Alpha-mangostin as a new therapeutic candidate for concanavalin A-induced autoimmune hepatitis.

Alpha-Mangostin as a New Therapeutic Candidate for Concanavalin A-Induced Autoimmune Hepatitis: Impact on the SIRT1/Nrf2 and NF-κB Crosstalk.

Awad A Shehata, Hossein M Elbadawy, Salam A Ibrahim, Ghada F Mohamed, Wael M Elsaed, Aisha A Alhaddad, N Ahmed, Hany Abo-Haded, Dina S El-Agamy

Plants (Basel)

Sep 18, 2022

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Abstract

Alpha-mangostin (α-MN) is a xanthone obtained fromthat has diverse anti-oxidative and anti-inflammatory potentials. However, its pharmacological activity against autoimmune hepatitis (AIH) has not been investigated before. Concanavalin A (Con A) was injected into mice to induce AIH and two doses ofα-MN were tested for their protective effects against Con A-induced AIH. The results demonstrated the potent hepatoprotective activity ofα-MN evidenced by a remarkable decrease of serum indices of the hepatic injury and amendment of the histological lesions.α-MN significantly attenuated the level and immuno-expression of myeloperoxidase (MPO) indicating a decrease in the neutrophil infiltration into the liver. Additionally, the recruitment of the CD4+ T cell was suppressed in theα-MN pre-treated animals.α-MN showed a potent ability to repress the Con A-induced oxidative stress evident by the reduced levels of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and protein carbonyl (PC), as well as the enhanced levels of antioxidants as the reduced glutathione (GSH), superoxide dismutase (SOD), and total antioxidant capacity (TAC). The ELISA, RT-PCR, and IHC analyses revealed thatα-MN enhanced the sirtuin1/nuclear factor erythroid 2 related factor-2 (SIRT1/Nrf2) signaling and its downstream cascade genes concurrently with the inhibition of the nuclear factor kappa B (NF-κB) and the inflammatory cytokines (tumor necrosis factor-alpha and interleukine-6) signaling. Taken together, these results inferred that the hepatoprotective activity ofα-MN could prevent Con A-induced AIH through the modulation of the SIRT1/Nrf2/NF-κB signaling. Hence,α-MN may be considered as a promising candidate for AIH therapy.