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

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.

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

Diabetes ◽

10.2337/db11-0416 ◽

2011 ◽

Vol 61 (1) ◽

pp. 217-228 ◽

Cited By ~ 143

Author(s):

Z. Zheng ◽

H. Chen ◽

J. Li ◽

T. Li ◽

B. Zheng ◽

...

Keyword(s):

High Glucose ◽

Sirtuin 1 ◽

Metabolic Memory ◽

Therapeutic Effects

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Astragalus Polysaccharide Regulates miR-182/Bcl-2 Axis to Relieve Metabolic Memory through Suppressing Mitochondrial Damage-Mediated Apoptosis in Retinal Pigment Epithelial Cells

Pharmacology ◽

10.1159/000515901 ◽

2021 ◽

pp. 1-14

Author(s):

Li-Mo Gao ◽

Shun Fu ◽

Fen Liu ◽

Han-Bing Wu ◽

Wen-Jie Li

Keyword(s):

Diabetic Retinopathy ◽

Epithelial Cells ◽

High Glucose ◽

Retinal Pigment Epithelial ◽

Retinal Pigment ◽

Mitochondrial Damage ◽

Retinal Pigment Epithelial Cells ◽

Metabolic Memory ◽

Pigment Epithelial ◽

Pigment Epithelial Cells

Introduction: Metabolic memory is one of the causes of diabetic retinopathy, and astragalus polysaccharide (APS) has great advantages in the treatment of diabetes. However, the effect of APS on metabolic memory remains to be investigated. Methods: Retinal pigment epithelial cell line ARPE-19 and primary retinal pigment epithelial cells were used to verify the effect of APS on mitochondria damage and apoptosis induced by high glucose-induced metabolic memory. The relationship between miR-182 and Bcl-2 was confirmed by a luciferase activity assay. Western blotting and quantitative reverse-transcriptase polymerase chain reaction were conducted to investigate the changes in mitochondrial damage- and apoptosis-associated markers. The cell mitochondrial membrane potential was assessed by JC-1 fluorescence. Terminal deoxynucleotidyl transferase dUTP nick end labelling staining and flow cytometry assays were performed to determine the occurrence of apoptosis. Results: Treatment with high glucose followed by normal glucose significantly upregulated the expression of miR-182 and downregulated the expression of its target Bcl-2, and APS treatment reversed the above effects. Additionally, APS treatment restored mitochondrial function and inhibited apoptosis in cells in a state of metabolic memory. The effects of APS against mitochondrial damage and apoptosis were partially inhibited after miR-182 overexpression. Conclusion: APS alleviated mitochondrial damage and apoptosis induced by metabolic memory by regulating the miR-182/Bcl-2 axis, which might serve as a new strategy for the treatment of diabetic retinopathy.

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

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/9846325 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 1

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.

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Protective Effects ofPanax notoginsengSaponins against High Glucose-Induced Oxidative Injury in Rat Retinal Capillary Endothelial Cells

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2016/5326382 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 19

Author(s):

Yue Fan ◽

Yuan Qiao ◽

Jianmei Huang ◽

Minke Tang

Keyword(s):

Endothelial Cells ◽

Diabetic Retinopathy ◽

High Glucose ◽

Microvascular Dysfunction ◽

Panax Notoginseng ◽

Protective Effects ◽

Pronounced Increase ◽

Nadph Oxidase 4 ◽

Retinal Capillary ◽

Capillary Endothelial Cells

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 ofPanax notoginsengSaponins (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.

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Serum microRNA-211 as a biomarker for diabetic retinopathy via modulating Sirtuin 1

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2018.10.052 ◽

2018 ◽

Vol 505 (4) ◽

pp. 1236-1243 ◽

Cited By ~ 10

Author(s):

He-Nan Liu ◽

Nan-Jue Cao ◽

Xun Li ◽

Wei Qian ◽

Xiao-Long Chen

Keyword(s):

Diabetic Retinopathy ◽

Sirtuin 1 ◽

Serum Microrna

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P0100CALORIC RESTRICTION ALLEVIATES AGING-RELATED FIBROSIS OF KIDNEY THROUGH MIR-21 DOWNREGULATION IN EXTRACELLULAR VESICLES

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0100 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Guang-Yan Cai

Keyword(s):

Caloric Restriction ◽

Extracellular Vesicles ◽

High Glucose ◽

Interstitial Fibrosis ◽

Rat Kidney ◽

Signalling Pathway ◽

Peroxisome Proliferator ◽

Mesenchymal Transition ◽

Ad Libitum

Abstract Background and Aims The mechanism of renal interstitial fibrosis occurs with kidney aging is unknown. Caloric restriction and caloric restriction mimetics (CRM) alleviate aging-related-fibrosis. The aim of this study is to investigate whether extracellular microvesicles (EVs) derived from senescent cells facilitate fibrosis development in aging kidney and the potential signalling pathway involved in the process. Method In this study, animal experiments included 3-mon-old ad libitum(YAL) rats, 24-mon-old ad libitum(OAL) rats and 24-mon-old caloric restriction(OCR) rats, which was given 70% of OAL’s for 8 months. Senescent cells were induced in proximal tubular epithelial cells(PTCs) by high glucose and further treated with resveratrol as CRM. The expression of miR-21, peroxisome proliferator-activated receptor(PPARα), hypoxia-inducible factor(HIF1α) in the kidney of rats and PTCs were examined. Epithelial to mesenchymal transition (EMT) and the related signalling pathway were detected by up- or down-regulation of miR-21, respectively. Results Long-term caloric restriction ameliorated senescent changes and aging-related fibrosis in aged ad libitum rat kidney. Caloric restriction blunted the increased expressions of miR-21 and HIF1α, the decreased expression of PPARα in renal tissue of old rats. High glucose induced PTCs senesence phenotype and EMT. miR-21 was detected in extracellular vesicles secreted by senescent PTC cells. CRMs resveratrol prevented EMT through downregulation of miR-21 in extracellular vesicles from the senescent PTC cells. Further, inhibiting miR-21 of donor senescent cells prevented the occurrence of EMT in recipient PTC cells. Finally, miR-21 induced EMT mainly through targeting PPARα protein and enhancing HIF1α expression. Conclusion This study demonstrated that miR-21-containing extracellular microvesicles derived from the senescent cells could facilitate tubular phenotype transition of neighbouring PTC cells via PPARα-HIF1α signalling pathway. Long-term caloric restriction and caloric restriction mimetics alleviate aging-related renal fibrosis through downregulation of miR-21 excretion.

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