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

Cells and exosomes derived from them are extensively used as biological carrier systems. Cells demonstrate superior targeting specificity and prolonged circulation facilitated by their rich array of surface proteins, while exosomes, due to their small size, cross barriers and penetrate tumors efficiently. However, challenges remain, cells' large size restricts tissue penetration, and exosomes have limited targeting accuracy and short circulation times. To address these challenges, we developed a novel concept termed exosomal spheres. This approach involved incorporating platelet-derived exosomes shielded with phosphatidylserine (PS) and linked via pH-sensitive bonds for drug delivery applications. The study demonstrated that, compared with exosomes, the exosomal spheres improved blood circulation through the upregulation of CD47 expression and shielding of phosphatidylserine, thereby minimizing immune clearance. Moreover, the increased expression of P-selectin promoted adhesion to circulating tumor cells, thereby enhancing targeting efficiency. Upon reaching the tumor site, the hydrazone bonds of exosome spheres were protonated in the acidic tumor microenvironment, leading to disintegration into uniform-sized exosomes capable of deeper tumor penetration compared to platelets. These findings suggested that exosome spheres addressed the challenges and offered significant potential for efficient and precise drug delivery.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease lacking effective therapy. Metformin, an antidiabetic medication, has shown promising therapeutic properties in preclinical fibrosis models; however, its precise cellular targets and associated mechanisms in fibrosis resolution remain incompletely defined. Most research on metformin's effects has focused on mesenchymal and inflammatory responses with limited attention to epithelial cells. In this study, we utilized Sftpc lineage-traced and Fgfr2b conditional knockout mice, along with BMP2/PPARγ and AMPK inhibitors, to explore metformin's impact on alveolar epithelial cells in a bleomycin-induced pulmonary fibrosis model and cell culture. We found that metformin increased the proliferation and differentiation of alveolar type 2 (AT2) cells, particularly the recently identified injury-activated alveolar progenitors (IAAPs)-a subpopulation characterized by low SFTPC expression but enriched for PD-L1. Single-cell RNA sequencing revealed a reduction in apoptosis among mature AT2 cells. Interestingly, metformin's therapeutic effects were not significantly affected by BMP2 or PPARγ inhibition, which blocked the lipogenic differentiation of myofibroblasts. However, Fgfr2b deletion in Sftpc lineage cells significantly impaired metformin's ability to promote fibrosis resolution, a process linked to AMPK signaling. In conclusion, metformin alleviates fibrosis by directly activating AT2 cells, especially the IAAPs, through a mechanism that involves AMPK and FGFR2b signaling, but is largely independent of BMP2/PPARγ pathways.

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*

The second plenary session of the 20th Central Commission for Discipline Inspection proposed the"develop-ment of a five-year plan for information technology construction to establish a digital disciplinary inspection and supervision system that covers the entire process and all elements."This provides guidance and momentum for disciplinary inspection agencies at all levels to implement the strategic deployment of the Party's 20th National Congress regarding comprehensive and strict governance of the Party.In this context,utilizing information technology to enhance the efficiency of supervision,discipline enforcement,and accountability while ensuring the high-quality development of public hospitals has become a key task for their disciplinary inspec-tion departments.The Disciplinary Inspection Commission of a public hospital has explored the establishment of a disciplinary in-spection management platform to achieve modular management of inspection tasks.By utilizing functions such as task allocation,statistical analysis,data migration,and early warning reminders,the platform aims to improve the efficiency of disciplinary in-spection work.This approach helps address the challenges of heavy workloads and limited inspection resources in hospitals,enab-ling real-time supervision,early warning correction,and time-bound oversight,thereby providing strong support for the construc-tion of integrity in the hospital.

Objective To address the challenges of poor performance and lack of interpretability in existing models,the SHAP algorithm is used to develop an interpretable machine learning model that offers a novel approach to wound age estimation,Methods Based on the previous discovery of the expression of 35 wound age healing-related genes in contused skeletal muscle,the woun age estimaton model was constructed using four algorithms,namly,Multilayer Perceptron(MLP),Random Forest(RF),LightGBM(LGBM),and Support Vector Machine(SVM).The SHAP(Shapley Additive Explanation)algorithm was used to rank the importance of genetic features,eliminate redundant attributes,and optimize the model for accurate wound age estimation.the genetic features of the optimal model were analyzed using SHAP's local interpretation capabilities.Results The best results were obtained using model of MLP(area under the curve(AUC)=0.99)The wound ages were classified into four categories:4～12 h,16～24 h,28～36 h,and 40～48 h,using only 15 gene features.According to SHAP analysis,Fam210a was identified as the most relevant gene.Local analysis revealed that high expression of Fam210a contributed to an increase in the predicted probability of 4 h～12 h,while high expression of Rae1 contributed to an increase in the predicted probability of 16 h～24 h.Additionally,low expression of Tbx18 contributed to an increase in the predicted probability of 28 h～36 h,whereas high expression of Tbx18 contributed to an increase in the predicted probability of 40 h～48 h.Conclusions The combined MLP and SHAP model can be used to predict wound age.Using the SHAP interpreter can better understand the degree of contribution of feature genes to the model prediction,and lay the foundation for further in-depth study of wound age estimation.

Objective To explore the photodynamic treatment method and therapeutic effect of oral verrucous carci-noma and to provide a reference for the clinic.Methods This study follows the requirements of medical ethics.This paper summarized the photodynamic treatment of an oral verrucous carcinoma with a diameter of approximately 2.5 cm in the right buccal mucosa and retrospectively analyzed the characteristics and treatment of oral verrucous carcinoma and the photodynamic treatment of potential malignant lesions of the oral mucosa through a review of the literature.Results After four rounds of photodynamic therapy,the size of the right buccal lesion was significantly reduced.After 6 months of follow-up,the white verrucous hyperplasia of the right buccal mucosa had completely subsided,and there was no obvious scar formation.Three years after treatment,there was no recurrence of the lesion in the right buccal mu-cosa and no obvious scar formation in the treated area.The degree of mouth opening was 3 fingers,and there was no lymph node enlargement in the bilateral submandibular,submental or neck.The literature review shows that oral verru-cous carcinoma is a rare subtype of squamous cell carcinoma with the characteristics and biological behaviors of slow growth,low malignancy,and rare metastasis.Surgery is the preferred treatment,but there are some limitations.Photody-namic therapy is a minimally invasive,repeatable treatment with mild adverse reactions.In recent years,photodynamic therapy has been gradually applied for the treatment of potential malignant disorders of the oral mucosa and early oral squamous cell carcinoma and has achieved positive results,but it has not been reported for the treatment of oral verru-cous cancer.Conclusion Photodynamic therapy is a new option for nonsurgical resection of oral verrucous carcinoma.

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

Objective To explore the effects and mechanisms of deoxycholic acid(DCA)on oxidative stress in human BAR-T cells.Methods The human Barrett epithelial cell line BAR-T was cultured in vitro,and the BAR-T cells were intervened with different concentrations of DCA(100,200,and 300 μmol/L)and different action time(30 min,60 min,3 h and 6 h).The mRNA and protein expression of COX-2 were detected by Real-time PCR and Western blotting assay.The intracellular reactive oxygen species(ROS)content was detected by direct microscope observation and flow cytometry,and was compared with that of 200 μmol/L DCA+5 mmol/L NAC(ROS scavenger N-acetylcysteine)group;cellular immunofluorescence was used to detect the entry of cellular p65 protein into the nucleus,which was then compared with 200 μmol/L DCA+PDTC(100 μmol/L,NF-κB pathway inhibitor)group.Results Compared to the control group,DCA increased ROS content in BAR-T cells in a dose-dependent manner.Additionally,5 mmol/L NAC significantly inhibited DCA-induced ROS release.Furthermore,both 200 μmol/L and 300 μmol/L DCA significantly increased COX-2 mRNA expression compared to the control group at the same intervention time.The 6 h groups for both 200 μmol/L and 300 μmol/L DCA showed a significant increase in COX-2 mRNA expression compared to the 1 h group.Compared to the control group,treatment with 200 μmol/L DCA significantly increased the expression of COX-2 protein.Meanwhile,200 μmol/L DCA promoted the nucleation of p65 protein,which was inhibited by PDTC.Conclusion DCA activates the NF-κB signaling pathway and upregulates the expression of COX-2 by elevating the intracellular ROS expression and promoting the entry of p65 protein into the nucleus.