Erythropoietin ameliorates PA-induced insulin resistance through the IRS/AKT/FOXO1 and GSK-3β signaling pathway, and inhibits the inflammatory response in HepG2 cells

Tris(2-chloroethyl)phosphate plus benzo (a) pyrene induced inflammatory response in HepG2 cells through the activation of EGFR-ERK1/2 signaling pathway.

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Based on Network Pharmacology Tools to Investigate the Molecular Mechanism of Cordyceps sinensis on the Treatment of Diabetic Nephropathy

Journal of Diabetes Research ◽

10.1155/2021/8891093 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Yan Li ◽

Lei Wang ◽

Bojun Xu ◽

Liangbin Zhao ◽

Li Li ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Diabetic Nephropathy ◽

Inflammatory Response ◽

Signaling Pathway ◽

Molecular Mechanisms ◽

Target Genes ◽

Cordyceps Sinensis ◽

Network Pharmacology ◽

Active Ingredients

Background. Diabetic nephropathy (DN) is one of the most common complications of diabetes mellitus and is a major cause of end-stage kidney disease. Cordyceps sinensis (Cordyceps, Dong Chong Xia Cao) is a widely applied ingredient for treating patients with DN in China, while the molecular mechanisms remain unclear. This study is aimed at revealing the therapeutic mechanisms of Cordyceps in DN by undertaking a network pharmacology analysis. Materials and Methods. In this study, active ingredients and associated target proteins of Cordyceps sinensis were obtained via Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) and Swiss Target Prediction platform, then reconfirmed by using PubChem databases. The collection of DN-related target genes was based on DisGeNET and GeneCards databases. A DN-Cordyceps common target interaction network was carried out via the STRING database, and the results were integrated and visualized by utilizing Cytoscape software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to determine the molecular mechanisms and therapeutic effects of Cordyceps on the treatment of DN. Results. Seven active ingredients were screened from Cordyceps, 293 putative target genes were identified, and 85 overlapping targets matched with DN were considered potential therapeutic targets, such as TNF, MAPK1, EGFR, ACE, and CASP3. The results of GO and KEGG analyses revealed that hub targets mainly participated in the AGE-RAGE signaling pathway in diabetic complications, TNF signaling pathway, PI3K-Akt signaling pathway, and IL-17 signaling pathway. These targets were correlated with inflammatory response, apoptosis, oxidative stress, insulin resistance, and other biological processes. Conclusions. Our study showed that Cordyceps is characterized as multicomponent, multitarget, and multichannel. Cordyceps may play a crucial role in the treatment of DN by targeting TNF, MAPK1, EGFR, ACE, and CASP3 signaling and involved in the inflammatory response, apoptosis, oxidative stress, and insulin resistance.

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Four sesquiterpene glycosides from loquat (Eriobotrya japonica) leaf ameliorates palmitic acid-induced insulin resistance and lipid accumulation in HepG2 Cells via AMPK signaling pathway

PeerJ ◽

10.7717/peerj.10413 ◽

2020 ◽

Vol 8 ◽

pp. e10413

Author(s):

Jiawei Li ◽

Xiaoqin Ding ◽

Tunyu Jian ◽

Han Lü ◽

Lei Zhao ◽

...

Keyword(s):

Insulin Resistance ◽

Palmitic Acid ◽

Signaling Pathway ◽

Lipid Accumulation ◽

Hepg2 Cells ◽

Eriobotrya Japonica ◽

Expression Levels ◽

Ampk Signaling ◽

Insulin Resistant ◽

Compound C

Insulin resistance (IR), caused by impaired insulin signal and decreased insulin sensitivity, is generally responsible for the pathophysiology of type 2 diabetes mellitus (T2DM). Sesquiterpene glycosides (SGs), the exclusive natural products from loquat leaf, have been regarded as potential lead compounds owing to their high efficacy in hypoglycemia and hypolipidemia. Here, we evaluated the beneficial effects of four single SGs isolated from loquat leaf, including SG1, SG2, SG3 and one novel compound SG4 against palmitic acid-induced insulin resistance in HepG2 cells. SG1, SG3 and SG4 could significantly enhance glucose uptake of insulin-resistant HepG2 cells at non-cytotoxic concentration. Meanwhile, Oil Red O staining showed the decrease of both total cholesterol and triglyceride content, suggesting the amelioration of lipid accumulation by SGs in insulin-resistant HepG2 cells. Further investigations found that the expression levels of phosphorylated AMPK, ACC, IRS-1, and Akt were significantly up-regulated after SGs treatment, on the contrary, the expression levels of SREBP-1 and FAS were significantly down-regulated. Notably, AMPK inhibitor Compound C (CC) blocked the regulative effects, while AMPK activator AICAR mimicked the effects of SGs in PA-treated insulin-resistant HepG2 cells. In conclusion, SGs (SG4>SG1≈SG3>SG2) improved lipid accumulation in insulin-resistant HepG2 cells through the AMPK signaling pathway.

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Insulin resistance contributes to multidrug resistance in HepG2 cells via activation of the PERK signaling pathway and upregulation of Bcl-2 and P-gp

Oncology Reports ◽

10.3892/or.2016.4632 ◽

2016 ◽

Vol 35 (5) ◽

pp. 3018-3024 ◽

Cited By ~ 4

Author(s):

XINYUE LIU ◽

LINJING LI ◽

JING LI ◽

YAN CHENG ◽

JING CHEN ◽

...

Keyword(s):

Insulin Resistance ◽

Multidrug Resistance ◽

Signaling Pathway ◽

Hepg2 Cells

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Sulforaphane Prevents Hepatic Insulin Resistance by Blocking Serine Palmitoyltransferase 3-Mediated Ceramide Biosynthesis

Nutrients ◽

10.3390/nu11051185 ◽

2019 ◽

Vol 11 (5) ◽

pp. 1185 ◽

Cited By ~ 10

Author(s):

Wendi Teng ◽

Yuan Li ◽

Min Du ◽

Xingen Lei ◽

Siyu Xie ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Signaling Pathway ◽

Glucose Homeostasis ◽

Hepg2 Cells ◽

Hepatic Insulin Resistance ◽

Serine Palmitoyltransferase ◽

Insulin Resistant ◽

Ceramide Production

Sulforaphane (SFA), a naturally active isothiocyanate compound from cruciferous vegetables used in clinical trials for cancer treatment, was found to possess potency to alleviate insulin resistance. But its underlying molecular mechanisms are still incompletely understood. In this study, we assessed whether SFA could improve insulin sensitivity and glucose homeostasis both in vitro and in vivo by regulating ceramide production. The effects of SFA on glucose metabolism and expression levels of key proteins in the hepatic insulin signaling pathway were evaluated in insulin-resistant human hepatic carcinoma HepG2 cells. The results showed that SFA dose-dependently increased glucose uptake and intracellular glycogen content by regulating the insulin receptor substrate 1 (IRS-1)/protein kinase B (Akt) signaling pathway in insulin-resistant HepG2 cells. SFA also reduced ceramide contents and downregulated transcription of ceramide-related genes. In addition, knockdown of serine palmitoyltransferase 3 (SPTLC3) in HepG2 cells prevented ceramide accumulation and alleviated insulin resistance. Moreover, SFA treatment improved glucose tolerance and insulin sensitivity, inhibited SPTLC3 expression and hepatic ceramide production and reduced hepatic triglyceride content in vivo. We conclude that SFA recovers glucose homeostasis and improves insulin sensitivity by blocking ceramide biosynthesis through modulating SPTLC3, indicating that SFA may be a potential candidate for prevention and amelioration of hepatic insulin resistance via a ceramide-dependent mechanism.

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The key role of Akt protein kinase in metabolic-inflammatory pathways cross-talk: TNF-α down-regulation and improving of insulin resistance in HepG2 cell line

Current Molecular Medicine ◽

10.2174/1566524020666200427102209 ◽

2020 ◽

Vol 20 ◽

Author(s):

Iraj Alipourfard ◽

Salar Bakhtiyari ◽

Ali Gheysarzadeh ◽

Laura Di Renzo ◽

Antonio De Lorenzo ◽

...

Keyword(s):

Insulin Resistance ◽

Signaling Pathway ◽

Insulin Signaling ◽

Hepg2 Cells ◽

Insulin Signaling Pathway ◽

Target Cells ◽

Down Regulation ◽

Akt Phosphorylation ◽

Insulin Resistant ◽

Tnf Α

Background: Elevation of plasma free fatty acids as a principal aspect of type 2 diabetes maintains etiologically insulin insensitivity in target cells. TNF-α inhibitory effects on key insulin signaling pathway elements remain to be verified in insulin-resistant hepatic cells. Thus, TNF-α knockdown effects on the key elements of insulin signaling were investigated in the palmitate-induced insulin-resistant hepatocytes. The Akt serine kinase, a key protein of the insulin signaling pathway, phosphorylation was monitored to understand the TNF-α effect on probable enhancing of insulin resistance. Methods: Insulin-resistant HepG2 cells were produced using 0.5 mM palmitate treatment and shRNA-mediated TNF-α gene knockdown and its down-regulation confirmed using ELISA technique. Western blotting analysis used to assess the Akt protein phosphorylation status. Results: Palmitate-induced insulin resistance caused TNF-α protein overexpression 1.2-, 2.78, and 2.25- fold as compared to the control cells at post-treatment times of 8 h, 16 h, and 24 h, respectively. In the presence of palmitate, TNF-α expression showed around 30% reduction in TNF-α knockdown cells as compared to normal cells. In the TNF-α down-regulated cell, Akt phosphorylation was approximately 62% more than control cells after treatment with 100 nM insulin in conjugation with 0.5 mM palmitate. Conclusions: The obtained data demonstrated that TNF-α protein expression reduction improved insulin-stimulated Akt phosphorylation in the HepG2 cells and decreased lipid-induced insulin resistance of the diabetic hepatocytes.

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