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  • MicroRNAs miRNAs are endogenous small RNA

    2021-12-02

    MicroRNAs (miRNAs) are endogenous small RNA molecules 20–25 nucleotides in length; they regulate multiple genes by binding to target mRNAs, thereby controlling the stability and translation of protein coding mRNAs (Esteller, 2011, Guo et al., 2010). It has been established that Tempol synthesis of the innate and adaptive immune system express more than 100 miRNAs that are involved in mediating many functions, including cell proliferation and apoptosis. In addition, miRNAs are expressed in many developing tissues and are active in regulating inflammation (Ambros, 2004). Recent evidence suggests that miRNAs are differentially expressed in UC and have a key role as negative regulators of inflammation and innate immunity (Wu et al., 2008). miRNAs mir-21 and mir-216 are differentially expressed in active versus inactive UC. Further, it has been shown that induced miR-101b and miR-455 miRNAs mediates anti-inflammatory properties in colitis and associated colon cancer (Altamemi et al., 2014, Feng et al., 2012). However, the differential expression of miRNAs and their role in experimental colitis have not been investigated.
    Materials and methods
    Results
    Discussion We have identified the effectiveness of FAAH-II inhibitor in ameliorating inflammation in a well-established DSS-induced model of colitis. Considerable immunological evidence and similarities in the pathology of experimental mouse models that mimic with IBD suggest that this model can be used to explore novel therapeutics. Here, we demonstrated that administration of select FAAH-II inhibitor reversed the severity of DSS-induced colitis. Treatment of colitic mice with FAAH-II reversed weight loss, improved inflammation scores, and decreased disease severity. The increased frequency of mucosal and systemic activated T cells, macrophages, neutrophils, and NKT cells during experimental colitis were also significantly reduced by FAAH-II treatment. Taken together, these results indicate that FAAH-II abrogates DSS-induced colitis by suppressing the activation of CD4+ T cells and reducing the frequency of macrophages and NKT cells, thereby reducing other inflammatory cells at sites of inflammation. Recent studies suggest that both exogenous and endogenous cannabinoids inhibit the inflammatory response and suppress severity of colitis (Stella et al., 1997, Storr et al., 2008). Storr et al.’s study suggests that inhibition of FAAH at a later stage may alleviate disease symptoms by activating endogenous cannabinoids. To this end, mice lacking CB1-, CB2-, or both receptors, showed augmented inflammation in a TNBS-induced model of colitis (Engel et al., 2010). Further, blocking the degradation of endocannabinoids or cellular reuptake inhibited inflammation and maintained normal colon length (Storr et al., 2008). Furthermore, CB-receptor- knockout mice in which levels of anandamide were elevated by deficiency in or inhibition of FAAH showed significant resistance to TNBS-induced colitis (Izzo and Sharkey, 2010). The results of these studies have been supported by clinical reports of increased levels of an endocannabinoid, AEA, in biopsies of the submucosal layer, but not the mucosal layer of the inflamed colon of human UC patients (D’Argenio et al., 2006). Another study indicated that anandamide modulates the CB receptor to mediate a decrease in contractility and secretion using CB1 and decreasing proinflammatory cytokines by CB2 receptors (Izzo and Camilleri, 2009). Further, FAAH inhibitors have already been tested in preclinical and clinical trials and may be an important potential target for the treatment of IBD (Kimball et al., 2006, Massa et al., 2004, Singh et al., 2012, Storr et al., 2008, Storr et al., 2009). These findings, as well as the results of this study, clearly demonstrate that FAAH inhibition in DSS-induced colitis can improve disease severity, recover body weight, prevent disease progression and ameliorate colitis. Several IBD models of experimental colitis indicate not only that CD4+ T cells are important in the induction of IBD, that much of the intestinal damage caused by this disease is a result of T-cell-mediated injury (Elson et al., 1996, Singh et al., 2012, Singh et al., 2008a). These findings are consistent with those of the current study, in which we found that the percentage of activated CD4+ T cells in spleens, MLNs, PPs and LPL increased significantly during experimental colitis and decreased after FAAH-II treatment. Earlier, we showed in spontaneous model that during severe colitis the numbers of IFN-γ+ expressing CD4+ T cells are elevated in the LPL (Singh et al., 2008b). Based on these findings, we suggest that both systemic and mucosal site decreases in activated T cells might decrease the inflammatory cytokine environment to amend the Tempol synthesis colitis symptoms. These observations suggest that inhibition of FAAH suppresses colitis by downregulating T-cell activation responses.