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Reports have indicated that autoimmune bowel disorders affect an increasing number of people on every continent; therefore, it is important to better understand inflammatory bowel disease (IBD) and to explore new treatment options for patients suffering from it. Research has indicated the important role of enterocytes in IBD. Understanding the role of the intestinal epithelium in the pathogenesis of IBD may contribute to a better understanding of the inflammatory processes and aid in the identification of potential therapeutic treatments. The present study aimed to evaluate the effects of tofacitinib on Caco-2 cells cultured in an inflammatory environment induced using cytokines naturally found in patients with ulcerative colitis. Tofacitinib is an orally administered inhibitor of Janus kinases (JAKs) which, by modifying the JAK/STAT signaling pathway, reduces the effect of inflammatory cytokines in the gut. Caco-2 cells were used to model the intestinal epithelium and the culture conditions included the proinflammatory cytokine TNFα and tofacitinib. At the end of the culture period, enzymes involved in oxidative stress (superoxide dismutase 1, catalase, nicotinamide adenine dinucleotide phosphate), a marker of apoptosis (Bcl-2) and a key player in intracellular inflammatory signaling (nuclear factor κB) were assessed by quantitative PCR and western blotting. The in vitro phenotype of Caco-2 cells exposed to an inflammatory environment was observed to be similar to that observed in ulcerative colitis. Notably, tofacitinib was able to improve TNFα-induced changes in an in vitro model of ulcerative colitis, and a reduction in the activity of enzymes associated with oxidative stress was observed. In addition, tofacitinib-induced upregulation of Bcl-2 and claudin-1 may contribute to the beneficial effects of tofacitinib on the intestinal epithelium. Tofacitinib appears to have a protective effect on Caco-2 cells. Notably, in the present study, exposure to TNFα stimulated oxidative stress and apoptotic effects, and disrupted intercellular connectivity. The addition of tofacitinib decreased the activity of the examined parameters of oxidative and apoptotic stress, while increasing the activity of the parameter examined to evaluate the degree of intercellular connections. In conclusion, the inhibitory effects of tofacitinib on oxidative stress, as well as its anti-apoptotic and regenerative effects, provide important information regarding the positive effect of tofacitinib on Caco-2 cells, and therefore constitute potential information about the beneficial effect of the evaluated drug in UC. [ABSTRACT FROM AUTHOR]

GLP-1 agonists such as exenatide and liraglutide are novel drugs for the treatment of diabetes and obesity. While improvements in glycemic control can rely on an incretin effect, the mechanisms behind the loss of weight following therapy have yet to be completely elucidated, and seem to be associated with alterations in eating habits, resulting from changes in cytokines e.g. interleukin 1β (IL-1β) and oxidative signaling in the central nervous system (CNS). Increased levels of IL-1β and reactive oxygen species have been demonstrated to exert anorexigenic properties, and astrocytes appear to actively participate in maintaining the integrity of the CNS, which includes the paracrine secretion of inflammatory cytokines and involvement in the redox status. Therefore, the present study decided to explore the influence of exenatide [a glucagon-like peptide 1 (GLP-1 agonist)] on inflammatory and oxidative stress markers in cultured human astrocytes as a potential target for weight reduction therapies. In an experimental setting, normal human astrocytes were subjected to various glycemic conditions, including 40 mg/dl-hypoglycemic, 100 mg/dl-normoglycemic and 400 mg/dl-hyperglycemic, and exenatide, which is a GLP-1 agonist. The involvement of intracellular signaling by a protein kinase A (PKA) in the action of exenatide was estimated using a specific PKA inhibitor-PKI (14–22). The expression levels of IL-1β, nuclear factor kappa κB (NFκB), glial-fibrillary acidic protein (GFAP), p22 NADPH oxidase, glutathione peroxidase, catalase, superoxide dismutase 1, and reactive oxidative species were measured. The present study demonstrated that varying glucose concentrations in the culture media did not affect the protein expression or the level of reactive oxygen species. Conversely, exenatide led to an increase in IL-1β in normoglycemic culture conditions, which was accompanied by the increased expression of p22, glutathione peroxidase and the reduced expression of GFAP. Changes in the expression of IL-1β and p22 were dependent on the activation of PKA. The present study concluded that exenatide predominantly affected astrocytes in normoglycemic conditions, and hypothesize that this impact demonstrated one of novel mechanisms associated with astrocyte signaling that may contribute to weight loss. [ABSTRACT FROM AUTHOR]