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

Cemental tear is a rare and indetectable condition unless obvious clinical signs present with the involvement of surrounding periodontal and periapical tissues. Due to its clinical manifestations similar to common dental issues, such as vertical root fracture, primary endodontic diseases, and periodontal diseases, as well as the low awareness of cemental tear for clinicians, misdiagnosis often occurs. The critical principle for cemental tear treatment is to remove torn fragments, and overlooking fragments leads to futile therapy, which could deteriorate the conditions of the affected teeth. Therefore, accurate diagnosis and subsequent appropriate interventions are vital for managing cemental tear. Novel diagnostic tools, including cone-beam computed tomography (CBCT), microscopes, and enamel matrix derivatives, have improved early detection and management, enhancing tooth retention. The implementation of standardized diagnostic criteria and treatment protocols, combined with improved clinical awareness among dental professionals, serves to mitigate risks of diagnostic errors and suboptimal therapeutic interventions. This expert consensus reviewed the epidemiology, pathogenesis, potential predisposing factors, clinical manifestations, diagnosis, differential diagnosis, treatment, and prognosis of cemental tear, aiming to provide a clinical guideline and facilitate clinicians to have a better understanding of cemental tear.
Humans ; Dental Cementum/injuries* ; Consensus ; Diagnosis, Differential ; Cone-Beam Computed Tomography ; Tooth Fractures/therapy*

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Objective To evaluate the impact of ultra-high-molecular-weight polyethylene(UHMWPE)-Ribbond fi-bers,when combined with different restorative materials,on fracture resistance and marginal adaptation of isolated pri-mary molar defects,to provide a reference for clinical practice.Methods This study was approved by the Ethics Re-view Committee.A total of 72 extracted primary molars with complete crowns were collected,and 66 primary molars were randomly assigned as experimental groups for the fracture resistance and microleakage tests.The molars were di-vided into six groups(n=11)based on the type of restorative materials and the application of Ribbond fibers:Group A1,3M Filtek Z250+Ribbond;Group A2,3M Filtek Z250;Group B1,Beautifil Ⅱ LS+Ribbond;Group B2,Beautifil Ⅱ LS;Group C1,3M Filtek Bulk Fill+Ribbond;and Group C2,3M Filtek Bulk Fill.Groups A1,B1 and C1 received the fiber-reinforcing technique,whereas Groups A2,B2 and C2 received the direct restorative technique;the remainings were in Group D(blank control group),which did not receive treatment for the fracture resistance test.The fracture re-sistance test was divided into six experimental groups and one blank control group(n=6).Primary molar teeth in each experimental group were prepared with Class Ⅱ cavities and filled.The fracture load of all samples was detected,and the fracture mode was analyzed after thermal cycling.The microleakage test was divided into six experimental groups,with five in each group.Class Ⅰ cavities with a diameter of 3 mm and depth of 2.5 mm were prepared within the mesial and distal marginal ridges on the occlusal surface and filled for primary molars in each group.Marginal microleakage was assessed after thermal cycling.Results The fracture resistance test results showed that the fracture resistance in groups that received the fiber-reinforcing technique was greater than that in groups that received the direct restorative technique:Group A1>Group A2,Group B1>Group B2,Group C1>Group C2(P<0.05).The application of Ribbond fibers increased fracture resistance to all tested restorative materials by 37.08％to 39.34％.The proportion of tooth frac-ture decreased significantly in groups A1,C1 compared with A2,C2,with a significant increase in the occurrence rate of"Repairable"(P<0.05).The fracture resistance in Group A1 was significantly greater than that in Group B1 and Group C1(P<0.05).The marginal microleakage test results showed that the microleakage depth in groups that received the fiber-reinforcing technique was smaller than that in groups that received the direct restorative technique:Group A1

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with unclear etiology and limited treatment options. The median survival time for IPF patients is approximately 2-3 years and there is no effective intervention to treat IPF other than lung transplantation. As important components of lung tissue, endothelial cells (ECs) are associated with pulmonary diseases. However, the role of endothelial dysfunction in pulmonary fibrosis (PF) is incompletely understood. Sphingosine-1-phosphate receptor 1 (S1PR1) is a G protein-coupled receptor highly expressed in lung ECs. Its expression is markedly reduced in patients with IPF. Herein, we generated an endothelial-conditional S1pr1 knockout mouse model which exhibited inflammation and fibrosis with or without bleomycin (BLM) challenge. Selective activation of S1PR1 with an S1PR1 agonist, IMMH002, exerted a potent therapeutic effect in mice with bleomycin-induced fibrosis by protecting the integrity of the endothelial barrier. These results suggest that S1PR1 might be a promising drug target for IPF therapy.

With the global increase in the prevalence of allergic diseases and the rising life expectancy, it is anticipated that the number of elderly patients affected by allergies will also increase. While it was previously believed that allergies primarily affected children and adolescents and diminished with age, epidemiological studies indicate a growing prevalence of allergies in the elderly. Various allergic diseases have similar prevalence rates in the elderly as in the general population, and some, like drug allergies, are even more prevalent in this age group. Allergic diseases in the elderly often present with atypical symptoms, leading to challenges in differential diagnosis and treatment. This paper discusses immunosenescence and the distinct features of allergic diseases in older individuals. The goal is to raise awareness among healthcare providers about allergies in older adults, encourage preventive measures, and improve the quality of life for elderly patients with allergies. By managing allergies better, it can also help with the management of other chronic diseases in the elderly and contribute to better overall health for everyone.

With the global increase in the prevalence of allergic diseases and the rising life expectancy, it is anticipated that the number of elderly patients affected by allergies will also increase. While it was previously believed that allergies primarily affected children and adolescents and diminished with age, epidemiological studies indicate a growing prevalence of allergies in the elderly. Various allergic diseases have similar prevalence rates in the elderly as in the general population, and some, like drug allergies, are even more prevalent in this age group. Allergic diseases in the elderly often present with atypical symptoms, leading to challenges in differential diagnosis and treatment. This paper discusses immunosenescence and the distinct features of allergic diseases in older individuals. The goal is to raise awareness among healthcare providers about allergies in older adults, encourage preventive measures, and improve the quality of life for elderly patients with allergies. By managing allergies better, it can also help with the management of other chronic diseases in the elderly and contribute to better overall health for everyone.

Objective: To assess the effectiveness of transanal drainage tube (TDT) in reducing the incidence of anastomotic leak following anterior resection in patients with rectal cancer. Methods: We conducted a systematic search for relevant studies published from inception to October 2022 across multiple databases, including PubMed, Embase, Web of Science, Cochrane Library, CNKI, Wanfang, and VIP. Meta-analysis was performed using Review Manager 5.4 software. The primary outcomes included total incidence of anastomotic leak, grade B and C anastomotic leak rates, reoperation rate, anastomotic bleeding rate, and overall complication rate. Results: Three randomized controlled trials involving 1115 patients (559 patients in the TDT group and 556 in the non-TDT group) were included. Meta-analysis showed that the total incidences of anastomotic leak and of grade B anastomotic leak were 5.5% (31/559) and 4.5% (25/559), respectively, in the TDT group and 7.9% (44/556) and 3.8% (21/556), respectively, in the non-TDT group. These differences are not statistically significant (P=0.120, P=0.560, respectively). Compared with the non-TDT group, the TDT group had a lower incidence of grade C anastomotic leak (1.6% [7/559] vs. 4.5% [25/556]) and reoperation rate (0.9% [5/559] vs. 4.3% [24/556]), but a higher incidence of anastomotic bleeding (8.2% [23/279] vs. 3.6% [10/276]). These differences were statistically significant (P=0.003, P=0.001, P=0.030, respectively). The overall complication rate was 26.5%(74/279) in the TDT group and 27.2% (75/276) in the non-TDT group. These differences are not statistically significant (P=0.860). Conclusions: TDT did not significantly reduce the total incidence of anastomotic leak but may have potential clinical benefits in preventing grade C anastomotic leak. Notably, placement of TDT may increase the anastomotic bleeding rate.
Humans ; Anastomotic Leak/etiology* ; Rectal Neoplasms/complications* ; Drainage ; Anastomosis, Surgical/adverse effects* ; Reoperation/adverse effects* ; Hemorrhage ; Retrospective Studies

OBJECTIVE: To observe the clinical effect of electroacupuncture at acupoints of yangming meridians for sarcopenia. METHODS: A total of 60 patients with sarcopenia were randomized into an observation group and a control group, 30 cases in each group. In the control group, conventional nutrition intervention for sarcopenia was adopted. In the observation group, on the basis of the treatment in the control group, acupuncture was applied at bilateral Binao (LI 14), Quchi (LI 11), Zusanli (ST 36), Yanglingquan (GB 34), etc.,ipsilateral Quchi (LI 11) and Zusanli (ST 36) were connected to electroacupuncture, with discontinuous wave, 2 Hz in frequency, 1-10 mA in intensity, 2 times a week, with a interval of 3 days. A total of 12-week treatment was required in the two groups. Before and after treatment, the appendicular skeletal muscle mass index (ASMI), grip strength, 6 m-walking time, body fat percentage and body moisture percentage were observed in the two groups. RESULTS: Compared with those before treatment, after treatment, ASMI and grip strength were increased while 6 m-walking time was shortened in the two groups (P<0.05); body fat percentage was decreased while body moisture percentage was increased in the observation group (P<0.05). After treatment, in the observation group, ASMI, grip strength and body moisture percentage were increased (P<0.05), 6 m-walking time was shortened and body fat percentage was decreased (P<0.05) compared with those in the control group. CONCLUSION Electroacupuncture at acupoints of yangming meridians can effectively improve the skeletal muscle mass, muscle function, body fat percentage and body moisture percentage in patients with sarcopenia, and make the distribution of muscle and fat more reasonable.
Humans ; Meridians ; Acupuncture Points ; Electroacupuncture ; Sarcopenia/therapy* ; Acupuncture Therapy

COVID-19 pandemic caused by SARS-CoV-2 infection severely threatens global health and economic development. No effective antiviral drug is currently available to treat COVID-19 and any other human coronavirus infections. We report herein that a macrolide antibiotic, carrimycin, potently inhibited the cytopathic effects (CPE) and reduced the levels of viral protein and RNA in multiple cell types infected by human coronavirus 229E, OC43, and SARS-CoV-2. Time-of-addition and pseudotype virus infection studies indicated that carrimycin inhibited one or multiple post-entry replication events of human coronavirus infection. In support of this notion, metabolic labelling studies showed that carrimycin significantly inhibited the synthesis of viral RNA. Our studies thus strongly suggest that carrimycin is an antiviral agent against a broad-spectrum of human coronaviruses and its therapeutic efficacy to COVID-19 is currently under clinical investigation.