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IRS-2/Akt/GSK-3β/Nrf2 Pathway Contributes to the Protective Effects of Chikusetsu Saponin IVa against Lipotoxicity

Chronic hyperlipidemia leads to pancreatic β-cell apoptosis and dysfunction through inducing oxidative stress. Chikusetsu saponin IVa (CHS) showed antioxidant and antidiabetic properties in our previous studies; however, its protective effects against lipotoxicity-induced β-cell oxidative stress and...

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Autores principales: Wang, Lei, Duan, Jialin, Jia, Na, Liu, Meiyou, Cao, Shanshan, Weng, Yan, Zhang, Wei, Cao, Jinyi, Li, Ruili, Cui, Jia, Wang, Jingwen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041533/
https://www.ncbi.nlm.nih.gov/pubmed/33884100
http://dx.doi.org/10.1155/2021/8832318
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author Wang, Lei
Duan, Jialin
Jia, Na
Liu, Meiyou
Cao, Shanshan
Weng, Yan
Zhang, Wei
Cao, Jinyi
Li, Ruili
Cui, Jia
Wang, Jingwen
author_facet Wang, Lei
Duan, Jialin
Jia, Na
Liu, Meiyou
Cao, Shanshan
Weng, Yan
Zhang, Wei
Cao, Jinyi
Li, Ruili
Cui, Jia
Wang, Jingwen
author_sort Wang, Lei
collection PubMed
description Chronic hyperlipidemia leads to pancreatic β-cell apoptosis and dysfunction through inducing oxidative stress. Chikusetsu saponin IVa (CHS) showed antioxidant and antidiabetic properties in our previous studies; however, its protective effects against lipotoxicity-induced β-cell oxidative stress and dysfunction are not clear. This study was designed to investigate the effects of CHS against lipotoxicity-induced β-cell injuries and its possible mechanism involved. High-fat (HF) diet and a low dose of streptozotocin- (STZ-) induced type 2 diabetes mellitus (T2DM) model in vivo and βTC3 cells subjected to 0.5 mM palmitate (PA) to imitate the lipotoxic model in vitro were performed. Pancreatic functions, ROS, and antioxidant protein measurements were performed to evaluate the effects of CHS on cell injuries. Protein expression levels were measured by Western blotting. Furthermore, siRNA-targeted Nrf2, PI3K/Akt inhibitor (LY294002), or GSK-3β inhibitor (LiCl) was used to investigate the crosstalk relationships between proteins. As the results showed, CHS treatment inhibited apoptosis, promoted insulin release, and reduced oxidative stress. CHS treatment significantly increased the expression of Nrf2 in the cytoplasm and nuclear protein. The antioxidative and benefit effects of CHS were inhibited by siNrf2. The phosphorylation of IRS-2, PI3K, Akt, and GSK-3β was markedly increased by CHS which were inhibited by PA. In addition, inhibition of PI3K/Akt or GSK-3β with specific inhibitors dramatically abrogated the protective effects of CHS, revealing that the IRS-2/Akt/GSK-3β signaling axis was involved in the protective effects of CHS. These results demonstrate that CHS protected βTC3 cells against PA-induced oxidative stress and cell dysfunction through Nrf2 by the IRS-2/Akt/GSK-3β-mediated pathway.
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spelling pubmed-80415332021-04-20 IRS-2/Akt/GSK-3β/Nrf2 Pathway Contributes to the Protective Effects of Chikusetsu Saponin IVa against Lipotoxicity Wang, Lei Duan, Jialin Jia, Na Liu, Meiyou Cao, Shanshan Weng, Yan Zhang, Wei Cao, Jinyi Li, Ruili Cui, Jia Wang, Jingwen Oxid Med Cell Longev Research Article Chronic hyperlipidemia leads to pancreatic β-cell apoptosis and dysfunction through inducing oxidative stress. Chikusetsu saponin IVa (CHS) showed antioxidant and antidiabetic properties in our previous studies; however, its protective effects against lipotoxicity-induced β-cell oxidative stress and dysfunction are not clear. This study was designed to investigate the effects of CHS against lipotoxicity-induced β-cell injuries and its possible mechanism involved. High-fat (HF) diet and a low dose of streptozotocin- (STZ-) induced type 2 diabetes mellitus (T2DM) model in vivo and βTC3 cells subjected to 0.5 mM palmitate (PA) to imitate the lipotoxic model in vitro were performed. Pancreatic functions, ROS, and antioxidant protein measurements were performed to evaluate the effects of CHS on cell injuries. Protein expression levels were measured by Western blotting. Furthermore, siRNA-targeted Nrf2, PI3K/Akt inhibitor (LY294002), or GSK-3β inhibitor (LiCl) was used to investigate the crosstalk relationships between proteins. As the results showed, CHS treatment inhibited apoptosis, promoted insulin release, and reduced oxidative stress. CHS treatment significantly increased the expression of Nrf2 in the cytoplasm and nuclear protein. The antioxidative and benefit effects of CHS were inhibited by siNrf2. The phosphorylation of IRS-2, PI3K, Akt, and GSK-3β was markedly increased by CHS which were inhibited by PA. In addition, inhibition of PI3K/Akt or GSK-3β with specific inhibitors dramatically abrogated the protective effects of CHS, revealing that the IRS-2/Akt/GSK-3β signaling axis was involved in the protective effects of CHS. These results demonstrate that CHS protected βTC3 cells against PA-induced oxidative stress and cell dysfunction through Nrf2 by the IRS-2/Akt/GSK-3β-mediated pathway. Hindawi 2021-04-03 /pmc/articles/PMC8041533/ /pubmed/33884100 http://dx.doi.org/10.1155/2021/8832318 Text en Copyright © 2021 Lei Wang et al. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Wang, Lei
Duan, Jialin
Jia, Na
Liu, Meiyou
Cao, Shanshan
Weng, Yan
Zhang, Wei
Cao, Jinyi
Li, Ruili
Cui, Jia
Wang, Jingwen
IRS-2/Akt/GSK-3β/Nrf2 Pathway Contributes to the Protective Effects of Chikusetsu Saponin IVa against Lipotoxicity
title IRS-2/Akt/GSK-3β/Nrf2 Pathway Contributes to the Protective Effects of Chikusetsu Saponin IVa against Lipotoxicity
title_full IRS-2/Akt/GSK-3β/Nrf2 Pathway Contributes to the Protective Effects of Chikusetsu Saponin IVa against Lipotoxicity
title_fullStr IRS-2/Akt/GSK-3β/Nrf2 Pathway Contributes to the Protective Effects of Chikusetsu Saponin IVa against Lipotoxicity
title_full_unstemmed IRS-2/Akt/GSK-3β/Nrf2 Pathway Contributes to the Protective Effects of Chikusetsu Saponin IVa against Lipotoxicity
title_short IRS-2/Akt/GSK-3β/Nrf2 Pathway Contributes to the Protective Effects of Chikusetsu Saponin IVa against Lipotoxicity
title_sort irs-2/akt/gsk-3β/nrf2 pathway contributes to the protective effects of chikusetsu saponin iva against lipotoxicity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041533/
https://www.ncbi.nlm.nih.gov/pubmed/33884100
http://dx.doi.org/10.1155/2021/8832318
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