Mengyang Wang,Wei Liu,Zhuoqun Wang,Linxin Zhang,Jie Zhao,Yongwei Lai,Xiaoli Cui
Background Hypertension is an important risk factor for heart failure. Zhenwu Decoction (ZWD) is a classical Chinese medicinal recipe that has been extensively used to manage cardiovascular disorders throughout history. However, the fundamental processes involved in its effects were not clear. Objective In this study, we investigated the effects of ZWD on Ang II-induced cardiac remodeling and heart failure. Methods A hypertensive heart failure (HF) mice model was established via the micro-osmotic pump infusion of Ang II in C57BL/6 mice for 4 weeks. After two weeks of infusion, ZWD and valsartan were administered intragastrically for another two weeks to investigate their mechanisms of action.RNA sequencing of cardiac tissue was performed to investigate the mechanism of anti-heart failure action of ZWD, and potential binding proteins of Galloypaeoniflorin (GAL), an effective monomer component of ZWD, were verified by molecular docking, DARTS, CETSA and SPR. Results The results showed that ZWD conferred a protective effect against Ang II-induced cardiac dysfunction in mice by inhibiting cardiac hypertrophy and inflammation. RNA sequencing revealed that this cardioprotective effect was associated with the MAPKs/STAT2-NLRC5 signaling pathway. GAL alleviated the inflammatory response in mouse heart tissues and in vitro cultured cardiomyocytes by inhibiting the Ang II-stimulated MAPKs/STAT2-NLRC5 signaling pathway. The data suggest that deficiency of MAPKs or STAT2 in cardiomyocytes abolished the anti-inflammatory effects of GAL. Molecular docking, DARTS, CETSA and SPR techniques confirmed the binding of GAL and STAT2. Conclusion Our study suggests that ZWD protects the heart from damage caused by Ang II stimulation by targeting STAT2 through inhibiting the inflammatory response driven by the MAPK signaling pathway, indicating its promising application in the treatment of hypertensive heart failure.
To overcome the resistance of tumor cells to death through a single pathway, PANoptosis, a novel synergistic mode of cell death, can simultaneously activates pyroptosis, apoptosis, and necroptosis. Most current strategies for inducing PANoptosis focused on amplifying reactive oxygen species (ROS) through exogenous stimuli, while the regulatory role of tumor cell metabolic characteristic in this process has long been overlooked. We propose a ROS-Metabolism dual axis synergistic induction of PANoptosis, simultaneously enhancing antitumor immune responses, and construct a novel bionic nanoplatform named CVOVM. This platform consists of CoVO x nanocakes and the glutamine transporter inhibitor V-9302, with 4T1 cell membranes as camouflage. In tumors, CVOVM initiates a series of catalytic reactions: CoVO x promotes numerous ROS generation, while V-9302 disrupts glutamine metabolism, depleting glutathione (GSH) and nicotinamide adenine dinucleotide (NAD + ), thereby triggering the assembly of PANoptosome primarily composed of NLRP3 and NLRC5, which initiates pyroptosis, apoptosis, and necroptosis. The occurrence of PANoptosis promotes immunogenic cell death (ICD) to remodel tumor immunosuppressive microenvironment, and enhances immunotherapy and inhibits lung metastasis. Overall, we present a previously unreported mechanis to achieve the synergistic induction of PANoptosis through ROS amplification and metabolic inhibition, enhancing antitumor immunity, and potentially providing new opportunities and possibilities for combination cancer therapy.
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