3-Aminobenzamide Prevents Concanavalin A-Induced Acute Hepatitis by an Anti-inflammatory and Anti-oxidative Mechanism View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2018-12

AUTHORS

Joram Wardi, Orna Ernst, Anna Lilja, Hussein Aeed, Sebastián Katz, Idan Ben-Nachum, Iris Ben-Dror, Dolev Katz, Olga Bernadsky, Rajendar Kandhikonda, Yona Avni, Iain D. C. Fraser, Roy Weinstain, Alexander Biro, Tsaffrir Zor

ABSTRACT

BACKGROUND AND AIMS: Concanavalin A is known to activate T cells and to cause liver injury and hepatitis, mediated in part by secretion of TNFα from macrophages. Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors have been shown to prevent tissue damage in various animal models of inflammation. The objectives of this study were to evaluate the efficacy and mechanism of the PARP-1 inhibitor 3-aminobenzamide (3-AB) in preventing concanavalin A-induced liver damage. METHODS: We tested the in vivo effects of 3-AB on concanavalin A-treated mice, its effects on lipopolysaccharide (LPS)-stimulated macrophages in culture, and its ability to act as a scavenger in in vitro assays. RESULTS: 3-AB markedly reduced inflammation, oxidative stress, and liver tissue damage in concanavalin A-treated mice. In LPS-stimulated RAW264.7 macrophages, 3-AB inhibited NFκB transcriptional activity and subsequent expression of TNFα and iNOS and blocked NO production. In vitro, 3-AB acted as a hydrogen peroxide scavenger. The ROS scavenger N-acetylcysteine (NAC) and the ROS formation inhibitor diphenyleneiodonium (DPI) also inhibited TNFα expression in stimulated macrophages, but unlike 3-AB, NAC and DPI were unable to abolish NFκB activity. PARP-1 knockout failed to affect NFκB and TNFα suppression by 3-AB in stimulated macrophages. CONCLUSIONS: Our results suggest that 3-AB has a therapeutic effect on concanavalin A-induced liver injury by inhibiting expression of the key pro-inflammatory cytokine TNFα, via PARP-1-independent NFκB suppression and via an NFκB-independent anti-oxidative mechanism. More... »

PAGES

3382-3397

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s10620-018-5267-1

DOI

http://dx.doi.org/10.1007/s10620-018-5267-1

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1106894813

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30196390


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