Tofacitinib restores the balance of gamma delta Treg/gamma delta T17 cells in rheumatoid arthritis by inhibiting the NLRP3 inflammasome
Authors: Yang, Xinyu; Zhan, Ning; Jin, Yang; Ling, Hanzhi; Xiao, Chipeng; Xie, Zhen; Zhong, Hao; Yu, Xinxin; Tang, Runhua; Ma, Jinglan; Guan, Jubo; Yin, Guoyu; Wu, Gan; Lu, Liangjing; Wang, Jianguang
Objective: Tofacitinib (TOF) is a Janus kinase (JAK) inhibitor used in the treatment of rheumatoid arthritis (RA), but the mechanism of its action remains unclear. In this study, we investigated the influence of TOF on gamma delta regulatory T-cell (gamma delta Treg)/gamma delta T17 cell balance in RA and the role of the nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome in this process. Methods: We detected levels of inflammatory factors in the serum of RA patients before and after administration of TOF using an enzyme-linked immunosorbent assay (ELISA). A collagen-induced arthritis (CIA) model was constructed to investigate the effect of TOF on arthritis symptoms, gamma delta Treg/gamma delta T17 cell balance and the NLRP3 inflammasome. We used bone marrow-derived macrophages (BMDMs) to study the effect of TOF on NLRP3 inflammasome activation. Nlrp3(-/-) mice were introduced to assess the influence of NLRP3 on.dT17 cell activation in RA. Results: TOF treatment decreased levels of gamma delta T17 cell-related cytokine interleukin-17 (IL-17) in RA patients. In addition, TOF intervention in the CIA model reduced joint inflammation and damage, rebalanced the gamma delta Treg/gamma delta T17 cell ratio and inhibited excessive NLRP3 inflammasome activation in draining lymph nodes and arthritic joints. BMDM intervention experiments demonstrated that TOF decreased the level of secreted IL-1 beta via downregulation of NLRP3. Furthermore, experiments using Nlrp3(-/-) mice verified that the NLRP3 inflammasome mediated the effect of TOF on gamma delta T17 cell activation. Conclusions: Recovery of gamma delta Treg/gamma delta T17 cell balance was a novel mechanism by which TOF alleviated RA. Meanwhile, NLRP3 played a pivotal role in the process of TOF-mediated gamma delta T17 cell activation.
Anti-hyperglycemic and hypolipidemic effects of Saraca asoca (Roxb.) Wild. flowers in alloxan-treated diabetic rats
JOURNAL OF PHARMACY & PHARMACOGNOSY RESEARCH
Authors: Thilagam, Ellappan; Chidambaram, Kumarappan; Raviteja, Chinthamreddy; Vahana, Thalu; Vasudevan, Parameshwaran
Context: Saraca asoca (Leguminosae) has been widely used in the Ayurvedic system of medicine for various ailments, and it has been used to treat diabetes as a folk medicine. Aims: To investigate the anti-hyperglycemic and anti-hyperlipidemic effect of ethanolic extracts of S. asoca (EESA) flowers in alloxan-induced diabetic rats. Methods: The anti-hyperglycemic activity of EESA was evaluated by using normal and alloxan-induced (120 mg/kg, i.p.) diabetic rats. In the sub-chronic animal model of diabetes mellitus, EESA was orally administered to normal and alloxan-induced-diabetic rats at doses of 200 and 400 mg/ kg p.o. per day for 28 days. Results: Fasting blood glucose (FBG), insulin, glycated hemoglobin (HbA1c) levels, lipid profiles, alkaline phosphatase (ALP), and body weights were monitored at the end of 28 days in the EESA treated diabetic rats. The anti-hyperglycemic effect of EESA was more pronounced at the doses of 200 and 400 mg/ kg in alloxan-treated diabetic rats as compared with vehicle-treated rats. EESA also showed a significant (p<0.05) increase in serum insulin levels and body weights, while there was a significant reduction in the levels of ALP, HbA1c, serum triglyceride and total cholesterol. EESA also showed a significant anti-hyperlipidemic effect, as evidenced by the increased HDL-c level of alloxan-induced diabetic rats. Conclusions: The results of the current investigation indicate that EESA possesses a significant anti-hyperglycemic effect and anti-hyperlipidemic effect.