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 establish an index that can reflect the level of healthy aging promotion in a region.Methods:Establish an indicators system using expert consultation and then determine the weight for each indicator using the analytic hierarchy process. Finally, we can get the regional healthy aging promotion index.Results:Regional healthy aging promotion indicator system was established, including five first-level indicators (residence environment, medical service, public health, nurse and care, and supporting system) and 21 second-level indicators. The weight of every level-one indicator ranges from 0.073 to 0.346. Two indicators with the highest weight are residence environment and public health (0.346 and 0.325, respectively), while the indicator with the lowest weight is nurse and care (0.073). The importance of every level-two indicator ranges from 0.011 to 0.162. The consistency ratio of the regional healthy aging promotion index is 0.021, and the consistency test is qualified.Conclusion:Regional healthy aging promotion index established in this study is very scientific, reasonable, and applicable. It can be used to evaluate the region's situation or level of healthy aging promotion.

[ ABSTRACT] AIM:To investigate the expression of calprotectin ( CALP) in the rats with renal ischemia-reperfu-sion injury ( IRI) .METHODS:Male Sprague-Dawley rats were randomly divided into sham operation and IRI group ( n=25 in each group) .Blood samples and the kidneys were obtained at 6 h, 12 h, 24 h, 48 h and 72 h after reperfusion.The pathological changes of the kidneys were observed.The serum concentrations of blood urea nitrogen ( BUN) and serum cre-atinine (SCr) were measured.The serum levels of CALP, tumor necrosis factor-α(TNF-α) and interleukin-6 (IL-6) were detected by ELISA, and the expression of CALP, Toll-like receptor 4 ( TLR4) and NF-κB p65 in the renal tissues were de-termined by the methods of immunohistochemistry and Western blot.RESULTS: Different serial ischemia changes were observed in the renal tissues, mainly in the renal tubular epithelial cells and the mesenchyma, with the infiltration of in-flammatory cells.The serum levels of BUN, SCr, CALP, TNF-αand IL-6 in IRI group were markedly increased as com-pared with sham group (P<0.05).The protein expression of CALP, TLR4 and NF-κB p65 in the renal tubular epithelial cells in IRI group was greatly enhanced in comparison with that in sham group ( P<0.05) .CONCLUSION:The serum concentrations of CALP, TNF-αand IL-6, and the protein expression levels of CALP, TLR4 and NF-κB p65 in the renal tissue are significantly increased in the rats with IRI, suggesting that calprotectin plays an important role in the inflamma-tion in rats with IRI.

[ ABSTRACT] AIM:To investigate the role of the Notch pathway in Toll-like receptor 4 ( TLR4 )-mediated in-flammatory response in renal ischemia reperfusion injury ( IRI) in rats.METHODS: A total of 75 male sprague-Dawley rats were randomly divided into sham operation group , IRI group and DAPT treatment group .Blood samples and the kid-neys were obtained at 6 h, 12 h, 24 h, 48 h and 72 h after reperfusion .The concentrations of blood urea nitrogen ( BUN) and serum creatinine (Scr) were measured.The serum levels of tumor necrosis factor-α(TNF-α) and interleukin-6 (IL-6) were detected by ELISA, and the expression of Notch1, TLR4 and NF-κB p65 in the renal tissues was assessed by im-munohistochemistry and Western blot .RESULTS: The serum levels of BUN, Scr, TNF-αand IL-6 in IRI group were markedly increased as compared with sham group (P<0.05).The protein levels of Notch1, TLR4 and NF-κB p65 in re-nal tubular epithelial cells in IRI group was significantly enhanced as compared with sham group ( P<0.05 ) .In DAPT group, the serum levels of BUN, Scr, TNF-αand IL-6 were significantly reduced compared with IRI group (P<0.05), and the protein levels of Notch1, TLR4 and NF-κB p65 were apparently less than those in IRI group (P<0.05).CON-CLUSION:Significant changes of renal function , a rise of serum inflammatory factor including TNF-αand IL-6 and en-hanced expression of Notch 1, TLR4 and NF-κB p65 in the renal tissue occurred in the rats with IRI .γ-Secretase inhibitor DAPT attenuates TLR4-mediated inflammatory response in the renal IRI through the inhibition of Notch 1 and down-regula-tion of NF-κB.

Objective To investigate the influence of pre-administration of flurbiprofen on the hyperalgesia after remifentanil anesthesia.Methods This study included a total of 96 patients with abdominal surgery in the department of general surgery of our hospital.According to the random number table method,they were divided into 4 groups (n =24).Flurbiprofen axetil 1.5 mg/kg was injected intravenously before anesthesia in groups A1 and A2,flurbiprofen axetil was not injected in-travenously before anesthesia in groups B1 and B2.Anesthesia was maintained with infusion of remifentanil 0.1 μg·kg-1 ·min-1 in groups A1 and B1 0.4 μg·kg-1 ·min-1 in groups A2 and B2. The spontaneous breathing recovery time, consciousness recovery time,extubation time and anesthesia recover period of nausea,vomiting,restlessness and pain VAS scores were recorded. Results There was no significant difference in breath recovery time,consciousness recovery time and extubation time between the four groups.VAS score (9.0±1.8)was the highest in group B2,VAS score was significantly higher than the other three groups (P <0.05).VAS score (3.1±1.1)was the lowest in group A1, which was significantly lower than the other three groups (P < 0.05 ). Conclusion Pre-application of flurbiprofen 1.5 mg/kg can reduce postoperative hyperalgesia after remifentanil anesthesia in patients undergoing abdominal surgery.