Wei-Tong-Xin ameliorated cisplatin-induced mitophagy and apoptosis in gastric antral mucosa by activating the Nrf2/HO-1 pathway

Wei-Tong-Xin (WTX) originated from the famous ancient Chinese formula “Wan Ying Yuan”, recorded in the ancient Chinese medicine book “Zhong Zang Jing” by Hua Tuo. As “Jun” drugs, Dahuang and Muxiang have the effects of clearing heat and expelling fire, reducing food retention, regulating Qi and relieving pain. As “Chen” drug, Qianniuzi has the effect of assisting “Jun” drugs. Zhuyazao and Gancao, as “Zuo-Shi” drugs, can reduce toxicity and modulate the medicinal properties of other herbs. The present study aimed to investigate the effect and mechanism of WTX on the oxidative stress of gastric antrum mucosa in mice with cisplatin (CIS)-induced dyspepsia. A variety of experimental methods, including western blot, qRT-PCR, immunofluorescence and immunohistochemistry were performed in vivo and in vitro. In vivo, WTX restored the number and function of interstitial cells of Cajal (ICCs), accompanied by the inhibition of lipid peroxidation. Moreover, WTX inhibited the activation of Parkin-dependent mitophagy and apoptosis. In vitro, WTX activated the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway and inactivated mitophagy in GES-1 cells. To explore the role of Nrf2 in WTX's improvement of CIS-induced cell damage, Nrf2 inhibitor ML385 was used in cell experiments. We found that ML385 counteracted the regulation of WTX on mitophagy and apoptosis. Finally, N-acetylcysteine (NAC), a reactive oxygen species (ROS) scavenger, was applied in our experiments, and the results suggested that WTX suppressed the CIS-induced apoptosis via mitochondrial pathway. The above results, for the first time, indicated that WTX inhibited mitophagy and apoptosis of gastric antral mucosal cells induced by CIS through the Nrf2/HO-1 signaling pathway.