Xiaobanxia decoction alleviates chemotherapy-induced nausea and vomiting by inhibiting GSDME-mediated pyroptosis

Abstract

Ethnopharmacological relevance: Xiaobanxia Decoction (XBXD), a traditional antiemetic formula, is effective in preventing chemotherapy-induced nausea and vomiting (CINV), but its underlying mechanism has not been fully clarified.

Aim of the study: To investigate whether the antiemetic mechanisms of XBXD against CINV is associated with the reduction of GSDME-mediated pyroptosis and the alleviation of gastrointestinal inflammation induced by cisplatin.

Materials and methods: We established the in vivo pica rat model and the in vitro small intestinal epithelial cell (IEC-6 cell) injury model by cisplatin challenge. The levels of ROS, IL-1β, IL-18, HMGB1 were measured by ELISA. The histopathological changes of gastrointestinal (GI) tissues were examined by HE staining. The expression and localization of GSDME in GI tissues were determined by IHC. The GSDME mRNA expression in GI tissues was determined by RT-PCR. The IEC-6 cell viability was detected by CCK-8. The morphology of IEC-6 cells was observed by optical microscope and scanning electron microscopy. Pyroptosis was examined using Hoechst33342/PI staining. The intracellular ROS levels were measured with the fluorescent probe DCFH-DA. The expression levels of JNK, p-JNK, Bax, Bcl-2, caspase-9, caspase-3 and GSDME in GI tissues and IEC-6 cells were determined by WB.

Results: We found that the cumulative kaolin intake (pica behavior, analogous to emesis) significantly increased in cisplatin-treated rats, accompanied by significant inflammatory pathological changes of GI tissues. XBXD decreased the cumulative kaolin intake and alleviated GI inflammation in cisplatin-treated rats by inhibiting the activation of the ROS/JNK/Bax signaling pathway and by reducing GSDME-mediated pyroptosis. Additionally, cisplatin damaged IEC-6 cells by activating GSDME-dependent pyroptosis. XBXD reduced GSDME-mediated IEC-6 cell pyroptotic death by regulating the ROS/JNK/Bax signaling pathway.

Conclusions: This study suggested that GSDME-mediated pyroptosis greatly contributes to the occurrence of CINV, and suppressing GSDME-mediated pyroptosis is the important antiemetic mechanism of XBXD.

Keywords: Chemotherapy-induced nausea and vomiting; Gasdermins E; Gastrointestinal inflammation; Pyroptosis; Xiaobanxia decoction.