Sodium–glucose cotransporter 2 inhibitors (SGLT2i) have favorable cardiovascular outcomes in patients with diabetes. However, whether SGLT2i can improve obesity-related cardiac dysfunction is unknown. Sestrin2 is a novel stress-inducible protein that regulates AMPK–mammalian target of rapamycin (mTOR) and suppresses oxidative damage. The aim of this study was to determine whether empagliflozin (EMPA) improves obesity-related cardiac dysfunction via regulating Sestrin2-mediated pathways in diet-induced obesity. C57BL/6J mice and Sestrin2 knockout mice were fed a high-fat diet (HFD) for 12 weeks and then treated with or without EMPA (10 mg/kg) for 8 weeks. Treating HFD-fed C57BL/6J mice with EMPA reduced body weight and whole-body fat and improved metabolic disorders. Furthermore, EMPA improved myocardial hypertrophy/fibrosis and cardiac function and reduced cardiac fat accumulation and mitochondrial injury. Additionally, EMPA significantly augmented Sestrin2 levels and increased AMPK and endothelial nitric oxide synthase phosphorylation, but inhibited Akt and mTOR phosphorylation. These beneficial effects were partially attenuated in HFD-fed Sestrin2 knockout mice. Intriguingly, EMPA treatment enhanced the Nrf2/HO-1–mediated oxidative stress response, suggesting antioxidant and anti-inflammatory activity. Thus, EMPA improved obesity-related cardiac dysfunction via regulating Sestrin2-mediated AMPK-mTOR signaling and maintaining redox homeostasis. These findings provide a novel mechanism for the cardiovascular protection of SGLT2i in obesity.

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Transient receptor potential canonical 6 (TRPC6) proteins form receptor-operated Ca-permeable channels, which have been thought to bring benefit to the treatment of diseases, including cancer. However, selective antagonists for TRPC channels are rare and none of them has been tested against gastric cancer. Compound 14a and analogs were synthesized by chemical elaboration of previously reported TRPC3/6/7 agonist 4o. 14a had very weak agonist activity at TRPC6 expressed in HEK293 cells but exhibited strong inhibition on both 4o-mediated and receptor-operated activation of TRPC6 with an IC of about 1 μM. When applied to the culture media, 14a suppressed proliferation of AGS and MKN45 cells with IC values of 17.1 ± 0.3 and 18.5 ± 1.0 μM, respectively, and inhibited tube formation and migration of cultured human endothelial cells. This anti-tumor effect on gastric cancer was further verified in xenograft models using nude mice. This study has found a new tool compound which shows excellent therapeutic potential against human gastric cancer most likely through targeting TRPC6 channels.

Tubulin has been shown to be an effective target for the development of cytotoxic agents against prostate cancer. Previously, we reported that Lx2-32c is an anti-tubulin agent with high binding affinity to tubulin. In this study, we investigated the potential of Lx2-32c to act as an effective cytotoxic agent in the treatment of prostate cancer. MTT assays showed that Lx2-32c was cytotoxic to all tested prostate cancer cell lines. The Lx2-32c-treated cells typically exhibited a rounded morphology associated with the onset of apoptosis, as evidenced by immunocytochemical staining. Human prostate cancer cell lines treated with Lx2-32c arrest in the G2/M phase of the cell cycle and the treatment is associated with an increased ratio of cells in the sub-G0/G1 phase as determined by flow cytometry. Furthermore, expression of the cleaved form of poly (ADP-ribose) polymerase in prostate cancer cell lines treated with Lx2-32c was shown by Western blotting assay. Xenograft implants of LNCaP and PC3-derived tumors in nude mice showed that Lx2-32c treatment significant inhibited tumor growth with effects equivalent to those of docetaxel. These findings demonstrate the potential of Lx2-32c as a candidate antitumor agent for the treatment of prostate cancer.

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Ischemia/reperfusion (I/R) injury is the central cause of global death in cardiovascular diseases, which is characterized by disorders such as angina, stroke, and peripheral vascular disease, finally causing severe debilitating diseases and death. The increased rates of morbidity and mortality caused by I/R are parallel with aging. Aging-associated cardiac physiological structural and functional deterioration were found to contribute to abnormal reactive oxygen species (ROS) production during I/R stress. Disturbed redox homeostasis could further trigger the related signaling pathways that lead to cardiac irreversible damages with mitochondria dysfunction and cell death. It is notable that sirtuin proteins are impaired in aged hearts and are critical to maintaining redox homeostasis via regulating substrate metabolism and inflammation and thus preserving cardiac function under stress. This review discussed the cellular and functional alterations upon I/R especially in aging hearts. We propose that mitochondria are the primary source of reactive oxygen species (ROS) that contribute to I/R injury in aged hearts. Then, we highlight the cardiomyocyte protection of the age-related proteins Sirtuin1 (SIRT1) and Sirtuin1 (SIRT3) in response to I/R injury, and we discuss their modulation of cardiac metabolism and the inflammatory reaction that is involved in ROS formation.