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*

Nonobstructive azoospermia (NOA), one of the most severe types of male infertility, etiology often remains unclear in most cases. Therefore, this study aimed to detect four biallelic detrimental variants (0.5%) in the minichromosome maintenance domain containing 2 ( MCMDC2 ) genes in 768 NOA patients by whole-exome sequencing (WES). Hematoxylin and eosin (H&E) demonstrated that MCMDC2 deleterious variants caused meiotic arrest in three patients (c.1360G>T, c.1956G>T, and c.685C>T) and hypospermatogenesis in one patient (c.94G>T), as further confirmed through immunofluorescence (IF) staining. The single-cell RNA sequencing data indicated that MCMDC2 was substantially expressed during spermatogenesis. The variants were confirmed as deleterious and responsible for patient infertility through bioinformatics and in vitro experimental analyses. The results revealed four MCMDC2 variants related to NOA, which contributes to the current perception of the function of MCMDC2 in male fertility and presents new perspectives on the genetic etiology of NOA.
Humans ; Male ; Azoospermia/genetics* ; Meiosis/genetics* ; Spermatogenesis/genetics* ; Adult ; Exome Sequencing ; Microtubule-Associated Proteins/genetics* ; Alleles ; Infertility, Male/genetics*

OBJECTIVE: To investigate the effect of 5-hydroxytryptamine (5-HT) on the proliferation, apoptosis and colony-forming unit-megakaryocyte (CFU-MK) of Meg-01 cells and its possible mechanisms. METHODS: The uptake and metabolism of 5-HT in Meg-01 cells were analysed by reverse-phase high-performance liquid chromatography (RP-HPLC) with electrochemical detection. The expression of 5-HT2B receptor (5-HT2BR) in megakaryocytes was detected by immunofluorescence staining. The cell proliferation and viability were measured by MTT and Trypan blue staining after Meg-01 cells were single-cultured or co-cultured with different concentrations of 5-HT/5-HT2BR inhibitor Ketanserin for 48 h. Meg-01 cells were incubated with 5-HT/ Ketanserin for 72 h, then the flow cytometry was used to detect early apoptosis of the cells and the activity of caspase-3. Using CFU-MK assay to investigate the effect of 5-HT on the differentiation of megakaryocytes. RESULTS: 5-HT could be uptaken by Meg-01 cells, and metabolized into 5-hydroxyindoleacetic acid (5-HIAA). The expression of 5-HT2BR on megakaryocytes could be detected after immunofluorescence staining. 5-HT could promote the proliferation of Meg-01 cells at a dose-dependent manner (r =0.82), with the most significant effect observed at a concentration of 200 nmol/L (P < 0.001). Trypan blue staining also indicated that 200 nmol/L 5-HT had the most significant effect on the viability of Meg-01 cells (P < 0.05). The proliferation of Meg-01 cells treated with 5-HT was increased compared with the untreated control (P < 0.001), while the combination of 5-HT with ketanserin downregulated this effect. 5-HT significantly reduced the early apoptosis rate (P < 0.001) and caspase-3 activity (P < 0.05) of Meg-01 cells, while addition of ketanserin significantly increased the early apoptosis rate of Meg-01 cells (P < 0.001) and caspase-3 activity also increased to some extent. 5-HT promoted the formation of CFU-MK in bone marrow cells in a dose-dependent manner (r =0.89). The addition of ketanserin reduced the promoting effect of 5-HT on CFU-MK formation (P < 0.01). CONCLUSION There may be monoamine oxidase present in megakaryocytes, which can metabolize and decompose 5-HT into 5-HIAA. 5-HT may promote the proliferation and differentiation of megakaryocytes through 5-HT2BR. Besides, 5-HT can also reduce the apoptosis of megakaryocytes, and its anti-apoptotic effect may be mediated by 5-HT2BR and caspase-3 pathways.
Apoptosis/drug effects* ; Cell Proliferation/drug effects* ; Megakaryocytes/metabolism* ; Serotonin/pharmacology* ; Humans ; Receptor, Serotonin, 5-HT2B/metabolism* ; Caspase 3/metabolism* ; Cell Differentiation

JMJD1C (Jumonji Domain Containing 1C), a member of the lysine demethylase 3 (KDM3) family, is universally required for the survival of several types of acute myeloid leukemia (AML) cells with different genetic mutations, representing a therapeutic opportunity with broad application. Yet how JMJD1C regulates the leukemic programs of various AML cells is largely unexplored. Here we show that JMJD1C interacts with the master hematopoietic transcription factor RUNX1, which thereby recruits JMJD1C to the genome to facilitate a RUNX1-driven transcriptional program that supports leukemic cell survival. The underlying mechanism hinges on the long N-terminal disordered region of JMJD1C, which harbors two inseparable abilities: condensate formation and direct interaction with RUNX1. This dual capability of JMJD1C may influence enhancer-promoter contacts crucial for the expression of key leukemic genes regulated by RUNX1. Our findings demonstrate a previously unappreciated role for the non-catalytic function of JMJD1C in transcriptional regulation, underlying a mechanism shared by different types of leukemias.
Core Binding Factor Alpha 2 Subunit/genetics* ; Humans ; Leukemia, Myeloid, Acute/pathology* ; Jumonji Domain-Containing Histone Demethylases/chemistry* ; Gene Expression Regulation, Leukemic ; Oxidoreductases, N-Demethylating/genetics* ; Cell Line, Tumor

OBJECTIVE: This study aimed to investigate the impact of glycemic control and diabetes duration on subsequent myocardial infarction (MI) in patients with both coronary heart disease (CHD) and type 2 diabetes (T2D). METHODS: We conducted a retrospective cohort study of 33,238 patients with both CHD and T2D in Shenzhen, China. Patients were categorized into 6 groups based on baseline fasting plasma glucose (FPG) levels and diabetes duration (from the date of diabetes diagnosis to the baseline date) to examine their combined effects on subsequent MI. Cox proportional hazards regression models were used, with further stratification by age, sex, and comorbidities to assess potential interactions. RESULTS: Over a median follow-up of 2.4 years, 2,110 patients experienced MI. Compared to those with optimal glycemic control (FPG < 6.1 mmol/L) and shorter diabetes duration (< 10 years), the fully-adjusted hazard ratio ( HR) (95% Confidence Interval [95% CI]) for those with a diabetes duration of ≥ 10 years and FPG > 8.0 mmol/L was 1.93 (95% CI: 1.59, 2.36). The combined effects of FPG and diabetes duration on MI were largely similar across different age, sex, and comorbidity groups, although the excess risk of MI associated with long-term diabetes appeared to be more pronounced among those with atrial fibrillation. CONCLUSION Our study indicates that glycemic control and diabetes duration significant influence the subsequent occurrence of MI in patients with both CHD and T2D. Tailored management strategies emphasizing strict glycemic control may be particularly beneficial for patients with longer diabetes duration and atrial fibrillation.
Humans ; Diabetes Mellitus, Type 2/blood* ; Male ; Female ; Middle Aged ; Aged ; Coronary Disease/complications* ; Myocardial Infarction/etiology* ; Retrospective Studies ; China/epidemiology* ; Glycemic Control ; Blood Glucose ; Adult ; Risk Factors ; Time Factors

Objective To analyze the influencing factors of chronic obstructive pulmonary disease(COPD)complicating pulmonary interstitial fibrosis,and to establish a nomogram prediction model.Methods The clinical data of 195 patients with COPD admitted and treated in this hospital from January 2019 to Feb-ruary 2021 were retrospectively analyzed.The factors possibly affecting the patients with COPD complicating pulmonary interstitial fibrosis were collected,and the patients were divided into 2 groups according to whether having pulmonary interstitial fibrosis.The independent risk factors were analyzed and screened by the multi-variate logistic regression.Then the nomogram prediction model was constructed.Results Among the includ-ed 195 cases of COPD in this study,there were 50 cases(25.64％)of complicating pulmonary interstitial fi-brosis.The univariate and multivariate logistic regression analysis results showed that the smoking history,duration of COPD,frequency of acute exacerbations onset,serum transforming growth factor β1(TGF-β1),basic fibroblast growth factor(bFGF)and angiotensin Ⅱ(AngⅡ)were the independent influencing factors of COPD complicating pulmonary interstitial fibrosis(P＜0.05).The nomogram model was constructed accord-ing to the results of multivariate analysis results,and the area under the receiver operating characteristic(ROC)curve was 0.956(95％CI:0.930-0.983),the average absolute error of internal verification by the Bootstrap method was 0.025,and the prediction model performance basically fitted the ideal model.Conclusion The nomogram model constructed by this study for predicting the pulmonary interstitial fibrosis in COPD patients has high accuracy and distinction degree.

Objective To observe the effects of acupoint catgut embedding therapy on body mass,lipid metabolism,serum leptin and mRNA and protein expressions of hypothalamic leptin receptor(LepR)-mediated Janus kinase 2(JAK2)/signal transducer and activator of transcription 3(STAT3)pathway in rats with diet-induced obesity(DIO).Methods Forty male SD rats were randomly divided into 10 in normal group and 30 in modeling group.A high-fat diet was used to establish the DIO rat model.After successful modeling,the modeled rats were randomly divided into the model group,the acupoint catgut embedding group and the acupoint catgut embedding + AG490(JAK2/STAT3 pathway blocker)group,with 10 rats in each group.The acupoint catgut embedding group and the acupoint catgut embedding + AG490 group were embedded on day(s)1,8,15 and 22 after successful modeling,the acupoints were selected from the Zhongwan(RN12),Shuidao(ST28),Tianshu(ST25),Pishu(BL20),Weishu(BL21),Sanjiaoshu(BL22)with a total of 4 treatments,and the acupoint catgut embedding + AG490 group was injected intraperitoneally with 1 mg/kg of AG490 every day during the treatment period;the normal group and the model group were only grasped and fixed.Body mass was measured before and after treatment.Lipid metabolism indexes of triglyceride(TG),total cholesterol(TC),low-density lipoprotein cholesterol(LDL-C),high-density lipoprotein cholesterol(HDL-C),and serum leptin levels were measured after treatment,and the mRNA expressions of hypothalamus LepR,JAK2 and STAT3 were detected by real-time quantitative polymerase chain reaction(RT-PCR),and the protein expressions of hypothalamus LepR,JAK2 and STAT3 were detected by Western Blot.Results Before treatment,compared with the normal group,the body mass of the model group,the acupoint catgut embedding group,and the acupoint catgut embedding+AG490 group were all elevated(P＜0.01),and compared with the model group,there was no significant difference in the body mass between the acupoint catgut embedding group and the acupoint catgut embedding+AG490 group(P＞0.05).After treatment,compared with the normal group,body mass,leptin and TG,TC,LDL-C levels were increased,and mRNA and protein expression levels of LepR,JAK2,STAT3 were decreased in the model group(all P＜0.01);compared with the model group,body mass,leptin and TG,TC,LDL-C levels were decreased in the acupoint catgut embedding group,and mRNA and protein levels of LepR,JAK2,STAT3 were increased in the acupoint catgut embedding + AG490 group(all P＜0.01);compared with the acupoint catgut embedding + AG490 group,the body mass,leptin and TG,TC,LDL-C levels were decreased,and mRNA and protein levels of LepR,JAK2,STAT3 were increased in the acupoint catgut embedding group(P＜0.05 or P＜0.01).Conclusion Acupoint catgut embedding has a good effect on weight loss and lipid reduction in DIO rats,and its central mechanism may be related to the down-regulation of serum leptin level and activation of hypothalamic LepR-mediated JAK2/STAT3 pathway.

Threatened abortion is a common disease of obstetrics and gynecology and one of the diseases responding specifically to traditional Chinese medicine （TCM）. The China Association of Chinese Medicine organized experts in TCM obstetrics and gynecology， Western medicine obstetrics and gynecology， and pharmacology to deeply discuss the advantages of TCM and integrated Chinese and Western medicine treatment as well as the medication plans for threatened abortion. After discussion， the experts concluded that chromosome， endocrine， and immune abnormalities were the key factors for the occurrence of threatened abortion， and the Qi and blood disorders in thoroughfare and conception vessels were the core pathogenesis. In the treatment of threatened abortion， TCM has advantages in preventing miscarriages， alleviating clinical symptoms and TCM syndromes， relieving anxiety， regulating reproductive endocrine and immune abnormalities， personalized and diversified treatment， enhancing efficiency and reducing toxicity， and preventing the disease before occurrence. The difficulty in diagnosis and treatment of threatened abortion with traditional Chinese and Western medicine lies in identifying the predictors of abortion caused by maternal factors and the treatment of thrombophilia. Recurrent abortion is the breakthrough point of treatment with integrated traditional Chinese and Western medicine. It is urgent to carry out high-quality evidence-based medicine research in the future to improve the modern diagnosis and treatment of threatened abortion with TCM.

Objective To investigate the effect of Qufu Shengji ointment combined with ulinastatin in the treatment of wound healing after perianal surgery and its effect on the level of inflammatory factors.Methods Patients who underwent perianal surgery in Guilin Hospital of Integrated Traditional Chinese and Western Medicine from July 2020 to January 2022 were randomly divided into control group and test group.The patients in both groups were treated with conventional debridement therapy and ulinastatin,and the test group was treated with Qufu Shengji ointment.The wound healing efficacy,TCM symptom score,inflammatory factor level,growth factor level and treatment safety of the two groups were compared.Results A total of 116 patients were included in the study,including 58 patients in the test group and 58 in the control group.The total effective rate of the test group(91.38％)was higher than that of the control group(75.86％),and the difference was statistically significant(P＜0.05).After treatment,the TCM syndrome score levels of interleukin-17A(IL-17A),C-reactive protein(CRP)and serum amyloid A(SAA)in the test group were lower than those in the control group(P＜0.05).The levels of vascular endothelial growth factor receptor 1(VEGFR1),fibroblast growth factor receptor(FGFR)and transforming growth factor-β1(TGF-β1)were higher than those in the control group(P＜0.05).The anal function index was higher than that of the control group(P＜0.05).The incidence of adverse reactions between the two groups was 13.79％and 8.62％,respectively,and the difference was not statistically significant(P＞0.05).Conclusion The effect of Qufu Shengji ointment combined with ulinastatin in the treatment of wound healing after perianal surgery is significant,which can improve the TCM syndrome,reduce inflammatory factors,and upregulate growth factors,and has good safety.

Objective This study aimed to investigate the potential relationship between urinary metals copper (Cu), arsenic (As), strontium (Sr), barium (Ba), iron (Fe), lead (Pb) and manganese (Mn) and grip strength. Methods We used linear regression models, quantile g-computation and Bayesian kernel machine regression (BKMR) to assess the relationship between metals and grip strength.Results In the multimetal linear regression, Cu (β=-2.119), As (β=-1.318), Sr (β=-2.480), Ba (β=0.781), Fe (β= 1.130) and Mn (β=-0.404) were significantly correlated with grip strength (P < 0.05). The results of the quantile g-computation showed that the risk of occurrence of grip strength reduction was -1.007 (95％ confidence interval:-1.362, -0.652; P < 0.001) when each quartile of the mixture of the seven metals was increased. Bayesian kernel function regression model analysis showed that mixtures of the seven metals had a negative overall effect on grip strength, with Cu, As and Sr being negatively associated with grip strength levels. In the total population, potential interactions were observed between As and Mn and between Cu and Mn (Pinteractions of 0.003 and 0.018, respectively).Conclusion In summary, this study suggests that combined exposure to metal mixtures is negatively associated with grip strength. Cu, Sr and As were negatively correlated with grip strength levels, and there were potential interactions between As and Mn and between Cu and Mn.