Ge-Gen-Qin-Lian (GGQL) Decoction Attenuates Radiation Enteropathy by Regulating the HMGB1/TLR4/HO-1 Pathway by Activating PI3K/AKT Signalling

Abstract

Background: Radiation enteritis (RE) is a frequent side effect of radiotherapy for abdominal and pelvic malignancies that could cause reduced treatment tolerance and quality of life of in patients. GGQL decoction is a widely used traditional Chinese medicine that is clinically used to inhibit inflammation in RE, however potential mechanism is unclear. In the research, we investigated the effects and potential molecular mechanism of GGQL decoction treatment in RE model rats. Methods: RE model rats were established by exposing Sprague-Dawley (SD) rats to 9 Gy abdominal X-ray irradiation, with or without GGQL decoction administration. Enzyme-linked immunosorbent assay (ELISA) was employed to detect inflammatory cytokines, including IL-6, IL-1β, HMGB1 (high mobility group box 1) and TNF-α levels. Western blot was performed to detect inflammation-related signaling. Results: GGQL decoction treatment decreased IL-1β, HMGB1, IL-6 and TNF-α levels. Western blot analysis showed that GGQL decoction treatment significantly increased HO-1 (haem oxygenase-1) levels and decreased the downstream targets Toll-like receptor (TLR)4 and HMGB1, which were upregulated by irradiation exposure. Further investigation demonstrated that GGQL decoction treatment protected the rat intestinal epithelial cell line IEC6 and human umbilical vein endothelial cells (HUVECs) from irradiation-induced apoptosis but did not affect cell proliferation. In both cell lines, GGQL decoction treatment decreased TLR4, HMGB1, cleaved caspase3, and cleaved PARP (poly (ADP-ribose) polymerase) levels and increased HO-1 levels, which were affected by irradiation. GGQL decoction treatment increased AKT (protein kinase B) phosphorylation, which is necessary for regulating HO-1 levels and exerting protective effects. Conclusions: Therefore, these findings shed light on the pharmacologic mechanism of GGQL decoction as a treatment for radiation enteritis.