Huangqin decoction alleviated irinotecan-induced diarrhea by inhibiting endoplasmic reticulum stress through activating AMPK/mTOR-mediated autophagy

Abstract

Ethnopharmacological relevance

Huangqin decoction (HQD), a traditional Chinese antidiarrheal formula, is effective in treating chemotherapy-induced diarrhea (CID). However, its underlying mechanism has not been fully clarified.

Aim of the study

This study aimed to determine whether the underlying mechanism of HQD against CID is related to the activation of AMPK/mTOR-mediated autophagy inhibiting endoplasmic reticulum (ER) stress.

Materials and methods

Network pharmacology was used to screen potential targets and pathways. The CID mouse model was induced by intraperitoneal injection of 75 mg/kg irinotecan consecutively for four days. The effectiveness of HQD against CID was evaluated through diarrhea score, intestinal epithelial permeability, etc. The histopathological changes of colon were evaluated by HE staining. Alcian blue and immunofluorescence staining were used to assess mucous layer and the expression of MUC2, TJP-1, Occludin, and LC3, relatively. The level of GRP78 and CHOP was assessed by RT-qPCR and WB. Furthermore, the levels of LC3II/I, Beclin-1, P62, AMPK, p-AMPK, mTOR, p-mTOR were evaluated by WB.

Results

Network pharmacology highlighted that the therapeutic effects of HQD against CID may be related to ER stress, autophagy, AMPK, and mTOR signaling pathways, etc. Subsequently, we conducted animal experiments to validate the predicted results. HQD improved CID by attenuating diarrhea, intestinal permeability, etc. HQD could effectively repair intestinal mucous barrier by activating AMPK/mTOR-mediated autophagy to inhibit ER stress.

Conclusion

Irinotecan disrupted the intestinal barrier causing diarrhea, while HQD could repair intestinal barrier via inducing AMPK/mTOR-mediated autophagy inhibiting ER stress, thereby exerting therapeutic effects against CID.