51. Koumine ameliorates concanavalin A-induced autoimmune hepatitis in mice: involvement of the Nrf2, NF-κB pathways, and gut microbiota.
- Author
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Que, Wancai, Lin, Hailing, Li, Xueyong, Zhang, Bingqing, Liu, Maobai, Hu, Xin, Fu, Junsheng, Cheng, Yu, and Qiu, Hongqiang
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AUTOIMMUNE hepatitis , *GUT microbiome , *NUCLEAR factor E2 related factor , *ASPARTATE aminotransferase , *CHINESE medicine , *CONCANAVALIN A , *ISOQUINOLINE alkaloids - Abstract
• Koumine exerts significant anti-inflammatory antioxidant, and immunoregulatory effects on concanavalin A-induced autoimmune hepatitis in mice. • The underlying mechanisms are associated with the involvement of the Nrf2, NF-κB signaling pathway and gut microbiota. • Koumine may be a promising and effective new drug against autoimmune hepatitis. Gelsemium elegans (Gardner. & Chapm.) Benth. has long been considered a traditional Chinese medicine effective against rheumatoid pain, cancer, cirrhosis, and skin diseases. Koumine (KM), the most abundant alkaloid in G. elegans Benth., demonstrates a variety of biological effects, including antitumor, analgesic, anxiolytic, anti-inflammatory, antidepressant, antioxidant, immunoregulatory, and hepatoprotective effects. Furthermore, the relatively low toxicity of KM makes it a promising drug candidate. This study aimed to investigate the protective effects of KM and its possible mechanisms using a concanavalin A (Con A)-induced autoimmune hepatitis (AIH) model in mice. Mice were orally administered different doses of KM for 14 d before Con A tail vein injections. The effects of KM on serum biochemical markers and liver histopathology were then evaluated 12 h after Con A exposure. The Nrf2 and NF-κB signaling pathways and alterations in gut microbiota were determined using western blotting, immunohistochemistry, and 16S rRNA sequencing to explore the underlying mechanisms of KM exposure. KM pretreatment dose-dependently decreased serum liver injury markers (Alanine aminotransferase, and aspartate aminotransferase) and cytokine levels (Tumor necrosis factor-α and interleukin-6), as well as the liver pathological damage triggered by Con A. Furthermore, the results of the multi-technique analysis indicated that KM activated the Nrf2 pathway, upregulated the expression of anti-oxidation factors HO-1 and Nrf2, and downregulated the expression of Keap1. Moreover, the NF-κB signaling pathway was inhibited. Interestingly, pre-treatment with KM also significantly improved the composition of the gut microbiota probably because it increases the richness of probiotics. Our findings suggest that KM pretreatment could attenuate Con A-induced AIH, the Nrf2 and NF-κB signaling pathways, and that gut microbiota are involved in the process of the hepatoprotective effect. This study provides a theoretical basis for the development of KM as an effective agent against AIH. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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