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: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 observe the correlations of quantitative 99Tcm-methoxyisobutylisonitrile(99Tcm-MIBI)SPECT/CT imaging parameters,functional markers and disease severity of primary hyperparathyroidism(PHPT)related to parathyroid adenoma.Methods Fifty-eight patients with PHPT due to single parathyroid adenoma were retrospectively collected,clinical data including serum parathyroid hormone(PTH)levels were recorded,and quantitative 99Tcm-MIBI SPECT/CT imaging parameters were obtained.According to serum calcium level reflecting disease severity(2.55-2.80 mmol/L or＞2.80 mmol/L),the patients were categorized into type Ⅰ group(n=25)and type Ⅱ group(n=33).Quantitative metabolic parameters of lesions,i.e.standard uptake value(SUV)values(the maximum SUV[SUVmax],the mean SUV[SUVmean],the peak SUV[SUVpeak]),SUV values normalized by lean body mass(SUL,including the maximum SUL[SULmax],the mean SUL[SULmean]and the peak SUL[SULpeak]),total lesion volume(TLV)and total lesion uptake(TLU),as well as derived parameters such as lesion to background ratio(LBR)contrast to contralateral deltoid muscle and lesion density(LD)were obtained from reconstructed images and compared between groups.The area under curves(AUC)of the receiver operating characteristic(ROC)curves were used to evaluate the performance of each index and their combined logistic regression model for distinguishing the severity of PHPT.Results The serum PTH and serum calcium levels in type Ⅰ group were both significantly lower than those in type Ⅱ group(both P＜0.05).No statistically significant difference of detection rate of parathyroid adenoma with PHPT was found between 99Tcm-MIBI SPECT/CT and planar imaging(96.56％vs.91.38％,P=0.063).TLV and TLU were weakly correlated with serum PTH(rs=0.416,0.422)and serum calcium levels(rs=0.391,0.349)(all P＜0.05).TLV and TLU values in type Ⅰgroup were significantly lower than those in type Ⅱ group(both P＜0.05).The AUC of PTH,TLV and TLU for differentiating type Ⅰ and type Ⅱ PHPT related to parathyroid adenoma was 0.770,0.741 and 0.716,respectively,of the combination of all the three was 0.790,and no statistical difference was detected(Z=0.361-1.454,all P＞0.05).Conclusion 99Tcm-MIBI SPECT/CT quantitative metabolic parameters TLV and TLU could be used to evaluate the functional status of parathyroid and severity of PHPT related to parathyroid adenoma.

Objective To observe the correlations of quantitative 99Tcm-methoxyisobutylisonitrile(99Tcm-MIBI)SPECT/CT imaging parameters,functional markers and disease severity of primary hyperparathyroidism(PHPT)related to parathyroid adenoma.Methods Fifty-eight patients with PHPT due to single parathyroid adenoma were retrospectively collected,clinical data including serum parathyroid hormone(PTH)levels were recorded,and quantitative 99Tcm-MIBI SPECT/CT imaging parameters were obtained.According to serum calcium level reflecting disease severity(2.55-2.80 mmol/L or＞2.80 mmol/L),the patients were categorized into type Ⅰ group(n=25)and type Ⅱ group(n=33).Quantitative metabolic parameters of lesions,i.e.standard uptake value(SUV)values(the maximum SUV[SUVmax],the mean SUV[SUVmean],the peak SUV[SUVpeak]),SUV values normalized by lean body mass(SUL,including the maximum SUL[SULmax],the mean SUL[SULmean]and the peak SUL[SULpeak]),total lesion volume(TLV)and total lesion uptake(TLU),as well as derived parameters such as lesion to background ratio(LBR)contrast to contralateral deltoid muscle and lesion density(LD)were obtained from reconstructed images and compared between groups.The area under curves(AUC)of the receiver operating characteristic(ROC)curves were used to evaluate the performance of each index and their combined logistic regression model for distinguishing the severity of PHPT.Results The serum PTH and serum calcium levels in type Ⅰ group were both significantly lower than those in type Ⅱ group(both P＜0.05).No statistically significant difference of detection rate of parathyroid adenoma with PHPT was found between 99Tcm-MIBI SPECT/CT and planar imaging(96.56％vs.91.38％,P=0.063).TLV and TLU were weakly correlated with serum PTH(rs=0.416,0.422)and serum calcium levels(rs=0.391,0.349)(all P＜0.05).TLV and TLU values in type Ⅰgroup were significantly lower than those in type Ⅱ group(both P＜0.05).The AUC of PTH,TLV and TLU for differentiating type Ⅰ and type Ⅱ PHPT related to parathyroid adenoma was 0.770,0.741 and 0.716,respectively,of the combination of all the three was 0.790,and no statistical difference was detected(Z=0.361-1.454,all P＞0.05).Conclusion 99Tcm-MIBI SPECT/CT quantitative metabolic parameters TLV and TLU could be used to evaluate the functional status of parathyroid and severity of PHPT related to parathyroid adenoma.

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.