scholarly journals Sirtuin 1-Mediated Cellular Metabolic Memory of High Glucose Via the LKB1/AMPK/ROS Pathway and Therapeutic Effects of Metformin

Diabetes ◽  
2011 ◽  
Vol 61 (1) ◽  
pp. 217-228 ◽  
Author(s):  
Z. Zheng ◽  
H. Chen ◽  
J. Li ◽  
T. Li ◽  
B. Zheng ◽  
...  
Keyword(s):  
High Glucose ◽  
Sirtuin 1 ◽  
Metabolic Memory ◽  
Therapeutic Effects

scholarly journals Fenofibrate suppresses cellular metabolic memory of high glucose in diabetic retinopathy via a sirtuin 1-dependent signalling pathway

2015 ◽  
Vol 12 (4) ◽  
pp. 6112-6118 ◽  
Author(s):  
SHUZHI ZHAO ◽  
JUN LI ◽  
NA WANG ◽  
BINGQING ZHENG ◽  
TAO LI ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
High Glucose ◽  
Signalling Pathway ◽  
Sirtuin 1 ◽  
Metabolic Memory

Resveratrol inhibits high-glucose-induced inflammatory “metabolic memory” in human retinal vascular endothelial cells through SIRT1-dependent signaling

2019 ◽  
Vol 97 (12) ◽  
pp. 1141-1151 ◽  
Author(s):  
Tingting Jiang ◽  
Junxiang Gu ◽  
Wenwen Chen ◽  
Qing Chang
Keyword(s):  
Endothelial Cells ◽  
Inflammatory Cytokines ◽  
High Glucose ◽  
Glucose Concentration ◽  
Vascular Endothelial Cells ◽  
Sirtuin 1 ◽  
Metabolic Memory ◽  
Vascular Endothelial ◽  
High Glucose Concentration ◽  
Compound C

Diabetes induces vascular endothelial damage and this study investigated high-glucose-induced inflammation “metabolic memory” of human retinal vascular endothelial cells (HRVECs), the effects of resveratrol on HRVECs, and the underlying signaling. HRVECs were grown under various conditions and assayed for levels of sirtuin 1 (SIRT1); acetylated nuclear factor κB (Ac-NF-κB); NOD-like receptor family, pyrin domain containing 3 (NLRP3); and other inflammatory cytokines; and cell viability. A high glucose concentration induced HRVEC inflammation metabolic memory by decreasing SIRT1 and increasing Ac-NF-κB, NLRP3, caspase 1, interleukin-1β, inducible nitric oxide synthase, and tumor necrosis factor α, whereas exposure of HRVECs to a high glucose medium for 4 days, followed by a normal glucose concentration for an additional 4 days, failed to reverse these changes. A high glucose concentration also significantly reduced HRVEC viability. In contrast, resveratrol, a selective SIRT1 activator, markedly enhanced HRVEC viability and reduced the inflammatory cytokines expressions. In addition, high glucose reduced AMP-activated protein kinase (AMPK) phosphorylation and retained during the 4 days of the reversal period of culture. The effects of resveratrol were abrogated after co-treatment with the SIRT1 inhibitor nicotinamide and the AMPK inhibitor compound C. In conclusion, resveratrol was able to reverse high-glucose-induced inflammation “metabolic memory” of HRVECs by activation of the SIRT1/AMPK/NF-κB pathway.

scholarly journals Salvianolic Acid B Attenuates Apoptosis of HUVEC Cells Treated with High Glucose or High Fat via Sirt1 Activation

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Jinghui Zhai ◽  
Lina Tao ◽  
Yueming Zhang ◽  
Huan Gao ◽  
Xiaoyu Qu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
High Glucose ◽  
Molecular Mechanisms ◽  
Umbilical Vein ◽  
Salvianolic Acid B ◽  
Sirtuin 1 ◽  
High Fat ◽  
Salvianolic Acid ◽  
Huvec Cells ◽  
Diabetic Cardiopathy

High glucose and high fat are important inducements for the development and progression of diabetic cardiopathy. Salvianolic acid B (SAB), which is the most abundant and bioactive compound in Danshen, attenuates oxidative stress-related disorders, such as cardiovascular diseases, cerebral ischemia, and diabetes. However, the effect of SAB on diabetic cardiopathy is not clear. The aim of study was to investigate the effect and the underlying molecular mechanisms of SAB on diabetic cardiopathy in vitro model. The human umbilical vein endothelial (HUVEC) cells were treated with high glucose (HG, 30 mM) or high fat (palmitic acid, PA, 0.75 mM) in the presence or absence of SAB (100, 200, and 400 mg/L) and incubated for 24 h. We found that HG or PA induced apoptosis of HUVEC cells, while treatment with SAB inhibited the apoptosis. We also found that SAB reversed HG- or PA-induced oxidative stress, apoptosis cell cytokines production, and expression of thioredoxin-interacting protein (TXNIP). Moreover, SAB increased HG- or PA-induced expression of Sirtuin 1 (Sirt1), a nicotinamide adenine dinucleotide- (NAD+-) dependent histone deacetylase. Exposure of HUVEC cells to Ex527 (Sirt1 inhibitor) suppressed the effect of SAB on acetyl-p53 and procaspase-3 expressions. In conclusion, the results suggested that SAB could attenuate HUVEC cells damage treated with HG or PA via Sirt1 and might be a potential therapy agent for the diabetic cardiopathy treatment.

scholarly journals Mesenchymal Stem Cells Ameliorate Mitochondrial Dysfunction in α - cells and Hyperglucagonemia in type 2 Diabetes via SIRT1/FoxO3a Signaling

2021 ◽  
Author(s):  
Jia Song ◽  
Lingshu Wang ◽  
Xinghong Guo ◽  
Qin He ◽  
Chen Cui ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Glucagon Secretion ◽  
Sirtuin 1 ◽  
Enzyme Linked Immunosorbent Assay ◽  
Human Umbilical Cord ◽  
Therapeutic Effects

Abstract Background: Dysregulation of α-cells results in hyperglycemia and hyperglucagonemia in type 2 diabetes mellitus (T2DM). Mesenchymal stem cell (MSC)-based therapy increases oxygen consumption of islets and enhances insulin secretion. However, the underlying mechanism for the protective role of MSCs in α- cell mitochondrial dysfunction remains unclear. Here, we evaluated the efficacy and molecular mechanisms of human umbilical cord MSCs (hucMSCs) on α-cell mitochondrial function and glucagon secretion in T2DM.Methods: hucMSCs were used to treat two kinds of T2DM mice and αTC1-6 cells to explore the role of hucMSCs in improving α-cell mitochondrial dysfunction and hyperglucagonemia. Plasma and supernatant glucagon were detected by enzyme-linked immunosorbent assay (ELISA). Mitochondrial function of α-cells was assessed by the Seahorse Analyzer. To investigate the underlying mechanisms, Sirtuin 1 (SIRT1), Forkhead box O3a (FoxO3a), glucose transporter type1 (GLUT1), and glucokinase (GCK) were assessed by western blotting analysis.Results: In vivo, hucMSC infusion improved glucose and insulin tolerance, as well as hyperglycemia and hyperglucagonemia in T2DM mice. Meanwhile, hucMSC intervention rescued islet structure and decreased α- to β-cell ratio. Consistently, glucagon secretion from αTC1-6 cells was inhibited by hucMSCs in vitro. Meanwhile, hucMSC treatment activated intracellular SIRT1/FoxO3a signaling, promoted glucose uptake and activation, alleviated mitochondrial dysfunction, and enhanced ATP production. However, transfection of SIRT1 small interfering RNA (siRNA) or the application of SIRT1 inhibitor EX-527 weakened the therapeutic effects of hucMSCs on mitochondrial function and glucagon secretion.Conclusions: Our observations indicate that hucMSCs mitigate mitochondrial dysfunction and glucagon hypersecretion of α-cells in T2DM via SIRT1/FoxO3a signaling, which provides novel evidence demonstrating the potential for hucMSCs in treating T2DM.

Cilostazol improves hyperglycemia-induced impaired vasculo-angiogenesis through stimulating adiponectin/adiponectin receptor 1/Sirtuin 1 signaling pathway

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
T.H Chao ◽  
S.Y Tseng ◽  
Y.H Li
Keyword(s):  
Endothelial Cells ◽  
Signaling Pathway ◽  
High Glucose ◽  
Sirtuin 1 ◽  
Gene Knockdown ◽  
Adiponectin Receptor ◽  
Funding Source ◽  
Adiponectin Receptors ◽  
Adiponectin Receptor 1 ◽  
Transwell Insert

Abstract Background Cilostazol is an antiplatelet agent with vasodilating effect working through increasing intracellular concentration of cyclic adenosine monophosphate (AMP). We and others have previously found that cilostazol has a favorable effect on vasculo-angiogenesis. However, there is no study to evaluate the effect of cilostazol on adiponectin and its receptors. Purpose This study investigated the effects of cilostazol on adiponectin/adiponectin receptors and Sirtuin 1 (Sirt1)/AMP-activated protein kinase (AMPK) signaling pathway for preventing high glucose (HG)-induced impaired vasculo-angiogenesis in vitro and in vivo. Methods and results Human umbilical vein endothelial cells (HUVECs), seeded onto Transwell insert, and human aortic smooth muscle cells (HASMCs), seeded onto 6-well plate at lower level, were co-cultured in HG condition (25 mM). Adiponectin concentrations in the supernatant of 6-welll-plate and Transwell insert were significantly higher when HASMCs were treated with cilostazol in a dose-response manner but not significantly changed when only HUVECs were treated with cilostazol. HG downregulated protein expression of adiponectin receptor-1 (adipoR1), adipoR2, and Sirt1 and phosphorylation of AMPKα1, whereas cilostazol treatment restored expression of adipoR1 and Sirt1 proteins and upregulated phosphorylation of AMPKα1 in HUVECs treated with HG but not adipoR2. The stimulating effect of cilostazol on AMPKα1 or Sirt1 was attenuated with Sirt1 or AMPKα1 gene knockdown, respectively. By using gene knockdown of adiponectin receptors or AMPKα1, or treatment of the Sirt1 inhibitor, our data showed that cilostazol prevented apoptosis, and stimulated proliferation, chemotactic motility and capillary-like tube formation in HG-treated HUVECs through adipoR1, AMPK, and Sirt1 signaling pathway but not adipoR2. Fifteen-week-old male ICR hyperglycemic mice, induced by streptozosin injection and high cholesterol diet feeding, were treated intraperitoneally with cilostazol (10 mg/kg) 2 times per day since day 1 to day 7 after hindlimb ischemia. Recovery of blood flow ratio (ipsilateral/contralateral) in the ischemic hindlimb 14–21 days after surgery and circulating CD34+CD45dim cells were significantly attenuated by adipoR1 knockdown but not adipoR2. Capillary density in the ischemic muscles was significantly lower in both adipoR1- and adipoR2-knockdown mice. Expression of Sirt1 as well as phosphorylation of AMPKα1/acetyl-CoA carboxylase and Akt/endothelial nitric oxide synthase in ischemic muscles were significantly attenuated by gene knockdown of adipoR1 or adipoR2. Conclusions Our data suggest that cilostazol prevents high glucose-induced endothelial dysfunction in vascular endothelial cells as well as enhances vasculo-angiogenesis in hyperglycemic mice by upregulation of adiponectin/adipoR2 and its downstream signaling molecules, Sirt1/AMPK. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): The Ministry of Health and Welfare, Executive Yuan, Taiwan; The Ministry of Science and Technology, Executive Yuan, Taiwan

scholarly journals Cardioprotective effects of polydatin against myocardial injury in diabetic rats via inhibition of NADPH oxidase and NF-κB activities

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Ying-Ying Tan ◽  
Lei-Xin Chen ◽  
Ling Fang ◽  
Qi Zhang
Keyword(s):  
Nadph Oxidase ◽  
Diabetic Cardiomyopathy ◽  
High Glucose ◽  
Myocardial Injury ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Diabetic Patients ◽  
Therapeutic Effects ◽  
H9c2 Cells ◽  
Cardioprotective Effects

Abstract Background Diabetic cardiomyopathy is a main cause of the increased morbidity in diabetic patients, no effective treatment is available so far. Polydatin, a resveratrol glucoside isolated from the Polygonum cuspidatum, was found by our and others have antioxidant and cardioprotective activities. Therapeutic effects of polydatin on diabetic cardiomyopathy and the possible mechanisms remains unclear. This study aimed to investigate the cardioprotective effects and underlying mechanisms of polydatin on myocardial injury induced by hyperglycemia. Methods Diabetes in rats was made by high-fat diet combined with multiple low doses of streptozotocin, and then treated with polydatin (100 mg·kg-1·day-1, by gavage) for 8 weeks. Cardiac function was examined by echocardiography. Myocardial tissue and blood samples were collected for histology, protein and metabolic characteristics analysis. In cultured H9c2 cells with 30 mM of glucose, the direct effects of polydatin on myocyte injury were also observed. Results In diabetic rats, polydatin administration significantly improved myocardial dysfunction and attenuated histological abnormalities, as evidenced by elevating left ventricular shortening fraction and ejection fraction, as well as reducing cardiac hypertrophy and interstitial fibrosis. In cultured H9c2 cells, pretreatment of polydatin dose-dependently inhibited high glucose-induced cardiomyocyte injury. Further observation evidenced that polydatin suppressed the increase in the reactive oxygen species levels, NADPH oxidase activity and inflammatory cytokines production induced by hyperglycemia in vivo and in vitro. Polydatin also prevented the increase expression of NOX4, NOX2 and NF-κB in the high glucose -stimulated H9c2 cells and diabetic hearts. Conclusions Our results demonstrate that the cardioprotective effect of polydatin against hyperglycemia-induced myocardial injury is mediated by inhibition of NADPH oxidase and NF-κB activity. The findings may provide a novel understanding the mechanisms of the polydatin to be a potential treatment of diabetic cardiomyopathy.

scholarly journals Elevated Glucose and Insulin Levels Decrease DHA Transfer across Human Trophoblasts via SIRT1-Dependent Mechanism

Nutrients ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1271
Author(s):  
Jay S. Mishra ◽  
Hanjie Zhao ◽  
Sari Hattis ◽  
Sathish Kumar
Keyword(s):  
Fatty Acid ◽  
High Glucose ◽  
Molecular Mechanisms ◽  
Sirtuin 1 ◽  
Dependent Manner ◽  
Sirt1 Expression ◽  
Insulin Levels ◽  
Triglyceride Accumulation ◽  
Elevated Glucose ◽  
Fatty Acid Transporter

Gestational diabetes mellitus (GDM) results in reduced docosahexaenoic acid (DHA) transfer to the fetus, likely due to placental dysfunction. Sirtuin-1 (SIRT1) is a nutrient sensor and regulator of lipid metabolism. This study investigated whether the high glucose and insulin condition of GDM regulates DHA transfer and expression of fatty acid transporters and if this effect is related to SIRT1 expression and function. Syncytialized primary human trophoblasts were treated with and without glucose (25 mmol/L) and insulin (10−7 mol/L) for 72 h to mimic the insulin-resistance conditions of GDM pregnancies. In control conditions, DHA transfer across trophoblasts increased in a time- and dose-dependent manner. Exposure to GDM conditions significantly decreased DHA transfer, but increased triglyceride accumulation and fatty acid transporter expression (CD36, FABP3, and FABP4). GDM conditions significantly suppressed SIRT1 mRNA and protein expression. The SIRT1 inhibitor decreased DHA transfer across control trophoblasts, and recombinant SIRT1 and SIRT1 activators restored the decreased DHA transport induced by GDM conditions. The results demonstrate a novel role of SIRT1 in the regulation of DHA transfer across trophoblasts. The suppressed SIRT1 expression and the resultant decrease in placental DHA transfer caused by high glucose and insulin levels suggest new insights of molecular mechanisms linking GDM to fetal DHA deficiency.

scholarly journals A novel inverse relationship between metformin-triggered AMPK-SIRT1 signaling and p53 protein abundance in high glucose-exposed HepG2 cells

2012 ◽  
Vol 303 (1) ◽  
pp. C4-C13 ◽  
Author(s):  
Lauren E. Nelson ◽  
Rudy J. Valentine ◽  
José M. Cacicedo ◽  
Marie-Soleil Gauthier ◽  
Yasuo Ido ◽  
...  
Keyword(s):  
High Glucose ◽  
Hepg2 Cells ◽  
Metabolic Diseases ◽  
P53 Protein ◽  
Dominant Negative ◽  
Sirtuin 1 ◽  
Protein Abundance ◽  
Triglyceride Accumulation ◽  
Sirt1 Gene ◽  
Amp Activated Protein Kinase

AMP-activated protein kinase (AMPK) and the NAD+-dependent histone/protein deacetylase sirtuin 1 (SIRT1) are metabolic sensors that can increase each other's activity. They are also both activated by the antidiabetic drug metformin and downregulated in the liver under conditions of nutrient excess (e.g., hyperglycemia, high-fat diet, obesity). In these situations, the abundance of the tumor suppressor p53 is increased; however, the relevance of this to the changes in AMPK and SIRT1 is not known. In the present study we investigated this question in HepG2 cells under high glucose conditions. Metformin induced activation of AMPK and SIRT1 and decreased p53 protein abundance. It also decreased triglyceride accumulation and cytosolic oxidative stress (a trigger for p53 accumulation) and increased the deacetylation of p53 at a SIRT1-targeted site. The decrease in p53 abundance caused by metformin was abolished by inhibition of murine double minute 2 (MDM2), a ubiquitin ligase that mediates p53 degradation, as well as by overexpression of a dominant-negative AMPK or a shRNA-mediated knockdown of SIRT1. In addition, overexpression of p53 decreased SIRT1 gene expression and protein abundance, as well as AMPK activity in metformin-treated cells. It also diminished the triglyceride-lowering action of metformin, an effect that was rescued by incubation with the SIRT1 activator SRT2183. Collectively, these findings suggest the existence of a novel reciprocal interaction between AMPK/SIRT1 and p53 that may have implications for the pathogenesis and treatment of metabolic diseases.

Sign in / Sign up

Export Citation Format

Share Document