title: Inhibition of the JAK/STAT pathway by ruxolitinib ameliorates thioacetamide-induced hepatotoxicity.
abstract: In an attempt to explore the role of the JAK/STAT pathway in liver inflammation, we investigated the effect of intervening this pathway by ruxolitinib in thioacetamide (TAA)-induced hepatotoxicity. Ruxolitinib treatments were administered to male mice either before or after intoxication with TAA. The hepatic histopathological and serum biochemical assessment revealed that ruxolitinib pre-treatments dose-dependently reduced TAA-induced liver injury, caspase 3 cleavage and increase in number of hepatocytes positive for the pro-apoptotic Bax, as well as inflammatory cells positive for F4/80 and myeloperoxidase activity in the liver. Ruxolitinib pre-treatments also curbed TAA-induced rise in NF-κB nuclear expression and STAT3 phosphorylation. Ruxolitinib pre-treatments also lowered TAA-induced elevation of hepatic oxidative stress parameters (total nitrate/nitrite and 4-hydroxynonenal), but did not restore the hepatic antioxidant reduced glutathione. Interestingly, ruxolitinib, especially at a dose of 200 mg/kg, dampened the overproduction of pro-inflammatory cytokines (TNF-α, IL-1β, IFN-γ, IL-23 and IL-17A), which coincided with boosting the release of the anti-inflammatory cytokine IL-10. Ruxolitinib when used as a post-treatment (1 and 3 h after TAA-insult) could still spare the liver from injury and might be clinically applicable. In conclusion, the multimechanistic-hepatoprotective activity of ruxolitinib can be linked to its ameliorative properties on cellular death, oxidative stress and inflammation machinery.
authors.affiliation: Pharmacology and Toxicology Dept., Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address: mshaker2222@yahoo.com.
authors.forename: Mohamed E
authors.initials: ME
authors.lastname: Shaker
authors.affiliation: Pharmacology and Toxicology Dept., Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
authors.forename: Sara H
authors.initials: SH
authors.lastname: Hazem
authors.affiliation: Pathology Dept., Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt.
authors.forename: Sylvia A
authors.initials: SA
authors.lastname: Ashamallah
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000473:pathology; D005978:Glutathione / Q000378:metabolism; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D053612:Janus Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D009570:Nitriles; D018384:Oxidative Stress / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines; D050791:STAT Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013853:Thioacetamide / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000975:Antioxidants; D016328:NF-kappa B; D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; D050791:STAT Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D013853:Thioacetamide; C540383:ruxolitinib; D053612:Janus Kinases; D005978:Glutathione
keywords: Hepatotoxicity; JAK/STAT; Oxidative stress; Ruxolitinib; Thioacetamide