Smad4 Loss in the Mouse Intestinal Epithelium Alleviates the Pathological Fibrotic Response to Injury in the Colon.

Mucosal healing is associated with better clinical outcomes in patients with inflammatory bowel diseases (IBDs). Unresolved injury and inflammation, on the other hand, increases pathological fibrosis and the predisposition to cancer. Loss of Smad4, a tumor suppressor, is known to increase colitis-associated cancer in mouse models of chronic IBD. Since common biological processes are involved in both injury repair and tumor growth, we sought to investigate the effect of Smad4 loss on the response to epithelial injury. To this end, Smad4 was knocked out specifically in the intestinal epithelium and transcriptomic and morphological changes compared between wild type mice and Smad4 knock out mice after DSS-induced injury. We find that Smad4 loss alleviates pathological fibrosis and enhances mucosal repair. The transcriptomic changes specific to epithelium indicate molecular changes that affect epithelial extracellular matrix (ECM) and promote enhanced mucosal repair. These findings suggest that the biological processes that promote wound healing alleviate the pathological fibrotic response to DSS. Therefore, these mucosal repair processes could be exploited to develop therapies that promote normal wound healing and prevent fibrosis. NEW AND NOTEWORTHY: We show that transcriptomic changes due to Smad4 loss in the colonic epithelium alleviates the pathological fibrotic response to DSS in an IBD mouse model of acute inflammation. Most notably, we find that collagen deposition in the epithelial ECM, as opposed to that in the lamina propria, correlates with epithelial changes that enhance wound healing. This is the first report on a mouse model providing alleviated fibrotic response in a DSS-IBD mouse model in vivo .

The immunomodulatory effects of all-trans retinoic acid and docosahexaenoic acid combination treatment on the expression of IL-2, IL-4, T-bet, and GATA3 genes in PBMCs of multiple sclerosis patients.

OBJECTIVES: Multiple sclerosis (MS) is a potentially disabling autoimmune disease of the central nervous system. Neither the pathogenesis nor the effectiveness of treatment of MS has been fully understood. This in vitro trial evaluated the beneficial immunomodulatory effects of single and combined treatments of all-trans retinoic acid (ATRA) and docosahexaenoic acid (DHA) on the peripheral blood mononuclear cells (PBMCs) of relapsing-remitting MS (RRMS) patients who were receiving interferon beta (IFN-ß). METHODS: The PBMCs of 15 RRMS patients were isolated, cultured, and treated with single and combined treatments of ATRA and DHA. The expressions of IL-2, IL-4, T-bet, and GATA3 genes were evaluated using real-time PCR. RESULTS: The results showed that a single treatment of ATRA could significantly suppress the gene expression of the pro-inflammatory cytokine, IL-2 (P < 0.05), and related transcription factor, T-bet (P < 0.001). The gene expression level of the anti-inflammatory cytokine, IL-4, and its transcription factor, GATA3, were not significantly changed. The expression of IL-2 and T-bet genes was significantly decreased in combination treatments of ATRA and DHA (P < 0.001). Significant suppression of IL-2 and T-bet (P < 0.001) was observed in ATRA and DHA combination therapy with half doses of their single treatment, which suggested a synergistic effect of these components. DISCUSSION: Co-administration of vitamin A and DHA, an omega-3 fatty acid derivative, may exert a synergistic effect in modulating the immune system in MS patients; however, more studies are needed to evaluate the exact effects and mechanism of their actions on the immune cells.

Influence of Helicobacter pylori virulence factors CagA and VacA on pathogenesis of gastrointestinal disorders.

Helicobacter Pylori (H. pylori) is a gram-negative bacteria infecting numerous people all over the world. It has been established that H. pylori play an important role in pathogenesis of gastritis, peptic ulcer and gastric cancer. Pathogenic features of this bacterium are mainly attributes to the existence of pathogenic islands (PAI) genes. The most known genes in these islands are cytotoxin-associated gene A (CagA) and vacuolating cytotoxin gene (VacA). Most studies demonstrated various frequency of CagA and VacA in patient with peptic ulcer or gastritis in different countries. This variation in CagA and VacA frequency may be due to the capability of this bacterium to be genetically versatile and can alter the expression of these genes with geographic diversity. Although H. pylori infection is not usually associated with any clinical symptoms, but sometimes leads to inflammation in gastrointestinal system and resulted in peptic ulcer and gastric cancer. In this regard, this review will illustrate the importance of Helicobacter pylori in pathogenesis of gastrointestinal disorders with focusing on CagA and VacA virulence factors.