Paeoniflorin Inhibits ASK1-TF Axis by Up-Regulating SOCS3 to Alleviate Radiation Enteritis.

Lei Sheng,Lei Sheng,Lu Chen,Wen-Tao Liu,Jinhui Jia,Wenjing Fei,Wenjing Fei,Yufeng Gu,Rumeng Jia,Fan Hu,Liang Hu,Mi Yang,Yang Yang,Xueyou Tao,Hong Kong,Xueming He,Xueming He,Xia Zhu,Xia Zhu,Hanqing Yu,Jianxin Ma,Jianxin Ma,Chen Miao

doi:10.3389/fphar.2022.743708

Abstract

Radiation enteritis is one of the main adverse effects of radiotherapy, presenting with a poorly understood etiology and limited options for therapy. Intestinal inflammation and ischemia are the core mechanisms of radiation enteritis. Suppressor of cytokine signaling 3 (SOCS3) is an endogenous “inflammation brake.” We hypothesized that paeoniflorin, a pinane monoterpene bitter glycoside, could increase SOCS3 expression to reduce inflammation and ischemia and improve enteritis in mice. Laser Doppler flowmetry was used to detect changes in intestinal blood flow. RAW264.7 and human umbilical vein endothelial cells were used to investigate the mechanism of action of paeoniflorin. It was observed that radiation caused high mortality, intestinal inflammatory responses, and low blood flow in mice. Paeoniflorin effectively alleviated intestinal atrophy, prevented thrombosis, improved radiation enteritis, and reduced mortality in mice undergoing radiotherapy. In addition, paeoniflorin increased the release of growth arrest-specific gene 6 (Gas6) and phosphorylation of the Axl receptor, subsequently inducing the expression of SOCS3 and inhibiting the expression of p-apoptosis signal-regulating kinase 1 and tissue factor in vivo and in vitro. Based on our findings, we suggest that paeoniflorin is potentially effective in alleviating radiation enteritis via the activation of the Gas6/Axl/SOCS3 axis and subsequent reduction in intestinal inflammation and ischemia.

Highlights

Radiation enteritis (RE) is a gastrointestinal complication caused by radiotherapy that affects up to 13% of patients (Modlin et al, 2005)
Wang et al (2004) demonstrated that the expression of tissue factor (TF) and thrombin receptor increased in the intestinal vascular endothelial cells of rats after radiotherapy, and intervention with hirudin and thrombin inhibitors showed a significant protective effect against intestinal radiation toxicity
The precision of chemotherapy has significantly improved with advancements in technology (Abbasoğlu et al, 2006), enteritis-related injuries caused by radiotherapy cannot currently be avoided and cured

Summary

Introduction

Radiation enteritis (RE) is a gastrointestinal complication caused by radiotherapy that affects up to 13% of patients (Modlin et al, 2005). Most clinical treatment methods are limited to the alleviation of symptoms, such as diarrhea and bloody stools, Paeoniflorin Alleviates Radiation Enteritis caused by enteritis, including antibacterial and anti-infective drugs. Intestinal inflammation is involved in the development of chemotherapy-induced enteritis. Wang et al (2004) demonstrated that the expression of tissue factor (TF) and thrombin receptor increased in the intestinal vascular endothelial cells of rats after radiotherapy, and intervention with hirudin and thrombin inhibitors showed a significant protective effect against intestinal radiation toxicity. High expression of TF may induce microthrombus formation, ischemia, and disorder of the intestinal microcirculation system, which may be an important pathological mechanism for the persistence of RE

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Conclusion