title: Ethyl 3',4',5'-trimethoxythionocinnamate modulates NF-κB and Nrf2 transcription factors.
abstract: Recently, we identified a novel cinnamate analog, ethyl 3',4',5'-trimethoxythionocinnamate (ETMTC) as a potent inhibitor of cell adhesion molecules (CAMs), such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin. However, its mechanism of action has not been elucidated so far. Since, nuclear factor-kappa B (NF-κB) is the major transcription factor involved in the regulation of ICAM-1, VCAM-1 and E-selectin expression, we determined the status of NF-κB activation in ETMTC treated human endothelial cells. Here, we demonstrate that ETMTC inhibits TNF-α-induced nuclear translocation and activation of NF-κB by inhibiting phosphorylation and degradation of IκBα. The inhibition of IκBα phosphorylation and degradation by ETMTC was found to be due to its ability to inhibit IκB kinase activity. In addition, oxidative stress is known to regulate NF-κB activation through TNF-α signaling cascade, therefore, we examined the effect of ETMTC on TNF-α-induced reactive oxygen species generation. We observed that ETMTC significantly inhibits TNF-α-induced reactive oxygen species generation in endothelial cells. To further elucidate the anti-oxidant potential of ETMTC, we examined its effect on induction of anti-oxidant genes viz. glutamate-cysteine ligase, modifier subunit (GCLM), heme oxygenase-1 (HO1) and NAD (P)H:quinone oxidoreductase 1 (NQO1) in human bronchial epithelial cells. Interestingly, ETMTC significantly induces the anti-oxidant genes viz. GCLM, HO1 and NQO1 by activating nuclear factor-erythroid 2 p45-related factor 2 (Nrf2). Thus, ETMTC could be useful towards developing potent anti-inflammatory molecules.
authors.affiliation: Molecular Immunogenetics Laboratory, CSIR-Institute of Genomics and Integrative Biology, Mall Road, Delhi 110007, India.
authors.forename: Sarvesh
authors.initials: S
authors.lastname: Kumar
authors.forename: Brajendra K
authors.initials: BK
authors.lastname: Singh
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Prasad
authors.forename: Virinder S
authors.initials: VS
authors.lastname: Parmar
authors.forename: Shyam
authors.initials: S
authors.lastname: Biswal
authors.forename: Balaram
authors.initials: B
authors.lastname: Ghosh
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002934:Cinnamates / Q000494:pharmacology*; D019040:E-Selectin / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
chemical_list: D002934:Cinnamates; D019040:E-Selectin; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495635:NFE2L2 protein, human; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C581817:ethyl 3',4',5'-trimethoxythionocinnamate; D018799:Intercellular Adhesion Molecule-1; D051550:I-kappa B Kinase