Sitagliptin Mitigates Diabetic Nephropathy in a Rat Model of Streptozotocin-Induced Type 2 Diabetes: Possible Role of PTP1B/JAK-STAT Pathway.

Diabetic nephropathy (DN) is a microvascular complication of diabetes mellitus. This study examined the therapeutic effects of sitagliptin, a dipeptidyl peptidase inhibitor, on DN and explored the underlying mechanism. Male Wistar albino rats (n = 12) were intraperitoneally administered a single dose of streptozotocin (30 mg/kg) to induce diabetes. Streptozotocin-treated and untreated rats (n = 12) were further divided into normal control, normal sitagliptin-treated control, diabetic control, and sitagliptin-treated diabetic groups (n = 6 in each). The normal and diabetic control groups received normal saline, whereas the sitagliptin-treated control and diabetic groups received sitagliptin (100 mg/kg, p.o.). We assessed the serum levels of DN and inflammatory biomarkers. Protein tyrosine phosphatase 1 B (PTP1B), phosphorylated Janus kinase 2 (P-JAK2), and phosphorylated signal transducer activator of transcription (P-STAT3) levels in kidney tissues were assessed using Western blotting, and kidney sections were examined histologically. Sitagliptin reduced DN and inflammatory biomarkers and the expression of PTP1B, p-JAK2, and p-STAT3 (p < 0.001) and improved streptozotocin-induced histological changes in the kidney. These results demonstrate that sitagliptin ameliorates inflammation by inhibiting DPP-4 and consequently modulating the PTP1B-related JAK/STAT axis, leading to the alleviation of DN.

Inflammation and Treatment-Resistant Depression from Clinical to Animal Study: A Possible Link?

The aim of this study was to investigate the relationship between treatment-resistant depression (TRD) and inflammation in humans and experimental models. For the human study, a retrospective cohort study was conducted with 206 participants; half were on antidepressants for major depressive disorder. The patients were divided into healthy and depressed groups. Inflammation was assessed based on the values of the main inflammatory biomarkers (CRP, WBC and ESR). For the animal experiments, 35 adult male Wistar rats were assigned to stressed and non-stressed groups. Inflammation and stress were induced using lipopolysaccharide and chronic unpredictable mild stress. A 10 mg/kg intraperitoneal injection of fluoxetine (FLX), a known antidepressant, was simultaneously administered daily for 4 weeks. Behavioral tests were performed. The plasma levels of inflammatory and stress biomarkers were measured and were significantly higher in the stressed and non-responsive groups in both studies. This study provides evidence of the link between inflammation and TRD. We further observed a possible link via the Phosphorylated Janus Kinase 2 and Phosphorylated Signal Transducer and Activator of Transcription 3 (P-JAK2/P-STAT3) signaling pathway and found that chronic stress and high inflammation hinder the antidepressant effects of FLX. Thus, non-response to antidepressants could be mitigated by treating inflammation to improve the antidepressant effect in patients with TRD.