BACKGROUND: The sirtuin family is well recognized for its crucial involvement in various cellular processes. Nevertheless, studies on its role in the human endometrium are limited. This study aimed to explore the expression and localization of the sirtuin family in the human endometrium, focusing on sirtuin 3 (SIRT3) and its potential role in the oxidative imbalance of the endometrium in polycystic ovary syndrome (PCOS). METHODS: Endometrial specimens were collected from both patients with PCOS and controls undergoing hysteroscopy at the Center for Reproductive Medicine, Peking University Third Hospital, from July to August 2015 and used for cell culture. The protective effects of SIRT3 were investigated, and the mechanism of SIRT3 in improving endometrial receptivity of patients with PCOS was determined using various techniques, including cellular bioenergetic analysis, small interfering ribonucleic acid (siRNA) silencing, real-time quantitative polymerase chain reaction, Western blot, immunofluorescence, immunohistochemistry, and flow cytometry analysis. RESULTS: The sirtuin family was widely expressed in the human endometrium, with SIRT3 showing a significant increase in expression in patients with PCOS compared with controls ( P <0.05), as confirmed by protein and gene assays. Concurrently, endometrial antioxidant levels were elevated, while mitochondrial respiratory capacity was reduced, in patients with PCOS ( P <0.05). An endometrial oxidative stress (OS) model revealed that the downregulation of SIRT3 impaired the growth and proliferation status of endometrial cells and reduced their receptivity to day 4 mouse embryos. The results suggested that SIRT3 might be crucial in maintaining normal cellular state by regulating antioxidants, cell proliferation, and apoptosis, thereby contributing to enhanced endometrial receptivity. CONCLUSIONS Our findings proposed a significant role of SIRT3 in improving endometrial receptivity in patients with PCOS by alleviating OS and regulating the balance between cell proliferation and apoptosis. Therefore, SIRT3 could be a promising target for predicting and improving endometrial receptivity in this patient population.
Humans ; Female ; Polycystic Ovary Syndrome/metabolism* ; Endometrium/metabolism* ; Sirtuin 3/genetics* ; Oxidative Stress/genetics* ; Adult ; Animals ; Mice ; Apoptosis/physiology* ; Immunohistochemistry ; Cell Proliferation/physiology*

Objective To explore the expression of coagulation indexes in rheumatoid arthritis (RA) and dry syndrome (pSS) and their relationships with inflammation and immune function. Methods A total of 61 patients with RA who were hospitalized in the Department of Rheumatology of Anhui Provincial Hospital of Traditional Chinese Medicine from March 12 to September 9, 2024 were selected as the RA group. And 61 patients with pSS who were hospitalized in the Department of Rheumatology of the same hospital September 4, 2023, to August 17, 2024, were selected as the pSS group. 61 healthy individuals who underwent routine medical checkups at the Physical Examination Center of Anhui Provincial Hospital of Traditional Chinese Medicine during the same period were included as the control group. Baseline clinical indexes before treatment were collected from patients in each group, including prothrombin time(PT), international normalized ratio(INR), thrombia time(TT), fibrinogen(FBG), activated partial thromboplastin time(APTT), fibrin (ogen) degradation products(FDP) and D-Dimer(D-D). Results The expression levels of PT, FBG, TT, FDP, and D-D in the RA group, the pSS group, and the normal group were significantly different. The expression levels of PT, FBG, FDP, and D-D in the RA group were all higher than those in the pSS group and the control group, respectively. And the expression level of TT in the pSS group was lower than that in control group. ROC curve analysis showed that the AUC of PT was 0.638, the AUC of FBG was 0.899, the AUC of FDP was 0.866, and the AUC of D-D was 0.919 in the RA group compared with the normal group. And the AUC of coagulation indexes for joint diagnosis of RA was higher than that of the indexes detected individually. pSS group had an AUC of PT of 0.618 compared with that of the normal group. The AUC of TT was 0.645, and the AUC of coagulation indexes for the joint diagnosis of pSS was higher than the AUC of each index detected separately. Association rule analysis showed that elevated D-D in RA patients had a significant correlation with elevated hs-CRP, CCP and RF, and elevated FBG had a significant correlation with elevated hs-CRP, ESR, RF and CCP. Elevated D-D in pSS patients had a correlation with elevated hs-CRP and anti-SSA, and elevated INR has correlation with elevated hs-CRP, anti-SSA and anti-SSB. Correlation analysis showed that PT, INR, FBG, FDP, and D-D were positively correlated with CRP and ESR, and TT was negatively correlated with CRP and ESR in the RA group. FBG, FDP, and D-D were positively correlated with CRP and ESR in the pSS group. Moreover, coagulation indexes were positively correlated with immune indexes in RA group and pSS group which were all significant. The results of multiple linear regression analysis showed that FBG was a positive correlate of hs-CRP and ESR in RA patients. For PSS patients, FBG and FDP were positive correlates of hs-CRP. APTT and FBG were positive correlates of ESR. Conclusion Compared with pSS, coagulation indexes (especially PT, FBG, FDP and D-D) are more informative for the early diagnosis of RA and the judgment of the degree of the disease, and can be used as an important predictor for the confirmation of the diagnosis of RA.
Humans ; Female ; Male ; Arthritis, Rheumatoid/diagnosis* ; Middle Aged ; Fibrin Fibrinogen Degradation Products/analysis* ; Blood Coagulation ; Adult ; Fibrinogen/metabolism* ; Partial Thromboplastin Time ; Prothrombin Time ; Aged ; Inflammation/immunology* ; ROC Curve

Recent studies have indicated that the expression of ubiquitin-specific protease 51 (USP51), a novel deubiquitinating enzyme (DUB) that mediates protein degradation as part of the ubiquitin‒proteasome system (UPS), is associated with tumor progression and therapeutic resistance in multiple malignancies. However, the underlying mechanisms and signaling networks involved in USP51-mediated regulation of malignant phenotypes remain largely unknown. The present study provides evidence of USP51's functions as the prominent DUB in chemoresistant triple-negative breast cancer (TNBC) cells. At the molecular level, ectopic expression of USP51 stabilized the 78 kDa Glucose-Regulated Protein (GRP78) protein through deubiquitination, thereby increasing its expression and localization on the cell surface. Furthermore, the upregulation of cell surface GRP78 increased the activity of ATP binding cassette subfamily B member 1 (ABCB1), the main efflux pump of doxorubicin (DOX), ultimately decreasing its accumulation in TNBC cells and promoting the development of drug resistance both in vitro and in vivo. Clinically, we found significant correlations among USP51, GRP78, and ABCB1 expression in TNBC patients with chemoresistance. Elevated USP51, GRP78, and ABCB1 levels were also strongly associated with a poor patient prognosis. Importantly, we revealed an alternative intervention for specific pharmacological targeting of USP51 for TNBC cell chemosensitization. In conclusion, these findings collectively indicate that the USP51/GRP78/ABCB1 network is a key contributor to the malignant progression and chemotherapeutic resistance of TNBC cells, underscoring the pivotal role of USP51 as a novel therapeutic target for cancer management.

Background: s/Aims: Anti-mitochondrial M2 antibody (AMA-M2) is a specific marker for primary biliary cholangitis (PBC) and it could be also present in non-PBC individuals. Methods: A total of 72,173 Chinese health check-up individuals tested AMA-M2, of which non-PBC AMA-M2 positive individuals were performed follow-up. Baseline data of both clinical characteristics and laboratory examinations were collected in all AMA-M2-positive individuals. Least absolute shrinkage and selection operator (LASSO) regression was performed to investigate the potential variables for developing PBC. Results: A total of 2,333 individuals were positive with AMA-M2. Eighty-two individuals had a medical history of PBC or fulfilled the diagnostic criteria of PBC at baseline, and 2,076 individuals were non-PBC. After a median follow-up of 6.6 years, 0.6% developed PBC, with an accumulative 5-year incidence rate of 0.5%. LASSO regression showed that levels of alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), immunoglobulin M (IgM), eosinophilia proportion (EOS%), gamma globulin percentage, and hemoglobin (HGB) were potential variables for developing PBC. Multivariate Cox regression is used to construct a predictive model based on 7 selected variables, and time-dependent receiver operating characteristic analysis showed that the area under the curve of the prediction model at 3, 5, and 10 years were, respectively, 1.000, 0.875, and 0.917. Conclusions This study offers insights into the onset of PBC among individuals who tested positive for AMA-M2 during routine health check-ups. The prediction model based on ALP, GGT, IgM, EOS%, gamma globulin percentage, HGB, and sex has a certain predictive ability for the occurrence of PBC in this population.

Objective:To investigate the distribution of health needs and healthcare workforce demands among potential service users in community health service institurions (CHSIs) and establish a comprehensive health needs profile for targeted service development.Methods:This is a cross-sectional study. A questionnaire survey (55 items for adults and 39 items for minors) was conducted among 564 residents aged 3-65 in Dapuqiao Subdistrict, Shanghai from March to May 2024. A health sketch model was developed, encompassing five dimensions (intake, basal metabolism, consumption, influencing factors, and somatosensory perception). Health issues were mapped to standardized healthcare services, and annual standardized workloads (SW) were calculated to quantify human resource demands. Results:Among 534 valid responses (94.68% response rate), 355 from the adults and 179 from minors, the top health issues for adults were irregular diet, nutritional imbalance, obesity, somatic fatigue, and disordered eating; for minors, they were nutritional imbalance, medication overuse, insufficient physical activity, picky eating, and anorexia. The total annual SW required to address these needs was 3 906 807.93. Among them, the total SW for each age group was as follows: the total annual SW demand for children aged between 3 and 5 years old was 24 108.90, for children aged between 6 and 11 years old was 141 355.70, for adolescents aged between 12 and 17 years old was 29 813.74, 223 475.50 for 18-24 year olds, 476 426.53 for 25-34 year olds, 1 221 105.84 for 35-44 year olds, 812 200.22 for 45-54 year olds; and 978 321.50 for 55-65 year olds. Workforce allocation analysis revealed a total demand for 139.84 standardized personnel, with rehabilitation therapists (38.16), general practitioners (35.69), and nurses (27.34) being the top three required roles.Conclusions:Health needs and workforce demands vary significantly across age groups. This study provides a data-driven framework for optimizing community health services through stratified health needs profiling and precision resource allocation. Future strategies should prioritize tailored interventions and workforce planning to bridge service gaps and enhance health outcomes.

Objective:To investigate the descrepancy between current supply and demand based on standardiized workload for rational human resource allocation in community health service centers.Methods:A retrospective study was conducted in Dapuqiao Community Health Service Center of Shanghai Huangpu District from January 1st to December 3lst 2023. The current status of demand and supply were analyzed using the 2023 data of the institution. The standardised workload was measured according to the potential basic medical and public health service needs based on the disease profile and population groups in the community. The discrepancy between the current supply and theoretical demand was analyzed.Results:A total of 36 634 patients paid 277 262 visits in outpatient clinics of Dapuqiao Community Health Service Center in 2023. There are total 161 employees in the center, 124 of whom are female (77.02%). The actual calibrated workload of basic medical care and public health service in the center calculated on fee-based medical service items in 2023 was 2 888 425.61 and 455 898.35, respectively; while the theoretically calibrated workload was 5 416 492.42 and 711 230.94, respectively. The center employed 131 medical and health workers currently, calibrated as 90.67 employees based on current demand, while it should be 183.74 calibrated on the theoretical demand, there was a certain discrepancy between the current staffing and the standard staffing based on the standardized workload calculation.Conclusion:At present, the actual standardized workload of basic medical and public health services in Dapuqiao Community Health Service Center still has room for improvement, but there is a certain gap between the current human resource allocation and the demand.

Objective To explore the value of combining apparent diffusion coefficient(ADC)heterogeneity with morphological indicators in assessing the pathological grading of non-muscle invasive bladder cancer(NMIBC).Methods The MRI images of 86 patients confirmed with NMIBC by surgical pathology were analyzed retrospectively.All patients underwent T2WI,diffusion weighted ima-ging(DWI),and dynamic contrast enhancement(DCE)examinations.Two radiologists independently measured tumor largest diam-eter(LD),actual tumor-wall contact length(ACTCL),ADCmean,ADCmin,and ADCmax values.ADC heterogeneity was calculated using the formula(ADCmax-ADCmin)/ADCmean.Differences in quantitative parameters between low-and high-grade NMIBC were compared using the Mann-Whitney U test,while differences in qualitative parameters were compared using the chi-square test.Univariate and multivariate logistic regression analyses were used to identify independent predictors of high-grade NMIBC,and receiver operating characteristic(ROC)curves were drawn to evaluate the performance of ADC heterogeneity combined with morphological indicators in assessing high-grade NMIBC.Results ADC heterogeneity and ACTCL were independent predictors for preoperative assessment of NMIBC pathological grading.The area under the curve(AUC)of ADC heterogeneity and ACTCL in assessing high-grade NMIBC were 0.843 and 0.744,respectively.The combined AUC was 0.902.The difference was statistically significant(P<0.05).Conclusion The combination of ADC heterogeneity with ACTCL can effectively improve the efficiency of preoperative assessment of NMIBC pathological grading,and providing more precise clinical decision-making and prognosis monitoring.

Objective: To investigate the chemical compositions of Maxing Shigan Decoction (麻杏石甘汤, MXSGD) and elucidate its anti-influenza A virus (IAV) mechanism from prediction to validation. Methods: Ultra high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was employed to analyze the chemical compositions of MXSGD. Network pharmacology theories were used to screen and identify shared targets of both the potential targets of active ingredients of MXSGD and IAV. A protein-protein interaction (PPI) network was then constructed, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The binding stability between core bioactive compounds and key targets was validated by molecular docking and dynamic simulations. A total of 24 BALB/c mice were infected with IAV to build IAV mouse models. After successful modelling, the mouse models were randomly divided into model, MXSGD high-dose (2.8 g/kg), MXSGD low-dose (1.4 g/kg), and oseltamivir (20.14 mg/kg) groups, with an additional normal mice as control group (n = 6 per group). The treatments were administered by gavage daily between 8:00 a.m. and 10:00 a.m. for five consecutive days. Upon completion of the administration, the body weight ratio, lung index, protein content in the bronchoalveolar lavage fluid (BALF), and the levels of inflammatory factors including interleukin (IL)-6 and tumor necrosis factor (TNF)-α in mice were measured to preliminarily analyze the therapeutic efficacy of MXSGD against IAV infection. Furthermore, the expression levels of mechanistic target of rapamycin (mTOR), hypoxia inducible factor (HIF)-1α, and vascular endothelial growth factor (VEGF) proteins in the HIF-1 signaling pathway, which was enriched by network pharmacology, were detected by Western blot. Results: A total of 212 chemical components in MXSGD were identified by the UPLC-MS/MS method. These chemical components can be classified into 9 primary categories and 31 secondary categories. After intersecting the chemical component targets with IAV-related targets, a total of 567 potential MXSGD components targeting IAV were identified. The construction of PPI network and the results of both GO and KEGG enrichment analyses revealed that the anti-IAV effects of MXSGD were associated with multiple pathways, including apoptosis, TNF, HIF-1, and IL-17 signaling pathways. The results of molecular docking demonstrated that the binding energies between the core compound 1-methoxyphaseollin and key targets including HIF-1α, mTOR, and VEGF were all lower than – 5.0 kcal/mol. Furthermore, molecular dynamics simulations confirmed the structural stability of the resulting complexes. Animal experiments showed that compared with the normal controls, IAV-infected mice showed significantly reduced body weight ratio, markedly increased lung index, protein content in BALF, and the levels of inflammatory factors such as IL-6 and TNF-α (P < 0.01), thereby causing damage to the lung tissue; consequently, the expression levels of mTOR, HIF-1α, and VEGF proteins in the lung tissues of these mice were significantly elevated (P < 0.01). However, after MXSGD treatment, the mouse models presented a significant increase in body weight ratio, as well as marked decreases in lung index, protein content in BALF, and the levels of inflammatory factors including IL-6 and TNF-α (P < 0.01). Furthermore, the therapy alleviated IAV-induced injuries and significantly downregulated the expression levels of mTOR, HIF-1α, and VEGF proteins in lung tissues (P < 0.01 or P < 0.05). Conclusion MXSGD exerts anti-IAV effects through multi-component, multi-target, and multi-pathway synergism. Among them, 1-methoxyphaseollin is identified as a potential key component, which alleviates virus-induced lung injury and inflammatory response via the regulation of HIF-1 signaling pathway, providing experimental evidence for the clinical application of MXSGD.

Objective Fasting hypometabolism regulation technology has broad application potential in long-term space flight and survival in extreme extraterrestrial environments.In-depth research on the substrate conversion of energy metabolism and the formation of new steady states under fasting hypometabolism will provide theoretical basis and experimental data support for formulating effective prolonged fasting application mode.Methods 30 SD rats were randomly divided into control group and fasting group(fasting for 1,2,3,and 5 days).Blood biochemical examination,qRT-PCR,and western blotting were performed to analyze the body weight,blood biochemistry,and expression changes of genes and proteins related to glucose and lipid metabolism during different fasting periods.Results Prolonged fasting significantly reduced the body weight,blood glucose,and triglyceride levels of rats;increased the blood ketone level,and replaced glucose as the main energy substance in the body.There are temporal and tissue-specific changes as a whole.Hepatic and renal gluconeogenesis play major roles respectively during different fasting periods.As the fasting time prolongs,the level of hepatic gluconeogenesis gradually decreases,the content of FFA in the blood increases,the expression level of genes related to fat synthesis decreases,fatty acid oxidation is enhanced,and the expression level of the key gene HMGCS2 for ketone body generation increases.Conclusion During prolonged fasting,there is a significant conversion of glucose-ketone energy supply substrates,and a new steady state of energy metabolism mainly supplied by ketone bodies is formed within 2-5 days of fasting.The body maintains a low metabolic state by regulating changes in key genes in pathways such as glucose and lipid metabolism.