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Metformin represses the pathophysiology of AAA by suppressing the activation of PI3K/AKT/mTOR/autophagy pathway in ApoE-/- mice.

ABSTRACT: Background:The protective effect of metformin (MET) on abdominal aortic aneurysm (AAA) has been reported. However, the related mechanism is still poor understood. In this study, we deeply investigated the role of metformin in AAA pathophysiology. Methods:Angiotensin II (Ang-II) was used to construct the AAA model in ApoE -/- mice. The related mechanism was explored using Western blot and quantitative real time PCR (qRT-PCR). We also observed the morphological changes in the abdominal aorta and the influence of metformin on biological behaviors of rat abdominal aortic VSMCs. Results:The PI3K/AKT/mTOR pathway was activated in aneurysmal wall tissues of AAA patients and rat model. Treatment with metformin inhibited the breakage and preserved the elastin structure of the aorta, the loss of collagen, and the apoptosis of aortic cells. In addition, metformin significantly suppressed the activation of the PI3K/AKT/mToR pathway and decreased the mRNA and protein levels of LC3B and Beclin1, which were induced by Ang-II. Moreover, PI3K inhibitors enhanced the effect of metformin while PI3K agonists largely reversed this effect. Interestingly, the cell proliferation, apoptosis, migration and autophagy of vascular smooth muscle cells (VSMCs) induced by Ang-II were also decreased following metformin treatment. PI3K inhibitors and agonists strengthened and weakened the effects of metformin in VSMCs, respectively. Conclusions:Metformin represses the pathophysiology of AAA by inhibiting the activation of PI3K/AKT/mTOR/autophagy pathway. This repression may be useful as a new therapeutic strategy for AAA.

SUBMITTER: Wang Z

PROVIDER: S-EPMC6712653 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Metformin represses the pathophysiology of AAA by suppressing the activation of PI3K/AKT/mTOR/autophagy pathway in ApoE<sup>-/-</sup> mice.

Wang Zhu Z Guo Jingjing J Han Xinqiang X Xue Ming M Wang Wenming W Mi Lei L Sheng Yuguo Y Ma Chao C Wu Jian J Wu Xuejun X

Cell & bioscience 20190827

<h4>Background</h4>The protective effect of metformin (MET) on abdominal aortic aneurysm (AAA) has been reported. However, the related mechanism is still poor understood. In this study, we deeply investigated the role of metformin in AAA pathophysiology.<h4>Methods</h4>Angiotensin II (Ang-II) was used to construct the AAA model in <i>ApoE</i> <sup>-<i>/</i>-</sup> mice. The related mechanism was explored using Western blot and quantitative real time PCR (qRT-PCR). We also observed the morphologi ...[more]

PMID: 31467666

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Project description:BackgroundDespite being a promising strategy, current chemotherapy for gastric cancer (GC) is limited due to adverse side effects and poor survival rates. Therefore, new drug-delivery platforms with good biocompatibility are needed. Recent studies have shown that nanoparticle-based drug delivery can be safe, eco-friendly, and nontoxic making them attractive candidates. Here, we develop a novel selenium-nanoparticle based drug-delivery agent for cancer treatment from plant extracts and selenium salts.ResultsSelenium cations were reduced to selenium nanoparticles using Kaempferia parviflora (black ginger) root extract and named KP-SeNP. Transmission electron microscopy, selected area electron diffraction, X-ray diffraction, energy dispersive X-ray, dynamic light scattering, and Fourier-transform infrared spectrum were utilized to confirm the physicochemical features of the nanoparticles. The KP-SeNPs showed significant cytotoxicity in human gastric adenocarcinoma cell (AGS cells) but not in normal cells. We determined that the intracellular signaling pathway mechanisms associated with the anticancer effects of KP-SeNPs involve the upregulation of intrinsic apoptotic signaling markers, such as B-cell lymphoma 2, Bcl-associated X protein, and caspase 3 in AGS cells. KP-SeNPs also caused autophagy of AGS by increasing the autophagic flux-marker protein, LC3B-II, whilst inhibiting autophagic cargo protein, p62. Additionally, phosphorylation of PI3K/Akt/mTOR pathway markers and downstream targets was decreased in KP-SeNP-treated AGS cells. AGS-cell xenograft model results further validated our in vitro findings, showing that KP-SeNPs are biologically safe and exert anticancer effects via autophagy and apoptosis.ConclusionsThese results show that KP-SeNPs treatment of AGS cells induces apoptosis and autophagic cell death through the PI3K/Akt/mTOR pathway, suppressing GC progression. Thus, our research strongly suggests that KP-SeNPs could act as a novel potential therapeutic agent for GC.

Dataset Information

Metformin represses the pathophysiology of AAA by suppressing the activation of PI3K/AKT/mTOR/autophagy pathway in ApoE-/- mice.

Publications

Metformin represses the pathophysiology of AAA by suppressing the activation of PI3K/AKT/mTOR/autophagy pathway in ApoE<sup>-/-</sup> mice.

Similar Datasets

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