Polymorphism in the promoter region of the SERT gene can influence the expression of SERT mRNA and the levels of the SERT protein in the colonic mucosa, thereby playing a key role in motility-related symptoms of IBS patients.

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Background: Diabetes is a risk factor for cardiovascular disorders. TGR5 levels are increased in cardiomyocytes exposed to hyperglycaemia. The objective of this study was to investigate the potential mechanism(s) for the increase in TGR5 levels in the hearts of diabetic rats. Materials and methods:We used streptozotocin -induced diabetic rats (STZ rats) to assess the role of hyperglycaemia in increased cardiac TGR5 levels. The expression levels of TGR5 and signal transducer and activator of transcription 3, both its phosphorylated form (p-STAT3) and its native form (STAT3), in heart tissues were measured using Western blots. Results:The increased levels of TGR5 and the ratio of p-STAT3 to STAT3 in cardiac tissues exposed to hyperglycaemic conditions were reversed by treating the hyperglycaemia. Additionally, the potential mechanisms of this effect were confirmed in a cultured rat cardiac cell line (H9c2) incubated in high-glucose (HG) medium to mimic the changes observed in vivo. TGR5 expression increased in parallel with the increased ratio of p-STAT3 and STAT3 in H9c2 cells exposed to HG, and these effects were reversed by treatment with stattic at a dose sufficient to inhibit STAT3. Similarly, the antioxidant tiron also produced the same effects in H9c2 cells. Conclusion:Increased cardiac TGR5 levels in a type-1 diabetes model were related to hyperglycaemia, which produces free radicals to activate STAT3 for the higher expression of TGR5 in the heart. Therefore, an elevation in circulating bile acids from hepatic disorders and/or others shall be handled carefully in diabetic patients.

Objective Irritable bowel syndrome (IBS) is characterized by abdominal pain, bloating, and stool irregularity. However, its pathophysiological mechanisms, which trigger intestinal motility disorders and diarrhea leading to diarrhea-predominant IBS (D-IBS), remain largely unknown. Methods In the present study, we established a D-IBS rat model by mother–infant separation combined with restraint stress. Then we exposed the modelled rats to suberoylanilide hydroxamic acid (SAHA) treatment, followed by determination of their visceral sensitivity. Toluidine blue staining served to reveal the effects of SAHA treatment on mast cells of D-IBS model rats. Then we measured the expression of serotonin (5-hydroxytryptamine; 5-HT) and its receptors by ELISA. Results Construction of short hairpin RNA (sh)-serotonin transporter (SERT) lentivirus vectors verified the regulation of the 5-HT signaling pathway by phosphorylated (p)-STAT/SERT. SAHA treatment of D-IBS model rats reduced the fecal water content, electromyography integral change rate, abdominal withdrawal reflex score, and number of mast cells, as well as the expression of 5-HT type 3A (5-HT3AR), 3B receptor (5-HT3BR), and 4 receptor (5-HT4R) receptors. The treatment also elevated the expression of signal transducer and activator for transcription 3 (STAT3) and SERT. Activation of p-STAT3 may reverse the inhibitory effect of SAHA on the elevated visceral sensitivity of D-IBS model rats. Moreover, SAHA promoted the transcription of SERT through repression of the p-STAT3/5-HT signaling, thereby inhibiting the visceral sensitivity of D-IBS model rats. Conclusion This study highlights that SAHA treatment can alleviate D-IBS through regulation of the p-STAT3/SERT/5-HT signaling pathway.

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