Cornuside improves murine autoimmune hepatitis through inhibition of inflammatory responses

Background: Autoimmune hepatitis (AIH) poses an important public health concern worldwide, with few ther-apeutic options available. Cornuside, a primary cornel iridoid glycoside present in Cornus officinalis Sieb. et Zucc., is a well-known traditional Chinese medicine that possesses anti-inflammatory, antioxidant and anti-apoptotic properties. However, the effects of cornuside on autoimmune diseases including AIH is still not defined, neither is clear on the mechanisms of cornuside in the suppression of inflammatory responses. Purpose: The study was aimed to investigate the therapeutic effects of cornuside on AIH using murine models. Study design: A murine model of AIH induced by concanavalin A (Con A) was used to examine the pharmaco-logical activity of cornuside in suppressing the inflammatory responses in vivo. Methods: C57BL/6J mice were intravenously with different doses of cornuside and challenged with 18 mg/kg Con A 3 h later. Network pharmacological analysis was performed to identify the potential target genes and signaling pathways by cornuside in AIH. Next serum and liver tissues were collected 12 h after Con A injection to analyze the levels of markers for hepatic injury, apoptosis, oxidative stress, immune responses, and inflammation. Results: Network pharmacological analysis revealed that cornuside may modulate oxidative stress and apoptosis in AIH. Compared with the Con A group, cornuside pretreatment significantly reduced the serum levels of alanine aminotransferase and aspartate aminotransferase, improving histopathological damage and apoptosis in the livers. In addition, cornuside decreased the levels of malondialdehyde, myeloperoxidase, but increased superoxide dismutase levels, suggesting the relieving of oxidative stress. Furthermore, cornuside suppressed the activation of T and natural killer T cells, whereas the proportion of myeloid-derived suppressor cells was significantly increased. The production of proinflammatory cytokines, including interleukin (IL)-6, IL-12, IL-1 beta, and tumor necrosis factor-alpha (TNF-alpha), was also clearly decreased. Finally, western blot analysis displayed that cornuside inhibited the phosphorylation of extracellular receptor kinase (ERK) and c-Jun N-terminal kinase (JNK). Conclusions: We demonstrated that cornuside has protective effects for Con A-induced immune-mediated hepa-titis by suppressing the oxidative stress, apoptosis, and the inflammatory responses through the ERK and JNK signaling pathways, as well as by modulating the activation and recruitment of immune cells.