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.

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 To explore the determination of nicotine in cigarettes by fluorescein and fluorimetry-basic possession of bonuses system.Methods Nicotine could interfere with fluorescence energy transfer between fluorimetry-basic possession of bonuses.A new way of energy transfer was established to determinate nicotine according to the fluorescence increment of fluorimetry.Results The linear range was 0.2-7.0 mg/L for the concentration of nicotine.The correlative coefficient was 0.9992.The detection limit was 0.18 mg/L.The recovery rates were 99.0 %-105 %,and RSDs were 1.1 %-4.8 % respectively.Conclusion This method is simple,fast,accurate and sensitive.It can be used to determinate nicotine in cigarettes.

Objective:To investigate the application valve of bFGF to improve the viability of subdermal vascular network flap.Methods:Four white healthy pigs were used,each pig had 6 SVNF on back,16cm?4cm,totally 24 flaps were divided randomly into 2 groups:The bFGF groups and the control groups.On postoperative day 6,we observed the appearance of the flaps.The survival area of each flap was measured and the flap was harvested for histological analysis and the density of angiogenesis was also examined.Results:On postoperative day 6,the survival rates of the bFGF group and the control group were (81.2?1.7)% and (66.2?1.8)% respectively,the angiogenesis density of the middle and the distal segment in the bFGF group was (16.7?6.0)/mm2,(29.7?5.5)/mm2,(14.9?6.0)/mm2 respectively,while (16.6?4.0)/mm2,(21.4?5.2)/mm2,(3.5?5.1)/mm2 respectively in the control group.The bFGF group was superior to the control group in the appearance and histological analysis of the flaps.Conclusion:The results suggest that the injection of bFGF locally can promote the survival rate by accelerating the blood circulation of the SVNF’ bottom and edge,shorten the division time of SVNF and broaden the ratio of length and width.

Objective To compare curative effects between posterior approach microendoscopic discectomy (MED) and traditional open discectomyin the treatment of lumbar spinal stenosis (LSS). Methods A total of 70 cases of lumbar spinal stenosis from October 2000 to December 2002 were divided into two groups: the MED Group ( n =30) and the Open Group ( n =40). Curative outcomes were compared between the two groups. Results The rate of excellent or good results was 93.3% in the MED Group (28/30) and 90.0% in the Open Group (36/40), without statistically significant difference ( ? 2 =0.819, P =0.664). The operation time was significantly shorter in the MED Group than in the Open Group ( t =2.295, P =0.025). The intraoperative blood loss was significantly less in the MED Group than in the Open Group ( t =-42.344, P =0.000). The time to normal activities in the MED Group was significantly shorter than that in the Open Group ( t =-30.123, P =0.000). Conclusions Curative effects of MED are identical with those of traditional surgery in the treatment of lumbar spinal stenosis, but shorter operation time, less blood loss and quicker postoperative recovery are achieved in MED.