BACKGROUND: Fibrosis of the connective tissue in the vaginal wall predominates in pelvic organ prolapse (POP), which is characterized by excessive fibroblast-to-myofibroblast differentiation and abnormal deposition of the extracellular matrix (ECM). Our study aimed to investigate the effect of ECM stiffness on vaginal fibroblasts and to explore the role of methyltransferase 3 (METTL3) in the development of POP. METHODS: Polyacrylamide hydrogels were applied to create an ECM microenvironment with variable stiffness to evaluate the effects of ECM stiffness on the proliferation, differentiation, and expression of ECM components in vaginal fibroblasts. METTL3 small interfering RNA and an overexpression vector were transfected into vaginal fibroblasts to evaluate the effects of METTL3 silencing and overexpression on matrix stiffness-induced vaginal fibroblast-to-myofibroblast differentiation and abnormal modulation of the ECM. Both procedures were detected by 5-ethynyl-2'-deoxyuridine (EdU) staining, Western blotting (WB), quantitative real-time polymerase chain reaction (RT-qPCR), and immunofluorescence (IF). RESULTS: Vaginal fibroblasts from POP patients exhibited increased proliferation ability, increased expression of α-smooth muscle actin (α-SMA), decreased expression of collagen I/III, and significantly decreased expression of tissue inhibitors of matrix metalloproteinases (TIMPs) in the stiff matrix ( P <0.05). Compared with those from non-POP patients, vaginal wall tissues from POP patients demonstrated a significant increase in METTL3 content ( P <0.05). However, silencing METTL3 expression in vaginal fibroblasts with high ECM stiffness resulted in decreased proliferation ability, decreased α-SMA expression, an increased ratio of collagen I/III, and increased TIMP1 and TIMP2 expression. Conversely, METTL3 overexpression significantly promoted the process of increased proliferation ability, increased α-SMA expression, decreased ratio of collagen I/III and decreased TIMP1 and TIMP2 expression in the soft matrix ( P <0.05). CONCLUSIONS Elevated ECM stiffness can promote excessive proliferation, differentiation, and abnormal ECM modulation, and the expression of METTL3 plays an important role in alleviating or aggravating matrix stiffness-induced vaginal fibroblast-to-myofibroblast differentiation and abnormal ECM modulation.
Humans ; Female ; Extracellular Matrix/metabolism* ; Cell Differentiation/genetics* ; Methyltransferases/metabolism* ; Pelvic Organ Prolapse/pathology* ; Fibroblasts/metabolism* ; Myofibroblasts/metabolism* ; Vagina/metabolism* ; Cell Proliferation/physiology* ; Cells, Cultured ; Middle Aged

Increasing evidence shows that the early lesions of Parkinson's disease (PD) originate from gut, and correction of microbiota dysbiosis is a promising therapy for PD. FLZ is a neuroprotective agent on PD, which has been validated capable of alleviating microbiota dysbiosis in PD mice. However, the detailed mechanisms still need elucidated. Through metabolomics and 16S rRNA analysis, we identified glycoursodeoxycholic acid (GUDCA) was the most affected differential microbial metabolite by FLZ treatment, which was specially and negatively regulated by Clostridium innocuum, a differential microbiota with the strongest correlation to GUDCA production, through inhibiting bile salt hydrolase (BSH) enzyme. The protection of GUDCA on colon and brain were also clarified in PD models, showing that it could activate Nrf2 pathway, further validating that FLZ protected dopaminergic neurons through promoting GUDCA production. Our study uncovered that FLZ improved PD through microbiota-gut-brain axis, and also gave insights into modulation of microbial metabolites may serve as an important strategy for treating PD.

Although enteric glial cell (EGC) abnormal activation is reported to be involved in the pathogenesis of Parkinson's disease (PD), and inhibition of EGC gliosis alleviated gut and dopaminergic neuronal dysfunction was verified in our previous study, the potential role of gut microbiota on EGC function in PD still need to be addressed. In the present study, fecal microbiota transplantation revealed that EGC function was regulated by gut microbiota. By employing 16S rRNA and metabolomic analysis, we identified that 3-indolepropionic acid (IPA) was the most affected differential microbial metabolite that regulated EGC gliosis. The protective effects of IPA on PD were validated in rotenone-stimulated EGCs and rotenone (30 mg/kg i.g. for 4 weeks)-induced PD mice, as indicated by decreased inflammation, improved intestinal and brain barrier as well as dopaminergic neuronal function. Mechanistic study showed that IPA targeted pregnane X receptor (PXR) in EGCs, and inhibition of IL-13Rα1 involved cytokine-cytokine receptor interaction pathway, leading to inactivation of downstream JAK1-STAT6 pathway. Our data not only provided evidence that EGC gliosis was critical in spreading intestinal damage to brain, but also highlighted the potential role of microbial metabolite IPA in alleviating PD pathological damages through gut-brain axis.

[This corrects the article DOI: 10.1016/j.apsb.2025.02.029.].

Objective Summarize domestic and international community health management models and characteristics for elderly hypertensive patients,providing references for the development of community health management in China.Methods Employ literature research to retrieve relevant documents on community health management models for elderly hypertensive pa-tients,and analyze the characteristics and applicability of different models through summarization and comparative analysis.Results In China,community health management models for elderly hypertensive patients include family doctor contracting serv-ices,Hospital-Community-Home health management model,traditional Chinese medicine health management model,"Internet+"health management model,PDCA cycle model,PRECEDE-PROCEED model,and comprehensive community management model.Foreign studies can be categorized into self-management model,Health Rise model,Community Health2(CH2)model,and community pharmacy management model.Conclusion Conducting hypertension health management for elderly patients at the community level is effective,serving as a widely applicable strategy for chronic disease prevention and control.Continued ex-ploration of the scientific and effective aspects of different management models,improving the efficiency and effectiveness of com-munity health management,can contribute more evidence for the formulation of scientific and effective strategies for chronic dis-ease prevention and control.

Objective:To evaluate the medical service quality of psychiatric hospitals in Beijing based on diagnostic related group (DRG), analyze the evaluation effect, for refences to constructe a DRG performance evaluation system suitable for psychiatric hospitals.Methods:This study extracted data such as the number of DRG groups, etc. of hospitalized patients in 14 tertiary and secondary psychiatric hospitals in Beijing from 2018 to 2020 from the Beijing inpatient medical performance evaluation platform, and analyzed data on DRG performance evaluation indicators, as well as the average length of hospital stay and average cost of DRG enrolled cases. All data were analyzed using descriptive research methods, and inter group comparisons were conducted using the Mann Whitney U-test. Results:From 2018 to 2020, the average number of DRG groups in tertiary hospitals (28) was higher than that in secondary hospitals (10) ( P<0.05), and the average CMI values of both were the same(1.79); The average cost consumption index (1.15) of tertiary hospitals was higher than that of secondary hospitals (0.65) ( P<0.05), while the average time consumption index (1.11) was slightly lower than that of secondary hospitals (1.30); The mortality rate of the low-risk group in tertiary hospitals (0.01%) was generally lower than that in secondary hospitals (0.88%), and the average percentage of DRG admitted inpatients (82.8%) was significantly higher than that in secondary hospitals (27.3%) ( P>0.05). The average length of stay and cost per case for DRG enrolled inpatients in tertiary and secondary hospitals were lower than the overall hospital discharge cases ( P<0.05). Conclusions:The number of DRG groups, CMI value, and low-risk mortality rate could be used for evaluating the medical service capacity and safety of psychiatric hospitals, but the cost and time consumption index could not objectively reflect the efficiency of hospital medical services. DRG performance evaluation indicators are more suitable for evaluating short-term hospitalization of psychiatric patients. The proportion of DRG enrolled cases might be a potential indicator for evaluating the service quality of psychiatric hospitals.

Neoadjuvant chemotherapy has become an indispensable weapon against high-risk resectable cancers, which benefits from tumor downstaging. However, the utility of chemotherapeutics alone as a neoadjuvant agent is incapable of generating durable therapeutic benefits to prevent postsurgical tumor metastasis and recurrence. Herein, a tactical nanomissile (TALE), equipped with a guidance system (PD-L1 monoclonal antibody), ammunition (mitoxantrone, Mit), and projectile bodies (tertiary amines modified azobenzene derivatives), is designed as a neoadjuvant chemo-immunotherapy setting, which aims at targeting tumor cells, and fast-releasing Mit owing to the intracellular azoreductase, thereby inducing immunogenic tumor cells death, and forming an in situ tumor vaccine containing damage-associated molecular patterns and multiple tumor antigen epitopes to mobilize the immune system. The formed in situ tumor vaccine can recruit and activate antigen-presenting cells, and ultimately increase the infiltration of CD8⁺ T cells while reversing the immunosuppression microenvironment. Moreover, this approach provokes a robust systemic immune response and immunological memory, as evidenced by preventing 83.3% of mice from postsurgical metastasis or recurrence in the B16-F10 tumor mouse model. Collectively, our results highlight the potential of TALE as a neoadjuvant chemo-immunotherapy paradigm that can not only debulk tumors but generate a long-term immunosurveillance to maximize the durable benefits of neoadjuvant chemotherapy.

ObjectiveTo compare and evaluate the improvement degree of spermatogenic dysfunction mice at different recovery periods after cyclophosphamide modeling. MethodsForty-eight male ICR mice aged 4-5 weeks with the body weight of approximately 18-20 g were randomly divided into three control groups and three model groups, with 8 mice in each group. Each mouse of three model groups was intraperitoneally injected with 60 mg/kg cyclophosphamide continuously from the 1^st to 7^th day of the experiment, while each mouse of three control groups was intraperitoneally injected with the corresponding volume of normal saline. Then these mice were continued to be fed for another 7, 14 and 21 days after cyclophosphamide injection, respectively. A corresponding control group was set for each model group. The mice in each group were sacrificed after blood collection through orbital veins at corresponding time points. Testis, epididymis and seminal vesicle were taken and weighed, and their reproductive organ indexes were calculated. Histopathological changes of testis and epididymis were compared after HE staining.Sperm quality analysis was used to determine sperm-related indexes. Serum reproductive hormone content, testicular oxidative stress level and testicular signature enzyme activity were detected by ELISA and related kits.Results Compared with the control group, on the 7^th, 14^th and 21^st day after cyclophosphamide treatment, the testicular index of mice in the model group decreased significantly (P<0.01). The epididymis index decreased significantly on the 7^th and 14^th day, and the seminal vesicle index decreased obviously on the 7^th and 21^st day (P<0.05). And the histopathological damage of testis and epididymis of the model group gradually alleviated over time. On the 7^th and 14^th day after cyclophosphamide treatment, the sperm count of the model group declined remarkably (P<0.01), the serum testosterone (T) level reduced (P<0.05), the malonaldehyde (MDA) content of testis increased significantly (P<0.01), the content of reduced glutathione (GSH) and superoxide dismutase (SOD) decreased obviously (P<0.05),the lactic dehydrogenase (LDH) activity of testis reduced obviously (P<0.05), the gamma-glutamyl transpeptidase (γ-GT) activity increased significantly (P<0.05), the latter two of which are important testicular signature enzymes. Therein on the 7^th day after cyclophosphamide treatment, the sperm motility decreased significantly (P<0.001), the rate of sperm malformation increased obviously (P<0.05), the serum levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) increased notably (P<0.01). Nevertheless on the 21^st day after cyclophosphamide treatment, the sperm-related indexes, the content of serum reproductive hormone, the level of testicular oxidative stress and the activity of testicular signature enzyme did not change significantly (P＞0.05). ConclusionThe reproductive toxicity in mice was more apparent on the 7^th day after intraperitoneal injection with 60 mg/kg cyclophosphamide for seven days, at which time the more desirable spermatogenic dysfunction model of mice could be established. However, with the prolongation of the recovery period, the indexes of spermatogenic dysfunction in mice gradually recovered and approached the normal level on the 21^st day after cyclophosphamide treatment.

Objective:intrahepatic portocaval shunt (TIPS) in the treatment of hepatic sinusoidal obstruction syndrome (HSOS).Methods:A retrospective analysis was performed on 27 patients with HSOS who were treated with TIPS in our center from July 2018 to July 2020. The changes of portal vein pressure (PVP), portal vein pressure gradient (PPG) and liver function were observed, so as to evaluate the efficacy. Paired t test was adopted to evaluate the quantitative parameters, while χ2 test was used to analyze qualitative parameters, with P < 0.05 as statistical difference. Results:PVP decreased from (4.41 ± 0.18) kPa before shunt to (2.69 ± 0.11) kPa after shunt ( t = 82.41, P < 0.001), PPG decreased from (3.23 ± 0.18) kPa before shunt to (1.46 ± 0.23) kPa after shunt ( t = 32.41, P < 0.001). The liver function improved significantly after operation. After 24 months of follow-up, 3 patients developed stent restenosis and recanalized after balloon dilation. Three patients developed hepatic encephalopathy, which was improved after drug treatment. One patient underwent liver transplantation due to liver failure. Conclusion:TIPS is effective in the treatment of HSOS in the short and medium term, and can provide time for liver transplantation patients to wait for liver source.

Objective:To analyze the safety and clinical efficacy of invasive treatment for portal vein thrombosis after splenectomy or devascularization.Methods:Invasive treatment was retrospectively analyzed from Jan 2016 to Jan 2020. In 319 cases who met the inclusion criteria.Result:There were complications in 41 cases and no death;The average portal vein pressure before and after thrombus clearance treatment was (25.6±4.9) mmHg and (14.7±4.1) mmHg respectively ( t=2.53, P<0.05); Thrombus decreased significantly in most patients. Conclusion:Invasive therapy is a safe and effective method for patients complicated with portal vein thrombosis after splenectomy or devascularization.