Sigma-1 receptor (σ ₁R) has become a focus point of drug discovery for central nervous system (CNS) diseases. A series of novel 1-phenylethan-1-one O-(2-aminoethyl) oxime derivatives were synthesized. In vitro biological evaluation led to the identification of 1a, 14a, 15d and 16d as the most high-affinity (K _i < 4 nmol/L) and selective σ ₁R agonists. Among these, 15d, the most metabolically stable derivative exhibited high selectivity for σ ₁R in relation to σ ₂R and 52 other human targets. In addition to low CYP450 inhibition and induction, 15d also exhibited high brain permeability and excellent oral bioavailability. Importantly, 15d demonstrated effective antipsychotic potency, particularly for alleviating negative symptoms and improving cognitive impairment in experimental animal models, both of which are major challenges for schizophrenia treatment. Moreover, 15d produced no significant extrapyramidal symptoms, exhibiting superior pharmacological profiles in relation to current antipsychotic drugs. Mechanistically, 15d inhibited GSK3β and enhanced prefrontal BDNF expression and excitatory synaptic transmission in pyramidal neurons. Collectively, these in vivo proof-of-concept findings provide substantial experimental evidence to demonstrate that modulating σ ₁R represents a potential new therapeutic approach for schizophrenia. The novel chemical entity along with its favorable drug-like and pharmacological profile of 15d renders it a promising candidate for treating schizophrenia.

Objective:To analyze the association of sedentary time and physical activity with the risk of developing chronic obstructive pulmonary disease (COPD) in non-smoking women aged 40 years and above in Songjiang District, Shanghai.Methods:Based on a natural population-based cohort in Songjiang, a total of 18 707 non-smoking women who were aged 40 years and above and without COPD at baseline survey were enrolled in the study. Cox proportional risk regression model was used to analyze the associations of the duration of sedentary behavior, physical activity with the risk for COPD at baseline survey, and the hazard ratio ( HR) of risk for COPD and its 95% CI were calculated. Stratified analyses were performed based on age, BMI, history of respiratory diseases and so on. Sensitivity analyses were conducted by excluding the cases diagnosed with COPD within one year after the baseline survey. Results:As of March 31, 2024, a total of 691 new COPD cases had been recorded after a median follow-up time of 6.96 years with an incidence density of 53.22 per 10 000 person-years. After adjusting for relevant confounders, in the tertile subgroups of sedentary time, the risk for COPD reduced by 17% in the short sedentary time group compared with the long sedentary time group ( HR=0.83,95% CI:0.70-0.99). Compared with the low physical activity level and long sedentary time group, the risk for COPD reduced by 24% in the high physical activity level and short sedentary time group ( HR=0.76, 95% CI: 0.61-0.95) and by 23% in the low physical activity level and short sedentary time group ( HR=0.77, 95% CI: 0.60-0.97). Compared with the non-physical exercise and long sedentary time group, the risk for COPD reduced by 28% in the non-physical exercise and short sedentary time group ( HR=0.72, 95% CI: 0.60-0.87). These associations remained when the cases diagnosed with COPD within one year of the baseline survey were excluded. Conclusions:Increasing physical activity and reducing sedentary time have beneficial effects to prevent COPD in non-smoking women, and reducing sedentary time alone may also reduce the risk for COPD if increasing physical exercise or other physical activity is not possible.

The hippocampus, a major component of the limbic system, is the most important region related to emotion regulation and memory processing. Cognitive impairment and depressive symptoms observed in Alzheimer's disease (AD) patients may be attributed to hippocampal damage caused by amyloid β-protein (Aβ). Our previous studies have demonstrated that a steroid sulfatase inhibitor DU-14 can enhance hippocampal synaptic plasticity and spatial memory abilities in a chronic AD murine model by counteracting the toxic effects of Aβ. However, limited experimental evidence exists regarding the efficacy of steroid sulfatase inhibitor on depressive symptoms in AD animal models. In this study, we investigated the effects of DU-14 on depressive symptoms and theta-band neuronal oscillations in rats with intrahippocampal injection of Aβ_1-42 using various behavioral tests such as sucrose preference test, tail suspension test, forced swimming test, and in vivo hippocampal local field potential (LFP) recording. The results demonstrated that, in comparison to the control group: (1) rats in the Aβ group exhibited a decrease in sucrose preference, indicating a loss of interest in pleasurable activities; (2) rats in the Aβ group displayed aggravated depressive-like behavior characterized by prolonged immobility time during tail suspension and forced swimming tests; (3) Aβ disrupted the induction of theta rhythm via tail pinch stimulation, and resulted in a significant reduction in peak power of theta rhythm. In contrast to the Aβ group, pretreatment with DU-14 resulted in: (1) a significant improvement in Aβ-induced anhedonia, as evidenced by increased sucrose preference; (2) significant alleviation of Aβ-induced despair and depressive-like behaviors, reflected by reduced immobility time during tail suspension and forced swimming tests; (3) successful mitigation of Aβ-mediated inhibition on bilateral hippocampal theta rhythm. These findings indicate that steroid sulfatase inhibitor DU-14 can counteract neurotoxicity induced by Aβ, and prevent Aβ-induced depressive-like behavior and suppression of theta rhythm.
Animals ; Amyloid beta-Peptides/toxicity* ; Rats ; Depression/physiopathology* ; Theta Rhythm/drug effects* ; Hippocampus/physiopathology* ; Male ; Rats, Sprague-Dawley ; Alzheimer Disease/physiopathology* ; Steryl-Sulfatase/antagonists & inhibitors* ; Peptide Fragments ; Behavior, Animal/drug effects*

Objective:To analyze the association of sedentary time and physical activity with the risk of developing chronic obstructive pulmonary disease (COPD) in non-smoking women aged 40 years and above in Songjiang District, Shanghai.Methods:Based on a natural population-based cohort in Songjiang, a total of 18 707 non-smoking women who were aged 40 years and above and without COPD at baseline survey were enrolled in the study. Cox proportional risk regression model was used to analyze the associations of the duration of sedentary behavior, physical activity with the risk for COPD at baseline survey, and the hazard ratio ( HR) of risk for COPD and its 95% CI were calculated. Stratified analyses were performed based on age, BMI, history of respiratory diseases and so on. Sensitivity analyses were conducted by excluding the cases diagnosed with COPD within one year after the baseline survey. Results:As of March 31, 2024, a total of 691 new COPD cases had been recorded after a median follow-up time of 6.96 years with an incidence density of 53.22 per 10 000 person-years. After adjusting for relevant confounders, in the tertile subgroups of sedentary time, the risk for COPD reduced by 17% in the short sedentary time group compared with the long sedentary time group ( HR=0.83,95% CI:0.70-0.99). Compared with the low physical activity level and long sedentary time group, the risk for COPD reduced by 24% in the high physical activity level and short sedentary time group ( HR=0.76, 95% CI: 0.61-0.95) and by 23% in the low physical activity level and short sedentary time group ( HR=0.77, 95% CI: 0.60-0.97). Compared with the non-physical exercise and long sedentary time group, the risk for COPD reduced by 28% in the non-physical exercise and short sedentary time group ( HR=0.72, 95% CI: 0.60-0.87). These associations remained when the cases diagnosed with COPD within one year of the baseline survey were excluded. Conclusions:Increasing physical activity and reducing sedentary time have beneficial effects to prevent COPD in non-smoking women, and reducing sedentary time alone may also reduce the risk for COPD if increasing physical exercise or other physical activity is not possible.

Objective To explore the correlation of serum matrix metalloproteinase-9(MMP-9)and heat shock protein-47(HSP-47)levels with prognosis in patients with acute cerebral hemorrhage.Methods One hundred and forty-five patients with acute cerebral hemorrhage attending our hospital from March 2018 to May 2022 were selected,and assigned into good prognosis group(n=80)and poor prognosis group(n=65)according to their postoperative prognosis.General information of patients was recorded.The early morning of the day after admission fasting peripheral venous blood samples were collected for the detection of serum MMP-9 and HSP47 levels.Multivariate Logistic regression analysis was conducted to screen the risk factors affecting poor prognosis in patients with acute cerebral hemorrhage,and the predictive value of serum MMP-9 and HSP47 levels on prognosis of patients with acute cerebral hemorrhage was evaluated by plotting ROC curve.Results Statistical difference was found in shape and volume of hematoma between two groups(P＜0.05).Serum MMP-9 and HSP47 levels in poor prognosis group were higher than that in good prognosis group(P＜0.05).Multivariate Logistic regression analysis denoted that duration of surgery,hematoma shape,hematoma volume,serum MMP-9 and HSP47 levels were all risk factors for poor prognosis in patients with acute cerebral hemorrhage(P＜0.05).Patients with the time of onset to surgery＞24 hours irregular shaped hematoma,large hematoma volume,and elevated serum levels of MMP-9 and HSP47 suffered a high risk of poor prognosis.ROC curve analysis demonstrated that AUC of serum MMP-9 and HSP47 levels for predicting the postoperative prognosis of patients with acute cerebral haemorrhage were 0.718 and 0.827,with a sensitivity of 81.5％and 80.0％,and a specificity of 50.0％and 81.2％,respectively.The AUC,sensitivity and specificity of combined detection of serum MMP-9 and HSP47 for prognosis prediction were 0.891,86.2％and 85.0％.Conclusion Serum MMP-9 and HSP47 levels are elevated in patients with poor prognosis after acute cerebral haemorrhage,and irregular shaped hematoma,hematoma volume,and serum MMP-9 and HSP47 levels are risk factors for poor prognosis after acute cerebral haemorrhage.Furthermore,serum MMP-9 and HSP47 are of great predictive value for the prognosis of patients with acute cerebral haemorrhage,and the predictive efficacy of combined detection of the two is better than that of separate test.

In 2022, the National Cancer Center (NCC) of China reported the nationwide statistics of 2016 using population-based cancer registry data from all available cancer registries in China, which was mainly about the cancer incidence and mortality. Cancer remains a major health problem currently in our country and requires long term cooperation to deal with. This article provided a key point interpretation and analysis of cancer prevalence data in China, and provided an analysis of several main risk factors for cancer, which was conducive to the development of cancer prevention and control programs in different regions.

Objective Recombinase-aided polymerase chain reaction(RAP)is a sensitive,single-tube,two-stage nucleic acid amplification method.This study aimed to develop an assay that can be used for the early diagnosis of three types of bacteremia caused by Staphylococcus aureus(SA),Pseudomonas aeruginosa(PA),and Acinetobacter baumannii(AB)in the bloodstream based on recombinant human mannan-binding lectin protein(M1 protein)-conjugated magnetic bead(M1 bead)enrichment of pathogens combined with RAP. Methods Recombinant plasmids were used to evaluate the assay sensitivity.Common blood influenza bacteria were used for the specific detection.Simulated and clinical plasma samples were enriched with M1 beads and then subjected to multiple recombinase-aided PCR(M-RAP)and quantitative PCR(qPCR)assays.Kappa analysis was used to evaluate the consistency between the two assays. Results The M-RAP method had sensitivity rates of 1,10,and 1 copies/μL for the detection of SA,PA,and AB plasmids,respectively,without cross-reaction to other bacterial species.The M-RAP assay obtained results for<10 CFU/mL pathogens in the blood within 4 h,with higher sensitivity than qPCR.M-RAP and qPCR for SA,PA,and AB yielded Kappa values of 0.839,0.815,and 0.856,respectively(P<0.05). Conclusion An M-RAP assay for SA,PA,and AB in blood samples utilizing M1 bead enrichment has been developed and can be potentially used for the early detection of bacteremia.

Objective:To explore the incidence of chronic obstructive pulmonary disease (COPD) in a cohort aged 40 years and above in Songjiang District, Shanghai, and to analyze the association of Mediterranean diet pattern and dietary approaches in stopping hypertension pattern (DASH) with the risk of developing COPD.Methods:Based on a natural population cohort in Songjiang District, Shanghai, 27 474 adults aged 40 years and above who did not have COPD at baseline were enrolled in the study. The Cox proportional risk regression model was used to analyze the association of baseline Mediterranean diet pattern score and DASH score with the risk of COPD, and the hazard ratio ( HR) of the risk and its 95% CI were calculated. Restricted cubic spline was used to analyze the nonlinear association between the two diet scores and the risk of COPD. Stratified analyses were performed according to gender, age, smoking status, etcetera. Sensitivity analyses were conducted by censoring cases diagnosed within one year after the baseline survey or people with a history of malignant tumor disease. Results:As of June 30, 2023, after a median follow-up time of 6.21 years, there were 1 089 (4.0%) new COPD cases with an incidence density of 64.00 per 10 000 person-years. After adjusting for relevant confounders, in the Mediterranean tertile subgroups under diet pattern score, the risk of developing COPD could be reduced by approximately 14% in the intermediate scoring group ( HR=0.86, 95% CI: 0.75-0.99) and 15% in the highest scoring group ( HR=0.85, 95% CI: 0.72-0.99) compared to the lowest scoring group. The association remained after censoring cases diagnosed within one year of the baseline survey ( HR=0.82, 95% CI: 0.70-0.95; HR=0.82, 95% CI: 0.68-0.97) or censoring people with a history of malignant tumor disease ( HR=0.84, 95% CI: 0.73-0.97; HR=0.84, 95% CI: 0.71-0.99). No statistical association was found between the DASH score and the risk of COPD. Conclusions:The Mediterranean diet pattern was associated with a lower risk of COPD. Increasing the intake of vegetables, fruits, legumes, and whole grains and decreasing the intake of red meat and others can reduce the risk of COPD. No association was found between the DASH dietary pattern and the risk of COPD in this community population.

Objectives:To evaluate the clinical value of the Paris system for reporting urinary cytology (TPS) in the diagnosis of urothelial carcinoma (UC).Methods:A total of 1 744 cytological diagnostic records (from 751 cases) were collected retrospectively. All specimens were voided urines and histopathology as the gold standard. The sensitivity and specificity of urinary cytological diagnosis of UC and risk of high grade malignant (ROHM) in each diagnostic category were compared.Results:There were 360 cases with histopathology. The percentage of negative for high-grade urothelial carcinoma (NHGUC) was 30.1% (226/751), atypical urothelial cells (AUC) was 29.8% (224/751), suspicious for high-grade urothelial carcinoma (SHGUC) was 16.8% (126/751), high grade urothelial carcinoma (HGUC) was 21.2% (159/751), and non-urothelial malignancy (NUM) was 2.1% (16/751). The histpathologic ROHM corresponding to each cytological diagnosis category were 27.3% for NHGUC, 32.7% for AUC, 74.7% for SHGUC, 96.6% for HGUC and 100.0% for NUM, respectively. ROHM of SHGUC was significantly higher than that of AUC group, and the difference between the two groups was statistically significant ( P＜0.001). ROHM of HGUC group was significantly higher than that of SHGUC group, and the difference was statistically significant ( P＜0.001). With SHGUC as the cut-off value, the sensitivity and specificity of cytological diagnosis of HGUC were 76.7% (165/215) and 85.7% (18/21), and with HGUC as the cut-off value, the sensitivity and specificity of cytological diagnosis of HGUC were 53.0% (114/215) and 100.0% (21/21), respectively. Conclusions:Urine cytology has high sensitivity and specificity in the diagnosis of HGUC. The malignant risk of TPS varies with different diagnosis category. The high malignant risk population in cancer hospital leads to the relatively high malignant proportion and ROHM in each diagnosis category. Urinary cytology TPS reporting system is helpful to clinical management and has good clinical application value.

Objectives:To evaluate the clinical value of the Paris system for reporting urinary cytology (TPS) in the diagnosis of urothelial carcinoma (UC).Methods:A total of 1 744 cytological diagnostic records (from 751 cases) were collected retrospectively. All specimens were voided urines and histopathology as the gold standard. The sensitivity and specificity of urinary cytological diagnosis of UC and risk of high grade malignant (ROHM) in each diagnostic category were compared.Results:There were 360 cases with histopathology. The percentage of negative for high-grade urothelial carcinoma (NHGUC) was 30.1% (226/751), atypical urothelial cells (AUC) was 29.8% (224/751), suspicious for high-grade urothelial carcinoma (SHGUC) was 16.8% (126/751), high grade urothelial carcinoma (HGUC) was 21.2% (159/751), and non-urothelial malignancy (NUM) was 2.1% (16/751). The histpathologic ROHM corresponding to each cytological diagnosis category were 27.3% for NHGUC, 32.7% for AUC, 74.7% for SHGUC, 96.6% for HGUC and 100.0% for NUM, respectively. ROHM of SHGUC was significantly higher than that of AUC group, and the difference between the two groups was statistically significant ( P＜0.001). ROHM of HGUC group was significantly higher than that of SHGUC group, and the difference was statistically significant ( P＜0.001). With SHGUC as the cut-off value, the sensitivity and specificity of cytological diagnosis of HGUC were 76.7% (165/215) and 85.7% (18/21), and with HGUC as the cut-off value, the sensitivity and specificity of cytological diagnosis of HGUC were 53.0% (114/215) and 100.0% (21/21), respectively. Conclusions:Urine cytology has high sensitivity and specificity in the diagnosis of HGUC. The malignant risk of TPS varies with different diagnosis category. The high malignant risk population in cancer hospital leads to the relatively high malignant proportion and ROHM in each diagnosis category. Urinary cytology TPS reporting system is helpful to clinical management and has good clinical application value.