sleep-promoting neurons are selectively excited by glucose within physiological range. This glucose-induced excitation implies the catabolism of glucose, leading to a closure of ATP-sensitive potassium (KATP) channels. The extracellular glucose concentration monitors the gating of KATP channels of sleep-promoting neurons, highlighting that these neurons can adapt their excitability according to the extracellular energy status. Together, these results provide evidence that glucose may participate in the mechanisms of SWS promotion and/or consolidation. Although the brain circuitry underlying vigilance states is well described, the molecular mechanisms responsible for sleep onset remain largely unknown. Combining in vitro and in vivo experiments, we demonstrate that glucose likely contributes to sleep onset facilitation by increasing the excitability of sleep-promoting neurons in the ventrolateral preoptic nucleus (VLPO). We find here that these neurons integrate energetic signals such as ambient glucose directly to regulate vigilance states accordingly. Glucose-induced excitation of sleep-promoting VLPO neurons should therefore be involved in the drowsiness that one feels after a high-sugar meal. This novel mechanism regulating the activity of VLPO neurons reinforces the

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

    PubMed

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

    2012-09-28

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

  10. Protecting Youth, Preventing AIDS: A Guide for Effective High School HIV Prevention Programs.

    ERIC Educational Resources Information Center

    Freudenberg, Nicholas; Radosh, Alice

    This guidebook is for school administrators, teachers, health care workers, parents, and students who want to help their schools prevent HIV, sexually transmitted diseases, and unwanted pregnancy among young people. The experience in more than 120 high schools in New York City has been the basis for the guide, which was developed with the help of…

  11. Advances in the Prevention and Treatment of High Altitude Illness.

    PubMed

    Davis, Christopher; Hackett, Peter

    2017-05-01

    High altitude illness encompasses a spectrum of clinical entities to include: acute mountain sickness, high altitude cerebral edema, and high altitude pulmonary edema. These illnesses occur as a result of a hypobaric hypoxic environment. Although a mild case of acute mountain sickness may be self-limited, high altitude cerebral edema and high altitude pulmonary edema represent critical emergencies that require timely intervention. This article reviews recent advances in the prevention and treatment of high altitude illness, including new pharmacologic strategies for prophylaxis and revised treatment guidelines. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Canadian national high blood pressure prevention and control strategy.

    PubMed

    Chockalingam, A; Campbell, N; Ruddy, T; Taylor, G; Stewart, P

    2000-09-01

    Despite major efforts to prevent and control high blood pressure, it is one of the most common and important health problems facing Canadians. To address this issue, Health Canada, in collaboration with the Canadian Coalition for High Blood Pressure Prevention and Control, established an Expert Working Group to prepare a national strategy. The present report outlines a strategy to prevent and control high blood pressure. It is directed at policy makers at the local, provincial, and/or territorial and national levels in both the health and nonhealth sectors. The strategy is based on current research and expertise. A multifaceted, comprehensive approach is proposed because there is no one intervention that will accomplish the goal of improving the health of Canadians through high blood pressure prevention and control. The present report focuses on the general population. It does not address the unique needs of children, pregnant women or aboriginal peoples. Each of these groups needs to be studied in its own right, and, in particular, with the involvement of aboriginal people themselves. An implementation committee has been established to realize this strategy, and the Canadian Hypertension Society is a key stakeholder in this effort. Several initiatives are underway. Strong advocates are necessary to increase public awareness and to support the system changes required for a successful public health approach to reduce the prevalence of hypertension and its complications.

  13. 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…

  14. 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…

  15. 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.

  16. Effectiveness of a high school alcohol misuse prevention program.

    PubMed

    Shope, J T; Copeland, L A; Maharg, R; Dielman, T E

    1996-08-01

    An alcohol misuse prevention curriculum for tenth-grade students was developed, implemented, and evaluated through twelfth grade with 1041 students from four school districts. The curriculum emphasized social pressures resistance training, immediate effects of alcohol, risks of alcohol misuse, and social pressures to misuse alcohol. There were desirable program effects on alcohol misuse prevention knowledge (p < 0.001), alcohol misuse (p < 0.02), and refusal skills (p < 0.09). Gender by occasion differences were found on alcohol use, alcohol misuse, and driving after drinking, with boys' rates increasing more than those of girls. Exposure to a sixth-grade, as well as the tenth-grade, program did not result in better outcomes. Despite high levels of alcohol use among high school students, a tenth-grade curriculum can result in some desirable effects. Creative approaches are needed, however, especially for boys who tend to use and misuse alcohol at rates that increase more steeply than those of girls.

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

    PubMed

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

    2015-03-10

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

  18. 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

  19. 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.

  20. Prevention of high-pressure injection injuries to the hand.

    PubMed

    Hart, Raymond G; Smith, Gillian D; Haq, Adeel

    2006-01-01

    To identify populations at high risk for, and the usual mechanisms of injury in, high-pressure injection injuries to the hand. A case note review of a historical cohort of 76 patients, presenting with high-pressure injections injuries to the hand over a 12-year period, collected information including sex, age, hand dominance, and occupation of the patient and mechanism of injury, when documented. Eighty-two percent of these injuries were work-related, affecting mainly manual workers (84%), including 13 painters, 10 mechanics, 8 farmers, and 3 water blasters. The mechanism of injury, recorded in 63%, was most commonly a ruptured hose or inadvertent gun discharge during cleaning or use. Preventative measures could include a targeted safety program for equipment users, engineering improvements in gun and hose design, economic incentives, and workplace legislation.

  1. Preventing and Managing Toxicities of High-Dose Methotrexate.

    PubMed

    Howard, Scott C; McCormick, John; Pui, Ching-Hon; Buddington, Randall K; Harvey, R Donald

    2016-12-01

    : High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m(2), is used to treat a range of adult and childhood cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI) in 2%-12% of patients. Nephrotoxicity results from crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. AKI and other toxicities of high-dose methotrexate can lead to significant morbidity, treatment delays, and diminished renal function. Risk factors for methotrexate-associated toxicity include a history of renal dysfunction, volume depletion, acidic urine, and drug interactions. Renal toxicity leads to impaired methotrexate clearance and prolonged exposure to toxic concentrations, which further worsen renal function and exacerbate nonrenal adverse events, including myelosuppression, mucositis, dermatologic toxicity, and hepatotoxicity. Serum creatinine, urine output, and serum methotrexate concentration are monitored to assess renal clearance, with concurrent hydration, urinary alkalinization, and leucovorin rescue to prevent and mitigate AKI and subsequent toxicity. When delayed methotrexate excretion or AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase are usually sufficient to allow renal recovery without the need for dialysis. Prompt recognition and effective treatment of AKI and associated toxicities mitigate further toxicity, facilitate renal recovery, and permit patients to receive other chemotherapy or resume HDMTX therapy when additional courses are indicated.

  2. 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

  3. Involvement of the abscisic acid catabolic gene CYP707A2 in the glucose-induced delay in seed germination and post-germination growth of Arabidopsis.

    PubMed

    Zhu, Guohui; Liu, Yinggao; Ye, Nenghui; Liu, Rui; Zhang, Jianhua

    2011-12-01

    Earlier studies showed that sugars as signaling molecules play pivotal roles in the regulation of seed germination. ABA biosynthesis upregulation is suggested as one of the possible mechanisms mediating the glucose-induced delay in seed germination. In this study, the role of ABA catabolism in glucose-induced inhibition was investigated. Using Arabidopsis thaliana seeds, the results show that the repression of ABA catabolism by diniconazole aggravated the glucose-induced delay in seed germination. The transcript and protein profiles of CYP707A2, a key gene encoding ABA 8'-hydroxylase in ABA catabolism in Arabidopsis, were significantly decreased by exogenous glucose treatment. Transgenic experiments confirmed that the over-expression of the CYP707A2 gene alleviated the glucose-induced inhibition effect, whereas the cyp707a2 mutant seeds displayed a hypersensitivity to glucose during imbibition. Exogenous glucose also arrested the early seedling development of Arabidopsis. The CYP707A2 over-expression seedlings exhibited lower ABA levels and seemed less sensitive to exogenous glucose compared with wild type seedlings. In summary, the glucose-induced delay in seed germination and seedling development is directly related to the suppression of ABA catabolism through the repression of the CYP707A2 expression. Copyright © Physiologia Plantarum 2011.

  4. 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.

  5. 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

  6. Prevention

    MedlinePlus

    ... Error processing SSI file About Heart Disease & Stroke Prevention Heart disease and stroke are an epidemic in ... secondhand smoke. Barriers to Effective Heart Disease & Stroke Prevention Many people with key risk factors for heart ...

  7. Intermittent preventive treatment for the prevention of malaria during pregnancy in high transmission areas

    PubMed Central

    Briand, Valérie; Cottrell, Gilles; Massougbodji, Achille; Cot, Michel

    2007-01-01

    Malaria in pregnancy is one of the major causes of maternal morbidity and adverse birth outcomes. In high transmission areas, its prevention has recently changed, moving from a weekly or bimonthly chemoprophylaxis to intermittent preventive treatment (IPTp). IPTp consists in the administration of a single curative dose of an efficacious anti-malarial drug at least twice during pregnancy – regardless of whether the woman is infected or not. The drug is administered under supervision during antenatal care visits. Sulphadoxine-pyrimethamine (SP) is the drug currently recommended by the WHO. While SP-IPTp seems an adequate strategy, there are many issues still to be explored to optimize it. This paper reviewed data on IPTp efficacy and discussed how to improve it. In particular, the determination of both the optimal number of doses and time of administration of the drug is essential, and this has not yet been done. As both foetal growth and deleterious effects of malaria are maximum in late pregnancy women should particularly be protected during this period. Monitoring of IPTp efficacy should be applied to all women, and not only to primi- and secondigravidae, as it has not been definitively established that multigravidae are not at risk for malaria morbidity and mortality. In HIV-positive women, there is an urgent need for specific information on drug administration patterns (need for higher doses, possible interference with sulpha-based prophylaxis of opportunistic infections). Because of the growing level of resistance of parasites to SP, alternative drugs for IPTp are urgently needed. Mefloquine is presently one of the most attractive options because of its long half life, high efficacy in sub-Saharan Africa and safety during pregnancy. Also, efforts should be made to increase IPTp coverage by improving the practices of health care workers, the motivation of women and their perception of malaria complications in pregnancy. Because IPTp is not applicable in early

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

    PubMed

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

    2015-01-01

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

  9. 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.

  10. Psychosis Prevention: A Modified Clinical High Risk Perspective From the Recognition and Prevention (RAP) Program

    PubMed Central

    Cornblatt, Barbara A.; Carrión, Ricardo E.; Auther, Andrea; McLaughlin, Danielle; Olsen, Ruth H.; John, Majnu; Correll, Christoph U.

    2016-01-01

    Objective Early intervention and prevention of psychosis remain a major challenge. Prediction would be greatly advanced with improved ability to identify individuals at true risk, which, at present, is moderate at best. The authors tested a modified strategy to improve prediction by selecting a more homogeneous high-risk sample (attenuated positive symptom criteria only, age range of mid-teens to early 20s) than is currently standard, combined with a systematic selection of neurodevelopmental deficits. Method A sample of 101 treatment-seeking adolescents (mean age, 15.9 years) at clinical high risk for psychosis were followed clinically for up to 5 years (mean follow-up time, 3.0 years, SD=1.6). Adolescents were included only if they exhibited one or more attenuated positive symptoms at moderate to severe, but not psychotic, severity levels. Cox regression was used to derive a risk index. Results The overall conversion rate to psychosis was 28.3%. The final predictor model, with a positive predictive validity of 81.8%, consisted of four variables: disorganized communication, suspiciousness, verbal memory deficits, and decline in social functioning during follow-up. Significant effects also suggest narrowing the risk age range to 15–22 years. Conclusions Clinical high risk criteria that emphasize disorganized communication and suspiciousness while also including compromised verbal memory and declining social functioning have the potential to improve predictive accuracy compared with attenuated positive symptoms used alone. On the resulting risk index (a weighted combination of the predictors), low scores were interpreted as signifying minimal risk, with little treatment necessary, high scores as suggesting aggressive intervention, and intermediate scores, although less informative, as supporting psychosocial treatment. PMID:26046336

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

    PubMed

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

    2007-03-01

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

  12. Unreported concussion in high school football players: implications for prevention.

    PubMed

    McCrea, Michael; Hammeke, Thomas; Olsen, Gary; Leo, Peter; Guskiewicz, Kevin

    2004-01-01

    To investigate the frequency of unreported concussion and estimate more accurately the overall rate of concussion in high school football players. Retrospective, confidential survey completed by all subjects at the end of the football season. A total of 1,532 varsity football players from 20 high schools in the Milwaukee, Wisconsin, area were surveyed. The structured survey assessed (1) number of concussions before the current season, (2) number of concussions sustained during the current season, (3) whether concussion during the current season was reported, (4) to whom concussion was reported, and (5) reasons for not reporting concussion. Of respondents, 29.9% reported a previous history of concussion, and 15.3% reported sustaining a concussion during the current football season; of those, 47.3% reported their injury. Concussions were reported most frequently to a certified athletic trainer (76.7% of reported injuries). The most common reasons for concussion not being reported included a player not thinking the injury was serious enough to warrant medical attention (66.4% of unreported injuries), motivation not to be withheld from competition (41.0%), and lack of awareness of probable concussion (36.1%). These findings reflect a higher prevalence of concussion in high school football players than previously reported in the literature. The ultimate concern associated with unreported concussion is an athlete's increased risk of cumulative or catastrophic effects from recurrent injury. Future prevention initiatives should focus on education to improve athlete awareness of the signs of concussion and potential risks of unreported injury.

  13. Prevention

    Treesearch

    Kerry Britton; Barbara Illman; Gary Man

    2010-01-01

    Prevention is considered the most cost-effective element of the Forest Service Invasive Species Strategy (USDA Forest Service 2004). What makes prevention difficult is the desire to maximize free trade and the resulting benefits to society while, at the same time, protecting natural resources. The role of science is to first identify which commodities pose an...

  14. Beta-casomorphin-7 prevents epithelial-mesenchymal transdifferentiation of NRK-52E cells at high glucose level: Involvement of AngII-TGF-β1 pathway.

    PubMed

    Zhang, Wei; Song, Shangxin; Liu, Fei; Liu, Yi; Zhang, Yuanshu

    2015-08-01

    Hyperglycemia is the most important risk factor in the progression of renal fibrosis in diabetic kidney. Based on previous studies, β-casomorphin-7 may exert anti-fibrotic activities in diabetic rats. However, the role of β-casomorphin-7 in the pathogenesis of renal tubulointerstitial fibrosis remains unclear. Thus, this study was designed to investigate the protective effect of β-casomorphin-7 on epithelial-mesenchymal transition (EMT) of NRK-52E cells treated under hyperglycemic condition and to explore the possible mechanism. NRK-52E cells were cultured in high glucose (30 mM) for 3 days. Different concentrations of β-casomorphin-7, naloxone (antagonist of opioid receptor) and losartan (antagonist of angiotensin II type I receptor) were added in the culture. Expression of α-smooth muscle actin (α-SMA), E-cadherin, vimentin and cytokeratin19 mRNA were determined by real-time PCR. Protein levels of E-cadherin and α-SMA were analyzed by Western blotting. The concentrations of angiotensin (Ang) II and transforming growth factor β1 (TGF-β1) in the culture medium were determined. High glucose-induced up-regulation of vimentin mRNA and α-SMA mRNA and protein were significantly inhibited by β-casomorphin-7. On the contrary, high glucose-induced down-regulation of cytokeratin19 mRNA and E-cad mRNA and protein was significantly reversed by β-casomorphin-7. β-casomorphin-7 significantly alleviate high glucose induced increase of AngII and TGF-β1 in the culture. Moreover, losartan significantly attenuated the expression of TGF-β1 and EMT of NRK-52E cells treated under hyperglycemic condition. But naloxone did not affect the EMT of NRK-52E cells treated by high glucose and β-casomorphin-7. We demonstrate that β-casomorphin-7 has the potential to inhibit high glucose-induced renal proximal tubular EMT partly by modulating AngII-TGF-β1 pathway, but not by opioid receptor. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. "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

  16. Involvement of AMPK in regulating the degradation of MAD2B under high glucose in neuronal cells.

    PubMed

    Meng, Xianfang; Chu, Guangpin; Ye, Chen; Tang, Hui; Qiu, Ping; Hu, Yue; Li, Man; Zhang, Chun

    2016-12-13

    Although our recent study has demonstrated that mitotic spindle assembly checkpoint protein (MAD2B) mediates high glucose-induced neuronal apoptosis, the mechanisms for MAD2B degradation under hyperglycaemia have not yet been elucidated. In this study, we first found that the activation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) was decreased in neurons, accompanied with the increased expression of MAD2B. Mechanistically, we demonstrated that activation of AMPK with its activators such as AICAR and metformin decreased the expression of MAD2B, indicating a role of AMPK in regulating the expression of MAD2B. Moreover, activation of AMPK prevented neuronal cells from high glucose-induced injury as demonstrated by the reduced expression of cyclin B1 and percentage of apoptosis as detected by TUNEL. We further found that when total protein synthesis was suppressed by chlorhexidine, the degradation of MAD2B was slower in high glucose-treated neurons and was mainly dependent on the ubiquitin-proteasome system. Finally, it was indicated that high glucose inhibited the ubiquitination of MAD2B, which could be reversed by activation of AMPK. Collectively, this study demonstrates that AMPK acts as a key regulator of MAD2B expression, suggesting that activation of AMPK signalling might be crucial for the treatment of high glucose-induced neuronal injury.

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

    PubMed

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

    2017-03-01

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

  18. 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. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  19. 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

  20. Mechanisms of defective glucose-induced insulin release in human pancreatic islets transplanted to diabetic nude mice.

    PubMed

    Eizirik, D L; Jansson, L; Flodström, M; Hellerström, C; Andersson, A

    1997-08-01

    We have previously observed that human islets, transplanted under the kidney capsule of hyperglycemic nude mice, show a longlasting impairment in glucose-induced insulin release. To investigate the cause(s) of this phenomenon, we transplanted human islets into normoglycemic or alloxan-diabetic nude mice for a 4- to 6-week period. In a third experimental group, aimed at evaluating reversibility of hyperglycemia effects, diabetic nude mice bearing a human islet graft were cured by a second intrasplenic transplant of mouse islets, and the human islets were exposed to a further 2 weeks of normoglycemia. Four to 6 weeks of hyperglycemia induced a severe impairment of glucose- and arginine-induced insulin release, as demonstrated by perfusion of the graft-bearing kidney. This defective release was not restored by a subsequent 2-week period of normoglycemia, and it was accompanied by normal (pro)insulin biosynthesis, glucose oxidation, and expression of insulin messenger RNA. Taken together with our previous study, these observations indicate that impaired glucose metabolism, depletion of insulin messenger RNA, decreased (pro)insulin biosynthesis, increased glycogen accumulation, and depletion of insulin reserves cannot explain the deleterious effects of the diabetic state on human islet insulin release. This, and the similar inhibition of glucose- and arginine-induced insulin release, suggest that prolonged hyperglycemia may exert its deleterious effect on insulin release at a step distal to closure of ATP-sensitive K-channels.

  1. Glucose-induced electrical activities and insulin secretion in pancreatic islet β-cells are modulated by CFTR

    PubMed Central

    Guo, Jing Hui; Chen, Hui; Ruan, Ye Chun; Zhang, Xue Lian; Zhang, Xiao Hu; Fok, Kin Lam; Tsang, Lai Ling; Yu, Mei Kuen; Huang, Wen Qing; Sun, Xiao; Chung, Yiu Wa; Jiang, Xiaohua; Sohma, Yoshiro; Chan, Hsiao Chang

    2014-01-01

    The cause of insulin insufficiency remains unknown in many diabetic cases. Up to 50% adult patients with cystic fibrosis (CF), a disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), develop CF-related diabetes (CFRD) with most patients exhibiting insulin insufficiency. Here we show that CFTR is a regulator of glucose-dependent electrical acitivities and insulin secretion in β-cells. We demonstrate that glucose elicited whole-cell currents, membrane depolarization, electrical bursts or action potentials, Ca2+ oscillations and insulin secretion are abolished or reduced by inhibitors or knockdown of CFTR in primary mouse β-cells or RINm5F β-cell line, or significantly attenuated in CFTR mutant (DF508) mice compared with wild-type mice. VX-809, a newly discovered corrector of DF508 mutation, successfully rescues the defects in DF508 β-cells. Our results reveal a role of CFTR in glucose-induced electrical activities and insulin secretion in β-cells, shed light on the pathogenesis of CFRD and possibly other idiopathic diabetes, and present a potential treatment strategy. PMID:25025956

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

    PubMed Central

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

    2016-01-01

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

  3. Glucose-induced phosphorylation of the insulin receptor. Functional effects and characterization of phosphorylation sites.

    PubMed Central

    Pillay, T S; Xiao, S; Olefsky, J M

    1996-01-01

    Elevated glucose concentrations have been reported to inhibit insulin receptor kinase activity. We studied the effects of high glucose on insulin action in Rat1 fibroblasts transfected with wild-type human insulin receptor (HIRcB) and a truncated receptor lacking the COOH-terminal 43 amino acids (delta CT). In both cell lines, 25 mM glucose impaired receptor and insulin receptor substrate-1 phosphorylation by 34%, but IGF-1 receptor phosphorylation was unaffected. Phosphatidylinositol 3-kinase activity and bromodeoxyuridine uptake were decreased by 85 and 35%, respectively. This was reversed by coincubation with a protein kinase C (PKC) inhibitor or microinjection of a PKC inhibitor peptide. Phosphopeptide mapping revealed that high glucose or PMA led to serine/threonine phosphorylation of similar peptides. Inhibition of the microtubule-associated protein (MAP) kinase cascade by the MAP kinase kinase inhibitor PD98059 did not reverse the impaired phosphorylation. We conclude that high glucose inhibits insulin action by inducing serine phosphorylation through a PKC-mediated mechanism at the level of the receptor at sites proximal to the COOH-terminal 43 amino acids. This effect is independent of activation of the MAP kinase cascade. Proportionately, the impairment of insulin receptor substrate-1 tyrosine phosphorylation is greater than that of the insulin receptor resulting in attenuated phosphatidylinositol 3-kinase activation and mitogenic signaling. PMID:8609215

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

    PubMed

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

    2005-01-01

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

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

    PubMed

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

    2014-06-01

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

  6. Oleanolic acid prevents cartilage degeneration in diabetic mice via PPARγ associated mitochondrial stabilization.

    PubMed

    Kang, Xia; Yang, Zhikui; Sheng, Jun; Liu, Jin-Biao; Xie, Qing-Yun; Zheng, Wei; Chen, Ken

    2017-08-26

    Hyperglycemia-induced cartilage degeneration induces osteoarthritis (OA). Since oleanolic acid (OLA) have several pharmacological effects such as anti-inflammatory, anti-oxidant, we hypothesized it possesses protection against high glucose injured cartilage. We now report that OLA decreased type X collagen and reversed the cartilage degeneration in growth plate from db/db mice. OLA increased type Ⅱ collagen expression in a concentration-dependent manner (10-50 μΜ) in high glucose-treated chondrocytes. OLA prevented the high glucose induced cell injury and decreased the level of MMP-13, PGE2 and IL-6 due to decreasing mitochondrial membrane potential and stimulated the ATP production. Moreover, OLA treatment inhibited apoptosis. And the reversed SOD2 expression and activity may be ascribed to decreased SOD2 protein degradation by OLA treatment, via PPPAγ. In conclusion, OLA protected against the high-glucose-induced cartilage injury via PPARγ/SOD2 pathway. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. 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.

  8. 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

  9. Glucose induces expression of stearoyl-CoA desaturase in 3T3-L1 adipocytes.

    PubMed Central

    Jones, B H; Standridge, M K; Claycombe, K J; Smith, P J; Moustaïd-Moussa, N

    1998-01-01

    Stearoyl-CoA desaturase (SCD; EC 1.14.99.5) is a key enzyme in the synthesis polyunsaturated fatty acids. Liver and ose tissue are the predominant sites of SCD expression. Regulation of tic SCD by various nutritional and hormonal ors, such as insulin, dietary carbohydrates and polyunsaturated fatty s, has been well documented. Little is known, ver, about adipocyte SCD regulation despite high levels of SCD activity adipose tissue. The present study was gned to investigate SCD regulation in adipocytes by examining the cts of glucose and insulin on SCD expression. We rt here that glucose availability directly increased SCD gene scription in 3T3-L1 adipocytes. This response was pendent of insulin, and insulin alone in the absence of glucose had no ct on SCD mRNA levels. SCD thus represents a l model in which to investigate the mechanisms of direct regulation of expression by glucose in adipose cells. PMID:9867800

  10. Reaping the prevention benefits of highly active antiretroviral treatment: policy implications of HIV Prevention Trials Network 052.

    PubMed

    Forsyth, Andrew D; Valdiserri, Ronald O

    2012-03-01

    This review explores the policy implications of findings from the HIV Prevention Trials Network (HPTN 052) treatment as prevention (TasP) study. To date, the potential of antiretrovirals to prevent sexual transmission of HIV by infected persons has been grounded in observational cohort, ecological, mathematical modeling, and meta-analytic studies. HPTN 052 represents the first randomized controlled trial to test the secondary prevention benefit of HIV transmission using antiretroviral treatment in largely asymptomatic persons with high CD4 cell counts. The US National HIV/AIDS Strategy has among its key goals the reduction of incident HIV infections, improved access to quality care and associated outcomes, and the reduction in HIV-associated health disparities and inequities. HPTN 052 demonstrates that providing TasP, in combination with other effective prevention strategies offers the promise of achieving these life-saving goals. But HPTN 052 also highlights the need for cautious optimism and underscores the importance of addressing current gaps in the HIV prevention, treatment, and care continuum in order for 'TasP' strategies to achieve their full potential. Among these are necessary improvements in the capacity to expand HIV testing, facilitate effective linkage and retention in care, and improve treatment initiation, maintenance, and virus suppression.

  11. HB-EGF release mediates glucose-induced activation of the epidermal growth factor receptor in mesangial cells.

    PubMed

    Uttarwar, L; Peng, F; Wu, D; Kumar, S; Gao, B; Ingram, A J; Krepinsky, J C

    2011-04-01

    Glomerular matrix accumulation is a hallmark of diabetic nephropathy. We showed that transactivation of the epidermal growth factor receptor (EGFR) is an important mediator of matrix upregulation in mesangial cells (MC) in response to high glucose (HG). Here, we study the mechanism of EGFR transactivation. In primary MC, EGFR transactivation by 1 h of HG (30 mM) was unaffected by inhibitors of protein kinase C, reactive oxygen species, or the angiotensin II AT1 receptor. However, general metalloprotease inhibition, as well as specific inhibitors of heparin-binding EGF-like growth factor (HB-EGF), prevented both EGFR and downstream Akt activation. HB-EGF was released into the medium by 30 min of HG, and this depended on metalloprotease activity. One of the metalloproteases shown to cleave proHB-EGF is ADAM17 (TACE). HG, but not an osmotic control, activated ADAM17, and its inhibition prevented EGFR and Akt activation and HB-EGF release into the medium. siRNA to either ADAM17 or HB-EGF prevented HG-induced EGFR transactivation. We previously showed that EGFR/Akt signaling increases transforming growth factor (TGF)-β1 transcription through the transcription factor activator protein (AP)-1. HG-induced AP-1 activation, as assessed by EMSA, was abrogated by inhibitors of metalloproteases, HB-EGF and ADAM17. HB-EGF and ADAM17 siRNA also prevented AP-1 activation. Finally, these inhibitors and siRNA prevented TGF-β1 upregulation by HG. Thus, HG-induced EGFR transactivation in MC is mediated by the release of HB-EGF, which requires activity of the metalloprotease ADAM17. The mechanism of ADAM17 activation awaits identification. Targeting upstream mediators of EGFR transactivation including HB-EGF or ADAM17 provides novel therapeutic targets for the treatment of diabetic nephropathy.

  12. 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

  13. 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.

  14. High Glucose Up-regulates ADAM17 through HIF-1α in Mesangial Cells*

    PubMed Central

    Li, Renzhong; Uttarwar, Lalita; Gao, Bo; Charbonneau, Martine; Shi, Yixuan; Chan, John S. D.; Dubois, Claire M.; Krepinsky, Joan C.

    2015-01-01

    We previously showed that ADAM17 mediates high glucose-induced matrix production by kidney mesangial cells. ADAM17 expression is increased in diabetic kidneys, suggesting that its up-regulation may augment high glucose profibrotic responses. We thus studied the effects of high glucose on ADAM17 gene regulation. Primary rat mesangial cells were treated with high glucose (30 mm) or mannitol as osmotic control. High glucose dose-dependently increased ADAM17 promoter activity, transcript, and protein levels. This correlated with augmented ADAM17 activity after 24 h versus 1 h of high glucose. We tested involvement of transcription factors shown in other settings to regulate ADAM17 transcription. Promoter activation was not affected by NF-κB or Sp1 inhibitors, but was blocked by hypoxia-inducible factor-1α (HIF-1α) inhibition or down-regulation. This also prevented ADAM17 transcript and protein increases. HIF-1α activation by high glucose was shown by its increased nuclear translocation and activation of the HIF-responsive hypoxia-response element (HRE)-luciferase reporter construct. Assessment of ADAM17 promoter deletion constructs coupled with mutation analysis and ChIP studies identified HIF-1α binding to its consensus element at −607 as critical for the high glucose response. Finally, inhibitors of epidermal growth factor receptor (EGFR) and downstream PI3K/Akt, or ADAM17 itself, prevented high glucose-induced HIF-1α activation and ADAM17 up-regulation. Thus, high glucose induces ADAM17 transcriptional up-regulation in mesangial cells, which is associated with augmentation of its activity. This is mediated by HIF-1α and requires EGFR/ADAM17 signaling, demonstrating the potentiation by ADAM17 of its own up-regulation. ADAM17 inhibition thus provides a potential novel therapeutic strategy for the treatment of diabetic nephropathy. PMID:26175156

  15. Staphylococcus aureus glucose-induced biofilm accessory proteins, GbaAB, influence biofilm formation in a PIA-dependent manner.

    PubMed

    You, Yibo; Xue, Ting; Cao, Linyan; Zhao, Liping; Sun, Haipeng; Sun, Baolin

    2014-07-01

    The Gram-positive bacteria Staphylococcus aureus and Staphylococcus epidermidis are capable of attaching to a biomaterial surface and forming resistant biofilms. The identification of biomolecular and regulatory factors involved in staphylococcal adhesion and biofilm formation is needed to understand biofilm-associated infection in humans. Here, we have identified a new operon, gbaAB (glucose induced biofilm accessory gene), that affects biofilm formation in S. aureus NCTC8325. Real-time reverse transcription PCR (RT-PCR) and electrophoretic mobility shift assay showed that GbaA and GbaB are transcribed from the same transcript, and GbaA directly inhibits the transcription of the gbaAB operon through self-repression. Our results indicated that the gbaA mutant displayed enhanced biofilm formation compared with the wild type. However, the gbaB and the gbaAB double mutant displayed reduced biofilm formation, suggesting that the gbaAB operon is involved in biofilm formation and that gbaB might be the key gene in biofilm regulation. Phenotypic analysis suggested that the gbaAB operon mediated biofilm formation of S. aureus at the multicellular aggregation stage rather than during initial attachment. In addition, real-time RT-PCR analysis showed that icaA was upregulated in the gbaA mutant and downregulated in the gbaB and gbaAB mutants compared with the wild type. In addition, the gbaA and the gbaB mutants affected the induction of biofilm formation by glucose. Our results suggest that the gbaAB operon is involved in the regulation of the multicellular aggregation step of S. aureus biofilm formation in response to glucose and that this regulation may be mediated through the ica operon. Copyright © 2014 Elsevier GmbH. All rights reserved.

  16. 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

  17. 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…

  18. Ginseng Extracts Restore High-Glucose Induced Vascular Dysfunctions by Altering Triglyceride Metabolism and Downregulation of Atherosclerosis-Related Genes

    PubMed Central

    Chan, Gabriel Hoi-huen; Law, Betty Yuen-kwan; Chu, John Man-tak; Yue, Kevin Kin-man; Jiang, Zhi-hong; Lau, Chi-wai; Huang, Yu; Chan, Shun-wan; Ying-kit Yue, Patrick; Wong, Ricky Ngok-shun

    2013-01-01

    The king of herbs, Panax ginseng, has been used widely as a therapeutic agent vis-à-vis its active pharmacological and physiological effects. Based on Chinese pharmacopeia Ben Cao Gang Mu and various pieces of literature, Panax ginseng was believed to exert active vascular protective effects through its antiobesity and anti-inflammation properties. We investigated the vascular protective effects of ginseng by administrating ginseng extracts to rats after the induction of diabetes. We found that Panax ginseng can restore diabetes-induced impaired vasorelaxation and can reduce serum triglyceride but not cholesterol level in the diabetic rats. The ginseng extracts also suppressed the expression of atherosclerosis-related genes and altered the expression of lipid-related genes. The results provide evidence that Panax ginseng improves vascular dysfunction induced by diabetes and the protective effects may possibly be due to the downregulation of atherosclerosis-related genes and altered lipid metabolism, which help to restore normal endothelium functions. PMID:24194784

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

    PubMed

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

    2016-08-01

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

  20. Ginseng extracts restore high-glucose induced vascular dysfunctions by altering triglyceride metabolism and downregulation of atherosclerosis-related genes.

    PubMed

    Chan, Gabriel Hoi-Huen; Law, Betty Yuen-Kwan; Chu, John Man-Tak; Yue, Kevin Kin-Man; Jiang, Zhi-Hong; Lau, Chi-Wai; Huang, Yu; Chan, Shun-Wan; Ying-Kit Yue, Patrick; Wong, Ricky Ngok-Shun

    2013-01-01

    The king of herbs, Panax ginseng, has been used widely as a therapeutic agent vis-à-vis its active pharmacological and physiological effects. Based on Chinese pharmacopeia Ben Cao Gang Mu and various pieces of literature, Panax ginseng was believed to exert active vascular protective effects through its antiobesity and anti-inflammation properties. We investigated the vascular protective effects of ginseng by administrating ginseng extracts to rats after the induction of diabetes. We found that Panax ginseng can restore diabetes-induced impaired vasorelaxation and can reduce serum triglyceride but not cholesterol level in the diabetic rats. The ginseng extracts also suppressed the expression of atherosclerosis-related genes and altered the expression of lipid-related genes. The results provide evidence that Panax ginseng improves vascular dysfunction induced by diabetes and the protective effects may possibly be due to the downregulation of atherosclerosis-related genes and altered lipid metabolism, which help to restore normal endothelium functions.

  1. The Prevalence of Effective Substance Use Prevention Curricula in the Nation’s High Schools

    PubMed Central

    Ringwalt, Chris; Hanley, Sean; Vincus, Amy A.; Ennett, Susan T.; Rohrbach, Louise A.; Bowling, J. Michael

    2009-01-01

    Despite a substantial proportion of high school students who initiate substance use following middle school, the implementation of universal evidence-based prevention curricula appears to be scant. We report data collected in 2005 from 1392 school-district based drug prevention coordinators, from a national, representative study of school-based substance use prevention practices. Altogether, 10.3% of districts that included high school grades reported administering one of six such curricula that were then rated as effective by the Substance Abuse and Mental Health Services Administration’s National Registry of Effective Programs and Practices or Blueprints for Violence Prevention, and 5.7% reported that they used one of these curricula the most. Only 56.5% of the nation’s districts with high school grades administered any substance use prevention programming in at least one of their constituent high schools. PMID:19015989

  2. Parents' Expectations of High Schools in Firearm Violence Prevention.

    PubMed

    Payton, Erica; Khubchandani, Jagdish; Thompson, Amy; Price, James H

    2017-05-19

    Firearm violence remains a significant problem in the US (with 2787 adolescents killed in 2015). However, the research on school firearm violence prevention practices and policies is scant. Parents are major stakeholders in relation to firearm violence by youths and school safety in general. The purpose of this study was to examine what parents thought schools should be doing to reduce the risk of firearm violence in schools. A valid and reliable questionnaire was mailed to a national random sample of 600 parents who had at least one child enrolled in a public secondary school (response rate = 47%). Parents perceived inadequate parental monitoring/rearing practices (73%), peer harassment and/or bullying (58%), inadequate mental health care services for youth (54%), and easy access to guns (51%) as major causes of firearm violence in schools. The school policies perceived to be most effective in reducing firearm violence were installing an alert system in schools (70%), working with law enforcement to design an emergency response plan (70%), creating a comprehensive security plan (68%), requiring criminal background checks for all school personnel prior to hiring (67%), and implementing an anonymous system for students to report peer concerns regarding potential violence (67%). Parents seem to have a limited grasp of potentially effective interventions to reduce firearm violence.

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

    PubMed Central

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

    2013-01-01

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

  4. A Preventive Dental Program for "High Risk" Children

    ERIC Educational Resources Information Center

    Meskin, Lawrence H.; And Others

    1977-01-01

    A dental health program in an elementary school succeeded in identifying children considered to be "high risk" in oral health and, through treatment and education, significantly improved their dental health. (JD)

  5. Participation in Counseling Programs: High-Risk Participants are Reluctant to Accept HIV-Prevention Counseling

    ERIC Educational Resources Information Center

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

    2009-01-01

    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,…

  6. 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…

  7. Participation in Counseling Programs: High-Risk Participants are Reluctant to Accept HIV-Prevention Counseling

    ERIC Educational Resources Information Center

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

    2009-01-01

    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,…

  8. High dietary fiber intake prevents stroke at a population level.

    PubMed

    Casiglia, Edoardo; Tikhonoff, Valérie; Caffi, Sandro; Boschetti, Giovanni; Grasselli, Carla; Saugo, Mario; Giordano, Nunzia; Rapisarda, Valentina; Spinella, Paolo; Palatini, Paolo

    2013-10-01

    This research was aimed at clarifying whether high dietary fiber intake has an impact on incidence and risk of stroke at a population level. In 1647 unselected subjects, dietary fiber intake (DFI) was detected in a 12-year population-based study, using other dietary variables, anagraphics, biometrics, blood pressure, heart rate, blood lipids, glucose, insulin, uricaemia, fibrinogenaemia, erytrosedimentation rate, diabetes, insulin resistance, smoking, pulmonary disease and left ventricular hypertrophy as covariables. In adjusted Cox models, high DFI reduced the risk of stroke. In analysis based on quintiles of fiber intake adjusted for confounders, HR for incidence of stroke was lower when the daily intake of soluble fiber was >25 g or that of insoluble fiber was >47 g. In multivariate analyses, using these values as cut-off of DFI, the risk of stroke was lower in those intaking more that the cut-off of soluble (HR 0.31, 0.17-0.55) or insoluble (HR 0.35, 0.19-0.63) fiber. Incidence of stroke was also lower (-50%, p < 0.003 and -46%, p < 0.01, respectively). Higher dietary DFI is inversely and independently associated to incidence and risk of stroke in general population. Copyright © 2012 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

  9. 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

  10. Sustaining the utilization and high quality implementation of tested and effective prevention programs using the communities that care prevention system.

    PubMed

    Fagan, Abigail A; Hanson, Koren; Briney, John S; David Hawkins, J

    2012-06-01

    This paper describes the extent to which communities implementing the Communities That Care (CTC) prevention system adopt, replicate with fidelity, and sustain programs shown to be effective in reducing adolescent drug use, delinquency, and other problem behaviors. Data were collected from directors of community-based agencies and coalitions, school principals, service providers, and teachers, all of whom participated in a randomized, controlled evaluation of CTC in 24 communities. The results indicated significantly increased use and sustainability of tested, effective prevention programs in the 12 CTC intervention communities compared to the 12 control communities, during the active phase of the research project when training, technical assistance, and funding were provided to intervention sites, and 2 years following provision of such resources. At both time points, intervention communities also delivered prevention services to a significantly greater number of children and parents. The quality of implementation was high in both conditions, with only one significant difference: CTC sites were significantly more likely than control sites to monitor the quality of implementation during the sustainability phase of the project.

  11. Geniposide protects pancreatic β cells from high glucose-mediated injury by activation of AMP-activated protein kinase.

    PubMed

    Liu, Chunyan; Hao, Yanan; Yin, Fei; Zhang, Yonglan; Liu, Jianhui

    2017-05-01

    Our previous works indicated that geniposide could regulate glucose-stimulated insulin secretion (GSIS), and improved chronic high glucose-induced dysfunctions in pancreatic β cells, but the molecular mechanisms remain largely unknown. In the present study, we investigated the role of 5'-AMP-activated protein kinase (AMPK) in high glucose induced cell injury and explored the associated molecular mechanisms in rat INS-1 pancreatic β cells. Data suggested that geniposide obviously prevented the cell damage induced by high (25 mM) glucose in INS-1 cells, which increased the protein levels of cell apoptosis-associated enzymes, including heme oxygenase-1 (HO-1), and Bcl-2, but apparently attenuated the protein level of Bax, an apoptotic protein. In addition, Compound C, an AMPK inhibitor, remarkably inhibited the effects of geniposide on the protein levels of HO-1, Bcl-2, and Bax, but AICAR, an AMPK activator, potentiated the role of geniposide on the protein levels of HO-1, Bcl-2, and Bax. More importantly, geniposide directly prevented the cleavage of caspase-3 induced by high glucose, and this effect was also evidently prohibited by the pre-incubation of compound C in high glucose-treated INS-1 cells. Furthermore, using the method of RNA interfere, we further proved that treatment with AMPK siRNA attenuated the effects of geniposide on the apoptosis-associated proteins and cell viability. All these data suggest that AMPK plays a crucial role on geniposide antagonizing high glucose-induced pancreatic β cells injury. © 2017 International Federation for Cell Biology.

  12. High school coaches' assessments, intentions to use, and use of a concussion prevention toolkit: Centers for Disease Control and Prevention's heads up: concussion in high school sports.

    PubMed

    Sawyer, Richard J; Hamdallah, Myriam; White, Debbie; Pruzan, Marcia; Mitchko, Jane; Huitric, Michele

    2010-01-01

    This study evaluated school coaches' perceptions, assessments, and use of a toolkit to prevent and manage concussions among school athletes. A computer-assisted telephone survey was conducted with a stratified, random sample of high school coaches (n = 497; response rate = 39.3%; cooperation rate = 81.5%) from five states. Most reported that they had used or planned to use kit materials. Most (81%) in schools with a written plan for preventing and managing concussions indicated that the toolkit could be used to improve it and 96% of coaches in schools without a plan indicated that the kit could be used to develop one. Most assessed the kit as visually appealing, easy to use, and containing appropriate content. There were no significant differences among coaches with differing professional experience or for sports with different injury rates. Among those with other concussion-prevention materials, most indicated greater satisfaction with the toolkit.

  13. Taurine prevents collagen abnormalities in high fructose-fed rats.

    PubMed

    Nandhini, A T Anitha; Thirunavukkarasu, V; Anuradha, C V

    2005-08-01

    Accumulation of collagen and changes in its physiochemical properties contribute to the development of secondary complications of diabetes. We undertook this study to see the effects of taurine on the content and characteristics of collagen from tail tendon of rats fed with high fructose diet. The rats were divided into four groups of six each: control group (CON), taurine-supplemented control group (CON+TAU), taurine supplemented (FRU+TAU) and not supplemented fructose-fed group (FRU). The physico-chemical properties of collagen isolated from the tail tendon were studied. Fructose administration caused accumulation of collagen in tail tendon. Enhanced glycation and advanced glycation end products (AGE)-linked fluorescence together with alterations in aldehyde content, solubility pattern, susceptibility to denaturing agents and shrinkage temperature were observed in fructose-fed rats. Elevated b component of type I collagen was evidenced from the SDS gel pattern of collagen from the fructose-fed rats. Simultaneous administration of taurine alleviated these changes. Taurine administration to fructose-rats had a positive influence on both quantitative and qualitative properties of collagen. The results of the present study suggested a role for the action of taurine in delaying diabetic complications and the possible use of taurine as an adjuvant therapeutic measure in the management of diabetes and its complications.

  14. A drop-out prevention program for high-risk inner-city youth.

    PubMed

    Lever, Nancy; Sander, Mark A; Lombardo, Sylvie; Randall, Camille; Axelrod, Jennifer; Rubenstein, Michelle; Weist, Mark D

    2004-07-01

    Inner-city youth are at high risk for dropping out of high school. Within this article, risk factors associated with dropout and strategies for effective prevention and intervention are reviewed. An example of a school-based drop-out prevention program is highlighted. The FUTURES Program is a school-based drop-out prevention program designed to address the needs of high-risk youth through smaller classes, character development, career preparation, case management/mentoring, positive incentives, and access to mental health services. Components of the program are described in detail and data evaluating the effectiveness of the program are presented. Directions for the future development of programs and conducting research to prevent dropout by inner-city youth are discussed.

  15. Relative Effectiveness of Continued, Lapsed, and Delayed Smoking Prevention Intervention in Senior High School Students.

    ERIC Educational Resources Information Center

    Eckhardt, Laura; And Others

    1997-01-01

    Reports findings from the final year of a tobacco use prevention project for junior and senior high school students. After three years of intervention with junior high students, researchers assessed the relative effectiveness of continued, lapsed, and delayed interventions in high school. In grade 11, continued intervention students had the lowest…

  16. High school health-education teachers' perceptions and practices related to teaching HIV prevention.

    PubMed

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

    2012-11-01

    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. A total of 800 surveys were sent to a national random sample of high school health teachers and 50% responded. There was almost complete agreement (99%) among respondents that HIV prevention instruction is needed. The factors that emerged as significantly influencing the attitudes and perceptions of high school health teachers about teaching HIV prevention were related to teacher preparation, training, and years of experience teaching health education. A state mandate requiring HIV prevention instruction was significantly associated with higher teacher efficacy expectations and more perceived benefits, but did not have a significant influence in relation to practices in the classroom. Characteristics of high school health teachers that were significantly related to attitudes, perceptions, and instructional practices included the instructor's age, sex, and race/ethnicity. High school health teachers who reported the least experience teaching health education had the least supportive attitudes, perceived the most barriers, and had the lowest efficacy and outcome expectations related to teaching about HIV prevention. Whereas these findings support the importance of teacher preparation and training, they also suggest that more recent college graduates may not be fully prepared to provide effective instruction in HIV prevention. © 2012, American School Health Association.

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

    PubMed Central

    Datar, Savita; Bhonde, Ramesh R.

    2005-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  19. [Dementia prevention: potential treatments and how to target high risk patients].

    PubMed

    Samaras, Nikolaos; Samaras, Dimitrios; Frangos, Emilia; Forster, Alexandre

    2013-05-22

    The burden related to the ever-increasing dementia prevalence in older individuals, imposes the implementation of prevention strategies. It is now known that brain lesions related to Alzheimer's disease precede the onset of the first symptoms. Consequently, prevention strategies should be implemented early, before clinically overt dementia. Blood and spine fluid tests, electroencephalogram, brain magnetic resonance and brain nuclear imaging should help physicians to better target "high-risk" patients prone to benefit from such strategies, already in a preclinical disease stage. Since no efficient pharmacological treatments exist for the time being, lifestyle factors such as nutritionand physical exercise are the cornerstones for dementia prevention.

  20. Optimizing violence prevention programs: an examination of program effectiveness among urban high school students.

    PubMed

    Thompkins, Amanda C; Chauveron, Lisa M; Harel, Ofer; Perkins, Daniel F

    2014-07-01

    While demand for youth violence prevention programs increases, the ability of the school-day schedule to accommodate their time requirements has diminished. Viable school-based prevention programs must strike a balance between brevity and effectiveness. This article reports results from an effectiveness trial of a 12-session curriculum-based universal violence prevention program that promotes healthy conflict resolution skills among urban adolescents. Using a review of program record data and a multisite quasi-experimental study design, we examined the effectiveness of a New York City-based violence prevention program entitled the Violence Prevention project (VPP) optimized to meet school needs. We analyzed survey data from 1112 9th- and 10th-grade students in 13 New York City public high schools across 4 consecutive school years. Both participants and nonparticipants were surveyed. Review of program record data indicated that the program was implemented with acceptable fidelity to the core component structure, and that participant responsiveness to the model was high. Multilevel modeling indicated that VPP participation was protective for academic self-concept and promoted conflict resolution skills. Findings indicate that semester-long violence prevention programs optimized to meet the needs of a typical high school can be effective at promoting healthy conflict resolution skills in urban adolescents. © 2014, American School Health Association.

  1. 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…

  2. A Positive Model for Reducing and Preventing School Burnout in High School Students

    ERIC Educational Resources Information Center

    Aypay, Ayse

    2017-01-01

    This study aims to develop and test the validity of a model limited to attitude towards the future and subjective well-being for reducing and preventing the school burnout that high school students can experience. The study is designed as a relational screening model conducted over 389 high school students. The data in this study are analyzed…

  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. Effects on High School Students of Teaching a Cross-Age Alcohol Prevention Program

    ERIC Educational Resources Information Center

    Padget, Alison; Bell, Mary Lou; Shamblen, Stephen R.; Ringwalt, Chris

    2005-01-01

    This study examined the impact on high school students who taught elementary students MADD's Protecting You/Protecting Me (PY/PM), an alcohol use prevention and vehicle safety program. High school students (N = 188) enrolled in a peer helping course completed surveys before and after teaching PY/PM, and a comparison group of peer helper students…

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

    PubMed Central

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

    2017-01-01

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

  6. 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

  7. Transdermal deferoxamine prevents pressure-induced diabetic ulcers.

    PubMed

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

    2015-01-06

    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.

  8. Travelling safely to places at high altitude - Understanding and preventing altitude illness.

    PubMed

    Parise, Ivan

    2017-06-01

    Greater numbers of people are travelling to places at high altitude each year. Altitude illness is common in places at high altitude and may be life-threatening. General practitioners (GPs) are best placed to provide evidence-based advice to keep travellers well informed of the possible risks they may encounter in places at high altitude. The aim of this article is to review knowledge on altitude illness in order to help GPs assist patients to travel safely to places at high altitude. Acclimatisation to high altitude is a complex process and when inadequate leads to the pathological changes of altitude illness, including high-altitude headache, cerebral oedema, pulmonary oedema and acute mountain sickness. Higher ascent, faster rate of ascent and a previous history of altitude illness increase the risk of altitude illness. Acetazolamide and other medications used to prevent altitude illness are discussed in detail, including the finding that inhaled budesonide may prevent altitude illness.

  9. 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. |

  10. Implementing exertional heat illness prevention strategies in US high school football.

    PubMed

    Kerr, Zachary Y; Marshall, Stephen W; Comstock, R Dawn; Casa, Douglas J

    2014-01-01

    Approximately 6500 high school football athletes are treated annually for exertional heat illness (EHI). In 2009, the National Athletic Trainers Association (NATA)-led Inter-Association Task Force (NATA-IATF) released preseason heat acclimatization guidelines to help athletes become accustomed to environmental factors contributing to EHI. This study examines compliance with NATA-IATF guidelines and related EHI prevention strategies. The study used a cross-sectional survey completed by 1142 certified athletic trainers (AT), which captured compliance with 17 NATA-IATF guidelines and EHI prevention strategies in high school football during the 2011 preseason. On average, AT reported football programs complying with 10.4 NATA-IATF guidelines (SD = 3.2); 29 AT (2.5%) reported compliance with all 17. Guidelines with the lowest compliance were as follows: "Single-practice days consisted of practice no more than three hours in length" (39.7%); and "During days 3-5 of acclimatization, only helmets and shoulder pads should be worn" (39.0%). An average of 7.6 EHI prevention strategies (SD = 2.5) were used. Common EHI prevention strategies were as follows: having ice bags/cooler available (98.5%) and having a policy with written instructions for initiating emergency medical service response (87.8%). Programs in states with mandated guidelines had higher levels of compliance with guidelines and greater prevalence of EHI prevention strategies. A low proportion of surveyed high school football programs fully complied with all 17 NATA-IATF guidelines. However, many EHI prevention strategies were voluntarily implemented. State-level mandated EHI prevention guidelines may increase compliance with recognized best practices recommendations. Ongoing longitudinal monitoring of compliance is also recommended.

  11. G-protein-coupled receptor Gpr1 and G-protein Gpa2 of cAMP-dependent signaling pathway are involved in glucose-induced pexophagy in the yeast Saccharomyces cerevisiae.

    PubMed

    Nazarko, Volodymyr Y; Thevelein, Johan M; Sibirny, Andriy A

    2008-05-01

    In yeast cell, glucose induces various changes of cellular metabolism on genetic and metabolic levels. One of such changes is autophagic degradation of dispensable peroxisomes (pexophagy) which occurs in vacuoles. We have found that in Saccharomyces cerevisiae, defect of G-protein-coupled receptor Gpr1 and G-protein Gpa2, both the components of cAMP-signaling pathway, strongly suppressed glucose-induced degradation of matrix peroxisomal protein thiolase. We conclude that proteins Gpr1 and Gpa2 are involved in glucose sensing and signal transduction during pexophagy process in yeast.

  12. Melatonin prevents memory impairment induced by high-fat diet: Role of oxidative stress.

    PubMed

    Alzoubi, Karem H; Mayyas, Fadia A; Mahafzah, Rania; Khabour, Omar F

    2018-01-15

    Consumption of high-fat diet (HFD) induces oxidative stress in the hippocampus that leads to memory impairment. Melatonin has antioxidant and neuroprotective effects. In this study, we hypothesized that chronic administration of melatonin can prevent memory impairment induced by consumption of HFD. Melatonin was administered to rats via oral gavage (100mg/kg/day) for 4 weeks. HFD was also instituted for the same duration. Behavioral studies were conducted to test spatial memory using the radial arm water maze. Additionally, oxidative stress biomarkers were assessed in the hippocampus. Results showed that HFD impaired both short- and long- term memory (P<0.05), while melatonin treatment prevented such effects. Furthermore, melatonin prevented HFD-induced reduction in levels of GSH, and ratio of GSH/GSSG, and increase in GSSG in the hippocampus. Melatonin also prevented reduction in the catalase activity in hippocampus of animals on HFD. In conclusion, HFD induced memory impairment and melatonin prevented this impairment probably by preventing alteration of oxidative stress in the hippocampus. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Glucose-induced delay of seed germination in rice is mediated by the suppression of ABA catabolism rather than an enhancement of ABA biosynthesis.

    PubMed

    Zhu, Guohui; Ye, Nenghui; Zhang, Jianhua

    2009-03-01

    Both glucose and ABA play crucial roles in the regulation of seed germination and post-germination development. In Arabidopsis thaliana, up-regulation of ABA biosynthesis is suggested as one of the possible mechanisms mediating the glucose-induced delay in seed germination. Since the endogenous ABA level is controlled by the equilibrium between ABA biosynthesis and catabolism, we investigated how this equilibrium is related to the regulation of seed germination by glucose in rice. When ABA biosynthesis was inhibited by nordihydroguaiaretic acid (NDGA), an inhibitor of the ABA anabolic enzyme 9-cis-epoxycarotenoid dioxygenase (NCED), rice seed germination showed no response. In contrast, inhibition of ABA catabolism by diniconazole significantly arrested seed germination, suggesting that the regulation of ABA catabolism plays a major role. Further experiments indicated that the expression of OsABA8ox3, a key gene in ABA catabolism and encoding ABA 8'-hydroxylase in rice, was significantly increased during the first 6 h of imbibition, which was consistent with the decline of ABA content in the imbibed seeds. Expression of OsABA8ox genes, especially OsABA8ox2 and OsABA8ox3, was sensitively suppressed in the presence of exogenously supplied glucose. In contrast, the expression profiles of OsNCED genes that control the limiting step of ABA biosynthesis showed no significant changes in response to low levels of glucose. Our results demonstrated that the glucose-induced delay of seed germination is a result of the suppression of ABA catabolism rather than any enhancement of ABA biosynthesis during rice seed germination.

  14. 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

  15. 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…

  16. 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…

  17. Meta-Analysis on Dating Violence Prevention among Middle and High Schools

    ERIC Educational Resources Information Center

    Ting, Siu-Man Raymond

    2009-01-01

    Meta-analysis was applied to study the empirical research from 1990-2007 regarding the effectiveness of the dating violence prevention programs in middle and high schools on students' knowledge and attitudes. The results show that overall the program participants improved their knowledge and attitudes towards dating violence. Implications for…

  18. 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…

  19. 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…

  20. 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…

  1. 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…

  2. Meta-Analysis on Dating Violence Prevention among Middle and High Schools

    ERIC Educational Resources Information Center

    Ting, Siu-Man Raymond

    2009-01-01

    Meta-analysis was applied to study the empirical research from 1990-2007 regarding the effectiveness of the dating violence prevention programs in middle and high schools on students' knowledge and attitudes. The results show that overall the program participants improved their knowledge and attitudes towards dating violence. Implications for…

  3. 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…

  4. 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…

  5. 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…

  6. 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…

  7. 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…

  8. Enhancing Recruitment and Data Quality in a Junior High School-based Teen Pregnancy Prevention Study.

    ERIC Educational Resources Information Center

    Aarons, Sigrid; Rose, Allison; Walker, June; Lyles, Beverly; Jenkins, Renee; Raine, Tina

    2001-01-01

    Describes the methods used to maximize participation and enhance data quality in a randomized, controlled evaluation of an adolescent pregnancy prevention program targeting seventh graders in six urban junior high schools. Documents research procedures and evaluation survey design, discusses cross-cultural issues related to recruitment and survey…

  9. 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…

  10. 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. |

  11. 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.…

  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. An African-Centered Model of Prevention for African-American Youth at High Risk.

    ERIC Educational Resources Information Center

    Goddard, Lawford L., Ed.

    The chapters of this report provide a starting point for the development of authentic prevention strategies for use in the African-American community, specifically for high risk youth. It is neither a "how to" manual nor a mandate for specific program details, but it does highlight the key components of alcohol and other drug abuse…

  14. 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.…

  15. Project Peace: The Evaluation of a Skill-Based Violence Prevention Program for High School Adolescents.

    ERIC Educational Resources Information Center

    de Anda, Diane

    1999-01-01

    Describes a study of high school students who participated in a cognitive-behavioral violence prevention program. The basic premise was that changing behavior involves learning new behaviors, and thought processes mediate behaviors. Results indicated a significant improvement in students' sense of safety in the school environment, attitudes toward…

  16. 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…

  17. 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…

  18. A Curriculum Framework for Junior and Senior High Child Abuse Prevention Programs.

    ERIC Educational Resources Information Center

    Miller, Pamela R.

    This curriculum guide for junior and senior high child abuse prevention programs is designed for flexibility. Part 1, the introduction, discusses the goals and objectives for using the material, including designing presentations and assessing the needs of students. Part 2 provides a framework for presentations including examples of a 1-day and…

  19. 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…

  20. 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…

  1. 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.

  2. Serum amyloid P component prevents high-density lipoprotein-mediated neutralization of lipopolysaccharide.

    PubMed

    de Haas, C J; Poppelier, M J; van Kessel, K P; van Strijp, J A

    2000-09-01

    Lipopolysaccharide (LPS) is an amphipathic macromolecule that is highly aggregated in aqueous preparations. LPS-binding protein (LBP) catalyzes the transfer of single LPS molecules, segregated from an LPS aggregate, to high-density lipoproteins (HDL), which results in the neutralization of LPS. When fluorescein isothiocyanate-labeled LPS (FITC-LPS) is used, this transfer of LPS monomers to HDL can be measured as an increase in fluorescence due to dequenching of FITC-LPS. Recently, serum amyloid P component (SAP) was shown to neutralize LPS in vitro, although only in the presence of low concentrations of LBP. In this study, we show that SAP prevented HDL-mediated dequenching of FITC-LPS, even in the presence of high concentrations of LBP. Human bactericidal/permeability-increasing protein (BPI), a very potent LPS-binding and -neutralizing protein, also prevented HDL-mediated dequenching of FITC-LPS. Furthermore, SAP inhibited HDL-mediated neutralization of both rough and smooth LPS in a chemiluminescence assay quantifying the LPS-induced priming of neutrophils in human blood. SAP bound both isolated HDL and HDL in serum. Using HDL-coated magnetic beads prebound with SAP, we demonstrated that HDL-bound SAP prevented the binding of LPS to HDL. We suggest that SAP, by preventing LPS binding to HDL, plays a regulatory role, balancing the amount of LPS that, via HDL, is directed to the adrenal glands.

  3. Efficacy of ibuprofen on prevention of high altitude headache: A systematic review and meta-analysis.

    PubMed

    Xiong, Juan; Lu, Hui; Wang, Rong; Jia, Zhengping

    2017-01-01

    Ibuprofen is used to prevent high altitude headache (HAH) but its efficacy remains controversial. We conducted a systematic review and meta-analysis of randomized, placebo-controlled trials (RCTs) of ibuprofen for the prevention of HAH. Studies reporting efficacy of ibuprofen for prevention of HAH were identified by searching electronic databases (until December 2016). The primary outcome was the difference in incidence of HAH between ibuprofen and placebo groups. Risk ratios (RR) were aggregated using a Mantel-Haenszel random effect model. Heterogeneity of included trials was assessed using the I2 statistics. In three randomized-controlled clinical trials involving 407 subjects, HAH occurred in 101 of 239 subjects (42%) who received ibuprofen and 96 of 168 (57%) who received placebo (RR = 0.79, 95% CI 0.66 to 0.96, Z = 2.43, P = 0.02, I2 = 0%). The absolute risk reduction (ARR) was 15%. Number needed to treat (NNT) to prevent HAH was 7. Similarly, The incidence of severe HAH was significant in the two groups (RR = 0.40, 95% CI 0.17 to 0.93, Z = 2.14, P = 0.03, I2 = 0%). Severe HAH occurred in 3% treated with ibuprofen and 10% with placebo. The ARR was 8%. NNT to prevent severe HAH was 13. Headache severity using a visual analogue scale was not different between ibuprofen and placebo. Similarly, the difference between the two groups in the change in SpO2 from baseline to altitude was not different. One included RCT reported one participant with black stools and three participants with stomach pain in the ibuprofen group, while seven participants reported stomach pain in the placebo group. Based on a limited number of studies ibuprofen seems efficacious for the prevention of HAH and may therefore represent an alternative for preventing HAH with acetazolamide or dexamethasone.

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

    PubMed

    Groom, Amy G; Younis, Tallal

    2016-01-01

    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.

  5. Highly Conductive Carbon Fiber Reinforced Concrete for Icing Prevention and Curing.

    PubMed

    Galao, Oscar; Bañón, Luis; Baeza, Francisco Javier; Carmona, Jesús; Garcés, Pedro

    2016-04-12

    This paper aims to study the feasibility of highly conductive carbon fiber reinforced concrete (CFRC) as a self-heating material for ice formation prevention and curing in pavements. Tests were carried out in lab ambient conditions at different fixed voltages and then introduced in a freezer at -15 °C. The specimens inside the freezer were exposed to different fixed voltages when reaching +5 °C for prevention of icing and when reaching the temperature inside the freezer, i.e., -15 °C, for curing of icing. Results show that this concrete could act as a heating element in pavements with risk of ice formation, consuming a reasonable amount of energy for both anti-icing (prevention) and deicing (curing), which could turn into an environmentally friendly and cost-effective deicing method.

  6. Highly Conductive Carbon Fiber Reinforced Concrete for Icing Prevention and Curing

    PubMed Central

    Galao, Oscar; Bañón, Luis; Baeza, Francisco Javier; Carmona, Jesús; Garcés, Pedro

    2016-01-01

    This paper aims to study the feasibility of highly conductive carbon fiber reinforced concrete (CFRC) as a self-heating material for ice formation prevention and curing in pavements. Tests were carried out in lab ambient conditions at different fixed voltages and then introduced in a freezer at −15 °C. The specimens inside the freezer were exposed to different fixed voltages when reaching +5 °C for prevention of icing and when reaching the temperature inside the freezer, i.e., −15 °C, for curing of icing. Results show that this concrete could act as a heating element in pavements with risk of ice formation, consuming a reasonable amount of energy for both anti-icing (prevention) and deicing (curing), which could turn into an environmentally friendly and cost-effective deicing method. PMID:28773406

  7. 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. © 2016 The Histochemical Society.

  8. "The internet is a mask": High School students' suggestions for preventing cyberbullying.

    PubMed

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

    2014-08-01

    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. 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. 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. 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.

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

    PubMed Central

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

    2016-01-01

    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

  10. “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

  11. 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…

  12. 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…

  13. 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.

  14. Lanthanum prevents high phosphate-induced vascular calcification by preserving vascular smooth muscle lineage markers.

    PubMed

    Ciceri, Paola; Elli, Francesca; Brenna, Irene; Volpi, Elisa; Romagnoli, Solange; Tosi, Delfina; Braidotti, Paola; Brancaccio, Diego; Cozzolino, Mario

    2013-06-01

    Vascular calcification (VC) represents a major cardiovascular risk factor in chronic kidney disease patients. High phosphate (Pi) levels are strongly associated with VC in this population. Therefore, Pi binders are commonly used to control high Pi levels. The aim of this work was to study the mechanism of action of lanthanum chloride (LaCl3) on the progression of Pi-induced VC through its direct effect on vascular smooth muscle cells (VSMCs) in vitro. High Pi induced VSCM Ca deposition. We evaluated the action of LaCl3, compared to gadolinium chloride (GdCl3), and found different effects on the modulation of VSMC lineage markers, such as α-actin and SM22α. In fact, only LaCl3 preserved the expression of both VSMC lineage markers compared to high Pi-treated cells. Interestingly, both LaCl3 and GdCl3 reduced the high Pi-induced elevations of bone morphogenic protein 2 mRNA expression, with no reduction of the high core binding factor-alpha 1 mRNA levels observed in calcified VSMCs. Furthermore, we also found that only LaCl3 completely prevented the matrix GLA protein mRNA levels and osteonectin protein expression elevations induced by high Pi compared to GdCl3. Finally, LaCl3, in contrast to GdCl3, prevented the high Pi-induced downregulation of Axl, a membrane tyrosine kinase receptor involved in apoptosis. Thus, our results suggest that LaCl3 prevents VC by preserving VSMC lineage markers and by decreasing high Pi-induced osteoblastic differentiation.

  15. Aspirin prevents bone loss with little mechanical improvement in high-fat-fed ovariectomized rats.

    PubMed

    Lin, Sien; Lee, Wayne Y W; Huang, Meiling; Fu, Ziwei; Liang, Yanlong; Wu, Haiyou; Xu, Liangliang; Suen, Chun Wai; Huang, Jianping; Wu, Tie; Cui, Liao; Li, Gang

    2016-11-15

    Obesity and osteoporosis are often concurrently happened in the menopausal women. Obesity in menopausal women is not only related to a high risk of cardiovascular disease, but also results in a detrimental effect on bone health. This study aimed to investigate the effects of aspirin, a popular anti-thrombosis drug, on bone quantity and quality in the high-fat-fed animal model. Adult female rats were subjected to either sham operations or ovariectomized operations. The ovariectomized rats were orally administered with deionized water or standardized high fat emulsion with or without aspirin. All rats were injected with calcein before killed for the purpose of double in vivo labeling. Biochemistry, histomorphometry, micro-computed tomography analysis, mechanical test, and component analysis were performed after 12 weeks. In vitro cell culture was also performed to observe the effect of aspirin in osteogenesis. We found that high fat remarkably impaired bone formation and bone biomechanics. Aspirin treatment significantly prevented bone loss by increasing bone formation. In vitro studies also validated the enhancement of osteogenic differentiation. However, aspirin presented no significant improvement in bone mechanical properties. Component analysis shown aspirin could significantly increase the content of mineral, but had limited effect on the content of collagen. In conclusion, aspirin is beneficial for the prevention of bone loss; meanwhile, it may cause an imbalance in the components of bone which may weaken the mechanical properties. The current study provided further evidence that aspirin might not be powerful for the prevention of fracture in osteoporotic patients.

  16. The National Cross-Site Evaluation of High-Risk Youth Programs: Findings on Designing and Implementing Effective Prevention Programs for Youth at High Risk. Monograph Series.

    ERIC Educational Resources Information Center

    Hermann, Jack; Sambrano, Soledad; Springer, J. Fred; Nister, Mary; Sale, Elizabeth; Brounstein, Paul J.; Cordray, David; Shadish, Will; Kasim, Rafa; Pan, Wei

    This document summarizes findings from the Center for Substance Abuse Prevention's National Cross-Site Evaluation of High-Risk Youth Programs, which identified characteristics associated with strong substance abuse prevention outcomes in 48 prevention programs. It provides concrete guidance regarding what elements of design and implementation are…

  17. Adapting an HIV prevention intervention for high-risk, incarcerated adolescents.

    PubMed

    Hurd, Noelle M; Valerio, Melissa A; Garcia, Nicole M; Scott, Anthony A

    2010-02-01

    This study examined the effectiveness of an adapted 4-session HIV prevention program. Participants included 490 adolescents who participated in either the 8- or the adapted 4-session HIVEd program. Analyses to identify mean changes in HIV-related knowledge, attitudes, self-efficacy, and behavioral intentions between participants in either the 4- (n = 274) or 8-session (n = 216) programs were completed. Findings indicate participants in both programs had positive changes at post interview across all study outcomes. No significant differences in changes between participants in the 4- and 8-session programs were found except that male adolescents in the 4-session program had significantly higher mean changes in condom knowledge (p < .01). The adaptation of the 8-session HIVEd program was undertaken to better reach and accommodate the needs of a high risk incarcerated adolescent population. Findings demonstrate that HIV prevention interventions for high risk populations may be successfully adapted and condensed when based on rigorously evaluated and theoretically driven programs.

  18. How do high-risk youth use the Internet? Characteristics and implications for prevention.

    PubMed

    Wells, Melissa; Mitchell, Kimberly J

    2008-08-01

    Using data from the Second Youth Internet Safety Survey, a nationally representative telephone survey of 1,500 youth Internet users (ages 10 to 17), this study explores differences in Internet use characteristics between high risk youth and other Internet users. Those youth who engaged in aggressive behavior online and those who used the Internet on a cell phone were about twice as likely to be classified as high risk (having experienced high parent conflict or child maltreatment) as compared to other Internet users. Those youth who talked with known friends online were significantly less likely to be included in the high risk group. Controlling for demographic and Internet use characteristics, youth who received an aggressive sexual solicitation were almost 2.5 times as likely to report experiencing physical abuse, sexual abuse or high parent conflict. Implications for prevention are discussed, including avenues for reaching high risk populations of youth.

  19. Bystander Sexual Violence Prevention Program: Outcomes for High- and Low-Risk University Men.

    PubMed

    Elias-Lambert, Nada; Black, Beverly M

    2015-05-05

    This research reports the findings of an evaluation of a peer-facilitated, bystander sexual violence prevention program to determine its effectiveness at changing attitudes and behaviors related to sexual violence with university males who are at low- and high-risk of using sexually coercive behavior. Bystander interventions focus on men and women as bystanders to change social norms in a peer culture that supports abusive behaviors. Few studies have examined the effectiveness of these interventions with high-risk populations, which is the focus of this study. A bystander sexual violence prevention program was presented to 142 fraternity members. A quasi-experimental design utilizing pre-, post-, and follow-up surveys was used to compare the effectiveness of this prevention program with university males who are at low- and high-risk of using sexually coercive behavior in intervention and comparison groups. Participants' risk status was measured prior to the intervention using the Modified-Sexual Experiences Survey. The measures evaluated changes in attitudes (rape myth acceptance and bystander attitudes) and behaviors (sexually coercive behaviors, sexually coercive behavioral intentions, and bystander behaviors). Data analyses included Repeated-Measures Analysis of Covariances. The findings suggest that a bystander sexual violence prevention program has a positive impact on attitudes and behaviors related to sexual violence among fraternity members, however, the program had less impact on high-risk males. The results of this study will expand our ability to design programs that can have an impact on reducing sexual violence on campus by ensuring the programs are having the desired impact on the target audience.

  20. ERK1 is dispensable for mouse pancreatic beta cell function but is necessary for glucose-induced full activation of MSK1 and CREB.

    PubMed

    Leduc, Michele; Richard, Joy; Costes, Safia; Muller, Dany; Varrault, Annie; Compan, Vincent; Mathieu, Julia; Tanti, Jean-François; Pagès, Gilles; Pouyssegur, Jacques; Bertrand, Gyslaine; Dalle, Stéphane; Ravier, Magalie A

    2017-07-18

    Insufficient insulin secretion from pancreatic beta cells, which is associated with a decrease in beta cell mass, is a characteristic of type 2 diabetes. Extracellular signal-related kinase 1 and 2 (ERK1/2) inhibition in beta cells has been reported to affect insulin secretion, gene transcription and survival, although whether ERK1 and ERK2 play distinct roles is unknown. The aim of this study was to assess the individual roles of ERK1 and ERK2 in beta cells using ERK1 (also known as Mapk3)-knockout mice (Erk1 (-/-) mice) and pharmacological approaches. NAD(P)H, free cytosolic Ca(2+) concentration and insulin secretion were determined in islets. ERK1 and ERK2 subplasmalemmal translocation and activity was monitored using total internal reflection fluorescence microscopy. ERK1/2, mitogen and stress-activated kinase1 (MSK1) and cAMP-responsive element-binding protein (CREB) activation were evaluated by western blot and/or immunocytochemistry. The islet mass was determined from pancreatic sections. Glucose induced rapid subplasmalemmal recruitment of ERK1 and ERK2. When both ERK1 and ERK2 were inhibited simultaneously, the rapid transient peak of the first phase of glucose-induced insulin secretion was reduced by 40% (p < 0.01), although ERK1 did not appear to be involved in this process. By contrast, ERK1 was required for glucose-induced full activation of several targets involved in beta cell survival; MSK1 and CREB were less active in Erk1 (-/-) mouse beta cells (p < 0.01) compared with Erk1 (+/+) mouse beta cells, and their phosphorylation could only be restored when ERK1 was re-expressed and not when ERK2 was overexpressed. Finally, the islet mass of Erk1 (-/-) mice was slightly increased in young animals (4-month-old mice) vs Erk1 (+/+) mice (section occupied by islets [mean ± SEM]: 0.74% ± 0.03% vs 0.62% ± 0.04%; p < 0.05), while older mice (10 months old) were less prone to age-associated pancreatic peri-insulitis (infiltrated islets [mean

  1. Resveratrol potentiates rapamycin to prevent hyperinsulinemia and obesity in male mice on high fat diet

    PubMed Central

    Leontieva, O V; Paszkiewicz, G; Demidenko, Z N; Blagosklonny, M V

    2013-01-01

    High doses of rapamycin, an antiaging agent, can prevent obesity in mice on high fat diet (HFD). Obesity is usually associated with hyperinsulinemia. Here, we showed that rapamycin given orally, at doses that did not affect weight gain in male mice on HFD, tended to decrease fasting insulin levels. Addition of resveratrol, which alone did not affect insulin levels, potentiated the effect of rapamycin, so that the combination decreased obesity and prevented hyperinsulinemia. Neither rapamycin nor resveratrol, and their combination affected fasting levels of glucose (despite lowering insulin levels), implying that the combination might prevent insulin resistance. We and others previously reported that resveratrol at high doses inhibited the mTOR (Target of Rapamycin) pathway in cell culture. Yet, as we confirmed here, this effect was observed only at super-pharmacological concentrations. At pharmacological concentrations, resveratrol did not exert ‘rapamycin-like effects' on cellular senescence and did not inhibit the mTOR pathway in vitro, indicating nonoverlapping therapeutic mechanisms of actions of rapamycin and resveratrol in vivo. Although, like rapamycin, resveratrol decreased insulin-induced HIF-1-dependent transcription in cell culture, resveratrol did not inhibit mTOR at the same concentrations. Given distinct mechanisms of action of rapamycin and resveratrol at clinically relevant doses, their combination warrants further investigation as a potential antiaging, antiobesity and antidiabetic modality. PMID:23348586

  2. Reduced fatalism and increased prevention behavior after two high-profile lung cancer events.

    PubMed

    Portnoy, David B; Leach, Corinne R; Kaufman, Annette R; Moser, Richard P; Alfano, Catherine M

    2014-01-01

    The positive impact of media coverage of high-profile cancer events on cancer prevention behaviors is well-established. However, less work has focused on potential adverse psychological reactions to such events, such as fatalism. Conducting 3 studies, the authors explored how the lung cancer death of Peter Jennings and diagnosis of Dana Reeve in 2005 related to fatalism. Analysis of a national media sample in Study 1 found that media coverage of these events often focused on reiterating the typical profile of those diagnosed with lung cancer; 38% of the media mentioned at least 1 known risk factor for lung cancer, most often smoking. Data from a nationally representative survey in Study 2 found that respondents reported lower lung cancer fatalism, after, compared with before, the events (OR = 0.16, 95% CI [0.03, 0.93]). A sustained increase in call volume to the national tobacco Quitline after these events was found in Study 3. These results suggest that there is a temporal association between high-profile cancer events, the subsequent media coverage, psychological outcomes, and cancer prevention behaviors. These results suggest that high-profile cancer events could be leveraged as an opportunity for large-scale public heath communication campaigns through the dissemination of cancer prevention messages and services.

  3. Downregulation of AMPK Accompanies Leucine- and Glucose-Induced Increases in Protein Synthesis and Insulin Resistance in Rat Skeletal Muscle

    PubMed Central

    Saha, Asish K.; Xu, X. Julia; Lawson, Ebony; Deoliveira, Rosangela; Brandon, Amanda E.; Kraegen, Edward W.; Ruderman, Neil B.

    2010-01-01

    OBJECTIVE Branched-chain amino acids, such as leucine and glucose, stimulate protein synthesis and increase the phosphorylation and activity of the mammalian target of rapamycin (mTOR) and its downstream target p70S6 kinase (p70S6K). We examined in skeletal muscle whether the effects of leucine and glucose on these parameters and on insulin resistance are mediated by the fuel-sensing enzyme AMP-activated protein kinase (AMPK). RESEARCH DESIGN AND METHODS Rat extensor digitorum longus (EDL) muscle was incubated with different concentrations of leucine and glucose with or without AMPK activators. Muscle obtained from glucose-infused rats was also used as a model. RESULTS In the EDL, incubation with 100 or 200 μmol/l leucine versus no added leucine suppressed the activity of the α2 isoform of AMPK by 50 and 70%, respectively, and caused concentration-dependent increases in protein synthesis and mTOR and p70S6K phosphorylation. Very similar changes were observed in EDL incubated with 5.5 or 25 mmol/l versus no added glucose and in muscle of rats infused with glucose in vivo. Incubation of the EDL with the higher concentrations of both leucine and glucose also caused insulin resistance, reflected by a decrease in insulin-stimulated Akt phosphorylation. Coincubation with the AMPK activators AICAR and α-lipoic acid substantially prevented all of those changes and increased the phosphorylation of specific sites of mTOR inhibitors raptor and tuberous sclerosis complex 2 (TSC2). In contrast, decreases in AMPK activity induced by leucine and glucose were not associated with a decrease in raptor or TSC2 phosphorylation. CONCLUSIONS The results indicate that both leucine and glucose modulate protein synthesis and mTOR/p70S6 and insulin signaling in skeletal muscle by a common mechanism. They also suggest that the effects of both molecules are associated with a decrease in AMPK activity and that AMPK activation prevents them. PMID:20682696

  4. High-fat diet prevents adaptive peripartum-associated adrenal gland plasticity and anxiolysis

    PubMed Central

    Perani, Clara V.; Neumann, Inga D.; Reber, Stefan O.; Slattery, David A.

    2015-01-01

    Maternal obesity is associated with lower basal plasma cortisol levels and increased risk of postpartum psychiatric disorders. Given that both obesity and the peripartum period are characterized by an imbalance between adrenocorticotropic hormone (ACTH) and cortisol, we hypothesized that the adrenal glands undergo peripartum-associated plasticity and that such changes would be prevented by a high-fat diet (HFD). Here, we demonstrate substantial peripartum adrenal gland plasticity in the pathways involved in cholesterol supply for steroidogenesis in female rats. In detail, the receptors involved in plasma lipid uptake, low density lipoprotein (LDL) receptor (LDLR) and scavenger receptor class B type 1 (SRB1), are elevated, intra-adrenal cholesterol stores are depleted, and a key enzyme in de novo cholesterol synthesis, hydroxymethylglutaryl coenzyme A reductase (HMGCR), is downregulated; particularly at mid-lactation. HFD prevented the lactation-associated anxiolysis, basal hypercorticism, and exaggerated the corticosterone response to ACTH. Moreover, we show that HFD prevented the downregulation of adrenal cholesterol stores and HMGCR expression, and LDLR upregulation at mid-lactation. These findings show that the adrenal gland is an important regulator of peripartum-associated HPA axis plasticity and that HFD has maladaptive consequences for the mother, partly by preventing these neuroendocrine and also behavioural changes. PMID:26442440

  5. Effects of a Comprehensive, Multiple Risky Behavior Prevention Program on High School Students

    PubMed Central

    Onwuegbuzie, Anthony J.; LaChapelle, Alicia

    2016-01-01

    The purpose of this research study was to examine the effect of a multiple risky 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 noncurriculum prevention program was created based upon the key elements of effective prevention programming and the need to address the growing variety of risky behaviors that the youth face today. Results (n = 469 to 614) indicated that 7 out of 15 risky behaviors statistically significantly decreased throughout the 4-year study, with 6 behaviors involving alcohol and drugs. However, many of the targeted non-substance-use risky behaviors displayed inconsistent prevalence rate patterns without statistically significant changes. These findings indicate that the frequency and intensity of programming for non-substance-use behaviors should be increased to a value at least equal to that of the substance-use behaviors. Implications for schools, prevention specialists, and future program development and research are discussed. PMID:27672475

  6. Edible Bird's Nest Prevents High Fat Diet-Induced Insulin Resistance in Rats

    PubMed Central

    Yida, Zhang; Imam, Mustapha Umar; Ismail, Maznah; Ooi, Der-Jiun; Sarega, Nadarajan; Chan, Kim Wei; Hou, Zhiping; Yusuf, Norhayati Binti

    2015-01-01

    Edible bird's nest (EBN) is used traditionally in many parts of Asia to improve wellbeing, but there are limited studies on its efficacy. We explored the potential use of EBN for prevention of high fat diet- (HFD-) induced insulin resistance in rats. HFD was given to rats with or without simvastatin or EBN for 12 weeks. During the intervention period, weight measurements were recorded weekly. Blood samples were collected at the end of the intervention and oral glucose tolerance test conducted, after which the rats were sacrificed and their liver and adipose tissues collected for further studies. Serum adiponectin, leptin, F2-isoprostane, insulin, and lipid profile were estimated, and homeostatic model assessment of insulin resistance computed. Effects of the different interventions on transcriptional regulation of insulin signaling genes were also evaluated. The results showed that HFD worsened metabolic indices and induced insulin resistance partly through transcriptional regulation of the insulin signaling genes. Additionally, simvastatin was able to prevent hypercholesterolemia but promoted insulin resistance similar to HFD. EBN, on the other hand, prevented the worsening of metabolic indices and transcriptional changes in insulin signaling genes due to HFD. The results suggest that EBN may be used as functional food to prevent insulin resistance. PMID:26273674

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

    PubMed

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

    2013-01-15

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

  8. TRPV1 activation prevents high-salt diet-induced nocturnal hypertension in mice.

    PubMed

    Hao, Xinzhong; Chen, Jing; Luo, Zhidan; He, Hongbo; Yu, Hao; Ma, Liqun; Ma, Shuangtao; Zhu, Tianqi; Liu, Daoyan; Zhu, Zhiming

    2011-03-01

    High dietary salt-caused hypertension is associated with increasing reactive oxygen species generation and reduced nitric oxide (NO) bioavailability. Transient receptor potential vanilloid type 1 (TRPV1), a specific receptor for capsaicin, is proposed to be involved in Dahl salt-sensitive hypertension, as determined in acute or short-term experiments. However, it remains unknown whether activation of TRPV1 by dietary capsaicin could prevent the vascular oxidative stress and hypertension induced by a high-salt diet. Here, we report that consumption of a high-salt diet blunted endothelium-dependent relaxation in mesenteric resistance arteries and elevated nocturnal blood pressure in mice. These effects were associated with increased superoxide anion generation and reduced NO levels in mesenteric vessels in mice on a high-salt diet. However, chronic administration of capsaicin reduced the high-salt diet-induced endothelial dysfunction and nocturnal hypertension in part by preventing the generation of superoxide anions and NO reduction of mesenteric arteries through vascular TRPV1 activation. Our findings provide new insights into the role of TRPV1 channels in the long-term regulation of blood pressure in response to high-salt intake. TRPV1 activation through chronic dietary capsaicin may represent a promising lifestyle intervention in populations with salt-sensitive hypertension.

  9. [Tobacco: knowledge, reasoning and opinion of high school students in Doubs. Reflections on prevention].

    PubMed

    Michaud, C; Saraiva, I; Henry, Y; Dodane, M

    2003-03-01

    The prevalence of smoking has increased among young people aged 14 to 18 between 1993 and 1999, and most notably among girls within the same period. These observations illustrate the necessity for significant changes in mass media campaigns and education programmes related to the prevention of smoking among youth. The objective of this survey, initiated by the city of Besançon and the French National Mutual Insurance of Doubs, was to describe and analyse the knowledge and rationale of high school students on tobacco and their opinions in terms of prevention. Twelve public and private high schools in Besançon and Morteau (Doubs-France) participated in the survey; the group also represented a mix of general and professional schools. The questionnaire was filled out by 970 students selected at random. 96% of the students indicated cancer as being the main illness linked to tobacco and 94% stated that second-hand smoke constitutes a health risk. 61% admitted to seeking out the psychoactive effects of smoking. The students responses confirm that the types of messages relayed in a smoking prevention campaign which have an impact on them are: evoking fear of death (74%) and the use of humor (16%). One-third of high school students find that it is unacceptable to forbid smoking on school premises. The knowledge of the dangers related to smoking is not sufficient to keep young people from smoking and confirms that an educational approach based solely on knowledge and facts will not be sufficient to decrease their tobacco consumption. It is important to take into account the image that young people have of tobacco as a means to combat stress in future prevention strategies and campaigns.

  10. Cyclocarya paliurus prevents high fat diet induced hyperlipidemia and obesity in Sprague-Dawley rats.

    PubMed

    Yao, Xiaoming; Lin, Zi; Jiang, Cuihua; Gao, Meng; Wang, Qingqing; Yao, Nan; Ma, Yonglan; Li, Yue; Fang, Shengzuo; Shang, Xulan; Ni, Yicheng; Zhang, Jian; Yin, Zhiqi

    2015-08-01

    Cyclocarya paliurus (CP; qing qian liu), which is used as an herbal tea in China, has been confirmed to have therapeutic effects on hyperlipidemia and obesity, and therefore it is widely consumed to prevent metabolic diseases such as hyperlipidemia and diabetes. In this study, we investigated the preventive effects of CP on obesity and hyperlipidemia, as well as the underlying mechanisms involved in intestinal secretion of apolipoprotein (apo) B48. Sprague-Dawley rats were fed a high-fat diet (HFD) and with or without various concentrations of an ethanol extract of CP (CPE; 2, 4, or 8 g·(kg body mass)(-1)) administered by gavage for 8 weeks. From the results we see that CPE dose-dependently blocked increases in body mass, and decreased food utilization as well as visceral fat mass. Decreased serum levels of total cholesterol, triglycerides, and low density lipoprotein cholesterol, and elevated levels of high density lipoprotein cholesterol, as well as lowered levels of total cholesterol and triglycerides in the liver were also noticed in CPE-treated rats. Magnetic resonance images indicated that the abnormal fat storage induced by the HFD was obviously suppressed by CPE. In addition, ELISA analysis showed reduced fasting serum apoB48 in the CPE treatment groups. Based on the above results, CPE shows a promising preventive effect on obesity and hyperlipidemia, partially through suppressing intestinal apoB48 overproduction.

  11. High affinity binding site-mediated prevention of chemical absorption across the gastrointestinal tract.

    PubMed

    Rasmussen, M V; Barker, T T; Silbart, L K

    2001-12-15

    Preventing mucosal absorption of low-molecular weight compounds such as carcinogens, toxins and drugs could help prevent many diseases. To characterize the effects of dose and timing on high-affinity binding site mediated sequestration of specific chemical ligands in the gastrointestinal tract, avidin was perorally-administered to mice either prior to or mixed with 3H-biotin. Avidin enhanced fecal 3H-biotin excretion in a dose-dependent manner, consistent with the accepted mechanism of egg white-induced biotin deficiency syndrome. Avidin administration up to 4 h before 3H-biotin administration also enhanced fecal 3H-biotin excretion. Activated charcoal (AC) reduced 3H-biotin absorption when mixed with 3H-biotin before ingestion, but was ineffective when ingested prior to 3H-biotin. These studies suggest that ingestion of high-affinity protein binding sites can establish an absorptive barrier at the gastrointestinal mucosa to prevent the uptake of unwanted low molecular-weight chemicals.

  12. Preventing heel pressure ulcers and plantar flexion contractures in high-risk sedated patients.

    PubMed

    Meyers, Tina R

    2010-01-01

    An intervention using heel pressure ulcer and plantar flexion contracture prevention protocols for high-risk patients was established to promote earlier recognition of heel skin issues and provide effective prevention of both conditions. Fifty-three patients who were sedated, managed in an intensive care unit for 5 days or more, and had a Braden Scale score of 16 or less were treated with heel protector devices that maintained the foot in a neutral position and floated the heel off the bed. On admission to the intensive care unit, heel skin assessment and the Braden Scale were administered to all patients. Initial ankle range of motion was measured with a goniometer on admission and before the application of the heel protector. Goniometric measurements were documented every other day. Heel assessments and the Braden Scale for Predicting Pressure Sore Prevention and Ramsay Sedation Scale scores were recorded in every shift and recorded as part of the study every other day. Measurements continued until the patient was transferred, the heel protector boot was discontinued by the physician, or the patient's Braden Scale score rose above 16. Application of the heel protectors led to a 50% reduction in prevalence of abnormal heel position. No patients developed plantar flexion contractures or new heel ulcers. Patients with normal heels had significantly higher Braden Scale scores compared to those with abnormal heels (P 5 .0136). Despite their high risk, no patients using the heel protector device developed a heel pressure ulcer or plantar flexion contracture.

  13. High-school smoking prevention: results of a three-year longitudinal study.

    PubMed

    Johnson, C A; Hansen, W B; Collins, L M; Graham, J W

    1986-10-01

    This study compared two strategies for preventing cigarette smoking among high-school students. One strategy emphasized social-pressure resistance skills, while the other focused on education about health concerns which are relevant to high-school students. Additionally, the use of same-age peer leaders and the use of familiar models in media presentations were investigated. The results suggest that social-influences resistance training was efficacious in reducing transitions to higher use by those who had previously experimented with cigarettes. Health education was most effective in preventing initial experimentation among those who had not smoked prior to the beginning of the study. Neither program was effective in limiting transitions among those who had gone beyond the experimental stage of smoking, and neither had any effect on encouraging cessation. There were no differences which could be attributed to peer leaders or to familiar media models. During later adolescence, a combined health education and social skills training approach is advocated. It is suggested that while there are some gains by implementing programs during late adolescence, prevention programs targeted at younger students may be more effective generally.

  14. Bardoxolone Methyl Prevents Mesenteric Fat Deposition and Inflammation in High-Fat Diet Mice

    PubMed Central

    Dinh, Chi H. L.; Szabo, Alexander; Yu, Yinghua; Camer, Danielle; Wang, Hongqin; Huang, Xu-Feng

    2015-01-01

    Mesenteric fat belongs to visceral fat. An increased deposition of mesenteric fat contributes to obesity associated complications such as type 2 diabetes and cardiovascular diseases. We have investigated the therapeutic effects of bardoxolone methyl (BARD) on mesenteric adipose tissue of mice fed a high-fat diet (HFD). Male C57BL/6J mice were administered oral BARD during HFD feeding (HFD/BARD), only fed a high-fat diet (HFD), or fed low-fat diet (LFD) for 21 weeks. Histology and immunohistochemistry were used to analyse mesenteric morphology and macrophages, while Western blot was used to assess the expression of inflammatory, oxidative stress, and energy expenditure proteins. Supplementation of drinking water with BARD prevented mesenteric fat deposition, as determined by a reduction in large adipocytes. BARD prevented inflammation as there were fewer inflammatory macrophages and reduced proinflammatory cytokines (interleukin-1 beta and tumour necrosis factor alpha). BARD reduced the activation of extracellular signal-regulated kinase (ERK) and Akt, suggesting an antioxidative stress effect. BARD upregulates energy expenditure proteins, judged by the increased activity of tyrosine hydroxylase (TH) and AMP-activated protein kinase (AMPK) and increased peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and uncoupling protein 2 (UCP2) proteins. Overall, BARD induces preventive effect in HFD mice through regulation of mesenteric adipose tissue. PMID:26618193

  15. The NARCONON drug education curriculum for high school students: a non-randomized, controlled prevention trial.

    PubMed

    Lennox, Richard D; Cecchini, Marie A

    2008-03-19

    An estimated 13 million youths aged 12 to 17 become involved with alcohol, tobacco and other drugs annually. The number of 12- to 17-year olds abusing controlled prescription drugs increased an alarming 212 percent between 1992 and 2003. For many youths, substance abuse precedes academic and health problems including lower grades, higher truancy, drop out decisions, delayed or damaged physical, cognitive, and emotional development, or a variety of other costly consequences. For thirty years the Narconon program has worked with schools and community groups providing single educational modules aimed at supplementing existing classroom-based prevention activities. In 2004, Narconon International developed a multi-module, universal prevention curriculum for high school ages based on drug abuse etiology, program quality management data, prevention theory and best practices. We review the curriculum and its rationale and test its ability to change drug use behavior, perceptions of risk/benefits, and general knowledge. After informed parental consent, approximately 1000 Oklahoma and Hawai'i high school students completed a modified Center for Substance Abuse Prevention (CSAP) Participant Outcome Measures for Discretionary Programs survey at three testing points: baseline, one month later, and six month follow-up. Schools assigned to experimental conditions scheduled the Narconon curriculum between the baseline and one-month follow-up test; schools in control conditions received drug education after the six-month follow-up. Student responses were analyzed controlling for baseline differences using analysis of covariance. At six month follow-up, youths who received the Narconon drug education curriculum showed reduced drug use compared with controls across all drug categories tested. The strongest effects were seen in all tobacco products and cigarette frequency followed by marijuana. There were also significant reductions measured for alcohol and amphetamines. The program

  16. The NARCONON™ drug education curriculum for high school students: A non-randomized, controlled prevention trial

    PubMed Central

    Lennox, Richard D; Cecchini, Marie A

    2008-01-01

    Background An estimated 13 million youths aged 12 to 17 become involved with alcohol, tobacco and other drugs annually. The number of 12- to 17-year olds abusing controlled prescription drugs increased an alarming 212 percent between 1992 and 2003. For many youths, substance abuse precedes academic and health problems including lower grades, higher truancy, drop out decisions, delayed or damaged physical, cognitive, and emotional development, or a variety of other costly consequences. For thirty years the Narconon program has worked with schools and community groups providing single educational modules aimed at supplementing existing classroom-based prevention activities. In 2004, Narconon International developed a multi-module, universal prevention curriculum for high school ages based on drug abuse etiology, program quality management data, prevention theory and best practices. We review the curriculum and its rationale and test its ability to change drug use behavior, perceptions of risk/benefits, and general knowledge. Methods After informed parental consent, approximately 1000 Oklahoma and Hawai'i high school students completed a modified Center for Substance Abuse Prevention (CSAP) Participant Outcome Measures for Discretionary Programs survey at three testing points: baseline, one month later, and six month follow-up. Schools assigned to experimental conditions scheduled the Narconon curriculum between the baseline and one-month follow-up test; schools in control conditions received drug education after the six-month follow-up. Student responses were analyzed controlling for baseline differences using analysis of covariance. Results At six month follow-up, youths who received the Narconon drug education curriculum showed reduced drug use compared with controls across all drug categories tested. The strongest effects were seen in all tobacco products and cigarette frequency followed by marijuana. There were also significant reductions measured for alcohol and

  17. High-intensity interval training prevents oxidant-mediated diaphragm muscle weakness in hypertensive mice.

    PubMed

    Bowen, T Scott; Eisenkolb, Sophia; Drobner, Juliane; Fischer, Tina; Werner, Sarah; Linke, Axel; Mangner, Norman; Schuler, Gerhard; Adams, Volker

    2017-01-01

    Hypertension is a key risk factor for heart failure, with the latter characterized by diaphragm muscle weakness that is mediated in part by increased oxidative stress. In the present study, we used a deoxycorticosterone acetate (DOCA)-salt mouse model to determine whether hypertension could independently induce diaphragm dysfunction and further investigated the effects of high-intensity interval training (HIIT). Sham-treated (n = 11), DOCA-salt-treated (n = 11), and DOCA-salt+HIIT-treated (n = 15) mice were studied over 4 wk. Diaphragm contractile function, protein expression, enzyme activity, and fiber cross-sectional area and type were subsequently determined. Elevated blood pressure confirmed hypertension in DOCA-salt mice independent of HIIT (P < 0.05). Diaphragm forces were impaired by ∼15-20% in DOCA-salt vs. sham-treated mice (P < 0.05), but this effect was prevented after HIIT. Myosin heavy chain (MyHC) protein expression tended to decrease (∼30%; P = 0.06) in DOCA-salt vs. sham- and DOCA-salt+HIIT mice, whereas oxidative stress increased (P < 0.05). Enzyme activity of NADPH oxidase was higher, but superoxide dismutase was lower, with MyHC oxidation elevated by ∼50%. HIIT further prevented direct oxidant-mediated diaphragm contractile dysfunction (P < 0.05) after a 30 min exposure to H2O-2 (1 mM). Our data suggest that hypertension induces diaphragm contractile dysfunction via an oxidant-mediated mechanism that is prevented by HIIT.-Bowen, T. S., Eisenkolb, S., Drobner, J., Fischer, T., Werner, S., Linke, A., Mangner, N., Schuler, G., Adams, V. High-intensity interval training prevents oxidant-mediated diaphragm muscle weakness in hypertensive mice.

  18. Bone Loss from High Repetitive High Force Loading is Prevented by Ibuprofen Treatment

    PubMed Central

    Jain, Nisha X.; Barr-Gillespie, Ann E.; Clark, Brian D.; Kietrys, David M.; Wade, Christine K.; Litvin, Judith; Popoff, Steven N.; Barbe, Mary F.

    2014-01-01

    We examined roles of loading and inflammation on forearm bones in a rat model of upper extremity overuse. Trabecular structure in distal radius and ulna was examined in three groups of young adult rats: 1) 5% food-restricted that underwent an initial training period of 10 min/day for 5 weeks to learn the repetitive task (TRHF); 2) rats that underwent the same training before performing a high repetition high force task, 2 hours/day for 12 weeks (HRHF); and 3) food-restricted only (FRC). Subsets were treated with oral ibuprofen (IBU). TRHF rats had increased trabecular bone volume and numbers, osteoblasts, and serum osteocalcin, indicative of bone adaptation. HRHF rats had constant muscle pulling forces, showed limited signs of bone adaptation, but many signs of bone resorption, including decreased trabecular bone volume and bone mineral density, increased osteoclasts and bone inflammatory cytokines, and reduced median nerve conduction velocity (15%). HRHF+IBU rats showed no trabecular resorptive changes, no increased osteoclasts or bone inflammatory cytokines, no nerve inflammation, preserved nerve conduction, and increased muscle voluntary pulling forces. Ibuprofen treatment preserved trabecular bone quality by reducing osteoclasts and bone inflammatory cytokines, and improving muscle pulling forces on bones as a result of reduced nerve inflammation. PMID:24583543

  19. The High Calcium, High Phosphorus Rescue Diet Is Not Suitable to Prevent Secondary Hyperparathyroidism in Vitamin D Receptor Deficient Mice.

    PubMed

    Grundmann, Sarah M; Brandsch, Corinna; Rottstädt, Daniela; Kühne, Hagen; Stangl, Gabriele I

    2017-01-01

    The vitamin D receptor (VDR) knockout (KO) mouse is a common model to unravel novel metabolic functions of vitamin D. It is recommended to feed these mice a high calcium (2%), high phosphorus (1.25%) diet, termed rescue diet (RD) to prevent hypocalcaemia and secondary hyperparathyroidism. First, we characterized the individual response of VDR KO mice to feeding a RD and found that the RD was not capable of normalizing the parathyroid hormone (PTH) concentrations in each VDR KO mouse. In a second study, we aimed to study whether RD with additional 1 and 2% calcium (in total 3 and 4% of the diet) is able to prevent secondary hyperparathyroidism in the VDR KO mice. Wild type (WT) mice and VDR KO mice that received a normal calcium and phosphorus diet (ND) served as controls. Data demonstrated that the RD was no more efficient than the ND in normalizing PTH levels. An excessive dietary calcium concentration of 4% was required to reduce serum PTH concentrations in the VDR KO mice to PTH levels measured in WT mice. This diet, however, resulted in higher concentrations of circulating intact fibroblast growth factor 23 (iFGF23). To conclude, the commonly used RD is not suitable to normalize the serum PTH in VDR KO mice. Extremely high dietary calcium concentrations are necessary to prevent secondary hyperthyroidism in these mice, with the consequence that iFGF23 concentrations are being raised. Considering that PTH and iFGF23 exert numerous VDR independent effects, data obtained from VDR KO mice cannot be attributed solely to vitamin D.

  20. Glucose-induced regulatory defects in the Saccharomyces cerevisiae byp1 growth initiation mutant and identification of MIG1 as a partial suppressor.

    PubMed Central

    Hohmann, S; Huse, K; Valentin, E; Mbonyi, K; Thevelein, J M; Zimmermann, F K

    1992-01-01

    Saccharomyces cerevisiae byp1-3 mutants displayed a long lag phase when shifted from a nonfermentable carbon source to a medium containing glucose. The byp1-3 mutation also caused several defects in regulatory phenomena which occur during the transition from the derepressed state to the repressed state. As opposed to wild-type cells, the addition of glucose to cells of the byp1-3 mutant grown on nonfermentable carbon sources did not induce a cyclic AMP signal. Fructose-2,6-bisphosphate formation and inactivation of fructose-1,6-bisphosphatase were severely delayed, but trehalase activation was not affected. In addition, the induction of pyruvate decarboxylase both at the level of activity and that of transcription was very slow compared with that in wild-type cells. These pleotropic defects in glucose-induced regulatory phenomena might be responsible for the very long lag phase of byp1-3 cells and the inability of ascospores to initiate growth after germination on glucose media. Screening of a yeast gene library for clones complementing the byp1-3 phenotype resulted in the isolation of a truncated form of the previously described zinc finger transcription repressor MIG1. The entire MIG1 gene and the truncated form suppressed even on a single-copy vector the growth initiation defect but not the regulatory abnormalities of the byp1-3 mutant. MIG1 is not allelic to byp1-3. Images PMID:1597433

  1. MPGD for breast cancer prevention: a high resolution and low dose radiation medical imaging

    NASA Astrophysics Data System (ADS)

    Gutierrez, R. M.; Cerquera, E. A.; Mañana, G.

    2012-07-01

    Early detection of small calcifications in mammograms is considered the best preventive tool of breast cancer. However, existing digital mammography with relatively low radiation skin exposure has limited accessibility and insufficient spatial resolution for small calcification detection. Micro Pattern Gaseous Detectors (MPGD) and associated technologies, increasingly provide new information useful to generate images of microscopic structures and make more accessible cutting edge technology for medical imaging and many other applications. In this work we foresee and develop an application for the new information provided by a MPGD camera in the form of highly controlled images with high dynamical resolution. We present a new Super Detail Image (S-DI) that efficiently profits of this new information provided by the MPGD camera to obtain very high spatial resolution images. Therefore, the method presented in this work shows that the MPGD camera with SD-I, can produce mammograms with the necessary spatial resolution to detect microcalcifications. It would substantially increase efficiency and accessibility of screening mammography to highly improve breast cancer prevention.

  2. Sexual abuse prevention with high-risk males: the roles of victim empathy and rape myths.

    PubMed

    Schewe, P A; O'Donohue, W

    1993-01-01

    The outcome of two sexual abuse prevention programs, one emphasizing victim empathy and the other stressing modifying rape myths, was evaluated with high-risk males. Sixty-eight high-risk males, as determined by self-reported likelihood of committing sexual abuse, were randomly assigned to an empathy-treatment, a facts-treatment, or a no-treatment control group. Treatment effects were assessed using subjects' pre- and post-treatment scores on the Likelihood of Sexually Abusing scale, the Rape Empathy Scale, the Acceptance of Interpersonal Violence scale, the Adversarial Sexual Beliefs Scale, and a test of self-reported sexual arousal to forced versus consenting sex. In addition, posttest scores on an Asch-type conformity measure were obtained. Results of validity checks indicated that high-risk subjects differed from low-risk subjects on a number of rape-related variables, that the victim-empathy condition increased subjects' empathy, and that subjects found both treatments to be credible and helpful. Comparisons between the empathy-, facts-, and no-treatment group contraindicated the practice of dispelling rape myths as a method of preventing rape among high-risk males.

  3. Treating High-grade Lesions to Prevent Anal Cancer in HIV-infected People

    Cancer.gov

    This study, called the ANCHOR trial, will investigate whether screening and prevention methods similar to those used to prevent cervical cancer can help prevent anal cancer in HIV-infected men and women.

  4. Resveratrol Increases Glucose Induced GLP-1 Secretion in Mice: A Mechanism which Contributes to the Glycemic Control

    PubMed Central

    Dao, Thi-Mai Anh; Waget, Aurélie; Klopp, Pascale; Serino, Matteo; Vachoux, Christelle; Pechere, Laurent; Drucker, Daniel J.; Champion, Serge; Barthélemy, Sylvain; Barra, Yves; Burcelin, Rémy; Sérée, Eric

    2011-01-01

    Resveratrol (RSV) is a potent anti-diabetic agent when used at high doses. However, the direct targets primarily responsible for the beneficial actions of RSV remain unclear. We used a formulation that increases oral bioavailability to assess the mechanisms involved in the glucoregulatory action of RSV in high-fat diet (HFD)-fed diabetic wild type mice. Administration of RSV for 5 weeks reduced the development of glucose intolerance, and increased portal vein concentrations of both Glucagon-like peptid-1 (GLP-1) and insulin, and intestinal content of active GLP-1. This was associated with increased levels of colonic proglucagon mRNA transcripts. RSV-mediated glucoregulation required a functional GLP-1 receptor (Glp1r) as neither glucose nor insulin levels were modulated in Glp1r-/- mice. Conversely, levels of active GLP-1 and control of glycemia were further improved when the Dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin was co-administered with RSV. In addition, RSV treatment modified gut microbiota and decreased the inflammatory status of mice. Our data suggest that RSV exerts its actions in part through modulation of the enteroendocrine axis in vivo. PMID:21673955

  5. Resveratrol increases glucose induced GLP-1 secretion in mice: a mechanism which contributes to the glycemic control.

    PubMed

    Dao, Thi-Mai Anh; Waget, Aurélie; Klopp, Pascale; Serino, Matteo; Vachoux, Christelle; Pechere, Laurent; Drucker, Daniel J; Champion, Serge; Barthélemy, Sylvain; Barra, Yves; Burcelin, Rémy; Sérée, Eric

    2011-01-01

    Resveratrol (RSV) is a potent anti-diabetic agent when used at high doses. However, the direct targets primarily responsible for the beneficial actions of RSV remain unclear. We used a formulation that increases oral bioavailability to assess the mechanisms involved in the glucoregulatory action of RSV in high-fat diet (HFD)-fed diabetic wild type mice. Administration of RSV for 5 weeks reduced the development of glucose intolerance, and increased portal vein concentrations of both Glucagon-like peptid-1 (GLP-1) and insulin, and intestinal content of active GLP-1. This was associated with increased levels of colonic proglucagon mRNA transcripts. RSV-mediated glucoregulation required a functional GLP-1 receptor (Glp1r) as neither glucose nor insulin levels were modulated in Glp1r-/- mice. Conversely, levels of active GLP-1 and control of glycemia were further improved when the Dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin was co-administered with RSV. In addition, RSV treatment modified gut microbiota and decreased the inflammatory status of mice. Our data suggest that RSV exerts its actions in part through modulation of the enteroendocrine axis in vivo.

  6. Preventing High Fat Diet-induced Obesity and Improving Insulin Sensitivity through Neuregulin 4 Gene Transfer

    PubMed Central

    Ma, Yongjie; Gao, Mingming; Liu, Dexi

    2016-01-01

    Neuregulin 4 (NRG4), an epidermal growth factor-like signaling molecule, plays an important role in cell-to-cell communication during tissue development. Its function to regulate energy metabolism has recently been reported. This current study was designed to assess the preventive and therapeutic effects of NRG4 overexpression on high fat diet (HFD)-induced obesity. Using the hydrodynamic gene transfer method, we demonstrate that Nrg4 gene transfer in mice suppressed the development of diet-induced obesity, but did not affect pre-existing adiposity and body weight in obese mice. Nrg4 gene transfer curbed HFD-induced hepatic steatosis by inhibiting lipogenesis and PPARγ-mediated lipid storage. Concurrently, overexpression of NRG4 reduced chronic inflammation in both preventive and treatment studies, evidenced by lower mRNA levels of macrophage marker genes including F4/80, Cd68, Cd11b, Cd11c, and macrophage chemokine Mcp1, resulting in improved insulin sensitivity. Collectively, these results demonstrate that overexpression of the Nrg4 gene by hydrodynamic gene delivery prevents HFD-induced weight gain and fatty liver, alleviates obesity-induced chronic inflammation and insulin resistance, and supports the health benefits of NRG4 in managing obesity and obesity-associated metabolic disorders. PMID:27184920

  7. An evaluation of a Canadian peer-driven injury prevention programme for high-risk adolescents.

    PubMed

    Tenn, L; Dewis, M E

    1996-02-01

    The mortality and morbidity resulting from serious trauma in adolescence, particularly head and spinal cord injury, constitutes a health problem of major proportions. Although many community-based prevention programmes have been reported in this last decade, few of these describe an evaluation component. In this study, a school-based prevention programme was developed by a peer group and presented by them to high-risk adolescents. The study aimed to test the efficacy of this intervention compared to the delivery of a prevention presentation to a similar group by a health care professional and compared to a control group. Measures of health locus of control, self-efficacy and behavioural intent were supplemented by open-ended items related to risk-taking behaviour change. At post-test and at 4-month follow-up, there was little evidence in the quantitative measures to support the effectiveness of the intervention for reducing injury risk factors. More encouraging findings were seen in the qualitative data. Explanations for why the intervention did not result in the expected outcomes are offered.

  8. Neonatal air leak syndrome and the role of high-frequency ventilation in its prevention.

    PubMed

    Jeng, Mei-Jy; Lee, Yu-Sheng; Tsao, Pei-Chen; Soong, Wen-Jue

    2012-11-01

    Air leak syndrome includes pulmonary interstitial emphysema, pneumothorax, pneumomediastinum, pneumopericardium, pneumoperitoneum, subcutaneous emphysema, and systemic air embolism. The most common cause of air leak syndrome in neonates is inadequate mechanical ventilation of the fragile and immature lungs. The incidence of air leaks in newborns is inversely related to the birth weight of the infants, especially in very-low-birth-weight and meconium-aspirated infants. When the air leak is asymptomatic and the infant is not mechanically ventilated, there is usually no specific treatment. Emergent needle aspiration and/or tube drainage are necessary in managing tension pneumothorax or pneumopericardium with cardiac tamponade. To prevent air leak syndrome, gentle ventilation with low pressure, low tidal volume, low inspiratory time, high rate, and judicious use of positive end expiratory pressure are the keys to caring for mechanically ventilated infants. Both high-frequency oscillatory ventilation (HFOV) and high-frequency jet ventilation (HFJV) can provide adequate gas exchange using extremely low tidal volume and supraphysiologic rate in neonates with acute pulmonary dysfunction, and they are considered to have the potential to reduce the risks of air leak syndrome in neonates. However, there is still no conclusive evidence that HFOV or HFJV can help to reduce new air leaks in published neonatal clinical trials. In conclusion, neonatal air leaks may present as a thoracic emergency requiring emergent intervention. To prevent air leak syndrome, gentle ventilations are key to caring for ventilated infants. There is insufficient evidence showing the role of HFOV and HFJV in the prevention or reduction of new air leaks in newborn infants, so further investigation will be necessary for future applications.

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

    PubMed

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

    2013-07-02

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

  10. Ezetimibe prevents hepatic steatosis induced by a high-fat but not a high-fructose diet.

    PubMed

    Ushio, Masateru; Nishio, Yoshihiko; Sekine, Osamu; Nagai, Yoshio; Maeno, Yasuhiro; Ugi, Satoshi; Yoshizaki, Takeshi; Morino, Katsutaro; Kume, Shinji; Kashiwagi, Atsunori; Maegawa, Hiroshi

    2013-07-15

    Nonalcoholic fatty liver disease is the most frequent liver disease. Ezetimibe, an inhibitor of intestinal cholesterol absorption, has been reported to ameliorate hepatic steatosis in human and animal models. To explore how ezetimibe reduces hepatic steatosis, we investigated the effects of ezetimibe on the expression of lipogenic enzymes and intestinal lipid metabolism in mice fed a high-fat or a high-fructose diet. CBA/JN mice were fed a high-fat diet or a high-fructose diet for 8 wk with or without ezetimibe. High-fat diet induced hepatic steatosis accompanied by hyperinsulinemia. Treatment with ezetimibe reduced hepatic steatosis, insulin levels, and glucose production from pyruvate in mice fed the high-fat diet, suggesting a reduction of insulin resistance in the liver. In the intestinal analysis, ezetimibe reduced the expression of fatty acid transfer protein-4 and apoB-48 in mice fed the high-fat diet. However, treatment with ezetimibe did not prevent hepatic steatosis, hyperinsulinemia, and intestinal apoB-48 expression in mice fed the high-fructose diet. Ezetimibe decreased liver X receptor-α binding to the sterol regulatory element-binding protein-1c promoter but not expression of carbohydrate response element-binding protein and fatty acid synthase in mice fed the high-fructose diet, suggesting that ezetimibe did not reduce hepatic lipogenesis induced by the high-fructose diet. Elevation of hepatic and intestinal lipogenesis in mice fed a high-fructose diet may partly explain the differences in the effect of ezetimibe.

  11. Healthcare spending and preventive care in high-deductible and consumer-directed health plans.

    PubMed

    Beeuwkes Buntin, Melinda; Haviland, Amelia M; McDevitt, Roland; Sood, Neeraj

    2011-03-01

    To investigate the effects of high-deductible health plans (HDHPs) and consumer-directed health plans (CDHPs) on healthcare spending and on the use of recommended preventive care. Retrospective study. We analyzed claims and enrollment data for 808,707 households from 53 large US employers, 28 of which offered HDHPs or CDHPs. We estimated the effects of HDHP or CDHP enrollment on healthcare cost growth between 2004 and 2005 using a difference-in-difference method that compared cost growth for families who were enrolled in HDHPs or CDHPs for the first time in 2005 with cost growth for families who were not offered HDHPs or CDHPs. Control families were weighted using propensity score weights to match the treatment families. Using similar methods, we examined the effects of HDHP or CDHP enrollment on the use of preventive care and the effects of HDHP or CDHP offering by employers on the mean cost growth. Families enrolling in HDHPs or CDHPs for the first time spent 14% less than similar families enrolled in conventional plans. Families in firms offering an HDHP or a CDHP spent less than those in other firms. Significant savings for enrollees were realized only for plans with deductibles of at least $1000, and savings decreased with generous employer contributions to healthcare accounts. Enrollment in HDHPs or CDHPs was also associated with moderate reductions in the use of preventive care. The HDHPs or CDHPs with at least a $1000 deductible significantly reduced healthcare spending, but they also reduced the use of preventive care in the first year. This merits additional study because of concerns about enrollee health.

  12. High elastic modulus polymer electrolytes suitable for preventing thermal runaway in lithium batteries

    DOEpatents

    Mullin, Scott; Panday, Ashoutosh; Balsara, Nitash Pervez; Singh, Mohit; Eitouni, Hany Basam; Gomez, Enrique Daniel

    2014-04-22

    A polymer that combines high ionic conductivity with the structural properties required for Li electrode stability is useful as a solid phase electrolyte for high energy density, high cycle life batteries that do not suffer from failures due to side reactions and dendrite growth on the Li electrodes, and other potential applications. The polymer electrolyte includes a linear block copolymer having a conductive linear polymer block with a molecular weight of at least 5000 Daltons, a structural linear polymer block with an elastic modulus in excess of 1.times.10.sup.7 Pa and an ionic conductivity of at least 1.times.10.sup.-5 Scm.sup.-1. The electrolyte is made under dry conditions to achieve the noted characteristics. In another aspect, the electrolyte exhibits a conductivity drop when the temperature of electrolyte increases over a threshold temperature, thereby providing a shutoff mechanism for preventing thermal runaway in lithium battery cells.

  13. The National Cross-Site Evaluation of High-Risk Youth Programs: Making Prevention Effective for Adolescent Boys and Girls: Gender Differences in Substance Use and Prevention. Monograph Series.

    ERIC Educational Resources Information Center

    Springer, J. Fred; Sambrano, Soledad; Sale, Elizabeth; Kasim, Rafa; Hermann, Jack

    This document summarizes findings from the Center for Substance Abuse Prevention's National Cross-Site Evaluation of High-Risk Youth Programs, which identified characteristics associated with strong substance abuse prevention outcomes in 48 prevention programs. Results indicate that overall, boys and girls respond to prevention differently. Boys…

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

    PubMed

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

    2015-05-08

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

  15. Insulin/glucose induces natriuretic peptide clearance receptor in human adipocytes: a metabolic link with the cardiac natriuretic pathway.

    PubMed

    Bordicchia, M; Ceresiani, M; Pavani, M; Minardi, D; Polito, M; Wabitsch, M; Cannone, V; Burnett, J C; Dessì-Fulgheri, P; Sarzani, R

    2016-07-01

    Cardiac natriuretic peptides (NP) are involved in cardiorenal regulation and in lipolysis. The NP activity is largely dependent on the ratio between the signaling receptor NPRA and the clearance receptor NPRC. Lipolysis increases when NPRC is reduced by starving or very-low-calorie diet. On the contrary, insulin is an antilipolytic hormone that increases sodium retention, suggesting a possible functional link with NP. We examined the insulin-mediated regulation of NP receptors in differentiated human adipocytes and tested the association of NP receptor expression in visceral adipose tissue (VAT) with metabolic profiles of patients undergoing renal surgery. Differentiated human adipocytes from VAT and Simpson-Golabi-Behmel Syndrome (SGBS) adipocyte cell line were treated with insulin in the presence of high-glucose or low-glucose media to study NP receptors and insulin/glucose-regulated pathways. Fasting blood samples and VAT samples were taken from patients on the day of renal surgery. We observed a potent insulin-mediated and glucose-dependent upregulation of NPRC, through the phosphatidylinositol 3-kinase pathway, associated with lower lipolysis in differentiated adipocytes. No effect was observed on NPRA. Low-glucose medium, used to simulate in vivo starving conditions, hampered the insulin effect on NPRC through modulation of insulin/glucose-regulated pathways, allowing atrial natriuretic peptide to induce lipolysis and thermogenic genes. An expression ratio in favor of NPRC in adipose tissue was associated with higher fasting insulinemia, HOMA-IR, and atherogenic lipid levels. Insulin/glucose-dependent NPRC induction in adipocytes might be a key factor linking hyperinsulinemia, metabolic syndrome, and higher blood pressure by reducing NP effects on adipocytes. Copyright © 2016 the American Physiological Society.

  16. Glucose Induces Sensitivity to Oxygen Deprivation and Modulates Insulin/IGF-1 Signaling and Lipid Biosynthesis in Caenorhabditis elegans

    PubMed Central

    Garcia, Anastacia M.; Ladage, Mary L.; Dumesnil, Dennis R.; Zaman, Khadiza; Shulaev, Vladimir; Azad, Rajeev K.; Padilla, Pamela A.

    2015-01-01

    Diet is a central environmental factor that contributes to the phenotype and physiology of individuals. At the root of many human health issues is the excess of calorie intake relative to calorie expenditure. For example, the increasing amount of dietary sugars in the human diet is contributing to the rise of obesity and type 2 diabetes. Individuals with obesity and type 2 diabetes have compromised oxygen delivery, and thus it is of interest to investigate the impact a high-sugar diet has on oxygen deprivation responses. By utilizing the Caenorhabditis elegans genetic model system, which is anoxia tolerant, we determined that a glucose-supplemented diet negatively impacts responses to anoxia and that the insulin-like signaling pathway, through fatty acid and ceramide synthesis, modulates anoxia survival. Additionally, a glucose-supplemented diet alters lipid localization and initiates a positive chemotaxis response. Use of RNA-sequencing analysis to compare gene expression responses in animals fed either a standard or glucose-supplemented diet revealed that glucose impacts the expression of genes involved with multiple cellular processes including lipid and carbohydrate metabolism, stress responses, cell division, and extracellular functions. Several of the genes we identified show homology to human genes that are differentially regulated in response to obesity or type 2 diabetes, suggesting that there may be conserved gene expression responses between C. elegans fed a glucose-supplemented diet and a diabetic and/or obesity state observed in humans. These findings support the utility of the C. elegans model for understanding the molecular mechanisms regulating dietary-induced metabolic diseases. PMID:25762526

  17. Glucose-induced inhibition of the appetitive brain response to visual food cues in polycystic ovary syndrome patients.

    PubMed

    Van Vugt, Dean A; Krzemien, Alicja; Alsaadi, Hanin; Frank, Tamar C; Reid, Robert L

    2014-04-16

    We postulate that insulin regulation of food intake is compromised when insulin resistance is present. In order to investigate the effect of insulin sensitivity on appetitive brain responses, we conducted functional magnetic resonance imaging studies in a group of women diagnosed with polycystic ovary syndrome (PCOS) in which insulin sensitivity ranged from normal to resistant. Subjects (n=19) were imaged while viewing pictures of high calorie (HC) foods and low calorie (LC) foods after ingesting either 75 g glucose or an equivalent volume of water. The insulin sensitive group showed reduced blood oxygen level dependent (BOLD) signal in response to food pictures following glucose ingestion in numerous corticolimbic brain regions, whereas the insulin resistant group did not. There was a significant interaction between insulin sensitivity (sensitive vs resistant) and condition (water vs glucose). The largest clusters identified included the left insula, bilateral limbic/parahippocampal gyrus/culmen/midbrain, bilateral limbic lobe/precuneus, and left superior/mid temporal gyrus/parietal for HC and LC stimuli combined, the left parahippocampal gyrus/fusiform/pulvinar/midbrain for HC pictures, and the left superior/mid temporal gyrus/parietal and middle/inferior frontal gyrus/orbitofrontal cortex for LC pictures. Furthermore, BOLD signal in the anterior cingulate, medial frontal gyrus, posterior cingulate/precuneus, and parietal cortex during a glucose challenge correlated negatively with insulin sensitivity. We conclude the PCOS women with insulin resistance have an impaired brain response to a glucose challenge. The inability of postprandial hyperinsulinemia to inhibit brain responsiveness to food cues in insulin resistant subjects may lead to greater non-homeostatic eating. Copyright © 2014 Elsevier B.V. All rights reserved.

  18. Synaptotagmin-7 as a positive regulator of glucose-induced glucagon-like peptide-1 secretion in mice.

    PubMed

    Gustavsson, N; Wang, Y; Kang, Y; Seah, T; Chua, S; Radda, G K; Han, W

    2011-07-01

    Glucagon-like peptide-1 (GLP-1), a hormone with potent antihyperglycaemic effects, is produced and secreted from highly specialised gut endocrine L-cells. It regulates glucose homeostasis by promoting glucose-dependent insulin secretion, suppressing glucagon secretion and enhancing insulin sensitivity. Similar to islet alpha and beta cells, L-cells are electrically excitable, and express calcium channels and ATP-sensitive potassium channels. GLP-1 is also stored in secretory granules, the exocytosis of which is triggered by increased intracellular calcium levels. Although the calcium dependence of GLP-1 granule exocytosis is well established, the identities of calcium-sensing proteins in GLP-1 secretion remain elusive. Here we tested whether synaptotagmin-7, a calcium sensor in pancreatic alpha and beta cells, regulates GLP-1 secretion. We studied GLP-1 secretion using synaptotagmin-7 knockout (KO) mice and GLUTag cells with lentiviral-mediated synaptotagmin-7 silencing. We found that synaptotagmin-7 was co-localised with GLP-1 in intestinal L-cells. GLP-1 secretion was impaired in synaptotagmin-7 KO mice when they were challenged by glucose ingestion. Lentiviral knockdown (KD) of synaptotagmin-7 in GLUTag cells led to similar reductions in GLP-1 secretion, as determined by biochemical assays and by membrane capacitance measurements. Calcium response was not altered in synaptotagmin-7 KD cells. These results demonstrate that synaptotagmin-7 functions as a positive regulator of GLP-1 secretion in intestinal L-cells and GLUTag cells, consistent with its proposed role as a calcium sensor in GLP-1 secretion.

  19. The Effectiveness of School-Based Smoking Prevention Interventions among Low- and High-SES European Teenagers

    ERIC Educational Resources Information Center

    Mercken, L.; Moore, L.; Crone, M. R.; De Vries, H.; De Bourdeaudhuij, I.; Lien, N.; Fagiano, F.; Vitoria, P. D.; Van Lenthe, F. J.

    2012-01-01

    Preventing smoking initiation among adolescents of lower socio-economic groups is crucial for the reduction of socio-economic inequalities in health. The aim of the present study was to examine whether effective smoking prevention interventions in Europe are equally effective among adolescents of low- and high-socio-economic status (SES). As part…

  20. Impact of a School-Based Sexual Abuse Prevention Education Program on the Knowledge and Attitude of High School Girls

    ERIC Educational Resources Information Center

    Ogunfowokan, Adesola A.; Fajemilehin, Reuben B.

    2012-01-01

    Sexual abuse has been considered a public health issue because of the various health implications resulting from it. The school nurse has a responsibility in assisting the high school girl to prevent victimization. This study adopted a quasi-experimental design in which a sexual abuse prevention education package was developed and used to educate…

  1. A Study of High School Dropout Prevention and At-Risk Ninth Graders' Role Models and Motivations for School Completion

    ERIC Educational Resources Information Center

    Somers, Cheryl L.; Owens, Delila; Piliawsky, Monte

    2009-01-01

    This study describes the results of a research evaluation of a school dropout prevention program and adolescents' self-reported perceptions of their motivations and role models. The program was a partnership between an urban university and an urban school district that was designed to prevent 9th grade students from dropping out of high school. It…

  2. Integrating Life Skills Into a Theory-Based Drug-Use Prevention Program: Effectiveness among Junior High Students in Taiwan

    ERIC Educational Resources Information Center

    Huang, Chiu-Mieh; Chien, Li-Yin; Cheng, Chin-Feng; Guo, Jong-Long

    2012-01-01

    Background: Drug use has been noted among students in Taiwan during the past decade and schools have a role in preventing or delaying students' drug use. We developed and evaluated a school-based, drug-use prevention program integrating the theory of planned behavior (TPB) and life skills for junior high school students. Methods: We recruited 441…

  3. Violence Prevention in Schools: A Case Study of the Thurgood Marshall Academy Public Charter High School. Final Report

    ERIC Educational Resources Information Center

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

    2010-01-01

    This report 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. Based on an assessment of the school's violence prevention approach using qualitative and quantitative data from…

  4. Implementing an Alcohol and Other Drug Use Prevention Program Using University-High School Partnerships: Challenges and Lessons Learned

    ERIC Educational Resources Information Center

    Milroy, Jeffrey J.; Orsini, Muhsin Michael; Wyrick, David L.; Fearnow-Kenney, Melodie; Wagoner, Kimberly G.; Caldwell, Rebecca

    2015-01-01

    Background: School-based alcohol and other drug use prevention remains an important national strategy. Collaborative partnerships between universities and high schools have the potential to enhance prevention programming; however, there are challenges to sustaining such partnerships. Purpose: The purpose of this commentary is to underscore…

  5. Implementing an Alcohol and Other Drug Use Prevention Program Using University-High School Partnerships: Challenges and Lessons Learned

    ERIC Educational Resources Information Center

    Milroy, Jeffrey J.; Orsini, Muhsin Michael; Wyrick, David L.; Fearnow-Kenney, Melodie; Wagoner, Kimberly G.; Caldwell, Rebecca

    2015-01-01

    Background: School-based alcohol and other drug use prevention remains an important national strategy. Collaborative partnerships between universities and high schools have the potential to enhance prevention programming; however, there are challenges to sustaining such partnerships. Purpose: The purpose of this commentary is to underscore…

  6. High-Performance Workforce. National Dropout Prevention Center/Network Newsletter. Volume 19, Number 1, Winter 2007

    ERIC Educational Resources Information Center

    Duckenfield, Marty, Ed.

    2007-01-01

    The "National Dropout Prevention Newsletter" is published quarterly by the National Dropout Prevention Center/Network. This issue contains the following articles: (1) Preparing for the Demands of the New World Economy (Patrick J. O'Connor); (2) Connecting At-Risk Youth to the High-Performance Workforce (Patrick J. O'Connor); (3) Butler…

  7. The Effectiveness of School-Based Smoking Prevention Interventions among Low- and High-SES European Teenagers

    ERIC Educational Resources Information Center

    Mercken, L.; Moore, L.; Crone, M. R.; De Vries, H.; De Bourdeaudhuij, I.; Lien, N.; Fagiano, F.; Vitoria, P. D.; Van Lenthe, F. J.

    2012-01-01

    Preventing smoking initiation among adolescents of lower socio-economic groups is crucial for the reduction of socio-economic inequalities in health. The aim of the present study was to examine whether effective smoking prevention interventions in Europe are equally effective among adolescents of low- and high-socio-economic status (SES). As part…

  8. High-Performance Workforce. National Dropout Prevention Center/Network Newsletter. Volume 19, Number 1, Winter 2007

    ERIC Educational Resources Information Center

    Duckenfield, Marty, Ed.

    2007-01-01

    The "National Dropout Prevention Newsletter" is published quarterly by the National Dropout Prevention Center/Network. This issue contains the following articles: (1) Preparing for the Demands of the New World Economy (Patrick J. O'Connor); (2) Connecting At-Risk Youth to the High-Performance Workforce (Patrick J. O'Connor); (3) Butler…

  9. Integrating Life Skills Into a Theory-Based Drug-Use Prevention Program: Effectiveness among Junior High Students in Taiwan

    ERIC Educational Resources Information Center

    Huang, Chiu-Mieh; Chien, Li-Yin; Cheng, Chin-Feng; Guo, Jong-Long

    2012-01-01

    Background: Drug use has been noted among students in Taiwan during the past decade and schools have a role in preventing or delaying students' drug use. We developed and evaluated a school-based, drug-use prevention program integrating the theory of planned behavior (TPB) and life skills for junior high school students. Methods: We recruited 441…

  10. The Status of Preventive Behaviors in Traffic Accidents in Junior High School Students in Isfahan

    PubMed Central

    Hosseini, Leila; Tavazohi, Hossein; Shirdavani, Soheila; Heidari, Kamal; Nobari, Reza Fadaei; Kelishadi, Roya; Yalverdi, Narges

    2014-01-01

    Background: Population growth and use of the car in daily life entails new incidents and accidents everyday. Adolescents’ entering the new world of adults, their insufficient knowledge of rules, and high-risk behaviors expose them to more risks. Accordingly, a study was conducted with the aim to evaluate the status of preventive behaviors in traffic accidents in boy and girl junior high school students in Isfahan regarding vehicle use. Methods: A descriptive-analytical cross-sectional study was conducted on 7000 junior high school boy and girl students from 20 towns in Isfahan Province using multi-stage cluster sampling method in 2009–2010. A researcher-made questionnaire was used as data collection tool, which evaluated students’ practice and preventive behaviors with 21 questions, each examining students’ practice in accidents and incidents that may occur in school and on the way to school. Data were analyzed with Epi 6 and SPSS software using t-test and Chi-square test. Results: Girls comprised 49.9% of students and 50.1% were boys, 84% lived in urban areas and 15.5% in rural areas. The frequency of an accident location was school in 53.9% with 3739 cases and on the way to school in 10.6% with 732 cases. Mean practice score of preventive behaviors in traffic accidents involving cars, taxi, and school bus (72.6 ± 17.52 girls, 72.7 ± 18.31 boys, P = 0.88), motorbike (79.1 ± 14.048 girls, 74.1 ± 19.73 boys, P < 0.001), bicycle (71.4 ± 16.56 girls, 68.5 ± 14.69 boys, P = 0.152), bus and minibus (91.8 ± 13.16 girls, 87 ± 18.65 boys, P < 0.001), crossing the street (30.5 ± 26.67 girls, 32.7 ± 28.03 boys, P = 0.003), and skating (60.6 ± 29.103 girls, 61.2 ± 26.84 boys, P = 0.927). Results indicate that girls have better preventive practices than boys in use of motorbikes, buses, and minibuses. Conclusions: According to the results obtained, the majority of students walk to school and have the lowest practice score in this respect. It is recommended

  11. The first Iranian recommendations on prevention, evaluation and management of high blood pressure

    PubMed Central

    Noohi, Feridoun; Sarrafzadegan, Nizal; Khosravi, Alireza; Andalib, Elham

    2012-01-01

    This paper presents the complete report of the first Iranian Recommendations on Prevention, Evaluation and Management of High Blood Pressure. The purpose is to provide an evidence-based approach to the prevention, management and control of hypertension (HTN) by adapting the most internationally known and used guidelines to the local health care status with consideration of the currently available data and based on the locally conducted researches on HTN as well as social and health care requirements. A working group of national and international experts participated in discussions and collaborated in decision-making, writing and reviewing the whole report. Multiple subcommittees worked together to review the recent national and international literature on HTN in different areas. We used the evaluation tool that is called "AGREE" and considered a score of > 60% as a high score. We adapted the Canadian Hypertension Education Program (CHEP), the United Kingdom's National Institute for Health and Clinical Excellence (NICE) and the US-based joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC7). The key topics that are highlighted in this report include: The importance of ambulatory and self-measurement of blood pressure, evaluation of cardiovascular risk in HTN patients, the role of lifestyle modification in the prevention of HTN and its control with more emphasis on salt intake reduction and weight control, introducing pharmacotherapy suitable for uncomplicated HTN or specific situations and the available drugs in Iran, highlighting the importance of angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers and calcium channel blockers as the first line therapy in many situations, the non-use of beta blockers as the first time treatment except in specific conditions, treating HTN in women, children, obese and elderly patients, the patient compliance to improve HTN control, practical guidelines to improve

  12. Efficacy of an HIV Prevention Program Among African American Female Adolescents Reporting High Depressive Symptomatology

    PubMed Central

    Lang, Delia L.; Hardin, James W.; DiClemente, Ralph J.; Wingood, Gina M.

    2010-01-01

    Abstract Objectives We examined the efficacy of an HIV prevention intervention among African American adolescent females reporting at or above threshold depressive symptomatology. Methods In this analysis, a subgroup of participants (n = 245) reporting at or above threshold depressive symptoms involved in a randomized controlled trial were assessed at 6-month and 12-month follow-ups on condom use and psychosocial mediators associated with HIV prevention behaviors. The intervention emphasized HIV knowledge, condom attitudes, communication self-efficacy, and condom use skills. Results Relative to the comparison condition, participants randomized to the intervention reported using condoms more consistently, engaged in a greater proportion of condom protected intercourse acts, had fewer episodes of unprotected vaginal sex, were more likely to use a condom at last sex, and had higher HIV knowledge, favorable attitudes toward condoms, condom use self-efficacy, and condom use skills. Conclusions Overall, the pattern of effects found strengthen our confidence in the efficacy of the HIV intervention assessed for a broad range of young women, including those with high levels of depressive symptoms. Although young women with high depressive symptoms benefited from this HIV intervention, future studies employing interventions that specifically address the affective needs of this population might be even more effective in terms of sexual risk reduction and amelioration of depressive symptoms. PMID:20109119

  13. Effectiveness of Different Preventive Programs in Cariogram Parameters of Young Adults at High Caries Risk

    PubMed Central

    Ünlü, Nimet

    2017-01-01

    Objective To evaluate the effectiveness of different preventive programs in young adults at high caries risk using Cariogram software. Methods Sixty-six young adults with high caries risk were evaluated. Dental caries risk for all subjects was determined according to WHO criteria. Subjects were divided into three different preventive groups (control: OH, fluoride varnish: FV, and chlorhexidine varnish: CV). They were followed for 12 weeks (baseline: T0, 1 week: T1, 4 weeks: T2, and 12 weeks: T3). Plaque index, diet frequency, and salivary chairside tests (to record the flow rate, buffer capacity, and mutans streptococci and lactobacillus counts) were performed at each visit. Based on these data, ten caries-related variables were collected and inserted into the Cariogram software to calculate the predicted chance of avoiding caries for each subject. Results Significant changes were obtained about the Cariogram parameters (diet, bacteria, susceptibility, circumstances, and Cariogram risk group). No significant differences were found between the three methods regarding mean Cariogram scores after 3 months (p > 0.05). Conclusions The regular and effective short-term (three months) use of 1450 ppm fluoridated toothpaste, one visit application of fluoride, and chlorhexidine varnishes were effective for reducing caries risk in young adults, which can be clearly demonstrated using Cariogram software. PMID:28634492

  14. Scale prevention at high LSI, high cycles, and high pH without the need for acid feed

    SciTech Connect

    Perez, L.A.; Freese, D.T.

    1997-08-01

    Open recirculating cooling water systems are widely used in different industries, such as refineries, petrochemical, fertilizer, air conditioning, manufacturing operations, utility power stations, etc. Scale control at high LSI and high pH without acid feed is difficult to achieve. The problem dramatically increases in cooling towers when PVC tower film fill is used. Compounds that are able to enhance the performance of typical scale inhibitors have been developed. When topped off with these enhancing compounds, typical scale inhibitors are able to control calcium carbonate and silicate-related scale formation on metal heat exchanger and cooling water tower film fill surfaces in cycled waters having high LSI ({approximately} 3.0), high alkalinity (500--700 mg/L as CaCO{sub 3}), and high pH (8.5 or higher). The enhancing compounds have excellent chlorine and soluble iron tolerance and are compatible with traditional biocides.

  15. The involvement of calcium carriers and of the vacuole in the glucose-induced calcium signaling and activation of the plasma membrane H(+)-ATPase in Saccharomyces cerevisiae cells.

    PubMed

    Bouillet, L E M; Cardoso, A S; Perovano, E; Pereira, R R; Ribeiro, E M C; Trópia, M J M; Fietto, L G; Tisi, R; Martegani, E; Castro, I M; Brandão, R L

    2012-01-01

    Previous work from our laboratories demonstrated that the sugar-induced activation of plasma membrane H(+)-ATPase in Saccharomyces cerevisiae is dependent on calcium metabolism with the contribution of calcium influx from external medium. Our results demonstrate that a glucose-induced calcium (GIC) transporter, a new and still unidentified calcium carrier, sensitive to nifedipine and gadolinium and activated by glucose addition, seems to be partially involved in the glucose-induced activation of the plasma membrane H(+)-ATPase. On the other hand, the importance of calcium carriers that can release calcium from internal stores was analyzed in glucose-induced calcium signaling and activation of plasma membrane H(+)-ATPase, in experimental conditions presenting very low external calcium concentrations. Therefore the aim was also to investigate how the vacuole, through the participation of both Ca(2+)-ATPase Pmc1 and the TRP homologue calcium channel Yvc1 (respectively, encoded by the genes PMC1 and YVC1) contributes to control the intracellular calcium availability and the plasma membrane H(+)-ATPase activation in response to glucose. In strains presenting a single deletion in YVC1 gene or a double deletion in YVC1 and PMC1 genes, both glucose-induced calcium signaling and activation of the H(+)-ATPase are nearly abolished. These results suggest that Yvc1 calcium channel is an important component of this signal transduction pathway activated in response to glucose addition. We also found that by a still undefined mechanism Yvc1 activation seems to correlate with the changes in the intracellular level of IP(3). Taken together, these data demonstrate that glucose addition to yeast cells exposed to low external calcium concentrations affects calcium uptake and the activity of the vacuolar calcium channel Yvc1, contributing to the occurrence of calcium signaling connected to plasma membrane H(+)-ATPase activation. Copyright © 2011 Elsevier Ltd. All rights reserved.

  16. Changes in glucose-induced plasma active glucagon-like peptide-1 levels by co-administration of sodium-glucose cotransporter inhibitors with dipeptidyl peptidase-4 inhibitors in rodents.

    PubMed

    Oguma, Takahiro; Kuriyama, Chiaki; Nakayama, Keiko; Matsushita, Yasuaki; Hikida, Kumiko; Tsuda-Tsukimoto, Minoru; Saito, Akira; Arakawa, Kenji; Ueta, Kiichiro; Minami, Masabumi; Shiotani, Masaharu

    2016-12-01

    We investigated whether structurally different sodium-glucose cotransporter (SGLT) 2 inhibitors, when co-administered with dipeptidyl peptidase-4 (DPP4) inhibitors, could enhance glucagon-like peptide-1 (GLP-1) secretion during oral glucose tolerance tests (OGTTs) in rodents. Three different SGLT inhibitors-1-(β-d-Glucopyranosyl)-4-chloro-3-[5-(6-fluoro-2-pyridyl)-2-thienylmethyl]benzene (GTB), TA-1887, and canagliflozin-were examined to assess the effect of chemical structure. Oral treatment with GTB plus a DPP4 inhibitor enhanced glucose-induced plasma active GLP-1 (aGLP-1) elevation and suppressed glucose excursions in both normal and diabetic rodents. In DPP4-deficient rats, GTB enhanced glucose-induced aGLP-1 elevation without affecting the basal level, whereas metformin, previously reported to enhance GLP-1 secretion, increased both the basal level and glucose-induced elevation. Oral treatment with canagliflozin and TA-1887 also enhanced glucose-induced aGLP-1 elevation when co-administered with either teneligliptin or sitagliptin. These data suggest that structurally different SGLT2 inhibitors enhance plasma aGLP-1 elevation and suppress glucose excursions during OGTT when co-administered with DPP4 inhibitors, regardless of the difference in chemical structure. Combination treatment with DPP4 inhibitors and SGLT2 inhibitors having moderate SGLT1 inhibitory activity may be a promising therapeutic option for improving glycemic control in patients with type 2 diabetes mellitus. Copyright © 2016 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  17. Adolescent pregnancy prevention: An abstinence-centered randomized controlled intervention in a Chilean public high school.

    PubMed

    Cabezón, Carlos; Vigil, Pilar; Rojas, Iván; Leiva, M Eugenia; Riquelme, Rosa; Aranda, Waldo; García, Carlos

    2005-01-01

    To evaluate the efficacy of an abstinence-centered sex education program in adolescent pregnancy prevention, the TeenSTAR Program was applied in a high school in Santiago, Chile. A total of 1259 girls from a Santiago high school were divided into three cohorts depending on the year they started high school: the 1996 cohort of 425 students, which received no intervention; the 1997 cohort, in which 210 students received an intervention and 213 (control group) did not; and the 1998 cohort, in which 328 students received an intervention and 83 (control group) did not. Students were randomly assigned to control and intervention groups in these cohorts, before starting with the program. We conducted a prospective, randomized study using the application of the TeenSTAR sex education program during the first year of high school to the intervention groups in the 1997 and 1998 cohorts. All cohorts were followed up for 4 years; pregnancy rates were recorded and subsequently contrasted in the intervention and control groups. Pregnancy rates were measured and Risk Ratio with 95% confidence interval were calculated for intervention and control groups in each cohort. Pregnancy rates for the intervention and control groups in the 1997 cohort were 3.3% and 18.9%, respectively (RR: 0.176, CI: 0.076-0.408). Pregnancy rates for the intervention and control groups in the 1998 cohort were 4.4% and 22.6%, respectively (RR 0.195, CI: 0.099-0.384). The abstinence-centered TeenSTAR sex education intervention was effective in the prevention of unintended adolescent pregnancy.

  18. A Mechanism Underlying Preventive Effect of High-Intensity Training on Colon Cancer.

    PubMed

    Matsuo, Kaori; Sato, Koji; Suemoto, Ken; Miyamoto-Mikami, Eri; Fuku, Noriyuki; Higashida, Kazuhiko; Tsuji, Katsunori; Xu, Yuzhong; Liu, Xin; Iemitsu, Motoyuki; Hamaoka, Takafumi; Tabata, Izumi

    2017-09-01

    We examined effects of high-intensity training on chemically induced aberrant crypt foci (ACF) in rat colon. We also investigated mechanisms that may underlie the results obtained, with a focus on secreted protein acidic and rich in cysteine (SPARC), which has been proposed as an exercise-related factor of colon cancer prevention. After an administration of 1,2-dimethylhydrazine, F344 rats executed high-intensity intermittent swimming training (HIIST) (twelve 20-s swimming with a weight [16% body weight] with 10-s pauses between the bouts) 5 d·wk for 4 wk. The acute and chronic effects of the HIIST on SPARC were evaluated in rats. We evaluated the in vitro and in vivo effects of 5' AMP-activated protein kinase (AMPK) activator on SPARC in rat serum and epitrochlearis muscle. In human subjects, we determined serum SPARC after exhaustive bicycling consisting of six to seven bouts of exercise at 170% V˙O2max with 10-s rests between the bouts (high-intensity intermittent bicycling [HIIB]). The SPARC mRNA in human vastus lateralis was measured before and after the HIIB for 4 d·wk for 6 wk (HIIB-training [HIIBT]). The numbers of ACF were lower in the HIIST (47 ± 22) compared with the control (122 ± 47) rats (P < 0.05). SPARC in epitrochlearis and serum after HIIS of the trained rat was higher than that in the control resting rats. In vitro and vivo AMPK stimulation increased mRNA and SPARC protein in rat epitrochlearis, respectively. The human serum SPARC after the HIIB was elevated. SPARC mRNA in human muscle was elevated after the HIIBT. The results demonstrated that HIIST inhibits 1,2-dimethylhydrazine-induced colon ACF development. This effect may be explained by SPARC induction by the exercise intensity-related factor AMPK, potentially explaining the preventive effects of high-intensity intermittent exercise training against colon cancer.

  19. Enhanced glucose-induced intracellular signaling promotes insulin hypersecretion: pancreatic beta-cell functional adaptations in a model of genetic obesity and prediabetes.

    PubMed

    Irles, Esperanza; Ñeco, Patricia; Lluesma, Mónica; Villar-Pazos, Sabrina; Santos-Silva, Junia Carolina; Vettorazzi, Jean F; Alonso-Magdalena, Paloma; Carneiro, Everardo M; Boschero, Antonio C; Nadal, Ángel; Quesada, Ivan

    2015-03-15

    Obesity is associated with insulin resistance and is known to be a risk factor for type-2 diabetes. In obese individuals, pancreatic beta-cells try to compensate for the increased insulin demand in order to maintain euglycemia. Most studies have reported that this adaptation is due to morphological changes. However, the involvement of beta-cell functional adaptations in this process needs to be clarified. For this purpose, we evaluated different key steps in the glucose-stimulated insulin secretion (GSIS) in intact islets from female ob/ob obese mice and lean controls. Obese mice showed increased body weight, insulin resistance, hyperinsulinemia, glucose intolerance and fed hyperglycemia. Islets from ob/ob mice exhibited increased glucose-induced mitochondrial activity, reflected by enhanced NAD(P)H production and mitochondrial membrane potential hyperpolarization. Perforated patch-clamp examination of beta-cells within intact islets revealed several alterations in the electrical activity such as increased firing frequency and higher sensitivity to low glucose concentrations. A higher intracellular Ca(2+) mobilization in response to glucose was also found in ob/ob islets. Additionally, they displayed a change in the oscillatory pattern and Ca(2+) signals at low glucose levels. Capacitance experiments in intact islets revealed increased exocytosis in individual ob/ob beta-cells. All these up-regulated processes led to increased GSIS. In contrast, we found a lack of beta-cell Ca(2+) signal coupling, which could be a manifestation of early defects that lead to beta-cell malfunction in the progression to diabetes. These findings indicate that beta-cell functional adaptations are an important process in the compensatory response to obesity. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  20. Redox Signal-mediated Enhancement of the Temperature Sensitivity of Transient Receptor Potential Melastatin 2 (TRPM2) Elevates Glucose-induced Insulin Secretion from Pancreatic Islets.

    PubMed

    Kashio, Makiko; Tominaga, Makoto

    2015-05-08

    Transient receptor potential melastatin 2 (TRPM2) is a thermosensitive Ca(2+)-permeable cation channel expressed by pancreatic β cells where channel function is constantly affected by body temperature. We focused on the physiological functions of redox signal-mediated TRPM2 activity at body temperature. H2O2, an important molecule in redox signaling, reduced the temperature threshold for TRPM2 activation in pancreatic β cells of WT mice but not in TRPM2KO cells. TRPM2-mediated [Ca(2+)]i increases were likely caused by Ca(2+) influx through the plasma membrane because the responses were abolished in the absence of extracellular Ca(2+). In addition, TRPM2 activation downstream from the redox signal plus glucose stimulation enhanced glucose-induced insulin secretion. H2O2 application at 37 °C induced [Ca(2+)]i increases not only in WT but also in TRPM2KO β cells. This was likely due to the effect of H2O2 on KATP channel activity. However, the N-acetylcysteine-sensitive fraction of insulin secretion by WT islets was increased by temperature elevation, and this temperature-dependent enhancement was diminished significantly in TRPM2KO islets. These data suggest that endogenous redox signals in pancreatic β cells elevate insulin secretion via TRPM2 sensitization and activity at body temperature. The results in this study could provide new therapeutic approaches for the regulation of diabetic conditions by focusing on the physiological function of TRPM2 and redox signals. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  1. Caries prevention during orthodontic treatment: In-vivo assessment of high-fluoride varnish to prevent white spot lesions.

    PubMed

    Perrini, Federico; Lombardo, Luca; Arreghini, Angela; Medori, Silvia; Siciliani, Giuseppe

    2016-02-01

    Our objective was to evaluate the efficacy of a fluoridated varnish in preventing white spot lesions in patients with fixed appliances. A laser-induced fluorescence device was used to determine any correlations between the degree of demineralization and the length of the observation period, the arch sector, the frequency of varnish application, and the specific tooth site. A split-mouth study design was used for 24 orthodontic patients, allocated randomly to 2 subgroups with differing frequencies of Duraphat varnish (Colgate-Palmolive, New York, NY) application. Repeated measures of the degree of demineralization were taken on the vestibular surfaces of 12 teeth (6 varnished and 6 unvarnished controls). Measurements were taken at 4 sites using a DIAGNOdent Pen 2190 laser (KaVo, Biberach an der Riss, Germany) and then subjected to statistical analysis. Generalized linear model and coefficient model analysis showed differences in the degrees of demineralization between treated and untreated teeth, but this was not statistically significant in terms of time point, frequency of application, or specific tooth site. However, when we analyzed the position of the teeth, the varnished anterior teeth showed a statistically significant reduction in demineralization compared with their unvarnished counterparts. Periodic application of fluoride varnish can offer some protection against white spots, but not to a statistically significant degree if the patients have excellent oral hygiene. Copyright © 2016 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.

  2. Definition of high risk individuals to optimise strategies for primary prevention of cardiovascular diseases.

    PubMed

    Giampaoli, Simona; Palmieri, Luigi; Mattiello, Amalia; Panico, Salvatore

    2005-02-01

    The identification of high risk individuals is one of the main goals of cardiovascular primary prevention and constitutes the basis for implementing actions oriented toward reducing modifiable risk factors at individual level, from changing life styles to drug interventions. The most appropriate method for identifying high risk individuals is the evaluation of their absolute global risk, a probability indicator of incidence, predictable on the basis of risk factor levels. Risk functions, derived from longitudinal studies, are used to identify persons at high probability to develop cardiovascular diseases. The appropriateness of the use of these risk functions depends upon the characteristics of the population that generated them and of individuals which they are applied to. Risk charts are simply absolute global risks calculated by classes of risk factors; risk scores are more precise evaluation derived from absolute global risks calculated by continuous levels of risk factors. Risk charts and scores are formed through the risk functions derived from different studies: Framingham, PROCAM (Munster), Seven Countries Study, SCORE and Progetto CUORE. A further chart has been created using the Framingham Study and adapted to the guidelines of New Zealand regarding the treatment of dyslipidemias and blood pressure. Major differences can be found in the availability of risk factors in men and women and in the use of fatal and non-fatal coronary and cerebrovascular events as end-points. All these studies use different diagnostic criteria for identification, classification and validation of events. The awareness of the risk charts differences is a key issue to refine tools for prevention of cardiovascular disease in populations with different probabilities of disease frequency.

  3. High intracellular trehalase activity prevents the storage of trehalose in the yeast Dekkera bruxellensis.

    PubMed

    Leite, F C B; Leite, D V da R; Pereira, L F; de Barros Pita, W; de Morais, M A

    2016-09-01

    Dekkera bruxellensis hit the spotlight in the past decade mostly due to its rather high ability to adapt to several different fermentation processes. This yeast relies on different genetic and physiological aspects to achieve and preserve its high industrial fitness and some of these traits are shared with Saccharomyces cerevisiae. We have previously described that D. bruxellensis is unable to make use of accumulating trehalose as a strategy for cell adaptation and survival in the industrial scenario, as opposed to S. cerevisiae. Since trehalose is often involved in mechanisms related to cell protection, we aimed to investigate both cause and effect of the absence of this metabolite in the cell adaptive capacity in the industrial environment. Our results indicate that the major cause for the nonaccumulation of trehalose is the high constitutive activity of neutral trehalase. Therefore, the rate of trehalose degradation could be higher than its rate of synthesis, preventing accumulation. Altogether, our data elucidate the mechanisms involved in the lack of trehalose accumulation in D. bruxellensis as well as evaluates the implications of this feature. Dekkera bruxellensis can successfully take advantage of its peculiar physiological and genetic traits in order to adapt and survive in fermentation processes. So far, tolerance to stress has been credited to trehalose synthesis. The data presented in this work provided information on the underlying mechanism that prevents trehalose accumulation and corroborated the recent information that trehalose itself is not implicated in yeast stress tolerance. Second, it showed that D. bruxellensis responds differently to Saccharomyces cerevisiae to excess of sugar, which may explain its preference for respiration (oxidative metabolism) over fermentation (reductive metabolism) even at limited oxygen supply. These findings help to understand the drop on ethanol production in processes overtaken by this yeast. © 2016 The

  4. Flat spin and negative Gz in high-altitude free fall: pathophysiology, prevention, and treatment.

    PubMed

    Pattarini, James M; Blue, Rebecca S; Aikins, Luke T; Law, Jennifer; Walshe, Andrew D; Garbino, Alejandro; Turney, Matthew W; Clark, Jonathan B

    2013-09-01

    Red Bull Stratos was a commercial program that brought a test parachutist protected by a full pressure suit to 127,852 ft (38,964 m), via a stratospheric balloon with a pressurized capsule, from which he free fell and subsequently parachuted to the ground. In light of the uniqueness of the operation and the medical threats faced, medical protocols specific to distinctive injury patterns were developed. One unique threat was that of a flat spin during free fall with resultant exposure to -Gz (toe-to-head) acceleration. In preparation for stratospheric free fall, the medical team conducted a review of the literature on the spectrum of human and animal injury patterns attributable to -Gz exposures. Based on the findings, an emergency medical field response protocol was developed for the rapid assessment, diagnosis, and treatment of individuals suspected of -Gz injury. A systematic review was conducted on available literature on human and animal studies involving significant -Gz exposure, with subsequent development of an applicable field treatment protocol. The literature review identified pathophysiologic processes and mitigation strategies that were used to develop a prevention and treatment protocol, outlining appropriate interventions using current best medical practices. A medical field treatment protocol was successfully established for the high-altitude balloon program. Available literature provided insight into best medical practices for the prevention and treatment of significant -Gz exposures during high-altitude parachute activity. Using the protocol developed for the field medical response, injuries from sustained -Gz exposure can be effectively managed in similar high-altitude and space operations.

  5. Systematic Review of Abstinence-Plus HIV Prevention Programs in High-Income Countries

    PubMed Central

    Underhill, Kristen; Operario, Don; Montgomery, Paul

    2007-01-01

    Background Abstinence-plus (comprehensive) interventions promote sexual abstinence as the best means of preventing HIV, but also encourage condom use and other safer-sex practices. Some critics of abstinence-plus programs have suggested that promoting safer sex along with abstinence may undermine abstinence messages or confuse program participants; conversely, others have suggested that promoting abstinence might undermine safer-sex messages. We conducted a systematic review to investigate the effectiveness of abstinence-plus interventions for HIV prevention among any participants in high-income countries as defined by the World Bank. Methods and Findings Cochrane Collaboration systematic review methods were used. We included randomized and quasi-randomized controlled trials of abstinence-plus programs for HIV prevention among any participants in any high-income country; trials were included if they reported behavioural or biological outcomes. We searched 30 electronic databases without linguistic or geographical restrictions to February 2007, in addition to contacting experts, hand-searching conference abstracts, and cross-referencing papers. After screening 20,070 abstracts and 325 full published and unpublished papers, we included 39 trials that included approximately 37,724 North American youth. Programs were based in schools (10), community facilities (24), both schools and community facilities (2), health care facilities (2), and family homes (1). Control groups varied. All outcomes were self-reported. Quantitative synthesis was not possible because of heterogeneity across trials in programs and evaluation designs. Results suggested that many abstinence-plus programs can reduce HIV risk as indicated by self-reported sexual behaviours. Of 39 trials, 23 found a protective program effect on at least one sexual behaviour, including abstinence, condom use, and unprotected sex (baseline n = 19,819). No trial found adverse program effects on any behavioural outcome

  6. Postural muscle atrophy prevention and recovery and bone remodelling through high frequency proprioception for astronauts

    NASA Astrophysics Data System (ADS)

    Riva, Dario; Rossitto, Franco; Battocchio, Luciano

    2009-09-01

    The difficulty in applying active exercises during space flights increases the importance of passive countermeasures, but coupling load and instability remains indispensable for generating high frequency (HF) proprioceptive flows and preventing muscle atrophy and osteoporosis. The present study, in microgravity conditions during a parabolic flight, verified whether an electronic system, composed of a rocking board, a postural reader and a bungee-cord loading apparatus creates HF postural instability comparable to that reachable on the Earth. Tracking the subject, in single stance, to real-time visual signals is necessary to obtain HF instability situations. The bungee-cord loading apparatus allowed the subject to manage the 81.5% body weight load (100% could easily be exceeded). A preliminary training programme schedule on the Earth and in space is suggested. Comparison with a pathological muscle atrophy is presented. The possibility of generating HF proprioceptive flows could complement current countermeasures for the prevention and recovery of muscle atrophy and osteoporosis in terrestrial and space environments. These exercises combine massive activation of spindles and joint receptors, applying simultaneously HF variations of pressure to different areas of the sole of the foot. This class of exercises could improve the effectiveness of current countermeasures, reducing working time and fatigue.

  7. Evaluation of indicated suicide risk prevention approaches for potential high school dropouts.

    PubMed Central

    Thompson, E A; Eggert, L L; Randell, B P; Pike, K C

    2001-01-01

    OBJECTIVES: This study evaluated the efficacy of 2 indicated preventive interventions, postintervention and at 9-month follow-up. METHODS: Drawn from a pool of potential high school dropouts, 460 youths were identified as being at risk for suicide and participated in 1 of 3 conditions randomly assigned by school: (1) Counselors CARE (C-CARE) (n = 150), a brief one-to-one assessment and crisis intervention; (2) Coping and Support Training (CAST) (n = 155), a small-group skills-building and social support intervention delivered with C-CARE; and (3) usual-care control (n = 155). Survey instruments were administered pre-intervention, following C-CARE (4 weeks), following CAST (10 weeks), and at a 9-month follow-up. RESULTS: Growth curve analyses showed significant rates of decline in attitude toward suicide and suicidal ideation associated with the experimental interventions. C-CARE and CAST, compared with usual care, also were effective in reducing depression and hopelessness. Among females, reductions in anxiety and anger were greater in response to the experimental programs. CAST was most effective in enhancing and sustaining personal control and problem-solving coping for males and females. CONCLUSIONS: School-based, indicated prevention approaches are feasible and effective for reducing suicidal behaviors and related emotional distress and for enhancing protective factors. PMID:11344882

  8. Preventing Violence Among High-Risk Youth and Communities with Economic, Policy, and Structural Strategies.

    PubMed

    Massetti, Greta M; David-Ferdon, Corinne

    2016-02-12

    Youth violence is preventable, and the reduction of health disparities is possible with evidence-based approaches. Achieving community-wide reductions in youth violence and health disparities has been limited in part because of the lack of prevention strategies to address community risk factors. CDC-supported research has resulted in three promising community-level approaches: Business Improvement Districts (BIDs) in Los Angeles, California; alcohol policy to reduce youth access in Richmond, Virginia; and the Safe Streets program in Baltimore, Maryland. Evaluation findings indicated that BIDs in Los Angeles were associated with a 12% reduction in robberies (one type of violent crime) and an 8% reduction in violent crime overall. In Richmond's alcohol policy program, investigators found that the monthly average of ambulance pickups for violent injuries among youth aged 15-24 years had a significantly greater decrease in the intervention (19.6 to 0 per 1,000) than comparison communities (7.4 to 3.3 per 1,000). Investigators of Safe Streets found that some intervention communities experienced reductions in homicide and/or nonfatal shootings, but results were not consistent across communities. Communitywide rates of violence can be changed in communities with disproportionately high rates of youth violence associated with entrenched health disparities and socioeconomic disadvantage. Community-level strategies are a critical part of comprehensive approaches necessary to achieve broad reductions in violence and health disparities.

  9. Longitudinal Impact of Two Universal Preventive Interventions in First Grade on Educational Outcomes in High School

    PubMed Central

    Bradshaw, Catherine P.; Zmuda, Jessika H.; Kellam, Sheppard G.; Ialongo, Nicholas S.

    2013-01-01

    This study examined the longitudinal effects of 2 first-grade universal preventive interventions on academic outcomes (e.g., achievement, special education service use, graduation, postsecondary education) through age 19 in a sample of 678 urban, primarily African American children. The classroom-centered intervention combined the Good Behavior Game (H. H. Barrish, Saunders, & Wolfe, 1969) with an enhanced academic curriculum, whereas a second intervention, the Family–School Partnership, focused on promoting parental involvement in educational activities and bolstering parents’ behavior management strategies. Both programs aimed to address the proximal targets of aggressive behavior and poor academic achievement. Although the effects varied by gender, the classroom-centered intervention was associated with higher scores on standardized achievement tests, greater odds of high school graduation and college attendance, and reduced odds of special education service use. The intervention effects of the Family–School Partnership were in the expected direction; however, only 1 effect reached statistical significance. The findings of this randomized controlled trial illustrate the long-term educational impact of preventive interventions in early elementary school. PMID:23766545

  10. Dietary Rosa mosqueta (Rosa rubiginosa) oil prevents high diet-induced hepatic steatosis in mice.

    PubMed

    D'Espessailles, Amanda; Dossi, Camila G; Espinosa, Alejandra; González-Mañán, Daniel; Tapia, Gladys S

    2015-09-01

    The effects of dietary Rosa mosqueta (RM, Rosa rubiginosa) oil, rich in α-linolenic acid, in the prevention of liver steatosis were studied in mice fed a high fat diet (HFD). C57BL/6j mice were fed either a control diet or HFD with or without RM oil for 12 weeks. The results indicate that RM oil supplementation decreases fat infiltration of the liver from 43.8% to 6.2%, improving the hepatic oxidative state, insulin levels, HOMA index, and both body weight and adipose tissue weight of HFD plus RM treated animals compared to HFD without supplementation. In addition, the DHA concentration in the liver was significantly increased in HFD fed mice with RM oil compared to HFD (3 vs. 1.6 g per 100 g FAME). The n-6/n-3 ratio was not significantly modified by treatment with RM. Our findings suggest that RM oil supplementation prevents the development of hepatic steatosis and the obese phenotype observed in HFD fed mice.

  11. Longitudinal Impact of Two Universal Preventive Interventions in First Grade on Educational Outcomes in High School.

    PubMed

    Bradshaw, Catherine P; Zmuda, Jessika H; Kellam, Sheppard G; Ialongo, Nicholas S

    2009-11-01

    This study examined the longitudinal effects of 2 first-grade universal preventive interventions on academic outcomes (e.g., achievement, special education service use, graduation, postsecondary education) through age 19 in a sample of 678 urban, primarily African American children. The classroom-centered intervention combined the Good Behavior Game (H. H. Barrish, Saunders, & Wolfe, 1969) with an enhanced academic curriculum, whereas a second intervention, the Family-School Partnership, focused on promoting parental involvement in educational activities and bolstering parents' behavior management strategies. Both programs aimed to address the proximal targets of aggressive behavior and poor academic achievement. Although the effects varied by gender, the classroom-centered intervention was associated with higher scores on standardized achievement tests, greater odds of high school graduation and college attendance, and reduced odds of special education service use. The intervention effects of the Family-School Partnership were in the expected direction; however, only 1 effect reached statistical significance. The findings of this randomized controlled trial illustrate the long-term educational impact of preventive interventions in early elementary school.

  12. Alcohol, tobacco, and other drug misuse prevention and cessation programming for alternative high school youth: a review.

    PubMed

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

    2014-11-01

    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. A systematic, exhaustive literature search was completed to identify ATOD misuse prevention and cessation research studies with AHS youth. For the AHS population, 23 ATOD misuse prevention or cessation program evaluations were located. This review indicated that successful efforts have focused on instruction in motivation enhancement, life coping skills, and decision making. Alcohol, tobacco, and other drug misuse prevention and cessation programming for AHSs is effective, delivered in the classroom or as a school-based clinic. There is little evidence, though, that this programming is effective when delivered through other modalities such as via computer or bridging beyond the school setting. More research and application of evidence-based programming are recommended for youth in AHS settings. © 2014, American School Health Association.

  13. Citrus flavanones prevent systemic inflammation and ameliorate oxidative stress in C57BL/6J mice fed high fat diet

    USDA-ARS?s Scientific Manuscript database

    It was investigated the preventive effects of the flavanones hesperidin, eriocitrin and eriodictyol on the oxidative stress and systemic inflammation induced by high-fat diet in C57BL/6J mice. The mice received a standard diet (9.5% kcal from fat), high-fat diet (45% kcal from fat) or high fat diet ...

  14. Grape seed and skin extract prevents high-fat diet-induced brain lipotoxicity in rat.

    PubMed

    Charradi, Kamel; Elkahoui, Salem; Karkouch, Ines; Limam, Ferid; Hassine, Fethy Ben; Aouani, Ezzedine

    2012-09-01

    Obesity is related to an elevated risk of dementia and the physiologic mechanisms whereby fat adversely affects the brain are poorly understood. The present investigation analyzed the effect of a high fat diet (HFD) on brain steatosis and oxidative stress and the intracellular mediators involved in signal transduction, as well as the protection offered by grape seed and skin extract (GSSE). HFD induced ectopic deposition of cholesterol and phospholipid but not triglyceride. Moreover brain lipotoxicity is linked to an oxidative stress characterized by increased lipoperoxidation and carbonylation, inhibition of glutathione peroxidase and superoxide dismutase activities, depletion of manganese and a concomitant increase in ionizable calcium and acetylcholinesterase activity. Importantly GSSE alleviated all the deleterious effects of HFD treatment. Altogether our data indicated that HFD could find some potential application in the treatment of manganism and that GSSE should be used as a safe anti-lipotoxic agent in the prevention and treatment of fat-induced brain injury.

  15. Expectations and high school change: teacher-researcher collaboration to prevent school failure.

    PubMed

    Weinstein, R S; Soulé, C R; Collins, F; Cone, J; Mehlhorn, M; Simontacchi, K

    1991-06-01

    Describes the multilevel outcomes of a collaborative preventive intervention for ninth-graders at risk for school failure using qualitative and quasi-experimental methods. Teachers, administrators, and researchers implemented innovative practices communicating positive expectations for low-achieving adolescents in their transition to high school. Changes were made in the practices of curriculum, grouping, evaluation, motivation, student responsibility, and relationships (in the classroom, with parents, and in the school). Both implementation and evaluation evolved as a function of collaboration. Change was promising but not uniform. Project teachers became more positive about students and colleagues, expanded their roles, and changed school tracking policies. The 158 project students, in contrast to the 154 comparison students showed improved grades and disciplinary referrals post-intervention and increased retention in school 1 year later, but their absences rose and improved performance was not maintained. The implications of this analysis for school-based interventions and its evaluation are discussed.

  16. Lack of Thromboxane Synthase Prevents Hypertension and Fetal Growth Restriction after High Salt Treatment during Pregnancy.

    PubMed

    Pai, Chen-Hsueh; Yen, Ching-Tzu; Chen, Chie-Pein; Yu, I-Shing; Lin, Shu-Wha; Lin, Shu-Rung

    2016-01-01

    Preeclampsia (PE) is a potentially fatal pregnancy-related hypertensive disorder characterized by poor placenta development that can cause fetal growth restriction. PE-associated pathologies, including thrombosis, hypertension, and impaired placental development, may result from imbalances between thromboxane A2 (TXA2) and prostacyclin. Low-dose aspirin, which selectively inhibits TXA2 production, is used to prevent high-risk PE. However, the role of TXA2 in aspirin-mediated protective effects in women with PE is not understood fully. In this study, we examined the role of prostanoids in PE using human samples and an induced PE mouse model. We demonstrated that the administration of salted drinking water (2.7% NaCl) to wild-type mice resulted in elevated placental TXA2 synthase (TXAS) and plasma TXA2, but not prostacyclin, levels, which was also found in our clinical PE placenta samples. The high salt-treated wild-type pregnant mice had shown unchanged maternal body weight, hypertension (MAP increase 15 mmHg), and decreased pup weight (~50%) and size (~24%), but these adverse effects were ameliorated in TXAS knockout (KO) mice. Moreover, increased expression of interleukin-1β and downstream phosphorylated-p38-mitogen-activated protein kinase were concordant with apoptosis induction in the placentas of salt water-treated wild-type mice. These alterations were not observed in TXAS KO mice. Together, our data suggest that TXA2 depletion has anti-PE effects due to the prevention of hypertension and placental damage through downregulation of the interleukin-1β pathway.

  17. High-sodium intake prevents pregnancy-induced decrease of blood pressure in