DMXB-Anabaseine

Previous research has demonstrated ɑ7nAch receptor (ɑ7nAchR) agonists to provide benefit for rheumatoid arthritis (RA) patients. However, the immunological mechanism of action for these ɑ7nAchR agonists has not been elucidated. Herein, the effect of GTS-21, a selective ɑ7nAchR agonist, on the differentiation of Th17 and Th2 cells was assessed. CD4 + T cells were obtained from the peripheral blood mononuclear cells (PBMCs) of RA patients and healthy donors. CD4 + T cells were separately differentiated into Th2 or Th17 cells with or without GTS-21 and with or without alpha-bungarotoxin (ɑBgt) (a ɑ7nAchR antagonist). The proportions of Th17 and Th2 cells were assessed by flow cytometry. Levels of the T cell cytokines, IL-17A and IL-4, were assessed by ELISA. Specific transcription factors, retinoic orphan receptor c (RORc), and GATA Binding Protein 3 (GATA-3) were detected by western blot. GTS-21 reduced IL-17A and increased IL-4 production by RA PBMCs. GTS-21 reduced the percentage of Th17 cells and increased the percentage of Th2 cells during Th17 and Th2 differentiation, respectively. GTS-21 downregulated RA CD4 + T cells RORc levels and reduced the secretion of IL-17A during Th17 differentiation. GTS-21 upregulated RA CD4 + T cells GATA3 and promoted IL-4 production during Th2 differentiation. ɑ-Bgt blocked the effects of GTS-21 during Th17 and Th2 differentiation. These results demonstrated that GTS-21 suppressed RA Th17 differentiation and promoted Th2 differentiation. As such, the use of GTS-21 may be a new therapeutic approach by which to treat RA patients. Key Points • GTS-21 suppressed RA Th17 differentiation and promoted Th2 differentiation via acting on ɑ7nAchR. • The protective effect of GTS-21 on RA may be related to its regulation of Th cell subsets.

The most common and serious complication among hospitalized and critically ill patients is sepsis-associated acute kidney damage (S-AKI), which raises the risk of comorbidities and is linked to a high mortality rate. Cholinergic anti-inflammatory pathway (CAP), an anti-inflammatory pathway mediated by the vagus nerve, acetylcholine, and α7 nicotinic acetylcholine receptors (α7nAChRs), offers new perspectives for the treatment of S-AKI. In this study, we investigated the role of CAP and α7nAChR in kidney injury by employing an LPS-induced septic kidney injury mouse model and GTS-21 intervention. C57BL/6 mice were injected with LPS, with or without GTS-21, in different subgroups. Kidney function was assessed by plasma creatinine, histology, and markers of kidney injury 24 h after intervention. The results demonstrated that GTS-21 could inhibit the systemic inflammatory response and directly protect the tubular cell injury from LPS. To explore the novel gene involved in this response, RNA sequencing of the renal proximal tubular epithelial cell (HK-2), pretreated with LPS and GTS-21, was conducted. The results indicate that GTS-21 administration reduces LPS-induced cytokines and chemokines secretion by HK-2, including CCL20, a potent chemokine attracting monocytes/macrophages. Furthermore, a macrophage transmigration assay revealed that GTS-21 inhibits macrophage transmigration by downregulating the expression of CCL20 in HK-2 cells. In conclusion, GTS-21, as an α7nAChR agonist, emerges as a noteworthy and versatile treatment for S-AKI. Its dual function of directly protecting renal tubular cells and regulating inflammatory responses represents a major advancement in the treatment of sepsis-induced AKI. This finding might pave the way for novel approaches to improving patient outcomes and reducing death rates in sepsis-related complications.