Alzheimer's disease (AD) is a common neurodegenerative disorder among the elderly, and BuChE has emerged as a potential therapeutic target. In this study, we reported the development of compound 8e, a selective reversible BuChE inhibitor (eqBuChE IC₅₀ = 0.049 μmol/L, huBuChE IC₅₀ = 0.066 μmol/L), identified through extensive virtual screening and lead optimization. Compound 8e demonstrated favorable blood-brain barrier permeability, good drug-likeness property and pronounced neuroprotective efficacy. Additionally, 8e exhibited significant therapeutic effects in zebrafish AD models and scopolamine-induced cognitive impairments in mice. Further, 8e significantly improved cognitive function in APP/PS1 transgenic mice. Proteomics analysis demonstrated that 8e markedly elevated the expression levels of very low-density lipoprotein receptor (VLDLR), offering valuable insights into its potential modulation of the Reelin-mediated signaling pathway. Thus, compound 8e emerges as a novel and potent BuChE inhibitor for the treatment of AD, with significant implications for further exploration into its mechanisms of action and therapeutic applications.

Intentional tooth replantation (ITR) is an advanced treatment modality and the procedure of last resort for preserving teeth with inaccessible endodontic or resorptive lesions. ITR is defined as the deliberate extraction of a tooth; evaluation of the root surface, endodontic manipulation, and repair; and placement of the tooth back into its original socket. Case reports, case series, cohort studies, and randomized controlled trials have demonstrated the efficacy of ITR in the retention of natural teeth that are untreatable or difficult to manage with root canal treatment or endodontic microsurgery. However, variations in clinical protocols for ITR exist due to the empirical nature of the original protocols and rapid advancements in the field of oral biology and dental materials. This heterogeneity in protocols may cause confusion among dental practitioners; therefore, guidelines and considerations for ITR should be explicated. This expert consensus discusses the biological foundation of ITR, the available clinical protocols and current status of ITR in treating teeth with refractory apical periodontitis or anatomical aberration, and the main complications of this treatment, aiming to refine the clinical management of ITR in accordance with the progress of basic research and clinical studies; the findings suggest that ITR may become a more consistent evidence-based option in dental treatment.
Humans ; Tooth Replantation/methods* ; Consensus ; Periapical Periodontitis/surgery*

Objective Bladder cancer(BLCA)is a common disease,and the pathogenesis of which is not clear.This study aims to find the key genes of bladder cancer for future prevention and treatment.Methods The bladder cancer dataset GSE121711 was obtained from the Gene Expression Omnibus(GEO)database of NCBI.The weighted gene coexpression network analysis(WGCNA)was performed on GEO data to identify the gene modules highly associated with BLCA in the samples.The intersecting genes of differentially expressed genes(DEG)and genes in the module were extracted.The common genes were analyzed by Gene Ontology(GO)and Kyoto Encyclopedi-a of Genes and Genomes(KEGG),and the key genes with the highest degree were further screened through the Protein-protein interac-tion(PPI)network.The cluster analysis is carried out.Finally,the LASSO is used to establish the diagnostic model.The expression of hub genes in BLCA tissues and normal tissues was detected by using reverse transcription real-time quantitative polymerase chain reaction(RT-qPCR).Results WGCNA showed the most significant association between the black module and bladder cancer.There were 611 genes in the black module and intersected with DEG for 449 common genes.A diagnostic model consisting of RAC3,APOL4,FASN and CLASRP was constructed using LASSO,and analysis was conducted using receiver operating characteristic(ROC)curves at time points of 365 days(1 year),1095 days(3 years)and 1825 days(5 years).The Area Under Curve(AUC)of 365(1 year),1095(3 years)and 1825(5 years)were 80％,82％and 85％,respectively.The results were verified on the combined dataset of GSE101723 and GSE83586,which were found to be similar to those of bioinformatics.The relative expression levels of hub genes RAC3,APOL4,FASN and CLASRP mRNA in BLCA tissues were significantly higher than those in normal tissues(t=8.074,P＜0.0001;t=3.577,P＜0.001;t=12.241,P＜0.0001;t=8.846,P＜0.0001).Conclusion We constructed a BLCA diagnostic model and found that RAC3,APOL4,FASN and CLASRP were potential biomarkers that may provide new insights to improve the early diagnosis and treatment of blad-der cancer.

Objective Bladder cancer(BLCA)is a common disease,and the pathogenesis of which is not clear.This study aims to find the key genes of bladder cancer for future prevention and treatment.Methods The bladder cancer dataset GSE121711 was obtained from the Gene Expression Omnibus(GEO)database of NCBI.The weighted gene coexpression network analysis(WGCNA)was performed on GEO data to identify the gene modules highly associated with BLCA in the samples.The intersecting genes of differentially expressed genes(DEG)and genes in the module were extracted.The common genes were analyzed by Gene Ontology(GO)and Kyoto Encyclopedi-a of Genes and Genomes(KEGG),and the key genes with the highest degree were further screened through the Protein-protein interac-tion(PPI)network.The cluster analysis is carried out.Finally,the LASSO is used to establish the diagnostic model.The expression of hub genes in BLCA tissues and normal tissues was detected by using reverse transcription real-time quantitative polymerase chain reaction(RT-qPCR).Results WGCNA showed the most significant association between the black module and bladder cancer.There were 611 genes in the black module and intersected with DEG for 449 common genes.A diagnostic model consisting of RAC3,APOL4,FASN and CLASRP was constructed using LASSO,and analysis was conducted using receiver operating characteristic(ROC)curves at time points of 365 days(1 year),1095 days(3 years)and 1825 days(5 years).The Area Under Curve(AUC)of 365(1 year),1095(3 years)and 1825(5 years)were 80％,82％and 85％,respectively.The results were verified on the combined dataset of GSE101723 and GSE83586,which were found to be similar to those of bioinformatics.The relative expression levels of hub genes RAC3,APOL4,FASN and CLASRP mRNA in BLCA tissues were significantly higher than those in normal tissues(t=8.074,P＜0.0001;t=3.577,P＜0.001;t=12.241,P＜0.0001;t=8.846,P＜0.0001).Conclusion We constructed a BLCA diagnostic model and found that RAC3,APOL4,FASN and CLASRP were potential biomarkers that may provide new insights to improve the early diagnosis and treatment of blad-der cancer.

Objective:To investigate the effects of Wnt5a on the vasculogenic mimicry(VM)and cancer stem cell(CSC)properties of prostate cancer(PCa)cells by upregulating the expression of miR-141-3p.Methods:Human prostate epithelial cell line RWPE-1 and PCa cell lines PC-3,LNCaP,and DU145 were cultured.qPCR was employed to detect miR-141-3p expression,and Western blotting(WB)was used to measure Wnt5a protein levels.Stable Wnt5a-knockdown or miR-141-3p-knockdown LNCaP and DU145 cell lines were established respectively via plasmid transfection.VM formation ability was assessed by three-dimensional culture assay.Cell proliferation ability and drug sensitivity were measured by CCK-8 assay.Cell migration and invasion abilities were detected using wound healing and Transwell assays,respectively.The expressions of VM-related molecules and CSC markers were detected by qPCR and WB.Colony formation ability was determined by clonogenic assay.The proportion of CD133+cells was sorted and calculated by flow cytometry.The expressions of miR-141-3p and Wnt5a in CD133+and CD133-cells were detected by qPCR and WB.Stable Wnt5a-overexpressing PCa cell lines were constructed via plasmid transfection.The effects of Wnt5a and different Wnt pathway downstream inhibitors on miR-141-3p expression and promoter activity were detected by qPCR and dual-luciferase reporter assays.Expression of c-Jun was knocked down in Wnt5a-overexpressing cells using si-c-Jun transfection.The target binding relationship between c-Jun and the miR-141-3p promoter was verified by qPCR,dual-luciferase reporter assay,and chromatin immunoprecipitation assay.Results:The expressions of miR-141-3p and Wnt5a were significantly higher in PCa cells compared with those in RWPE-1 cells,with the highest relative expression in DU145 cells and the lowest in LNCaP cells(P<0.001).Downregulation of Wnt5a or miR-141-3p significantly inhibited VM formation ability and stemness of PCa cells,and significantly suppressed the proliferation,migration,invasion abilities,and enhanced the sensitivity to bicalutamide of PCa cells(P<0.05 or P<0.01 or P<0.001).Downregulation of Wnt5a significantly inhibited miR-141-3p expression and promoter transcriptional activity(P<0.01 or P<0.05),whereas upregulation of Wnt5a significantly promoted miR-141-3p expression and promoter transcriptional activity(P<0.01 or P<0.001).The promoting effect of Wnt5a on miR-141-3p expression and promoter transcriptional activity could be inhibited by a JNK/c-Jun pathway inhibitor(P>0.05).Downregulation of c-Jun significantly inhibited the promoting effect of Wnt5a on miR-141-3p expression and promoter transcriptional activity(P>0.05).c-Jun could bind to the-348 to-295 sequence of the miR-141-3p promoter.In absence of this fragment Wnt5a wouldn't promote miR-141-3p expression(P>0.05).Conclusion:The Wnt5a/JNK/c-Jun signaling pathway can upregulate miR-141-3p expression,and thereby promote VM formation in PCa cells,possibly by activating CSC properties.

Objective To investigate the correlation of Wnt5a expression and vasculogenic mimicry (VM) in prostate cancer tissues, and analyze their relationships with cancer stem cells (CSCs) characteristics and epithelial–mesenchymal transition (EMT). Methods Immunohistochemistry was conducted to detect the expression of Wnt5a in 50 prostate cancer tissues and 50 benign prostatic hyperplasia tissues. The expression levels of CD133, vimentin, and E-cadherin were detected in the prostate cancer tissues, and CD34/PAS double staining was used to detect VM structures. We analyzed the difference in Wnt5a level between prostate cancer and benign prostatic hyperplasia tissues, the clinical significance of Wnt5a and VM, the relationship of Wnt5a expression and VM, and the relationships of Wnt5a expression and VM with CD133, Vimentin, E-cadherin. Results The expression of Wnt5a was significantly higher in prostate cancer tissues than in benign prostatic hyperplasia (P < 0.05). A positive correlation was observed between Wnt5a expression and VM (P < 0.05). The expression levels of Wnt5a and VM were positively correlated with those of CD133 and vimentin (P < 0.05). Wnt5a expression and VM were positively correlated with Gleason score, vas deferens invasion and lymphatic metastasis (P < 0.05) of prostate cancer, and VM was also positively correlated with T stage of prostate cancer (P < 0.05). Conclusion The expression level of Wnt5a in prostate cancer tissues is elevated and positively related with VM formation. Wnt5a expression and VM are correlated with cancer stem cells characteristics and the expression of epithelial–mesenchymal transition marker proteins.

Objective:Mycoplasma genitalium (Mg) is an opportunity pathogenic microorganism mainly transmitted through sexual contact. In recent years, scholars have paid more attention to Mg infection and pathogenicity. This study was aimed to understand the condition of Mg in the genitourinary tract of different populations in China and provide evidence for further study of its pathogenic characteristics. Methods:Cross-section studies of Mg infection in the Chinese community were searched by China National Knowledge Infrastructure (CNKI), Wanfang digital database, SinoMed, Pubmed, and Web of Science from database construction to March 10 th, 2020. Studies were sifted and screened independently by two evaluators based on inclusion and exclusion criteria, and Meta-analysis was conducted with R 1.1.463. If I 2≤50%, the fixed-effect model should be adopted, if I 2>50%, the random effect model should be adopted, and through subgroup analysis, the source of heterogeneity should be found out as far as possible. Results:A total of 47 research articles were included in this article, all of which were medium and high-quality articles. There was no obvious publication bias, and the results were more reliable. The research contained 19 provinces and Hong Kong Special administrative region, including 519 healthy people, 10 504 patients from clinics or hospitals of sexual transmitted disease (STD), 3 200 on Gynecology and 1 624 on Urology, 1 082 patients with men who have sex with men(MSM), 1 842 patients with Female sex worker(FSW), and 3 691 patients with HIV/AIDS. The infection rate of Mg in the genitourinary tract of the healthy population was 0.94% (95% CI: 0.07%-2.78%), the infection rate of Mg was 11.58% (95% CI: 8.57%-14.97%), 15.22% (95% CI: 7.99%-24.27%), 7.32% (95% CI: 4.24%-11.16%) among patients from clinics or hospitals of STD, gynecology and urology respectively. The infection rate of MSM was 9.70% (95% CI: 3.06%-19.52%),the infection rate of FSW was 13.49% (95% CI: 11.97%-15.08%). The infection rate of Mg among HIV infected patients was 20.46% (95% CI: 13.67%-28.22%). Conclusions:The infection rate of Mg in a healthy population was low. Mg infection rate in the genitourinary tract of other groups was still higher, which is worthy of further attention.

Objective:To evaluate the association of hyperuricemia with the risk for chronic kidney disease (CKD) in community adults.Methods:A community-based follow-up study comprising of 7 276 adults aged 20-74 years who attended the natural population cohort in Eastern China and had no CKD at baseline survey was performed in the Songjiang district, Shanghai. CKD was diagnosed according to the National Kidney Foundation Practice Guidelines for Chronic Kidney Disease criteria. Hyperuricemia was defined as serum uric acid level >420 μmol/L for men and >360 μmol/L for women. Cox proportional hazards model was used to examine the association of hyperuricemia with the risk for CKD.Results:During a median follow-up period of 2.65 year, 301 participants were newly diagnosed with CKD. The cumulative incidence rate and incidence density of CKD were 4.14%, and 16.01/1 000 person-years (95% CI: 14.20-17.82), respectively. A higher prevalence of hyperuricemia was observed in subjects with CKD compared with those without CKD. Multivariate Cox regression model analysis showed that hyperuricemia was associated with the increased risk for CKD, with an adjusted HR of 1.92 (95% CI: 1.46-2.53). Their positive associations remained in almost all the subgroups, including sex, age (<60, ≥60 years), BMI (<25.0, ≥25.0 kg/m 2), type 2 diabetes, and hypertension. A significant synergistic effect of the interaction between age and hyperuricemia on CKD was found, and the synergy index was 1.78 (95% CI: 1.18-2.68). Conclusion:The incidence of CKD in adults in Songjiang district was relatively high. Hyperuricemia is an independent risk factor for the development of CKD.

Objective:To study the incidence and classification of chromosomal abnormalities in villi of missed abortion patients with assisted reproductive technology (ART) and natural conception (NC).Methods:Totally 637 patients with missed abortion villi from the Reproductive Center of the Third Affiliated Hospital of Zhengzhou University during January 2016 and January 2020 were collected and divided into ART group and NC group according to the mode of pregnancy in this retrospective cohort study. The ART group was further divided into artificial insemination by husband (AIH), in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Next generation sequencing (NGS) was used to detect the copy number variations (CNVs) and chromosome number abnormalities of chorionic villi of missed abortion. Results:Among 637 missed abortion chorionic villi, 45.2% (288/637) of the samples had normal chromosome and 54.8% (349/637) had abnormal chromosome. CNVs accounted for 3.8% (14/637) of the total samples, and chromosome number abnormalities accounted for 52.5% (335/637) of the total samples. The abnormal rates of villi chromosome in ART group and NC group were 59.2% (226/382) and 51.0% (130/255), respectively, and there was no significant difference between ART group and NC group ( P>0.05). The abnormal rates of villus chromosome in AIH group, IVF group and ICSI group were 52.1% (25/48), 58.9% (146/248) and 64.0% (55/86), respectively. Compared with NC group, the abnormal rate of villus chromosome in IVF group and ICSI group was increased, but there was no significant difference ( P>0.008). Conclusion:In general, ART did not increase the incidence of chromosomal abnormalities in missed abortion villi. However, compared with natural pregnancy and AIH assisted pregnancy, IVF/ICSI had a higher chromosomal abnormality in missed abortion villi.

Objective:To study the incidence and classification of chromosomal abnormalities in villi of missed abortion patients with assisted reproductive technology (ART) and natural conception (NC).Methods:Totally 637 patients with missed abortion villi from the Reproductive Center of the Third Affiliated Hospital of Zhengzhou University during January 2016 and January 2020 were collected and divided into ART group and NC group according to the mode of pregnancy in this retrospective cohort study. The ART group was further divided into artificial insemination by husband (AIH), in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Next generation sequencing (NGS) was used to detect the copy number variations (CNVs) and chromosome number abnormalities of chorionic villi of missed abortion. Results:Among 637 missed abortion chorionic villi, 45.2% (288/637) of the samples had normal chromosome and 54.8% (349/637) had abnormal chromosome. CNVs accounted for 3.8% (14/637) of the total samples, and chromosome number abnormalities accounted for 52.5% (335/637) of the total samples. The abnormal rates of villi chromosome in ART group and NC group were 59.2% (226/382) and 51.0% (130/255), respectively, and there was no significant difference between ART group and NC group ( P>0.05). The abnormal rates of villus chromosome in AIH group, IVF group and ICSI group were 52.1% (25/48), 58.9% (146/248) and 64.0% (55/86), respectively. Compared with NC group, the abnormal rate of villus chromosome in IVF group and ICSI group was increased, but there was no significant difference ( P>0.008). Conclusion:In general, ART did not increase the incidence of chromosomal abnormalities in missed abortion villi. However, compared with natural pregnancy and AIH assisted pregnancy, IVF/ICSI had a higher chromosomal abnormality in missed abortion villi.