Evaluation of the therapeutic effects of mycophenolate mofetil targeting Nrf-2 and NLRP3 inflammasome in acetic acid induced ulcerative colitis in rats.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease that increases the risk of colorectal cancer. UC is highly associated with the disturbance of the immune system leading to oxidative stress and chronic inflammation of intestine. Therefore, the current study was conducted to investigate the potential anti-oxidant and anti-inflammatory effects of MMF against acetic acid-induced UC that might be associated with the regulation of Nrf-2 and NLRP3 inflammasome signaling. UC was induced in Sprague-Dawley rats by intracolonic instillation of acetic acid. Forty-eight hours post UC induction, MMF (50 mg/kg/day, orally) was given for 8 consecutive days. Then, colon tissues and blood samples were collected. Results showed that MMF significantly attenuated the acetic acid-induced functional, biochemical, and inflammatory injuries in colon. MMF significantly decreased oxidative stress as indicated by the decreased malondialdehyde concentration and the increased total antioxidant capacity, glutathione, catalase, and superoxide dismutase concentrations in colon tissues. MMF also significantly increased Nrf-2 and decreased NLRP3 inflammasome expressions. Moreover, MMF decreased expression of interferon-gamma and increased expression of interferon-alpha. MMF also significantly decreased expression of pro-inflammatory cytokines, interleukin (IL)-1β and IL-18. These results suggest that MMF has antioxidant and anti-inflammatory effects against acetic acid-induced UC through the upregulation of Nrf-2, and INF-α expression in addition to the suppression of NLRP3 inflammasome and subsequent release of IL1β, IL-18 and INF-γ.

Serrya MS ，El-Sheakh AR ，Makled MN 《-》

Protective effect of mirtazapine against acetic acid-induced ulcerative colitis in rats: Role of NLRP3 inflammasome pathway.

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) that causes long-lasting inflammation on the innermost lining of the colon and rectum. Mirtazapine (MRT) is a well-known antidepressant that was proven to have anti-inflammatory activity; however, to date, its role has not been investigated in UC. The current study aimed to investigate the role and mechanism of MRT in UC. Acetic acid (AA) was used for UC induction, and sulfasalazine (SLZ) was used as a positive control. Rats were divided into five equal groups; as follows; normal control, AA, SLZ (received SLZ in a dose of 250 mg/kg for 14 days), MRT10 (received MRT in a dose of 10 mg/kg/day for 14 days), and MRT30 (received MRT in a dose of 30 mg/kg/day for 14 days) groups. Macroscopic and microscopic examinations together with oxidative stress parameters evaluation were done. NOD-like receptors-3 (NLRP3), caspase-1, TNF-α, and nuclear factor kappa B (NF-κB) expression together with interleukin (IL)-1β and IL-18 levels were examined. MRT, in a dose-dependent manner, prevented the macroscopic and microscopic colonic damage and corrected the oxidative stress induced by AA. Moreover, MRT decreased the colonic tissue NLRP3 inflammasome, caspase-1, NF-κB, TNF-α expressions, IL-1β, and IL-18 levels that were elevated in colonic tissue by the AA. MRT has a dose-dependent protective effect against UC that was mediated mainly by its anti-inflammatory activity with modulation of NLRP3/caspase-1 inflammatory pathway.

Hafez HM ，Ibrahim MA ，Yehia Abdelzaher W ，Gad AA ，Mohammed Naguib Abdel Hafez S ，Abdel-Gaber SA ... -  《-》

Dapagliflozin, an SGLT2 inhibitor, ameliorates acetic acid-induced colitis in rats by targeting NFκB/AMPK/NLRP3 axis.

The development of effective treatment strategies has been hindered by the complex pathogenesis of ulcerative colitis (UC). UC patients treated with current therapeutic approaches experienced either treatment failure or suffered excessive adverse reactions. Overactivity of NLRP3 inflammasome enhances inflammation, resulting in aggravation of colonic damage. We were interested in exploring, for the first time, the potential coloprotective effect of dapagliflozin (DPZ) on acetic acid-induced UC in rats in comparison with 5-ASA. DPZ improved histologic and macroscopic features of colon tissues and prolonged survival of UC rats. DPZ also prevented colon shortening and declined disease activity. Additionally, DPZ lessened colon tissue neutrophil content and improved antioxidant defense machinery. Further, DPZ specifically declined the colonic inflammatory marker IL-6 and upregulated the anti-inflammatory cytokine IL-10. The pyroptosis process is constrained in consequence of the repressed caspase-1 activity and caspase-1-dependent release of the bioactive cytokines IL-1β and IL-18. These protective effects might be attributed to that DPZ on the one hand, prevented the priming step (signal 1) of NLRP3 inflammasome activation as revealed by modulating NFκB/AMPK interplay and on the other hand, inhibited the activation step (signal 2) as indicated by interrupting NLRP3/caspase-1 signaling. Since DPZ was found to be safe and well tolerated by healthy volunteers with no evidence of hypoglycemia, it might show promise in the future management of UC. However, further investigations are warranted to confirm the reversal of injury and that the coloprotective effect is substantial.

El-Rous MA ，Saber S ，Raafat EM ，Ahmed AAE ... -  《-》

The possible ameliorative effect of simvastatin versus sulfasalazine on acetic acid induced ulcerative colitis in adult rats.

Inflammatory bowel diseases (IBD) are chronic and recurrent disorders of the gastrointestinal tract with unknown etiology and have two major forms, ulcerative colitis (UC) and Crohn diseases. In view of the adverse effects and incomplete efficacy of currently administered drugs, it is essential to investigate new and harmless drugs with more desirable beneficial effects. Statins have many additional pleiotropic effects other than their lipid-lowering effect. This study aims to investigate the role of simvastatin (SIM) at different doses against induced UC in rats. SIM (10, 20 mg/kg), and sulfasalazine as a standard therapy (100 mg/kg) were given from five days before and seven days after induction of UC by acetic acid (AA). Colonic mucosal inflammation was evaluated macroscopically and microscopically. Furthermore, the colonic tissue tumor necrosis factor-α (TNF-α), interleukin 1beta (IL 1B), nod-like receptor family pyrin domain-1 containing 3 (NLRP3), malondialdehyde (MDA), reduced glutathione (GSH) and super oxide dismutase (SOD) were assayed in addition to immunohistochemistry of caspase-1 and cyclooxygenase-2 (COX2). SIM in a dose dependant manner significantly improved macroscopic and histological scores, diminished colonic levels of IL 1B, TNF-α, NLRP3, MDA, caspase-1 and COX2 and elevated GSH and SOD. SIM has anti-inflammatory, cytoprotective and antioxidants effects that are not directly related to its cholesterol lowering activity against AA induced colitis this makes it a new therapeutic target for UC.

Soliman NA ，Keshk WA ，Rizk FH ，Ibrahim MA ... -  《-》

Oxymatrine Attenuates Ulcerative Colitis through Inhibiting Pyroptosis Mediated by the NLRP3 Inflammasome.

Sun J ，Wang S ，Zhao Z ，Lu J ，Zhang Y ，An W ，Li W ，Yang L ，Tong X ... -  《MOLECULES》