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Cardiac hypertrophy is the main cause of heart failure and sudden death in patients. But the pathogenesis is unclear. Angiotensin II may contribute to cardiac hypertrophy in response to pressure overload. In angiotensin II‐treated cardiomyocytes, there is a larger cross‐sectional area, more apoptosis cells, and a reduction of irisin expression. An increase in P62, an autophagy flux index, as well as LC3II, were observed in cardiomyocytes after angiotensin II‐induced injury. Surprisely, irisin supplementation increased LC3II expression and decreased P62 expression, consisted of results of RFP‐GFP‐LC3B adenovirus transfection, and reduced cardiomyocyte apoptosis, meanwhile, the protection of irisin was reversed by the autophagy inhibitor 3‐methyladenine. In animal experiments, overexpression of irisin reduced cardiomyocyte apoptosis and alleviated myocardial hypertrophy caused by pressure overload. The above results indicate that irisin‐induced protective autophagy and alleviated the apoptosis signaling pathway in cardiomyocytes, consequently reducing cardiomyocyte apoptosis after angiotensin II‐induced injury. Hence, increasing irisin expression may be a new way to improve cardiac function and quality of life in patients with cardiac hypertrophy.

Endoplasmic reticulum stress (ERS) is usually involved in tumor development and progression, and anticancer agents have recently been recognized to induce ERS. Cucurbitacin‐I showed a potent anticancer action by inducing apoptosis through the inhibition of signal transducer and activator of transcription 3 pathway and triggering autophagic cell death. It is not known whether ERS mediates the cancer cell death induced by cucurbitacin‐I. Here, we investigated the role of ERS in cucurbitacin‐I‐treated SKOV3 ovarian cancer cells and PANC‐1 pancreatic cancer cells. We confirmed that cucurbitacin‐I caused cell death and stirred excessive ERS levels by activating inositol requiring enzyme 1α (IRE1α) and protein kinase R‐like endoplasmic reticulum kinase (PERK), as well as PERK downstream factors, including IRE1α and C/EBP homologous protein, but not activating transcription factor 6 (ATF6α) pathway, which was in parallel with the increased Bax and caspase‐12‐dependent ERS‐associated apoptosis, autophagy and autophagy flux levels and caspase‐independent nonapoptotic cell death. Furthermore, 4‐phenylbutyrate, an ERS inhibitor, suppressed cucurbitacin‐I‐induced apoptosis, autophagy, autophagy flux, and autophagic cell death. Simultaneously, there are positive correlations among ERS and cucurbitacin‐I‐induced reactive oxygen species and Ca 2+. Our results suggested that cucurbitacin‐I‐induced cancer cell death through the excessive ERS and CHOP‐Bax and caspase‐12‐dependent ERS‐associated apoptosis, as well as ERS‐dependent autophagy, autophagy flux, and caspase‐independent nonapoptotic cell death. These novel signaling insights may be useful for developing new, effective anticancer strategies in oncotherapy.

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Doxorubicin (DOX) is a potent available antitumor drug; however, its clinical use is limited by the cardiotoxicity. Salidroside (SLD), with strong antioxidative and cytoprotective actions, is of particular interest in the development of antioxidative therapies for oxidative injury in cardiac diseases. Now, the protection and underlying mechanisms of SLD against DOX-induced cardiotoxicity are still unknown. In the present study, we revealed both antioxidative mechanism and Bcl2-dependent survival signaling involved in SLD's protection. We observed that DOX exposure induced mortality elevation, body weight loss, and cardiac dysfunction in mice, increased lactate dehydrogenase leakage and cardiomyocyte apoptosis, but decreased cell viability and size in cardiac tissues and cultured H9c2 cells, respectively, which were effectively antagonized by SLD supplement. We further observed that SLD significantly reduced the intercellular oxidative stress level, partly by inhibiting NOX1 expression and augmenting the expression and activities of the endogenous antioxidative enzymes, catalase, and manganese superoxide dismutase. In addition, SLD treatment upregulated the antiapoptotic Bcl2 and downregulated the proapoptotic Bax and inhibited a downstream pathway of Bcl2/Bax and caspase-3 activity. Our results indicated that SLD effectively protected the cardiomyocytes against DOX-induced cardiotoxicity by suppressing the excessive oxidative stress and activating a Bcl2-mediated survival signaling pathway.

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