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.

AIM:This study aimed to explore the induction of ferroptosis in non-small-cell lung cancer(NSCLC)cells by tubeimoside II(TBMS II)and to elucidate the underlying molecular mechanisms.METHODS:H460 NSCLC cells were cultured in vitro.Cell survival rates were assessed by using MTT assays,and doses of TBMS II resulting in below 50%survival were selected for further experimentation.Cell migration was evaluated using Transwell assays and the effects of TBMS II on H460 cell proliferation were assessed by colony formation assays.Flow cytometry and fluores-cence microscopy were used to assess changes in lipid peroxidation(lipid ROS),and the levels of GSH,T-AOC,MDA,and Fe2+were measured using commercial kits.Protein levels of GPX4,SLC7A11,FTH1,NCOA4,P62,and LC3 were examined using Western blot.Changes in mitochondrial structure were detected by transmission electron microscopy,and immunofluorescence was used to assess LC3 co-localization of FTH1 and NCOA4,as well as co-localization of LC3 and NCOA4 with lysosomes.RESULTS:Compared with the control group,TBMS II dose-dependently reduced H460 cell via-bility,migration,and clone formation,accompanied by the appearance of vacuoles within the cells.TBMS II treatment al-so led to decreased GSH and T-AOC levels,while increasing the cellular contents of MDA,indicating oxidative stress.Ad-ditionally,there was a decrease in the expression of the antioxidant proteins SLC7A11 and GPX4 in the cells,while lipid ROS and Fe2+levels were increased in proportion to the TBMS II concentration.The ferroptosis inhibitor ferrostatin-1 re-versed cell death caused by TBMS II,suggesting ferroptosis induction.Furthermore,increasing the TBMS II concentra-tion resulted in an upregulation of the autophagy marker proteins LC3 II/LC3 I and P62,indicative of increased autopha-gy.TBMS II also affected mitochondrial morphology in the cells,as seen in reduced mitochondrial fluorescence intensity.Protein expression of NCOA4 increased with higher TBMS II concentrations,while that of FTH1 decreased.Co-localiza-tion of LC3 II with FTH1 and NCOA4,as well as the lysosomal association of LC3 II and FTH1,also increased in a dose-dependent manner.CONCLUSION:TBMS II induces ferritinophagy in H460 cells,leading to decreased cell viability and increased ferroptosis.

AIM:To study whether glycyrrhizic acid(GL)can resist the ototoxicity of cisplatin(CDDP)in mice and its molecular mechanism.METHODS:Male C57BL/6J mice were divided into 5 groups:control group,DMSO(5%)group,CDDP(4 mg/kg)group,CDDP+low-dose(50 mg/kg)GL group,and CDDP+high-dose(100 mg/kg)GL group(n=14).Auditory brainstem response(ABR)was used to detect hearing changes of mice.HE staining was used to observe the morphological change of cochlear stria vascular in mice.Evans blue(EB)staining was used to observe the per-meability change of the blood-labyrinth barrier(BLB).Immunohistochemical technique was used to detect the expression and distribution of adhesion protein VE-cadherin and tight junction protein ZO-1 on the cochlear stria.ELISA assay and immunofluorescence technology were employed to detect the expression of tumor necrosis factor-α(TNF-α)and interleu-kin-1β(1L-1β).RESULTS:In CDDP group,ABR waveforms of all frequencies were disturbed,the hearing threshold was significantly increased,and I wave latency was prolonged(P＜0.05).In CDDP+GL group,ABR waveforms of various frequencies were well differentiated,the hearing threshold was significantly decreased,and the latency of I-wave was shortened(P＜0.01).The disordered morphology and more vacuoles in the stria vascularis were observed by HE staining in CDDP group.The GL alleviated CDDP-induced damage in the stria vascularis.In EB staining,CDDP caused an increase in per-meability of BLB(P＜0.01),which was improved by GL treatment(P＜0.01).Immunohistochemical results showed that the expression of VE-cadherin and ZO-1 in CDDP group were decreased(P＜0.01),which was restored in CDDP+GL group(P＜0.01).The ELISA and immunofluorescence results showed that the expression of IL-1β and TNF-α was in-creased after CDDP treatment(P＜0.01),which was restored in CDDP+GL group(P＜0.01).CONCLUSION:The GL alleviates CDDP-induced hearing loss in mice by inhibiting CDDP-induced inflammation and reducing the permeability of BLB.

Objective:To evaluate the healthcare accessibility and quality of diagnosis and treatment services of Internet hospitals in China.Methods:One hundred and eighty Internet hospitals in 60 cities were seleted based on the sampling of development levels in the eastern, central and western regions of China. From April to May 2023, standardized patients methodology was applied to evaluate the accessibility(including the number of Internet hospitals, functional settings, online doctor status, the doctor′s attending rate and consultation fees) and diagnosis and treatment service quality(including the diagnosis and treatment services quality, response speed and patient′s evaluation) of Internet hospitals.Results:The average opening rate of Internet hospitals in China was 52.9% (560/1 058), the average online rate of doctors was 64.2% (1 099/1 713), the average doctor′s attending rate was 33.6% (112/333), the average consultation fee was 4.85 yuan, the average score of consultation was 1.92 out of 9, the average score of diagnosis and treatment was 1.12 out of 4, the average score of the response speed was 1.70 out of 3, and patient satisfaction was 2.73 out of 3.Conclusions:The Internet hospital accessibility in China is unevenly developed, and the overall quality of diagnosis and treatment is low. It is recommended to accurately position and optimize the function of Internet hospital, establish the incentive mechanism for online consultation doctors, construct and improve the regulatory system of Internet hospital diagnosis and treatment, so as to improve the accessibility and quality of diagnosis and treatment of Internet hospitals.

ObjectiveTo explore the mechanism of Huangqisan （HQS） in regulating autophagy to alleviate hepatic steatosis and improve non-alcoholic fatty liver disease （NAFLD） based on adenosine 5'-monophosphate-activated protein kinase （AMPK）/mammalian target of rapamycin （mTOR） signaling pathway. MethodThe main chemical components and targets of HQS and NAFLD-related targets were collected from database and the intersection targets were used for Gene Ontology （GO） functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment analysis. The protein-protein interaction （PPI） network was constructed， and in vivo experimental verification was conducted. Sixty C57BL/6J male mice were randomly divided into normal control group （NCD）， model group high-fat diet （HFD）， metformin group （MET， 0.25 g·kg^-1）， low-dose Huangqisan group （HQS-L， 0.5 g·kg^-1）， and the high-dose Huangqisan group （HQS-H， 1 g·kg^-1）， with 12 mice in each group after a one-week acclimatization period. NAFLD model was induced by HFD， and intragastric administration was performed at the same time， once a day for 13 weeks. Random blood glucose， serum total cholesterol （TC）， triglyceride （TG）， non-esterified fatty acid （NEFA）， low density lipoprotein-chdesterol （LDL-C） levels， and liver TG content were determined. The liver weight was weighed， and liver index was calculated. Hematoxylin-eosin （HE） staining， oil red O staining， transmission electron microscope （TEM）， real-time fluorescence quantitative polymerase chain reaction （Real-time PCR）， and Western blot were used to verify the effect and reveal the potential mechanism of C57BL/6J mice in vivo. ResultThrough network pharmacology analysis， combined with previous studies， it was predicted that HQS may improve NAFLD by regulating autophagy via the AMPK/mTOR signaling pathway. The result of in vivo experiment showed that， as compared with NCD group， random blood glucose， body weight， serum TC， LDL-C， NEFA， liver weight， liver index， and liver TG content of mice in the HFD groups were significantly increased （P<0.01）. HE staining showed massive lipid droplets （LDs） vacuolated， oil red O staining showed lipid accumulation in liver cells， and no obvious autophagosomes and autolysosome were observed under TEM. The relative mRNA expression of LC3A、LC3B、AMPKα1 and protein expression of AMPK， phosphory phosphorylated（p）-AMPK， and p-AMPK/AMPK were significantly down-regulated （P<0.01）， while the protein expression of microtubule-associated protein 1 light chain 3 （LC3）Ⅱ/Ⅰ and p-mTOR was significantly up-regulated （P<0.01）. As compared with HFD groups， liver weight， serum TG， and NEFA levels in HQS-L and HQS-H groups were significantly deceased （P<0.05， P<0.01）. HE staining and oil red O staining showed the improvement of liver pathological changes after HQS administration. Under TEM， a small amount of autophagosome and autolysosome were observed. Besides， liver index was significantly decreased in the HQS-L group （P<0.01）， and random blood glucose， serum TC level and liver TG content were significantly decreased in the HQS-H group （P<0.05）. The results of Western blot and Real-time PCR showed that the mRNA expression of LC3A and LC3B and the protein expression of LC3Ⅱ/Ⅰ， p-AMPK， and p-AMPK/AMPK were significantly up-regulated （P<0.01）， while the mRNA expressions of p62 and protein expression of p62 and p-mTOR were significantly down-regulated （P<0.05， P<0.01）. ConclusionHQS may promote autophagy and restore autophagy flux via the AMPK/mTOR signaling pathway to alleviate hepatic steatosis improving NAFLD.

Objective: To investigate the smartphone addiction among college students during the Coronavirus Disease 2019 (COVID-19) pandemic and its association with daily behaviors and mental health,and to provide reference for heath education and psychological counseling for college students. Methods: An observational study using online quyestionnaire was conducted among 10 357 college students of two provincial medical schools in Guangdong and Shanxi Province from February 24th to March 4th in 2020. Participants were investigated on demographic information, smartphone addiction, daily routine, physical activity, weight status, anxiety, and other health information. Logistic regression with inverse probability treatment weighting (IPTW) based on propensity score was used to analyze the association between smartphone addiction with daily behavior and mental health. Results: The prevalence of smartphone addiction was 59.42%. The prevalence of phone addiction was higher in postgraduates, senior undergraduates, students with non-medical major, students living in GuangDong and those without regular exercise habit before vacation(χ 2=47.91，17.78，42.75，138.58，P<0.05). With IPTW, there were significant associations between smartphone addiction and late bedtimes (OR=1.82, 95%CI=1.66-1.98) and wake-up times (OR=1.55, 95%CI=1.44-1.68), more sedentary behaviors (OR=1.21, 95%CI=1.12-1.31), less moderate to vigorous physical activity (OR=1.33, 95%CI=1.22-1.44), anxiety (OR=2.98, 95%CI=2.52-3.40), weight gain(OR=1.27，95%CI=1.17-1.37) and other detrimental daily behavior and feelings. Conclusion High prevalence of smartphone addiction has been observed during the COVID-19 pandemic, with impaired daily behavior and mental health.

Objective:To explore influence on physical development of children aged 18 months from HIV-positive mothers for prevention mother to child transmission of HIV (PMTCT) in Guangxi Zhuang autonomous region, and provide evidence for the improvement PMTCT program.Methods:This retrospective case control study was conducted in 554 HIV negative infants aged 18 months whose HIV positive mothers had received PMTCT services reported through PMTCT system database from January 1, 2010 to December 31, 2017 and 1 109 healthy infants born in 2017, whose mothers were healthy, in Lingshan, Luzhai, and Hengxian counties, ranking top three counties with high HIV infection prevalence, in Guangxi. PMTCT data and physical development data such as height, weight and head circumference of children aged 18 months were collected. The physical dysplasia in the infants was defined as at least one of the three main indicators of height, weight and head circumference below the normal range.Results:The number of HIV-positive mother and their infants in the case group were 667 and 554 respectively, and the PMTCT rates were 91.15 % (608/667) and 96.57 % (535/554) respectively. HIV positive rate, mortality rate and mother to child transmission rate of the infants aged 18 months were 1.44 % (8/554), 3.07 % (17/554) and 1.91 % (8/418) respectively, and the physical examination results of the infants aged 18 months showed that the physical dysplasia rate was 30.51 % (169/554). Among the 1 109 infants in the control group, the physical dysplasia rate was 9.83 % (109/1 109). The difference between the case group and the control group was significant ( P<0.01). Conclusion:The PMTCT rates of HIV positive mother and their children were more than 90.00 %, respectively. However, poor physical development rate of infants aged 18 months were more than 30.00 %. The possible influence of PMTCT on physical development of the infants aged 18 months of HIV positive mother’s needs to be further studied.

Objective:To understand the characteristics and associated factors of newly reported HIV/AIDS cases with non-marital or non-commercial heterosexual transmission, in Guangxi Zhuang Autonomous Region (Guangxi), 2015-2018.Methods:Information of newly reported HIV/AIDS cases aged ≥18 years in Guangxi between 2015 and 2018 was collected from the National Comprehensive HIV/AIDS Information System. Unconditional logistic regression model was used to access those factors that were associated with HIV infections through non-marital or non-commercial heterosexual contact.Results:Between 2015 and 2018, a total number of 35 497 HIV/AIDS cases, aged ≥18 years were newly reported in Guangxi. Among them, 32 648 (92.0 %) were infected heterosexually while 10 500 were infected through non-marital or non-commercial heterosexual behavior. Non-marital or non-commercial heterosexual transmission accounted for 29.6 % (10 500/35 497) of the newly reported HIV/AIDS cases, and 32.2 % (10 500/32 648) of those with heterosexual transmission. Males counted for 53.5 % (5 617/10 500) of non-marital or non-commercial heterosexual transmission and males to females ratio was 1.2∶1 (5 617∶4 883). Those married or had regular sexual partners counted for 55.9 % (5 873/10 500). Commercial heterosexual transmission appeared the main mode of HIV transmission for males (64.4 %,16 516/25 633) while main mode for females was non-marital or non-commercial heterosexual transmission and counted for 49.5 % (4 883/9 864). Results from the multivariate logistic regression analysis showed that adjusted OR of female HIV/AIDS infected HIV via non-marital or non-commercial heterosexual transmission, was 3.98 times (95 %CI: 3.78-4.20) hight than that of males. Among the group aged<50 years and the aged 50-59 years, the adjusted ORs were 1.35 times (95 %CI: 1.27-1.44) and 1.13 times (95 %CI: 1.05-1.21) hight than that of aged ≥60 years. Those who were single/divorced/widowed, the adjusted OR was 1.53 times (95 %CI: 1.45-1.61) hight than that of those married/regular partners. Those with junior high school education, high school education and above the adjusted ORs were 1.22 times (95 %CI: 1.16-1.29) and 1.18 times (95 %CI: 1.10-1.27), compared to those only with education levels of primary school or below. Conclusions:The number of HIV/AIDS cases via non-marital or non-commercial heterosexual transmission accounted for nearly 30.0 % of all the routes of HIV transmission in Guangxi, 2015-2018. Female, aged<60 years old, single/divorced/widowed and having had junior and above high school education etc., appeared as risk factors on non-marital or non-commercial heterosexual transmission, among newly reported HIV/AIDS in Guangxi.

Objective? To evaluate the Chinese version of Glaucoma Quality of Life 17 (Glau-QoL17) by item analysis on each item using item response theory(IRT), so as to provide tools in life quality evaluation in patients with glaucoma in China. Methods? By convenience sampling, 198 glaucoma patients admitted in the outpatient department of Opthalmic Center affiliated to Sun Yat-Sen University from May 2017 to July 2018 were selected and their life quality were evaluated by using the Chinese version of Glau-QoL17. MULTILOG 7.0 was used to analyze the collected data in IRT and calculate the discrimination and difficulty parameters of each item. Results? The Chinese version of Glau-QoL17 had good discrimination. The discrimination parameter (α) ranged from 1.50 to 5.23, and the difficulty increased monotonously. Except for the entry "Are you afraid of surgeries?", the other items ranged from-3 to 3; the coverage area under the item information curve was relatively large except for item "Currently, I am very well-informed about my visual problems." Conclusions? The Chinese version of Glau-QoL17 can be used in the evaluation of the glaucoma patients' quality of life in our country, however, it still needs further modification on its content so as to improve the accuracy of the evaluation.