Objective. Heart failure (HF) is the end stage of heart disease caused by various factors which mainly involves ventricular remodeling (VR). In HF patients with reduced ejection fraction, dapagliflozin (DAPA) reduced the risk of worsening HF or cardiovascular death. Thus, we attempted to clarify the specific role of DAPA underlying HF progression. Methods. The HF rat model was established to mimic characteristics of HF in vivo. HE staining assessed histopathological changes in left ventricular myocardial tissue of rats in each group. ELISA measured plasma ANP and BNP levels of rats in each group. M-mode echocardiography detected cardiac function of rats in each group. TUNEL staining detected apoptosis of infarct margin cells in myocardial tissue of rats in each group. Western blot detected levels of apoptosis-related proteins, autophagy-related proteins, and AMPK/mTOR-related proteins in myocardial tissue of rats in each group. Immunohistochemical staining detected caspase-3 or LC3B level in myocardial tissue of rats in each group. The HF cellular model was established to mimic characteristics of HF in vitro. Flow cytometry detected H9C2 cell apoptosis under different conditions. Western blot detected levels of apoptosis-related proteins, autophagy-related proteins, and AMPK/mTOR-related proteins in H9C2 cells under different conditions. Immunofluorescence detected caspase-3 or LC3B level in H9C2 cells under different conditions. Results. DAPA attenuated left VR and improved cardiac function in HF rats. DAPA attenuated cardiomyocyte apoptosis in HF rats. DAPA facilitated cardiomyocyte autophagy in HF rats via the AMPK/mTOR pathway. DAPA repressed hypoxia-induced H9C2 cell apoptosis by facilitating autophagy. DAPA repressed hypoxia-induced H9C2 cell apoptosis via the AMPK/mTOR pathway. Conclusion. DAPA suppresses ventricular remodeling in HF through activating autophagy via AMPK/mTOR pathway, which provides a potential novel insight for seeking therapeutic plans of HF.
Gastric cancer is a common malignancy worldwide. However, the molecular mechanisms underlying this malignancy remain unclear and there are a lack of effective drugs. The present study aimed to investigate the antitumor effect of Dihydroartemisinin (DHA) or inhibition of Tankyrases (TNKS), and determine the underlying molecular mechanisms of gastric cancer. Immunohistochemistry and immunofluorescence analyses were performed to detect the expression levels of TNKS, epithelial-to-mesenchymal transition (EMT) and Wnt/β-catenin pathway-related proteins in gastric cancer tissues and adjacent normal tissues. The Cell Counting Kit-8 assay was performed to assess the viability of HGC-27 and AGS cells following treatment with different concentrations of HLY78 (a Wnt activator) or DHA. Following treatment with HLY78, DHA or small interfering (si)-TNKS1/si-TNKS2, colony formation and migratory abilities were assessed via the colony formation, wound healing and Transwell assays. Furthermore, western blot and immunofluorescence analyses were performed to detect the expression levels of TNKS, EMT-and Wnt/β-catenin-related proteins. The results demonstrated that the expression levels of TNKS, AXI2, β-catenin, N-cadherin and Vimentin were upregulated, whereas E-cadherin expression was downregulated in gastric cancer tissues compared with normal tissues. Furthermore, HLY78 and DHA suppressed the viability of HGC-27 and AGS cells, in a concentration-independent manner. Notably, TNKS knockdown or treatment with DHA suppressed colony formation, migration, TNKS expression, EMT and the Wnt/β-catenin pathway. Opposing effects were observed following treatment with HLY78, which were ameliorated following co-treatment with DHA. Taken together, these results suggest that DHA or inhibition of TNKS can suppress the proliferation and migration of gastric cancer cells, which is partly associated with inactivation of the Wnt/β-catenin pathway and EMT process.
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