title: A novel fused 1,2,4-triazine aryl derivative as antioxidant and nonselective antagonist of adenosine A(2A) receptors in ethanol-activated liver stellate cells.
abstract: It has been detected that hepatic adenosine A(2A) receptors play an active role in the pathogenesis of hepatic fibrosis and suggest a novel therapeutic target in the treatment and prevention of hepatic cirrhosis. In this paper we examined if our new triazine derivative (IMT) can inhibit ethanol-induced activation of HSCs measured as increased α-SMA, collagen synthesis and enhanced oxidative stress in rat liver stellate cells. We also investigated its influence on cytokines (TGF-β, TNF-α) synthesis, MMP-2 and TIMP-1 production and ethanol-induced intracellular signal transduction. Moreover, with using of known adenosine A(2A) receptor agonist (CGS 21680), and antagonist (SCH 58261) we examined if this triazine derivative acts on adenosine receptors. We detected a strong antagonistic action of new triazine derivative (IMT) on ethanol-induced rat liver stellate cells activation, observed as a significant decrease in α-SMA, collagen synthesis, reactive oxygen species production, TGF-β, TNF-α, MMP-2 and TIMP-1 production as well as JNK, p38MAPK, NFκB, IκB, Smad3 phosphorylation. Moreover, IMT strongly inhibited activation of stellate cells by known selective agonist of adenosine A(2A) receptor (CGS 21680). When known A(2A) receptor antagonist (SCH 58261) was used together with IMT this effect was not spectacular. Additionally, only slight enhancement of inhibition was observed when cells were pretreated both IMT with SCH 58261, hence we suppose that IMT acts as nonselective antagonist of A(2A) receptors, and, besides its antioxidant activity, also by this way inhibited ethanol-induced stellate cell activation.
authors: Department of Virology and Immunology, Maria Curie-Skłodowska University, Lublin, Poland. szustera@hektor.umcs.lublin.pl
authors: Agnieszka
authors: A
authors: Szuster-Ciesielska
authors: Krzysztof
authors: K
authors: Sztanke
authors: Martyna
authors: M
authors: Kandefer-Szerszeń
mesh_terms: D000199:Actins / Q000378:metabolism; D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D000431:Ethanol; D055166:Hepatic Stellate Cells / Q000187:drug effects*; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology
chemical_list: D000199:Actins; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D000975:Antioxidants; D019086:Bridged Bicyclo Compounds, Heterocyclic; D016207:Cytokines; D000431:Ethanol; D006834:Hydrazines; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D043705:Receptor, Adenosine A2A; D014230:Triazoles; C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; C570019:8-(4-methoxyphenyl)-4-oxo-4,6,7,8-tetrahydroimidazo(2,1-c)(1,2,4)triazine-3-carbohydrazide; C498862:Acta2 protein, rat