Dataset Information

Rhein Inhibits Autophagy in Rat Renal Tubular Cells by Regulation of AMPK/mTOR Signaling.

ABSTRACT: Rhubarb and its bioactive component rhein are frequently used for the treatment of chronic kidney diseases (CKD) in eastern Asia countries. However, the potential therapeutic mechanism remains unclear. Autophagy plays an important role in CKD. However, there were some important related issues that remained unresolved in the role of autophagy in CKD and treatment by rhubarb and rhein. We designed a number of experiments to examine whether rhubarb may reduce renal fibrosis and autophagy in rats with adenine (Ade)-induced renal tubular injury, and whether rhein could affect autophagic pathways in rat renal tubular cells. We found that, autophagic activation accompanied with renal fibrosis in rats with Ade-induced renal tubular injury, and both autophagy and renal fibrosis were attenuated by rhubarb. In addition, we observed that rhein could inhibit autophagy through regulating the key molecules in the AMPK-dependent mTOR signaling pathways, as well as the Erk and p38 MAPKs signaling pathways. These findings may partly explain the therapeutic mechanisms of rhubarb and rhein in treating CKD patients in clinic, and further suggest that targeting autophagy and related signaling pathways may provide new strategies for the treatment of renal fibrosis in CKD.

SUBMITTER: Tu Y

PROVIDER: S-EPMC5333140 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Rhein Inhibits Autophagy in Rat Renal Tubular Cells by Regulation of AMPK/mTOR Signaling.

Tu Yue Y Gu Liubao L Chen Diping D Wu Wei W Liu Hong H Hu Hao H Wan Yigang Y Sun Wei W

Scientific reports 20170302

Rhubarb and its bioactive component rhein are frequently used for the treatment of chronic kidney diseases (CKD) in eastern Asia countries. However, the potential therapeutic mechanism remains unclear. Autophagy plays an important role in CKD. However, there were some important related issues that remained unresolved in the role of autophagy in CKD and treatment by rhubarb and rhein. We designed a number of experiments to examine whether rhubarb may reduce renal fibrosis and autophagy in rats wi ...[more]

PMID: 28252052

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Project description:BackgroundUbiquitin-conjugating enzyme E2T (UBE2T) acts as an oncogene in various types of cancer. However, the mechanisms behind its oncogenic role remain unclear in lung cancer. This study aims to explore the function and clinical relevance of UBE2T in lung cancer.MethodsLentiviral vectors were used to mediate UBE2T depletion or overexpress UBE2T in lung cancer cells. CCK8 analysis and western blotting were performed to investigate the effects of UBE2T on proliferation, autophagy, and relevant signaling pathways. To exploit the clinical significance of UBE2T, we performed immunohistochemistry staining with an anti-UBE2T antibody on 131 NSCLC samples. Moreover, we downloaded the human lung adenocarcinoma (LUAD) dataset from The Cancer Atlas Project (TCGA). Lasso Cox regression model was adopted to establish a prognostic model with UBE2T-correlated autophagy genes.ResultsWe found that UBE2T stimulated proliferation and autophagy, and silencing this gene abolished autophagy in lung cancer cells. As suggested by Gene set enrichment analysis, we observed that UBE2T downregulated p53 levels in A549 cells and vice versa. Blockade of p53 counteracted the inhibitory effects of UBE2T depletion on autophagy. Meanwhile, the AMPK/mTOR signaling pathway was activated during UBE2T-mediated autophagy, suggesting that UBE2T promotes autophagy via the p53/AMPK/mTOR pathway. Interestingly, UBE2T overexpression increased cisplatin-trigged autophagy and led to cisplatin resistance of A549 cells, whereas inhibiting autophagy reversed drug resistance. However, no association was observed between UEB2T and overall survival in a population of 131 resectable NSCLC patients. Therefore, we developed and validated a multiple gene signature by considering UBE2T and its relevance in autophagy in lung cancer. The risk score derived from the prognostic signature significantly stratified LUAD patients into low- and high-risk groups with different overall survival. The risk score might independently predict prognosis. Interestingly, nomogram and decision curve analysis demonstrated that the signature's prognostic accuracy culminated while combined with clinical features. Finally, the risk score showed great potential in predicting clinical chemosensitivity.ConclusionsWe found that UBE2T upregulates autophagy in NSCLC cells by activating the p53/AMPK/mTOR signaling pathway. The clinical predicting ability of UBE2T in LUAD can be improved by considering the autophagy-regulatory role of UBE2T.

Project description:Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been shown to decrease the adverse cardiac events and risks of cardiovascular mortality among patients with or without diabetes, which has made these drugs promising treatment options for patients with chronic heart failure. Cardiac dysfunction is a common and severe side effect induced by cancer chemotherapies, which seriously affects the prognosis and life quality of tumor patients. However, it is not clear whether SGLT2 inhibitors have cardiovascular benefits in patients with cancer chemotherapy-related cardiac dysfunction. We aimed to determine whether empagliflozin (EMPA), an SGLT2 inhibitor, has a protective role against sunitinib (SNT)-induced cardiac dysfunction in a mouse model. Methods: Male C57BL/6J mice were randomized into control (control, n = 8), empagliflozin (EMPA, n = 8), sunitinib (SNT, n = 12), or sunitinib and empagliflozin coadministration (SNT + EMPA, n = 12) groups. EMPA, SNT, or SNT-combined EMPA was given via oral gavage for consecutive 28 days. Cardiovascular functions and pathological changes were examined, and the underlying mechanisms of EMPA's effects were investigated in H9c2 cardiomyocytes. Results: Mice in the SNT group exhibited dramatically elevated blood pressure (systolic blood pressure [SBP] 134.30 ± 6.455 mmHg vs. 114.85 ± 6.30 mmHg) and impaired left ventricular function (left ventricular ejection fraction [LVEF] 50.24 ± 3.06% vs. 84.92 ± 2.02%), as compared with those of the control group. However, EMPA could ameliorate SNT-induced cardiotoxicity, both in terms of SBP (117.51 ± 5.28 mmHg vs. 134.30 ± 6.455 mmHg) and LVEF (76.18 ± 5.16% vs. 50.24 ± 3.06 %). In H9c2 cardiomyocytes, SNT-induced cardiomyocyte death and cell viability loss as well as dysfunction of adenosine 5'-monophosphate-activated protein kinase-mammalian target of rapamycin (AMPK-mTOR) signaling-mediated autophagy were restored by EMPA. However, these favorable effects mediated by EMPA were blocked by the inhibition of AMPK or autophagy. Conclusion: EMPA could ameliorate SNT-induced cardiac dysfunction via regulating cardiomyocyte autophagy, which was mediated by the AMPK-mTOR signaling pathway. These findings supported that SGLT2 inhibitor therapy could be a potential cardioprotective approach for cardiovascular complications among patients receiving SNT. However, these favorable effects still need to be validated in clinical trials.

Dataset Information

Rhein Inhibits Autophagy in Rat Renal Tubular Cells by Regulation of AMPK/mTOR Signaling.

Publications

Rhein Inhibits Autophagy in Rat Renal Tubular Cells by Regulation of AMPK/mTOR Signaling.

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