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    NLRX1 ligand, docosahexaenoic acid, ameliorates LPS-induced inflammatory hyperalgesia by decreasing TRAF6/IKK/IκB-α/NF-κB signaling pathway activity
    (C M B Assoc, 2023) Yilmaz, Dilsah Ezgi; Senol, Sefika Pinar; Temiz-Resitoglu, Meryem; Sahan-Firat, Seyhan; Tunctan, Bahar
    The nucleotide-binding oligomerization domain-like receptor X1 (NLRX1) has been associated with various anti-inflammatory mechanisms. We investigated whether the NLRX1 ligand docosahexaenoic acid (DHA) ameliorates lipopolysaccharide (LPS)-induced inflammatory hyperalgesia by interacting with tumor necrosis factor receptor-associated factor 6 (TRAF6)/inhibitor of KB (IKB) kinase (IKK)/IKB-alpha/nuclear factor-KB (NF -KB) signaling pathway in the central nervous system. Reaction time to thermal stimuli within 30 seconds was measured in male mice injected with saline, lipopolysaccharide (LPS), and/or DHA after 6 hours using the hot plate test. Co-immunoprecipitation and immunoblotting studies were performed to determine the activation of the TRAF6/IKK/IKB-alpha/NF-KB pathway in the brains and spinal cords of animals. Latency to the thermal stimulus was reduced by 30% in LPS-injected endotoxemic mice compared with saline-injected mice. Treatment with DHA significantly improved latency compared with endotoxemic mice. In the brain and spinal cord of LPS-injected mice, treatment with DHA also prevented the increase in the expression and/or activity of (1) IKK alpha/IKK beta, IKK gamma, and K63 U in the NLRX1-immunoprecipitated tissues, (2) IKK alpha/IKK beta, K63 U, and K48 U in the IKK gamma-immunoprecipitated tissues, and (3) IKB-alpha, NF-KB p65, and interleukin-1 beta associated with decreased IKB-alpha expression. These findings suggest that inhibition of IKK/IKB-alpha/NF-KB signaling by dissociation of NLRX1 from TRAF6 in response to LPS treatment contributes to the protective effect of DHA against inflammatory hyperalgesia.
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    Öğe
    Pro-inflammatory GPR75 and anti-apoptotic phospholipase signaling pathways contribute to the ameliorating effect of soluble epoxide hydrolase inhibition on chronic experimental autoimmune encephalomyelitis in mice
    (C M B Assoc, 2023) Horat, Mehmet Furkan; Senol, Sefika Pinar; Bahceli, Omer; Temiz-Resitoglu, Meryem; Sahan-Firat, Seyhan; Sevim, Serhan; Tunctan, Bahar
    Soluble epoxide hydrolase (sEH) inhibition has currently emerged as a therapeutic target in the treatment of various neuroinflammatory neurodegenerative diseases, including multiple sclerosis. Previously, we reported that treatment of mice with an sEH-selective inhibitor, 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy) phenyl]urea; TPPU), ameliorated chronic experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein 35-55 peptide immunization followed by injection of pertussis toxin to mice via regulating pro-inflammatory and anti-inflammatory pathways in the central nervous system. This study tested the hypothesis that the pro-inflammatory G protein-coupled receptor (GPR) 75 and anti-apoptotic phospholipase C (PLC) signaling pathways also contribute to the ameliorating effect of TPPU on chronic EAE. Brains and spinal cords of phosphate-buffered saline-, dimethyl sulfoxide-, or TPPU (3 mg/kg)-treated mice were used for the measurement of sEH, GPR75, G alpha q/11, activator protein (AP)-1, PLC beta 4, phosphoinositide lymphoma (Bcl)-2, semaphorin (SEMA) 3A, and myelin proteolipid protein (PLP) expression and/or activity by using the immunoblotting method. Expression of sEH, GPR75, G alpha q/11, c-jun, phosphorylated c-Jun, and SEMA3A was lower, while PLC beta 4, phosphorylated PI3K p85 alpha, phosphorylated Akt1, phosphorylated MEK1/2, phosphorylated ERK1/2, phosphorylated CREB1, Bcl-2, and myelin PLP expression was higher in the tissues of TPPU (3 mg/kg)-treated mice as compared with the EAE and vehicle control groups. Inhibition of sEH by TPPU ameliorates chronic EAE through suppressing pro-inflammatory GPR75/G alpha q/11/AP-1 pathway and reducing expression of the remyelination inhibitor, SEMA3A, as well as increasing anti-apoptotic PLC/PI3K/ Akt1/MEK1/2/ERK1/2/CREB1/Bcl-2 pathway activity and myelin PLP expression.