Main active components of Si-Miao-Yong-An decoction (SMYAD) attenuate autophagy and apoptosis via the PDE5A-AKT and TLR4-NOX4 pathways in isoproterenol (ISO)-induced heart failure models.

Heart failure (HF), the main cause of death in patients with many cardiovascular diseases, has been reported to be closely related to the complicated pathogenesis of autophagy, apoptosis, and inflammation. Notably, Si-Miao-Yong-An decoction (SMYAD) is a traditional Chinese medicine (TCM) used to treat cardiovascular disease; however, the main active components and their relevant mechanisms remain to be discovered. Based on our previous ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) results, we identified angoriside C (AC) and 3,5-dicaffeoylquinic acid (3,5-DiCQA) as the main active components of SMYAD. In vivo results showed that AC and 3,5-DiCQA effectively improved cardiac function, reduced the fibrotic area, and alleviated isoproterenol (ISO)-induced myocarditis in rats. Moreover, AC and 3,5-DiCQA inhibited ISO-induced autophagic cell death by inhibiting the PDE5A/AKT/mTOR/ULK1 pathway and inhibited ISO-induced apoptosis by inhibiting the TLR4/NOX4/BAX pathway. In addition, the autophagy inhibitor 3-MA was shown to reduce ISO-induced apoptosis, indicating that ISO-induced autophagic cell death leads to excess apoptosis. Taken together, the main active components AC and 3,5-DiCQA of SMYAD inhibit the excessive autophagic cell death and apoptosis induced by ISO by inhibiting the PDE5A-AKT and TLR4-NOX4 pathways, thereby reducing myocardial inflammation and improving heart function to alleviate and treat a rat ISO-induced heart failure model and cell heart failure models. More importantly, the main active components of SMYAD will provide new insights into a promising strategy that will promote the discovery of more main active components of SMYAD for therapeutic purposes in the future.

Identification and optimization of 3-bromo-N'-(4-hydroxybenzylidene)-4-methylbenzohydrazide derivatives as mTOR inhibitors that induce autophagic cell death and apoptosis in triple-negative breast cancer.

Triple negative breast cancer (TNBC) has a worse prognosis than other types of breast cancer due to its special biological behavior and clinicopathological characteristics. TNBC cell proliferation and progression to metastasis can be suppressed by inducing cytostatic autophagy. mTOR is closely related to autophagy and is involved in protein synthesis, nutrient metabolism and activating mTOR promotes tumor growth and metastasis. In this paper, we adopted the strategy of structure simplification, aimed to look for novel small-molecule inhibitors of mTOR by pharmacophore-based virtual screening and biological activity determination. We found a lead compound with 3-bromo-N'-(4-hydroxybenzylidene)-4-methylbenzohydrazide for rational drug design and structural modification, then studied its structure-activity relationship. After that, compound 7c with the best TNBC cells inhibitory activities and superior mTOR enzyme inhibitory activity was obtained. In addition, we found that compound 7c could induce autophagic cell death and apoptosis in MDA-MB-231 and MDA-MB-468 cell lines. In conclusion, these findings provide new clues for our 3-bromo-N'-(4-hydroxybenzylidene)-4-methylbenzohydrazide derivatives, which are expected to become drug candidates for the treatment of TNBC in the future.