Pelvic organ prolapse (POP), whose etiology is influenced by genetic and clinical risk factors, considerably impacts women's quality of life. However, the genetic underpinnings in non-European populations and comprehensive risk models integrating genetic and clinical factors remain underexplored. This study constructed the first polygenic risk score (PRS) for POP in the Chinese population by utilizing 20 disease-associated variants from the largest existing genome-wide association study. We analyzed a discovery cohort of 576 cases and 623 controls and a validation cohort of 264 cases and 200 controls. Results showed that the case group exhibited a significantly higher PRS than the control group. Moreover, the odds ratio of the top 10% risk group was 2.6 times higher than that of the bottom 10%. A high PRS was significantly correlated with POP occurrence in women older than 50 years old and in those with one or no childbirths. As far as we know, the integrated prediction model, which combined PRS and clinical risk factors, demonstrated better predictive accuracy than other existing PRS models. This combined risk assessment model serves as a robust tool for POP risk prediction and stratification, thereby offering insights into individualized preventive measures and treatment strategies in future clinical practice.
Humans ; Female ; Pelvic Organ Prolapse/epidemiology* ; Middle Aged ; Risk Assessment/methods* ; China/epidemiology* ; Multifactorial Inheritance ; Aged ; Risk Factors ; Genome-Wide Association Study ; Genetic Predisposition to Disease ; Case-Control Studies ; Adult ; Polymorphism, Single Nucleotide ; Genetic Risk Score ; East Asian People

This study identified six novel azaphilones, isochromophilones G-L (1-6), and three novel biosynthetically related congeners (7-9) from Diaporthe sp. SCSIO 41011. The structures and absolute configurations were elucidated through comprehensive spectroscopic analyses combined with experimental and calculated electronic circular dichroism (ECD) spectra. Significantly, three highly oxygenated azaphilones contain an acetyl group at the terminal chain (4) or linear conjugated polyenoid moieties (5 and 6), which occur infrequently in the azaphilone family. Additionally, several compounds demonstrated inhibition of lipopolysaccharide (LPS)-induced nuclear factor kappa-B (NF-κB) activation in RAW 264.7 macrophages at 20 μmol·L^-1. The novel compound (1) effectively inhibited receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation without exhibiting cytotoxicity in bone marrow and RAW 264.7 macrophages, indicating its potential as a promising lead compound for osteolytic disease treatment. This research presents the first documented evidence of azaphilone derivatives as inhibitors of RANKL-induced osteoclastogenesis.
Animals ; Mice ; RANK Ligand/genetics* ; RAW 264.7 Cells ; Osteoclasts/metabolism* ; Benzopyrans/isolation & purification* ; Osteogenesis/drug effects* ; Macrophages/metabolism* ; Molecular Structure ; Pigments, Biological/isolation & purification* ; Ascomycota/chemistry* ; NF-kappa B/genetics* ; Cell Differentiation/drug effects*

Objective:To discuss the ameliorative effect of total flavonoids from corn silk(TFCS)on kidney injury in the rats with urate nephropathy,and to clarify the possible mechanism.Methods:Sixty male Wistar rats were randomly divided into control group,model group,positive control group[benzbromarone(BZM)group,5 mg·kg-1·d-1],low dose of TFCS group(20 mg·kg-1·d-1),medium dose of TFCS group(40 mg·kg-1·d-1),and high dose of TFCS group(80 mg·kg-1·d-1),and there were 10 rats in each group.Except for control group,the rats in the other groups were administered potassium oxonate(350 mg·kg-1)and adenine(70 mg·kg-1)by gavage for 4 weeks to establish the hyperuricemic nephropthy models.The rats in different doses of TFCS groups were treated with TFCS for 2 weeks.Speckle blood flow imager was used to detect the renal blood perfusion of the rats in various groups and the kidney coefficients of the rats in various groups were caculated;HE staining and Masson staining were used to observe the pathomorphology and fibrosis degrees of kidney tissue of the rats in various groups and enzyme-linked immunosorbent assay(ELISA)method was used to detect the levels of uric acid(UA),creatinine(Cr),blood urea nitrogen(BUN),interleukin-6(IL-6),and tumor necrosis factor-α(TNF-α)in the serum and levels of β2-microglobulin(β2-MG)and microalbumin(ALB)in the urine of the rats in various groups;Western blotting method was used to detect the expression levels of urate transporter 1(URAT1),glucose transporter 9(GLUT9),and ATP-binding cassette transporter G2(ABCG2)proteins in kidney tissue of the rats in various groups.Results:Compared with control group,the renal blood perfusion volume of the rats in model group was significantly decreased(P<0.01).Compared with model group,the renal blood perfusion volumes of the rats in BZM group and low,medium,and high doses of TFCS groups were significantly increased(P<0.05 or P<0.01).Compared with control group,the kidney weight of the rats in model group was increased,with visible white granular spots on the surface,absence of blood color,and kidney volume was increased.Compared with model group,the kidney volumes of the rats in BZM group and medium and high doses of TFCS groups were decreased,with color tending toward that in control group,and the white granular spots on the surface were significantly reduced.Compared with model group,the kidney coefficients of the rats in BZM group and medium and high doses of TFCS groups were decreased(P<0.01).The HE staining results showed there were no abnormalities in kidney tissue structure in control group,while there were a small amount of brown-yellow urate crystal deposition and interstitial connective tissue hyperplasia in model group;compared with model group,the kidney tissue damage and inflammatory infiltration were alleviated to varying degrees in BZM group and different doses of TFCS groups.The Masson staining results revealed no obvious collagen fiber deposition in control group,whereas significant blue collagen fiber deposition in kidney tissue of the rats was found in model group,and the collagen volume fraction(CVF)was increased compared with control group(P<0.01);compared with model group,the CVFs of the rats in BZM group and different doses of TFCS groups were decreased(P<0.01).The ELISA results showed that compared with control group,the levels of UA,Cr,BUN,IL-6,and TNF-α in serum of the rats in model group were increased(P<0.01);compared with model group,the levels of UA,Cr,BUN,IL-6,and TNF-α in serum of the rats in BZM group and medium and high doses of TFCS groups were decreased(P<0.01).Compared with control group,the levels of β2-MG and ALB in urinary in model group were increased(P<0.01);compared with model group,the levels of β2-MG and ALB in urinary of the rats in different doses of TFCS groups were decreased(P<0.05 or P<0.01).The Western blotting results showed that compared with control group,the expression levels of URAT1 and GLUT9 proteins in kidney tissue of the rats in BZM group and model group were increased(P<0.01),while the expression level of ABCG2 protein was decreased(P<0.01).Compared with model group,the expression levels of URAT1 and GLUT9 proteins in kidney tissue of the rats in different doses of TFCS groups were decreased(P<0.05 or P<0.01),and the expression level of ABCG2 protein was increased(P<0.01).Conclusion:TFCS can significantly alleviate the kidney injury in the rats with urate nephropathy model,and its mechanism may be related to the downregulation of expression of URAT1 and GLUT9 proteins and upregulation of ABCG2 protein expression in kidney tissue.

Objective To investigate the role and potential molecular mechanisms of insulin-like growth factor 2 mRNA-binding protein 3(IGF2BP3)in preeclampsia(PE).Methods The expres-sion of IGF2BP3 in placental tissues from patients with PE was detected using quantitative reverse transcription polymerase chain reaction.IGF2BP3 was knocked down via RNA interference technology to evaluate its effects on the proliferation,invasion,apoptosis and cell cycle of HTR-8/SVneo and JEG-3 trophoblast cell lines.Transcriptome sequencing was employed to analyze changes in cellular biological functions and the stability of the potential downstream molecule circPAPPA following IGF2BP3 interference.RNA binding protein immunoprecipitation(RIP)and fluorescence in situ hy-bridization(FISH)were utilized to validate the direct targeting relationship between IGF2BP3 and circPAPPA.Results IGF2BP3 was significantly downregulated in PE placentas.Knockdown of IGF2BP3 inhibited trophoblast cell proliferation and invasion,promoted cell apoptosis and cellcycle arrest.Functional enrichment analysis revealed that IGF2BP3 was involved in invasion and hypoxia response,regulating signaling pathways such as phosphatidylinositol-3-kinase(PI3K),mitogen-activated protein kinase(MAPK)and hypoxia-inducible factor-1(HIF-1).Knockdown of IGF2BP3 led to a reduction in circPAPPA stability,and RIP and FISH experiments confirmed the direct targeting rela-tionship between IGF2BP3 and circPAPPA.Conclusion IGF2BP3 is downregulated in PE and reg-ulates the stability of circPAPPA in an N6-adenosine methylation(m6A)-dependent manner,there-by affecting trophoblast cell function.

Objective:To explore the risk factors of short-term prognosis of severe Budd-Chiari syndrome (BCS) patients,established and verified the nomogram prediction model for these BCS patients and evaluated its clinical application value.Methods:This study is a retrospective cohort study. The clinical data of 171 patients with severe BCS diagnosed were retrospectively analyzed in the Department of Hepatopancreatobiliary Surgery First Affiliated Hospital of Zhengzhou University from January 2018 to December 2023. There were 105 males and 66 females, aged (52.1±12.8) years (range: 18 to 79 years). The patients were divided into two groups based on whether they died within 28 days: the death group ( n=38) and the survival group ( n=133). The risk factors for short-term death of patients were analyzed,and independent risk factors were screened by univariate and multivariate analysis. Furthermore,these factors were used to establish the nomogram prediction model. The area under the curve(AUC),the Bootstrap Resampling,the Hosmer-Lemeshow test and the Decision Curve Analysis(DCA) were used to verify the model′s differentiation,internal verification,calibration degree and clinical effectiveness,respectively. Results:Univariate and multivariate Logistics regression analysis showed that the history of hepatic encephalopathy,white blood cell,glomerular filtration rate and prothrombin time were independent risk factors ( P<0.05). The above factors were used to successfully establish the prediction model with 0.908 of AUC and 0.895 of the internal verification of AUC,indicating that the predictive model was valuable. The 0.663 P-values in the Hosmer-Lemeshow test indicated the high calibration degree of the model. The clinical effectiveness of the model was proved by the 18% clinical benefit population using the DCA curve with the 17% probability threshold. Conclusions:The independent risk factors are the history of hepatic encephalopathy,white blood cell,glomerular filtration rate and prothrombin time. An adequate basis was acquired by establishing a nomogram prediction model of the short-term prognosis of severe BCS,which was helpful for early clinical screening and identification of high-risk patients with severe BCS who could die in the short term and timely providing timely intervention measures for improving the prognosis.

As the foremost among the four examinations in traditional Chinese medicine （TCM）， inspection and related equipment research face challenges in landing and transformation due to variations in evidence quality， lack of standardization， insufficient algorithm transparency， and poor reliability and stability of decision-making. Against the backdrop of rapid development of emerging technologies such as big data， the internet of things， and artificial intelligence， coupled with macro policy support from the government， digital and intelligent generalized inspection in TCM has emerged， with the aim of utilizing digital technologies to overcome the limitations of naked-eye inspection and comprehensively perceive and analyze facial and bodily expressions. The research in this field intelligently correlates Zang-fu organ functions with health conditions and disease progression and establishes a technical system for digital and intelligent inspection， multi-dimensional and multimodal perception， fusion analysis， and decision-making. This system aims to enhance the accuracy of disease risk warning and diagnosis， bridging the gap between inspection equipment and assistance in clinical decision-making. From an evidence-based perspective， this paper systematically examines the research ideas of digital and intelligent inspection and the development of related equipment， deeply explores how to propose clinical practice-oriented key scientific issues， comprehensively acquire and co-apply multi-dimensional data， establish precise inspection models driven by digital intelligence， optimize standards to enhance equipment interoperability and reliability， construct post-effect evaluation mechanisms to promote improvement， and actively address potential risks such as the black box nature and information security in the application of intelligent technology. This paper not only demonstrates the tremendous potential of digital technologies in improving the accuracy and clinical application efficiency of inspection but also provides new perspectives and ideas for the modernization of inspection in TCM， paving the way for the application of inspection in the global medical and health field.

Objective:To construct a diabetes foot prediction model for adult patients with type 2 diabetes based on retrospective cohort study using data from a regional health data platform.Methods:Using Yinzhou Health Information Platform of Ningbo, adult patients with newly diagnosed type 2 diabetes from January 1, 2015 to December 31, 2022 were included in this study and divided randomly the train and test sets according to the ratio of 7∶3. LASSO regression model and bidirectional stepwise regression model were used to identify risk factors, and model comparisons were conducted with net reclassification index, integrated discrimination improvement and concordance index. Univariate and multivariate Cox proportional hazard regression models were constructed, and a nomogram plot was drawn. Area under the curve (AUC) was calculated as a discriminant evaluation indicator for model validation test its calibration ability, and calibration curves were drawn to test its calibration ability.Results:No significant difference existed between LASSO regression model and bidirectional stepwise regression model, but the better bidirectional stepwise regression model was selected as the final model. The risk factors included age of onset, gender, hemoglobin A1c, estimated glomerular filtration rate, taking angiotensin receptor blocker and smoking history. AUC values (95% CI) of risk outcome prediction at year 5 and 7 were 0.700 (0.650-0.749) and 0.715(0.668-0.762) for the train set and 0.738 (0.667-0.801) and 0.723 (0.663-0.783) for the test set, respectively. The calibration curves were close to the ideal curve, and the model discrimination and calibration powers were both good. Conclusions:This study established a convenient prediction model for diabetic foot and classified the risk levels. The model has strong interpretability, good discrimination power, and satisfactory calibration and can be used to predict the incidence of diabetes foot in adult patients with type 2 diabetes to provide a basis for self-assessment and clinical prediction of diabetic foot disease risk.

Objective:To develop a prediction model for the risk of diabetic retinopathy (DR) in patients with newly diagnosed type 2 diabetes mellitus (T2DM).Methods:Patients with new diagnosis of T2DM recorded in Yinzhou Regional Health Information Platform between January 1, 2015 and December 31, 2022 were included in the study. The predictor variables were selected by using Lasso-Cox proportional hazards regression model. Cox proportional hazards regression models were used to establish the prediction model for the risk of DR. Bootstrap method (500 resamples) was used for internal validation, and the performance of the model was assessed by C-index, the receiver operating characteristic curve and area under the curve (AUC), and calibration curve.Results:The predictor variables included in the final model were age of T2DM onset, education level, fasting plasma glucose, glycated hemoglobin A1c, urinary albumin, estimated glomerular filtration rate, and history of lipid-lowering agent and angiotensin converting enzyme inhibitor uses. The C-index of the final model was 0.622, and the mean corrected C-index was 0.623 (95% CI: 0.607-0.634). The AUC values for predicting the risk of DR after 3, 5, and 7 years were 0.631, 0.620, and 0.624, respectively, with a high degree of overlap of the calibration curves with the ideal curves. Conclusion:In this study, a simple and practical risk prediction model for DR risk prediction was developed, which could be used as a reference for individualized DR screening and intervention in newly diagnosed T2DM patients.

Objective:To construct a risk prediction model for diabetes kidney disease (DKD).Methods:Patients newly diagnosed with type 2 diabetes mellitus (T2DM) between January 1, 2015, and December 31, 2022, were selected as study subjects from the Yinzhou Regional Health Information Platform in Ningbo City. The Lasso method was used to screen the risk factors, and the DKD risk prediction model was established using Cox proportional hazard regression models. Bootstrap 500 resampling was applied for internal validation.Results:The study included 49 706 subjects, with an median ( Q1, Q3) age of 60.00 (50.00, 68.00) years old, and 55% were male. A total of 4 405 subjects eventually developed DKD. Age at first diagnosis of T2DM, BMI, education level, fasting plasma glucose, glycated hemoglobin A1c, urinary albumin, past medical history (hyperuricemia, rheumatic diseases), triglycerides, and estimated glomerular filtration rate were included in the final model. The final model's C-index was 0.653, with an average of 0.654 after Bootstrap correction. The final model's area under the receiver operating characteristic curve for predicting 4-year, 5-year, and 6-year was 0.657, 0.659, and 0.664, respectively. The calibration curve was closely aligned with the ideal curve. Conclusions:This study constructed a DKD risk prediction model for newly diagnosed T2DM patients based on real-world data that is simple, easy to use, and highly practical. It provides a reliable basis for screening high-risk groups for DKD.

Objective:To discuss the inhibitory effect of chelerythrine(CHE)on the migration,invasion,and epithelial-mesenchymal transition(EMT)of the human ovarian cancer SKOV3 cells,and to clarify the associated mechanism.Methods:The SKOV3 cells were cultured in vitro and divided into control group and 2.5,5.0,10.0,20.0,and 40.0 μmol·L-1 CHE groups.Methylthiazolydiphenyl-tetrazolium(MTT)assay was used to detect the inhibitory rates of proliferation of the cells in various groups.The SKOV3 cells were cultured in vitro and divided into control group,transforming growth factor-β1(TGF-β1)group,TGF-β1+5 μmol·L-1 CHE group,and TGF-β1+10 μmol·L-1 CHE group.Cell scratch assay was used to detect the migration rates of the cells in various groups;Transwell chamber assay was used to detect the numbers of migration and invasion cells in various groups;Western blotting method was used to detect the expression levels of E-cadherin,N-cadherin,and Vimentin proteins in the cells in various groups;immunofluorescence staining method was used to detect the fluorescence intensities of E-cadherin and N-cadherin in the cells in various groups.Results:The MTT assay results showed that compared with control group,the inhibitory rates of proliferation of the cells in 5.0,10.0,20.0,and 40.0 μmol·L-1 CHE groups were significantly increased(P<0.05 or P<0.01).The cell scratch assay results showed that compared with control group,the migration rate of the cells in TGF-β1 group was increased(P<0.01);compared with TGF-β1 group,the migration rates of the cells in TGF-β1+5 μmol·L-1 CHE group and TGF-β1+10 μmol·L-1 CHE group were significantly decreased(P<0.01).The Transwell chamber assay results showed that compared with control group,the numbers of migration and invasion cells in TGF-β1 group were significantly increased(P<0.05);compared with TGF-β1 group,the numbers of migration and invasion cells in TGF-β1+5 μmo·l L-1 CHE group and TGF-β1+10 μmo·l L-1 CHE group were significantly decreased(P<0.01).The Western blotting results showed that compared with control group,the expression level of E-cadherin protein in the cells in TGF-β1 group was significantly decreased(P<0.01),while the expression levels of N-cadherin and Vimentin proteins were increased(P<0.05 or P<0.01);compared with TGF-β1 group,the expression levels of E-cadherin protein in the cells in TGF-β1+5 μmol·L-1 CHE group and TGF-β1+10 μmol·L-1 CHE group were significantly increased(P<0.01),and the expression levels of N-cadherin and Vimentin proteins were significantly decreased(P<0.01).The immunofluorescence staining results showed that compared with control group,the fluorescence intensity of E-cadherin in the cells in TGF-β1 group was decreased,and the fluorescence intensity of N-cadherin was increased;compared with TGF-β1 group,the fluorescence intensities of E-cadherin in the cells in TGF-β 1+5 μmol·L-1 CHE group and TGF-β1+10 μmol·L-1 CHE group were significantly increased,and the fluorescence intensities of N-cadherin were decreased.Conclusion:CHE can inhibit the proliferation,migration,invasion,and EMT of the human ovarian cancer SKOV3 cells.