title: The NF-κB inhibitor celastrol attenuates acute hepatic dysfunction induced by cecal ligation and puncture in rats.
abstract: Acute hepatic dysfunction associating sepsis is mediated mainly by toll-like receptor-4 (TLR-4)/nuclear factor kappa-B (NF-κB) inflammatory pathway. This study explores potential hepatoprotective effect of the NF-κB inhibitor celastrol in cecal ligation and puncture (CLP) model in rats. Protective effect of celastrol (1mg/kg, i.p., 1h before CLP) was illustrated after 24h by preventing CLP-induced hepatic histopathological changes and elevation in serum hepatic biomarkers [alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB) and gamma aminotransferase (γ-GT)] without affecting mortality. Celastrol anti-inflammatory effect was illustrated by inhibiting increased serum and hepatic mRNA expression of interleukin-6 (IL-6) without affecting IL-10 elevation. Furthermore, celastrol inhibited CLP-induced elevations in hepatic mRNA expression of nuclear factor inhibitory protein kappa-B alpha (NFκBia), TLR-4, 5-lipoxygenase (5-LOX) and prevented NF-κB/p65 nuclear translocation and activation. In conclusion, celastrol prevented CLP-induced acute hepatic dysfunction through its anti-inflammatory effect by attenuating NF-κB activation, TLR-4 and 5-LOX expression with subsequent reduction in pro-inflammatory IL-6.
authors.affiliation: Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Delta University for science and technology, Gamasa, Egypt.
authors.forename: Ghada S
authors.initials: GS
authors.lastname: El-Tanbouly
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt. Electronic address: mohamshh@yahoo.com.
authors.forename: Mohammed S
authors.initials: MS
authors.lastname: El-Awady
authors.affiliation: Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
authors.forename: Nermeen A
authors.initials: NA
authors.lastname: Megahed
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
authors.forename: Hatem A
authors.initials: HA
authors.lastname: Salem
authors.affiliation: Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Delta University for science and technology, Gamasa, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
authors.forename: Hassan A
authors.initials: HA
authors.lastname: El-Kashef
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000494:pharmacology; D002432:Cecum / Q000601:surgery; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D016753:Interleukin-10 / Q000097:blood / Q000235:genetics; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics; D008107:Liver Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D053978:Pentacyclic Triterpenes; D051381:Rats; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D014315:Triterpenes / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; C556062:IL10 protein, mouse; D015850:Interleukin-6; D016328:NF-kappa B; D053978:Pentacyclic Triterpenes; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014315:Triterpenes; C577686:interleukin-6, mouse; D016753:Interleukin-10; C050414:celastrol
keywords: 5-LOX; CLP; Celastrol; IL-6; NF-κB; TLR-4