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Ruxolitinib attenuates diethylnitrosamine-induced liver injury in mice: involvement of TLR4/MYD88/NF-κB and
Doaa H Hegazy1, Sara H Hazem2, Dalia H El-Kashef2
1Department of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt. doaa.hegazy.1998@mans.edu.eg.
Abstract:
The liver is a main target organ for xenobiotic-induced acute injury, with such toxicity frequently mediated through the oxidative stress generation and the subsequent activation of inflammatory signaling pathways like TLR4/MYD88/NF-κB and IL-6/JAK/STAT pathways. The current study investigated the potential protective effect of ruxolitinib (RUX) on liver injury induced by diethylnitrosamine (DEN). Mice were administered RUX prophylactically as a single dose orally, then DEN (150 mg/kg, i.p.) after an hour. Interestingly, RUX significantly alleviated liver injury induced by DEN as evidenced by marked improvement in liver architecture as illustrated in H&E-stained liver sections besides reduced blood levels of LDH, ALT and AST. Moreover, RUX restored cellular reserve of reduced glutathione (GSH) and hindered peroxidation of lipid and nitrosative stress as evidenced by dampened malondialdehyde (MDA) and nitric oxide (NO), respectively. Mechanistically, RUX down regulated both IL-6/JAK2/STAT3 and TLR4/MYD88/NF-κB pathways. IL-6/JAK2/STAT3 pathway has an important role in inflammation as it regulates many inflammatory cytokines' expression. Also, TLR4/MYD88/NF-κB pathway is another inflammatory pathway that induces release of pro-inflammatory cytokines. In summary, DEN-induced liver injury was mitigated by RUX by suppressing JAK2, which might be a promising tool for prohibiting liver injury induced by DEN or other exogenous chemicals.
Insights
Ruxolitinib (RUX) effectively protected against diethylnitrosamine (DEN)-induced liver injury in mice. RUX mitigated oxidative stress and inflammation by downregulating key signaling pathways, offering a potential therapeutic strategy for chemical-induced liver damage.
Area of Science:
- Hepatology
- Toxicology
- Pharmacology
Background:
- The liver is a primary target for xenobiotic-induced acute injury.
- Oxidative stress and inflammatory pathways, including TLR4/MYD88/NF-κB and IL-6/JAK/STAT, mediate liver toxicity.
- Diethylnitrosamine (DEN) is a known hepatotoxin.
Purpose of the Study:
- To investigate the protective effect of ruxolitinib (RUX) against DEN-induced liver injury.
- To elucidate the underlying molecular mechanisms of RUX's protective action.
Main Methods:
- Mice were pre-treated with RUX before DEN administration.
- Liver injury was assessed via histological examination (H&E staining) and biochemical markers (LDH, ALT, AST).
- Oxidative stress markers (GSH, MDA, NO) and inflammatory pathway activation (IL-6/JAK/STAT, TLR4/MYD88/NF-κB) were analyzed.
Main Results:
- RUX significantly alleviated DEN-induced liver damage, improving liver architecture and reducing serum enzyme levels.
- RUX treatment restored glutathione levels and reduced lipid peroxidation and nitrosative stress.
- Mechanistically, RUX suppressed both the IL-6/JAK2/STAT3 and TLR4/MYD88/NF-κB signaling pathways.
Conclusions:
- Ruxolitinib demonstrates significant hepatoprotective effects against DEN-induced liver injury.
- RUX mitigates liver damage by suppressing critical inflammatory and oxidative stress pathways, notably inhibiting JAK2.
- Ruxolitinib shows promise as a therapeutic agent for preventing chemical-induced liver injury.
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