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

Abstract

Alpha-mangostin (α-MN) is a xanthone obtained from Garcinia mangostana that 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 of α-MN were tested for their protective effects against Con A-induced AIH. The results demonstrated the potent hepatoprotective activity of α-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 the α-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 that α-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 of α-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.

Garcinone E Mitigates Oxidative Inflammatory Response and Protects against Experimental Autoimmune Hepatitis via Modulation of Nrf2/HO-1, NF-κB and TNF-α/JNK Axis

“…Con-A-induced hepatitis is a well-established model that resembles human acute viral hepatitis and AIH regarding to its pathogenesis [ 41 , 42 ]. Single Con-A injection can speedily produce grave immune-mediated inflammatory liver damage within 8–12 h [ 7 , 36 ]. Con A has a high tendency towards mannose-wealth glycoproteins on liver sinusoidal endothelial cells, leading to T cell activation, particularly the CD4+ T cells in the liver tissue.…”

“…The etiology of Con-A-induced hepatitis is multifactorial and includes many molecular pathogenic pathways. One of these is the suppression of the Nrf2/GCLc/HO-1 signaling resulting in the downregulation of the antioxidant enzymes and an increase in the oxidative burden [ 36 ]. Furthermore, the increased release of reactive-oxygen-species (ROS) for 12 h next to Con-A injection was found to augment lipid peroxidative injury and to greatly repress the liver’s antioxidant capacity [ 46 , 47 ].…”

“…In brief, after dewaxing of tissue samples and rehydration, samples’ peroxidases were neutralized using hydrogen peroxide (3%). The liver sections were immuno-stained utilizing primary antibodies: rabbit polyclonal antibody to CD4 (1:100, Abnova/Taipie/Taiwan), PCNA (1:100, Abcam/Cambridge/UK), and NF-κBp65 (1:200, Fisher Scientific Inc./Waltham/MA/USA), as formerly described [ 36 ]. Slides were visualized using diaminobenzidine and counterstained.…”

SIRT1/Nrf2/NF-κB Signaling Mediates Anti-Inflammatory and Anti-Apoptotic Activities of Oleanolic Acid in a Mouse Model of Acute Hepatorenal Damage

“…For IHC, paraffin sections of the liver and kidney were dewaxed and handled as previously demonstrated [ 30 , 33 ]. IHC was carried out using the primary antibodies: Nrf2 (1:200) (Fisher Scientific Inc., Waltham, MA, USA), rabbit-polyclonal-antibody against NF-κB p65 (1:200), caspase-3 (1:200), and Bcl2 (1:200) (Elabscience Biotechnology Inc., Houston, TX, USA).…”