BACKGROUND: G protein-coupled receptor kinase 2 (GRK2) could participate in the regulation of diverse cells via interacting with non-G-protein-coupled receptors. In the present work, we explored how paroxetine, a GRK2 inhibitor, modulates the differentiation and activation of immune cells in rheumatoid arthritis (RA). METHODS: The blood samples of healthy individuals and RA patients were collected between July 2021 and March 2022 from the First Affiliated Hospital of Anhui Medical University. C57BL/6 mice were used to induce the collagen-induced arthritis (CIA) model. Flow cytometry analysis was used to characterize the differentiation and function of dendritic cells (DCs)/T cells. Co-immunoprecipitation was used to explore the specific molecular mechanism. RESULTS: In patients with RA, high expression of GRK2 in peripheral blood lymphocytes, accompanied by the increases of phosphatidylinositol 3 kinase (PI3K), protein kinase B (AKT), and mammalian target of rapamycin (mTOR). In animal model, a decrease in regulatory T cells (T regs ), an increase in the cluster of differentiation 8 positive (CD8 + ) T cells, and maturation of DCs were observed. Paroxetine, when used in vitro and in CIA mice, restrained the maturation of DCs and the differentiation of CD8 + T cells, and induced the proportion of T regs . Paroxetine inhibited the secretion of pro-inflammatory cytokines, the expression of C-C motif chemokine receptor 7 in DCs and T cells. Simultaneously, paroxetine upregulated the expression of programmed death ligand 1, and anti-inflammatory cytokines. Additionally, paroxetine inhibited the PI3K-AKT-mTOR metabolic pathway in both DCs and T cells. This was associated with a reduction in mitochondrial membrane potential and changes in the utilization of glucose and lipids, particularly in DCs. Paroxetine reversed PI3K-AKT pathway activation induced by 740 Y-P (a PI3K agonist) through inhibiting the interaction between GRK2 and PI3K in DCs and T cells. CONCLUSION Paroxetine exerts an immunosuppressive effect by targeting GRK2, which subsequently inhibits the metabolism-related PI3K-AKT-mTOR pathway of DCs and T cells in RA.
G-Protein-Coupled Receptor Kinase 2/metabolism* ; Arthritis, Rheumatoid/immunology* ; Animals ; Dendritic Cells/metabolism* ; Paroxetine/therapeutic use* ; Proto-Oncogene Proteins c-akt/metabolism* ; Mice ; Humans ; Mice, Inbred C57BL ; Signal Transduction/drug effects* ; Male ; Phosphatidylinositol 3-Kinases/metabolism* ; Lymphocyte Activation/drug effects* ; Female ; T-Lymphocytes/metabolism* ; Middle Aged

Objective To investigate the association of PR gene exon 5 region H770H (rs1042839) single nucleotide polymorphism (SNP) with the genetic susceptibility to endometriosis (EM) in southern Han Chinese women. Methods Totally 431 EM patients and 499 non-EM women were collected and separated into EM group and control group, that all cases were confirmed by operation and pathology. A case-control study was performed in EM and control groups to evaluate the association of these SNP with the susceptibility to EM by using a fluorescent quantitative PCR-based high resolution melting (HRM) method. Results The C and T of PR H770H allele frequencies among the EM and control groups were 97.9%(844/862), 2.1% (18/862) and 99.4% (992/998), 0.6% (6/998), respectively. The CC, CT and TT of PR H770H genotype frequencies among the EM and control groups were 95.8%(413/431), 4.2%(18/431), 0 and 98.8%(493/499), 1.2%(6/499), 0, respectively. There were statistical significances in the PR H770H alleles and genotypes distributions between the two groups (χ2=7.386, P=0.007;χ2=8.135, P=0.004). Carrying allele C reduced the risk of EM (OR=0.986, 95%CI: 0.976-0.996), while carrying allele T enhanced the risk of EM (OR=3.319, 95%CI: 1.323-8.325); carrying genotype CC reduced the risk of EM 0.970 time (OR=0.970, 95%CI: 0.949-0.991), whereas carrying genotype CT enhanced the risk of EM 3.473 times (OR=3.473, 95%CI:1.391-8.671). Conclusion There is significant association between the polymorphism of PR H770H and genetic susceptibility to EM in southern Han Chinese women.

Objective To evaluate the effectiveness of anus misoprostol for cervial dilation for menopausal women in hysteroscopy.Methods 86 menopausal women before hysteroscopy were divided into two groups.The misoprostol group(46 cases) were handled with misoprostal through anus.The control group(40 cases) were injected with lidocaine through cervix.Results Compared with the control group,the effective cervial dilatation rate of misoprostol groupwas significantly higher,and the incidence of abortion syndrome was lower.Conclusion Anus misoprostol can significantly facilitate cervial dilation in menopausal women before hysteroscopy.