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 explore the mediating effect of sleep quality between somatic symptoms and severity of depression in patients with depression. Methods A total of 384 drug-naive patients diagnosed with depression were recruited from the Department of Psychological Medicine of Zhongshan Hospital, Fudan University, during the period from February to August 2024. The severity of depression, somatic symptoms, and sleep quality were assessed using Patient Health Qusetionaire (PHQ)-9, PHQ-15, and Pittsburgh sleep quality index (PSQI), respectively. Based on the PHQ-15 scores, all participants were stratified into two groups: a mild somatic symptoms group（＜10 points, n＝136）and a moderate-to-severe somatic symptoms group（≥10 points, n＝248）. Comparisons of sleep quality between the two groups were conducted, and partial correlation analysis was performed to examine the correlation between sleep quality and somatic symptoms. Additionally, linear regression and mediation analyses were conducted to investigate the mediating effect of sleep quality between somatic symptoms and severity of depression. Results The PSQI scores in moderate-to-severe somatic symptoms group were significantly higher than those in mild somatic symptoms group (P＜0.001). Partial correlation analysis indicated that, after controlling for depression severity, the positive correlation between PSQI and PHQ-15 scores remained significant in both groups (P＜0.01). Regression analysis identified both sleep quality and somatic symptoms as predictors of severity of depression (P＜0.001). Additionally, mediation analysis demonstrated that sleep quality partially mediated the relationship between somatic symptoms and severity of depression, accounting for 26.63% (0.090/0.338) of the total effect. Conclusions In patients with depression, sleep quality is associated with somatic symptoms, and both contribute to an increased risk of the severity of depression. Moreover, sleep quality plays a partial mediating effect between somatic symptoms and severity of depression, highlighting the importance of addressing sleep-related issues in the management of depression.

Objective To investigate the expression characteristics of poly(rC)-binding protein 1(PCBP1)in gastric cancer tissues and their clinical significances by bioinformatics analysis combined with experimental verification,and to identify its relationship with STIP1 homology and U-Box containing protein 1(STUB1).Specifically,this study aims to verify the expression patterns of PCBP1 and STUB1 in gastric cancer and determine their relationships with clinicopathological features by immunohistochemistry to provide a theoretical framework as well as potential intervention strategies for gastric cancer.Methods Data of PCBP1 expression in gastric cancer and adjacent tissues were obtained from TIMER 2.0 online analysis website.KEGG pathway enrichment analysis was performed using gastric cancer data(STAD)in the TCGA(the Cancer Genome Atlas)database,and its potential mechanism was determined.The main regulatory factor STUB1 was found in the fer-roptosis regulatory pathway.Subsequently,PCBP1 and STUB1 expressions in 33 cases of gastric cancer tissues and corresponding adjacent tissues were detected by immunohistochemistry.The collected cases were grouped according to different degrees of differentiation,age,gender,tumor size,depth of tumor invasion,TNM stage and pathological morphology.The positive expression rates of PCBP1 and STUB1 were observed.The correlation between the two proteins and the correlation between clinical and pathological features were analyzed by c2 test.Finally,the relationship between PCBP1 and STUB1 and malignancy of gastric cancer was further explored.Results Immunohistochemical results showed that the positive expression rate of PCBP1 in cancer tissues was 69.7%,which was significantly higher than that in adjacent tissues(48.5%).The positive expression rate of STUB1 in cancer tissues was 39.4%,which was lower than that in adjacent tissues(54.5%),statistically significant difference(P<0.05).The positive expression rate of PCBP1 was correlated with tumor differentiation,lymph node metastasis and Lauren classification(P<0.05),but not with patient's age,gender,depth of inva-sion,clinical stage,nerve infiltration,and intravascular tumor thrombus(P>0.05).The positive expression rate of STUB1 was correlated with tumor differentiation,depth of invasion,lymph node metastasis and Lauren classification(P<0.05).The Spearman correlation coefficient between PCBP1(cancer)and STUB1(cancer)was-0.413,with P=0.017(P<0.05),indicating that there was a significant negative correlation between them.Conclusion PCBP1 participates in the malignant progression of gastric cancer by regulating the main regulator STUB1 in the ferroptosis pathway.Theoretically,it provides a new insight into molecular mechanism as well as a potential therapeutic strategy for treating gastric cancer.

Background and Aims:Whether to close mesenteric fissures during laparoscopic radical resection of colorectal cancer remains controversial.Traditional suture closure is technically demanding and may injure mesenteric vessels.This study aimed to evaluate the safety and efficacy of using α-cyanoacrylate medical glue to close mesenteric fissures during laparoscopic colorectal cancer surgery.Methods:A retrospective analysis was conducted on patients who underwent laparoscopic radical resection of colorectal cancer in the Department of Colorectal Surgery,the Sixth Affiliated Hospital of Sun Yat-sen University,from January 2022 to December 2023.Seventy-eight patients who received intraoperative α-cyanoacrylate glue closure of mesenteric fissures were included as the observation group,and 74 patients without fissure closure were selected as the control group using the propensity score matching method.Perioperative parameters,postoperative recovery,and complications were compared between the two groups.Results:No significant differences were observed in baseline characteristics or main intraoperative variables between groups(all P>0.05).The observation group had significantly less ascitic drainage within 3 days after operation[(203.14±116.44)mL vs.(384.53±243.89)mL,P<0.01]and shorter postoperative gas passage,defecation,and drainage tube removal times(all P<0.01).The incidence of postoperative complications and intestinal obstruction was comparable between groups(all P>0.05).Multivariate analysis showed that intraoperative application of α-cyanoacrylate glue was an independent promoting factor for intestinal exhaust within 3 days after surgery(OR=5.739,P=0.000).Conclusion:The use of α-cyanoacrylate medical glue for closing mesenteric fissures during laparoscopic radical resection of colorectal cancer is safe and feasible.It effectively reduces postoperative ascitic drainage and accelerates bowel recovery,offering a simple and reliable alternative to traditional suture closure.

Objective:To investigate the relationship between thoracic aortic calcification (TAC) and autonomic nervous system (ANS) function in patients receiving continuous ambulatory peritoneal dialysis (CAPD).Methods:It was a cross-sectional study. The CAPD patients with dialysis duration >6 months between January and December 2022 were retrospectively enrolled. The baseline clinical data, heart rate variability (HRV) data such as standard deviation of all normal to normal intervals (SDNN), root mean square of successive differences between adjacent normal-to-normal intervals (RMSSD), high frequency (HF), very low frequency (VLF), low frequency (LF), LF/HF, acceleration capacity (AC) and deceleration capacity (DC), and skin sympathetic nerve activity (SKNA) were collected. TAC was defined as TAC score (TACS) >100 AU. The patients were divided into TACS >100 AU group and TACS≤100 AU group based on whether the thoracic aorta was calcified. The differences of those data between the two groups were compared. Logistic regression model was used to analyze the related factors of TAC. Spearman correlation analysis method was used to analyze the correlation between peripheral blood neuropeptide Y, ANS parameters, average amplitude SKNA (aSKNA) and TACS.　Cox regression model was used to analyze the risk factors of all-cause mortality in patients with CAPD.Results:The study included 106 CAPD patients with 50 males (47.2%), age of (46.04±11.10) years and dialysis duration of (41.55±30.52) months. TACS>100 AU group exhibited significantly lower heart rate ( t=2.015, P=0.046), DC ( t=2.131, P=0.035), LF/HF ( Z=3.332, P<0.001) and ln(LF/HF) ( t=3.326, P=0.001), and higher AC ( t=-2.392, P=0.019) than TACS≤100 AU group. Multivariate logistic regression analysis results showed that after adjusting for age and eosinophil count, lnVLF ( OR=0.66, 95% CI 0.45-0.98, P=0.038), lnLF ( OR=0.69, 95% CI 0.49-0.97, P=0.032), DC ( OR=0.79, 95% CI 0.64-0.99, P=0.039) and AC ( OR=1.32, 95% CI 1.04-1.68, P=0.021) were independently correlated with the risk of TAC. Spearman correlation analysis showed that neuropeptide Y level in peripheral blood was correlated with aSKNA ( r=0.23, P=0.017), lnSDNN ( r=-0.20, P=0.036) and TACS ( r=0.19, P=0.048). During the follow-up period of (25.8±4.2) months, 5 patients (4.72%) died, including 1 patient in the TACS≤100 AU group and 4 patients in the TACS>100 AU group. Compared with the survival group, the death group had higher TACS ( Z=-2.262, P=0.024) and lower LF/HF ( Z=-2.750, P=0.006). Cox regression analysis results showed that increased ln(LF/HF) was an independent influencing factor for all-cause mortality in CAPD patients ( HR=0.22, 95% CI 0.05-0.83, P=0.026). Conclusions:HRV parameters (lnVLF, lnLF, AC and DC) of CAPD patients are independently associated with TAC. The dysfunction of ANS in CAPD patients (especially the decreased vagus nerve activity) may promote TAC.

Objective To investigate the expression characteristics of poly(rC)-binding protein 1(PCBP1)in gastric cancer tissues and their clinical significances by bioinformatics analysis combined with experimental verification,and to identify its relationship with STIP1 homology and U-Box containing protein 1(STUB1).Specifically,this study aims to verify the expression patterns of PCBP1 and STUB1 in gastric cancer and determine their relationships with clinicopathological features by immunohistochemistry to provide a theoretical framework as well as potential intervention strategies for gastric cancer.Methods Data of PCBP1 expression in gastric cancer and adjacent tissues were obtained from TIMER 2.0 online analysis website.KEGG pathway enrichment analysis was performed using gastric cancer data(STAD)in the TCGA(the Cancer Genome Atlas)database,and its potential mechanism was determined.The main regulatory factor STUB1 was found in the fer-roptosis regulatory pathway.Subsequently,PCBP1 and STUB1 expressions in 33 cases of gastric cancer tissues and corresponding adjacent tissues were detected by immunohistochemistry.The collected cases were grouped according to different degrees of differentiation,age,gender,tumor size,depth of tumor invasion,TNM stage and pathological morphology.The positive expression rates of PCBP1 and STUB1 were observed.The correlation between the two proteins and the correlation between clinical and pathological features were analyzed by c2 test.Finally,the relationship between PCBP1 and STUB1 and malignancy of gastric cancer was further explored.Results Immunohistochemical results showed that the positive expression rate of PCBP1 in cancer tissues was 69.7%,which was significantly higher than that in adjacent tissues(48.5%).The positive expression rate of STUB1 in cancer tissues was 39.4%,which was lower than that in adjacent tissues(54.5%),statistically significant difference(P<0.05).The positive expression rate of PCBP1 was correlated with tumor differentiation,lymph node metastasis and Lauren classification(P<0.05),but not with patient's age,gender,depth of inva-sion,clinical stage,nerve infiltration,and intravascular tumor thrombus(P>0.05).The positive expression rate of STUB1 was correlated with tumor differentiation,depth of invasion,lymph node metastasis and Lauren classification(P<0.05).The Spearman correlation coefficient between PCBP1(cancer)and STUB1(cancer)was-0.413,with P=0.017(P<0.05),indicating that there was a significant negative correlation between them.Conclusion PCBP1 participates in the malignant progression of gastric cancer by regulating the main regulator STUB1 in the ferroptosis pathway.Theoretically,it provides a new insight into molecular mechanism as well as a potential therapeutic strategy for treating gastric cancer.

Background and Aims:Whether to close mesenteric fissures during laparoscopic radical resection of colorectal cancer remains controversial.Traditional suture closure is technically demanding and may injure mesenteric vessels.This study aimed to evaluate the safety and efficacy of using α-cyanoacrylate medical glue to close mesenteric fissures during laparoscopic colorectal cancer surgery.Methods:A retrospective analysis was conducted on patients who underwent laparoscopic radical resection of colorectal cancer in the Department of Colorectal Surgery,the Sixth Affiliated Hospital of Sun Yat-sen University,from January 2022 to December 2023.Seventy-eight patients who received intraoperative α-cyanoacrylate glue closure of mesenteric fissures were included as the observation group,and 74 patients without fissure closure were selected as the control group using the propensity score matching method.Perioperative parameters,postoperative recovery,and complications were compared between the two groups.Results:No significant differences were observed in baseline characteristics or main intraoperative variables between groups(all P>0.05).The observation group had significantly less ascitic drainage within 3 days after operation[(203.14±116.44)mL vs.(384.53±243.89)mL,P<0.01]and shorter postoperative gas passage,defecation,and drainage tube removal times(all P<0.01).The incidence of postoperative complications and intestinal obstruction was comparable between groups(all P>0.05).Multivariate analysis showed that intraoperative application of α-cyanoacrylate glue was an independent promoting factor for intestinal exhaust within 3 days after surgery(OR=5.739,P=0.000).Conclusion:The use of α-cyanoacrylate medical glue for closing mesenteric fissures during laparoscopic radical resection of colorectal cancer is safe and feasible.It effectively reduces postoperative ascitic drainage and accelerates bowel recovery,offering a simple and reliable alternative to traditional suture closure.

Objective:To investigate the relationship between thoracic aortic calcification (TAC) and autonomic nervous system (ANS) function in patients receiving continuous ambulatory peritoneal dialysis (CAPD).Methods:It was a cross-sectional study. The CAPD patients with dialysis duration >6 months between January and December 2022 were retrospectively enrolled. The baseline clinical data, heart rate variability (HRV) data such as standard deviation of all normal to normal intervals (SDNN), root mean square of successive differences between adjacent normal-to-normal intervals (RMSSD), high frequency (HF), very low frequency (VLF), low frequency (LF), LF/HF, acceleration capacity (AC) and deceleration capacity (DC), and skin sympathetic nerve activity (SKNA) were collected. TAC was defined as TAC score (TACS) >100 AU. The patients were divided into TACS >100 AU group and TACS≤100 AU group based on whether the thoracic aorta was calcified. The differences of those data between the two groups were compared. Logistic regression model was used to analyze the related factors of TAC. Spearman correlation analysis method was used to analyze the correlation between peripheral blood neuropeptide Y, ANS parameters, average amplitude SKNA (aSKNA) and TACS.　Cox regression model was used to analyze the risk factors of all-cause mortality in patients with CAPD.Results:The study included 106 CAPD patients with 50 males (47.2%), age of (46.04±11.10) years and dialysis duration of (41.55±30.52) months. TACS>100 AU group exhibited significantly lower heart rate ( t=2.015, P=0.046), DC ( t=2.131, P=0.035), LF/HF ( Z=3.332, P<0.001) and ln(LF/HF) ( t=3.326, P=0.001), and higher AC ( t=-2.392, P=0.019) than TACS≤100 AU group. Multivariate logistic regression analysis results showed that after adjusting for age and eosinophil count, lnVLF ( OR=0.66, 95% CI 0.45-0.98, P=0.038), lnLF ( OR=0.69, 95% CI 0.49-0.97, P=0.032), DC ( OR=0.79, 95% CI 0.64-0.99, P=0.039) and AC ( OR=1.32, 95% CI 1.04-1.68, P=0.021) were independently correlated with the risk of TAC. Spearman correlation analysis showed that neuropeptide Y level in peripheral blood was correlated with aSKNA ( r=0.23, P=0.017), lnSDNN ( r=-0.20, P=0.036) and TACS ( r=0.19, P=0.048). During the follow-up period of (25.8±4.2) months, 5 patients (4.72%) died, including 1 patient in the TACS≤100 AU group and 4 patients in the TACS>100 AU group. Compared with the survival group, the death group had higher TACS ( Z=-2.262, P=0.024) and lower LF/HF ( Z=-2.750, P=0.006). Cox regression analysis results showed that increased ln(LF/HF) was an independent influencing factor for all-cause mortality in CAPD patients ( HR=0.22, 95% CI 0.05-0.83, P=0.026). Conclusions:HRV parameters (lnVLF, lnLF, AC and DC) of CAPD patients are independently associated with TAC. The dysfunction of ANS in CAPD patients (especially the decreased vagus nerve activity) may promote TAC.

Background/Aims: Metabolic syndrome is common in patients with acute pancreatitis and its components have been reported to be associated with infectious complications. In this post hoc analysis, we aimed to evaluate whether metabolic abnormalities impact the effect of immuneenhancing thymosin alpha-1 (Tα1) therapy in acute necrotizing pancreatitis (ANP) patients. Methods: All data were obtained from the database for a multicenter randomized clinical trial that evaluated the efficacy of Tα1 in ANP patients. Patients who discontinued the Tα1 treatment prematurely were excluded. The primary outcome was 90-day infected pancreatic necrosis (IPN) after randomization. Three post hoc subgroups were defined based on the presence of hyperglycemia, hypertriglyceridemia, or both at the time of randomization. In each subgroup, the correlation between Tα1 and 90-day IPN was assessed using the Cox proportional-hazards regression model. Multivariable propensity-score methods were used to control potential bias. Results: Overall, 502 participants were included in this post hoc analysis (248 received Tα1 treatment and 254 received matching placebo treatment). Among them, 271 (54.0%) had hyperglycemia, 371 (73.9%) had hypertriglyceridemia and 229 (45.6%) had both. Tα1 therapy was associated with reduced incidence of IPN among patients with hyperglycemia (18.8% vs 29.7%: hazard ratio, 0.80; 95% confidence interval, 0.37 to 0.97; p=0.03), but not in the other subgroups. Additional multivariate regression models using three propensity-score methods yielded similar results. Conclusions Among ANP patients with hyperglycemia, immune-enhancing Tα1 treatment was associated with a reduced risk of IPN (ClinicalTrials.gov, Registry number: NCT02473406).

BACKGROUND:Overactive osteoclasts disrupt bone homeostasis and play a bad role in the pathological mechanisms of related skeletal diseases,such as osteoporosis,fragility fractures,and osteoarthritis.Studies have confirmed that ellagic acid and ellagtannin have the potential to inhibit osteoclast differentiation.As their natural metabolites,urolithin A has antioxidant,anti-inflammatory,anti-proliferative and anti-cancer effects,but its effect on osteoclast differentiation and its underlying molecular mechanisms remain unclear. OBJECTIVE:To explore the effect of urolithin A on osteoclast differentiation induced by receptor activator for nuclear factor-κB ligand and its mechanism. METHODS:Mouse mononuclear macrophage leukemia cells(RAW264.7)that grew stably were cultured in vitro.Toxicity of urolithin A(0,0.1,0.5,1.5,2.5 μmol/L)to RAW264.7 cells were detected by cytotoxic MTS assay to screen out the safe concentration.Different concentrations of urolithin A were used again to intervene with receptor activator for nuclear factor-κB ligand-induced differentiation of RAW264.7 cells in vitro.Then,tartrate-resistant acid phosphatase staining and F-actin ring and nucleus staining were performed to observe its effect on the formation and function of osteoclasts.Finally,the expressions of urolithin A on upstream and downstream genes and proteins in the MAPK signaling pathway were observed by western blot and RT-qPCR assays. RESULTS AND CONCLUSION:Urolithin A inhibited osteoclast differentiation and F-actin ring formation in a concentration-dependent manner and 2.5 μmol/L had the strongest inhibitory effect.Urolithin A inhibited the mRNA expression of Nfatc1,Ctsk,Mmp9 and Atp6v0d2 and the protein synthesis of Nfatc1 and Ctsk,related to osteoclast formation and bone resorption.Urolithin A inhibited the activity of osteoclasts by downregulating the phosphorylation of p38 protein to inhibit the mitogen-activated protein kinase signaling pathway.