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Mycophenolate mofetil attenuates concanavalin A-induced acute liver injury through modulation of TLR4/NF-κB and Nrf2/HO-1 pathways

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Abstract

Background

Acute liver injury (ALI) is a serious health condition associated with rising morbidity and sudden progression. This study was designed to investigate the possible hepatocurative potential of two dose levels (30 and 60 mg/kg) of Mycophenolate mofetil (MMF), an immune-suppressant agent, against Concanavalin A (Con A)-induced ALI in mice.

Method

A single dose of Con A (20 mg/kg, IV) was used to induce ALI in mice. MMF (30 mg/kg and 60 mg/kg) was administered orally for 4 days post Con A injection.

Results

MMF (30 mg/kg) failed to cause significant amelioration in Con A-induced ALI while MMF (60 mg/kg) significantly alleviated Con A-induced ALI. Administration of MMF (60 mg/kg) significantly decreased Con A-induced increase in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Additionally, MMF significantly restored the disrupted oxidant/antioxidants status induced by Con A. MMF caused marked increase in hepatic nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) levels. Moreover, MMF significantly reduced Con A-induced increase in the expression of hepatic toll-like receptor 4 (TLR4), nuclear factor kappa-B (NF-κB), tumor necrosis factor-α (TNF-α), interferon-γ (INF-γ) and interleukin-1β (Il-1β). Also, MMF administration significantly decreased Con A-induced increase in the immune-expression of pro-apoptotic Bcl-2-associated X protein (Bax) and markedly increased Con A-induced decrease in the anti-apoptotic B-cell lymphoma 2 protein (Bcl2).

Conclusion

The observed ameliorative effect of MMF against Con A-induce ALI may be contributed to its anti-inflammatory, anti-oxidant and anti-apoptotic potentials taking into consideration that TLR4/NF-κB and Nrf2/HO-1 are the main implicated pathways.

Graphic abstract

Schematic diagram summarizing the possible mechanisms underlying the ameliorative potential of Mycophenolate Mofetil against Con A-induced acute liver injury. Bax Bcl-2-associated X protein, Bcl2 B-cell lymphoma 2, MMF Mycophenolate mofetil, Con A Concanavalin A, GSH reduced glutathione, HO-1 Heme oxygenase-1, IL-1β Interleukin-1β, IFN-γ Interferon-γ, MDA Malondialdehyde, NF-κB Nuclear Factor Kappa B, Nrf2 Nuclear factor erythroid 2-related factor 2, NO Nitric Oxide, SOD Superoxide Dismutase, TLR4 Toll-like receptor 4, TNF-α tumor necrosis factor-α

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Abbreviations

ALI:

Acute liver injury

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

Bax:

Bcl-2-associated X protein

Bcl2:

B-cell lymphoma 2.

Con A:

Concanavalin A

GSH:

Reduced glutathione

HO-1:

Heme oxygenase-1

H&E:

Hematoxylin and eosin

IHC:

Immunohistochemical.

IL-1β:

Interleukin-1β

IFN-γ:

Interferon-γ

MDA:

Malondialdehyde

MMF:

Mycophenolate mofetil

NF-κB:

Nuclear factor kappa B

Nrf2:

Nuclear factor erythroid 2-related factor 2

NO:

Nitric oxide

SOD:

Superoxide dismutase

TLR4:

Toll-like receptor 4

TNF-α:

Tumor necrosis factor-α

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  1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt

    Marwa S. Serrya & Marwa S. Zaghloul

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Serrya, M.S., Zaghloul, M.S. Mycophenolate mofetil attenuates concanavalin A-induced acute liver injury through modulation of TLR4/NF-κB and Nrf2/HO-1 pathways. Pharmacol. Rep 72, 945–955 (2020). https://doi.org/10.1007/s43440-019-00055-4

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