scholarly journals Folic Acid Alleviates High Glucose and Fat-Induced Pyroptosis via Inhibition of the Hippo Signal Pathway on H9C2 Cells

2021 ◽  
Vol 8 ◽  
Author(s):  
Lei Hong ◽  
Yingjie Zha ◽  
Chen Wang ◽  
Shigang Qiao ◽  
Jianzhong An
Keyword(s):  
Folic Acid ◽  
Protective Effect ◽  
Cell Viability ◽  
High Glucose ◽  
High Fat Diet ◽  
Hippo Signaling ◽  
H9c2 Cells ◽  
High Fat ◽  
Hippo Signaling Pathway ◽  
Caspase 1

Diabetic cardiomyopathy (DCM) is the leading cause of death in diabetic patients. Folic acid has a protective effect on diabetes-induced cardiomyocyte damage. The aim of this study was to explore the effects of folic acid on cardiomyocytes cultured under high glucose and fat (HGF) conditions and type 2 diabetes mellitus (T2DM) mice, and elucidate the underlying mechanisms. Bioinformatics analysis was used to identify the potential drugs through the Drug-Gene Interaction database. H9C2 cardiomyocytes were cultured with 30 mM glucose and 500 nM palmitic acid in the presence or absence of folic acid or YAP1 inhibitor (verteporfin) or YAP1 siRNA. The cell viability and lactate dehydrogenase (LDH) release were measured using specific assay kits. Pyroptosis was detected by flow cytometry. The concentrations of IL-1β and IL-18 in the supernatants were measured by ELISA. The NLRP3, ASC and caspase-1 mRNA levels were detected by qRT-PCR and that the proteins expression of NLRP3, ASC, cleaved caspase-1 (p10), caspase-1, YAP1, p-YAP1, LATS1 and P-LATS1 were detected by Western blotting. C57BL/6 mice were fed with high fat diet (HFD) combined with streptozotocin (STZ) intraperitoneally to establish a T2DM model, folic acid or PBS treatment for 8 weeks by oral gavage, blood glucose and body weight were measured every 4 weeks, mouse heart tissue was used to detect pyroptosis and hippo signaling pathway related protein expression. We identified 427 differentially expressed genes in the cardiac tissues of high fat diet + streptozotocin mice, among the 30 most significantly DEGs, folic acid was predicted to be the most likely therapeutic drug. Folic acid alleviated HGF-induced cell damage in vitro and in vivo by decreasing activation of the Hippo pathway, as indicated by lower LDH release and increased cell viability, and decreased expression of NLRP3, ASC, cleaved caspase-1, IL-1β, IL-18, p-YAP and p-LATS. Verteporfin or YAP1 siRNA neutralized the protective effect of folic acid by reversing YAP1-induced pyroptosis. Folic acid reduced NLRP3 inflammasome-mediated pyroptosis by down-regulating the Hippo signaling pathway, thereby effectively reducing T2DM-induced damage in H9C2 cells and animals.

scholarly journals Lipopolysaccharide (LPS) Aggravates High Glucose- and Hypoxia/Reoxygenation-Induced Injury through Activating ROS-Dependent NLRP3 Inflammasome-Mediated Pyroptosis in H9C2 Cardiomyocytes

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Zhen Qiu ◽  
Yuhong He ◽  
Hao Ming ◽  
Shaoqing Lei ◽  
Yan Leng ◽  
...  
Keyword(s):  
Cell Viability ◽  
Nlrp3 Inflammasome ◽  
High Glucose ◽  
Cell Injury ◽  
H9c2 Cell ◽  
Ros Production ◽  
H9c2 Cells ◽  
Caspase 1 ◽  
H9c2 Cardiomyocytes ◽  
Hypoxia Reoxygenation

Diabetes aggravates myocardial ischemia-reperfusion (I/R) injury because of the combination effects of changes in glucose and lipid energy metabolism, oxidative stress, and systemic inflammatory response. Studies have indicated that myocardial I/R may coincide and interact with sepsis and inflammation. However, the role of LPS in hypoxia/reoxygenation (H/R) injury in cardiomyocytes under high glucose conditions is still unclear. Our objective was to examine whether lipopolysaccharide (LPS) could aggravate high glucose- (HG-) and hypoxia/reoxygenation- (H/R-) induced injury by upregulating ROS production to activate NLRP3 inflammasome-mediated pyroptosis in H9C2 cardiomyocytes. H9C2 cardiomyocytes were exposed to HG (30 mM) condition with or without LPS, along with caspase-1 inhibitor (Ac-YVAD-CMK), inflammasome inhibitor (BAY11-7082), ROS scavenger N-acetylcysteine (NAC), or not for 24 h, then subjected to 4 h of hypoxia followed by 2 h of reoxygenation (H/R). The cell viability, lactate dehydrogenase (LDH) release, caspase-1 activity, and intracellular ROS production were detected by using assay kits. The incidence of pyroptosis was detected by calcein-AM/propidium iodide (PI) double staining kit. The concentrations of IL-1β and IL-18 in the supernatants were assessed by ELISA. The mRNA levels of NLRP3, ASC, and caspase-1 were detected by qRT-PCR. The protein levels of NF-κB p65, NLRP3, ASC, cleaved caspase-1 (p10), IL-1β, and IL-18 were detected by western blot. The results indicated that pretreatment LPS with 1 μg/ml not 0.1 μg/ml could efficiently aggravate HG and H/R injury by activating NLRP3 inflammasome to mediate pyroptosis in H9C2 cells, as evidenced by increased LDH release and decreased cell viability in the cells, and increased expression of NLRP3, ASC, cleaved caspase-1 (p10), IL-1β, and IL-18. Meanwhile, Ac-YVAD-CMK, BAY11-7082, or NAC attenuated HG- and H/R-induced H9C2 cell injury with LPS stimulated by reversing the activation of NLRP3 inflammasome-mediated pyroptosis. In conclusion, LPS could increase the sensitivity of H9C2 cells to HG and H/R and aggravated HG- and H/R-induced H9C2 cell injury by promoting ROS production to induce NLRP3 inflammasome-mediated pyroptosis.

scholarly journals Folic Acid Has a Protective Effect on Retinal Vascular Endothelial Cells against High Glucose

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2326 ◽  
Author(s):  
Zhenglin Wang ◽  
Wei Xing ◽  
Yongli Song ◽  
Hongli Li ◽  
Yonggang Liu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Folic Acid ◽  
Protective Effect ◽  
High Glucose ◽  
Vascular Endothelial Cells ◽  
The Body ◽  
Water Soluble ◽  
Tube Length ◽  
Hippo Signaling ◽  
Vascular Endothelial

Diabetic retinopathy (DR) is a severe complication of diabetes, which seriously affects the life quality of patients. Because of the damage caused by DR, there is an urgent need to develop effective drugs. Folic acid, a water-soluble vitamin, is one of the vitamin B complexes. Folic acid is widely found in the meat and vegetables. In the clinic, low folic acid levels in the body may have a certain correlation with DR. However, there is no relevant basic research proving a relationship between folic acid levels and DR. The purpose of this study was therefore to investigate whether folic acid has a protective effect on the retinal vascular endothelial cells against high glucose levels. Moreover, the molecular mechanism of action of folic acid was further explored. The results showed that folic acid significantly suppressed the cell viability, tube length, migrated cells and the percentage of BrdU+ cells compared with the high glucose group. Moreover, folic acid decreased the mRNA expression of TEAD1 and the protein expression of TEAD1 and YAP1. These findings indicate that folic acid can protect retinal vascular endothelial cells from high glucose-induced injury by regulating the proteins in the Hippo signaling pathway.

Ethanol Extract of Crataegus Oxyacantha L. Ameliorate Dietary Non-Alcoholic Fatty Liver Disease in Rat

Drug Research ◽  
2018 ◽  
Vol 68 (10) ◽  
pp. 553-559
Author(s):  
Golbahar Saeedi ◽  
Fereshteh Jeivad ◽  
Mohammadhadi Goharbari ◽  
Gholamreza Gheshlaghi ◽  
Omid Sabzevari
Keyword(s):  
Fatty Liver ◽  
Protective Effect ◽  
High Fat Diet ◽  
Normal Diet ◽  
Oxidative Stress Marker ◽  
Histopathological Study ◽  
Potential Candidate ◽  
Diet Change ◽  
High Fat ◽  
Alcoholic Fatty Liver

Abstract Background Non-alcoholic fatty liver (NAFLD) is one the most prevalent disease worldwide which characterized by fat accumulation in liver with no established efficient therapy. We designed this study to investigate protective and therapeutic effect of Crataegus oxyacantha L. (C. oxyacantha) on NAFLD induced by high fat diet in rat models. Methods NAFLD was induced by High Fat Diet+fructose (HFD), 45 Wistar rats were divided to 8 groups including control, HFD, HFD+diet change, HFD+diet change+C. oxyacantha 20 mg/kg, co treatment of HFD+C. oxyacantha 10, 20 and 40 mg/kg, and normal diet+C. oxyacantha 40 mg. C. oxyacantha was administered orally. Effectiveness of the C. oxyacantha was assessed through measuring the biochemical factors, and oxidative stress marker (FRAP, GSH, and MDA). Histopathological study was performed using H & E staining. Results The diet change from high fat to low fat ameliorated liver damage. However, consumption of C. oxyacantha (10 & 20 mg/kg) caused significant reduction in the level of all examined liver biomarkers specially LDH, that showed C. oxyacantha can restore the hepatocyte damage due to HFD. The C. oxyacantha showed a protective effect which was more prominent in the animals treated with the 20 mg/kg C. oxyacantha. The administration of C. oxyacantha caused increased antioxidant status (GSH and FRAP levels) and decreased lipid peroxidation in treated animals. Major Conclusion Accordingly, C. oxyacantha have both therapeutic and protective effect for NAFLD and may be a potential candidate for further assessments in clinical studies.

scholarly journals Disrupting phosphatase SHP2 in macrophages protects mice from high-fat diet-induced hepatic steatosis and insulin resistance by elevating IL-18 levels

2020 ◽  
Vol 295 (31) ◽  
pp. 10842-10856 ◽  
Author(s):  
Wen Liu ◽  
Ye Yin ◽  
Meijing Wang ◽  
Ting Fan ◽  
Yuyu Zhu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Low Grade ◽  
High Fat ◽  
Caspase 1

Chronic low-grade inflammation plays an important role in the pathogenesis of type 2 diabetes. Src homology 2 domain-containing tyrosine phosphatase-2 (SHP2) has been reported to play diverse roles in different tissues during the development of metabolic disorders. We previously reported that SHP2 inhibition in macrophages results in increased cytokine production. Here, we investigated the association between SHP2 inhibition in macrophages and the development of metabolic diseases. Unexpectedly, we found that mice with a conditional SHP2 knockout in macrophages (cSHP2-KO) have ameliorated metabolic disorders. cSHP2-KO mice fed a high-fat diet (HFD) gained less body weight and exhibited decreased hepatic steatosis, as well as improved glucose intolerance and insulin sensitivity, compared with HFD-fed WT littermates. Further experiments revealed that SHP2 deficiency leads to hyperactivation of caspase-1 and subsequent elevation of interleukin 18 (IL-18) levels, both in vivo and in vitro. Of note, IL-18 neutralization and caspase-1 knockout reversed the amelioration of hepatic steatosis and insulin resistance observed in the cSHP2-KO mice. Administration of two specific SHP2 inhibitors, SHP099 and Phps1, improved HFD-induced hepatic steatosis and insulin resistance. Our findings provide detailed insights into the role of macrophagic SHP2 in metabolic disorders. We conclude that pharmacological inhibition of SHP2 may represent a therapeutic strategy for the management of type 2 diabetes.

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