1.Analysis on the Acupoint Selection Law of Acupuncture and Moxibustion for Pediatric Cerebral Palsy Based on Data Mining Techniques
Huijiao CHEN ; Yongyuan HUANG ; Minling ZHAO ; Dongmei RUAN ; Wenjing GUO ; Mengli ZHOU ; Yushan FAN
Chinese Journal of Information on Traditional Chinese Medicine 2025;32(3):51-57
Objective To analyze the acupoint selection law of acupuncture and moxibustion for pediatric cerebral palsy based on data mining techniques.Methods Clinical research literature about acupuncture and moxibustion for the treatment of pediatric cerebral palsy was retrieved from CNKI,Wanfang Data,VIP,CBM,PubMed,Web of Science,Embase and Cochrane Library from the establishment of the databases to April 1,2024.Excel 2021 was used to establish a database of prescription acupoints.The frequency of use of acupoints,attributed to the meridians,parts and specific acupoints were under statistically analysis,and SPSS Modeler 18.0 and SPSS Statistics 27.0 were used to conduct the association rules analysis,factor analysis and clustering analysis of acupoints.Results A total of 579 articles were included,579 prescriptions were extracted,containing 245 acupoints with the frequency of 6 422 times.The high-frequency acupoints were Zusanli,Baihui,Hegu,Sanyinjiao and Quchi,etc.The commonly used meridians were Governor Vessel,gall bladder meridian,stomach meridian,large intestine meridian and bladder meridian;mostly used acupoints were in the lower limbs,head and neck,upper limbs,waist and back.The association rules analysis showed that the top combinations were"Hegu-Quchi","Zusanli-Quchi","Zusanli-Quchi-Hegu","Hegu-Quchi-Zusanli";clustering analysis showed that 6 valid clusters were extracted;factor analysis extracted 7 valid common factors.Conclusion Acupuncture and moxibustion treatment for pediatric cerebral palsy is based on the principle of strengthening the brain,improving intelligence and tonifying the five zang organs,reflecting the principle of matching acupoints far and near.The core combination of acupoints is"Zusanli-Quchi-Hegu".
2.Loneliness in mid- to late pregnancy and risk of depressive and anxiety symptoms in late pregnancy: a longitudinal cohort study
Ziwei DING ; Lanfang ZHAO ; Le WANG ; Shuangqin YAN ; Lanci XIE ; Guopeng GAO ; Tianli ZHU ; Jingjing LIU ; Tuyan FAN ; Fengyu YANG ; Hui GAO ; Huayan MO ; Wenjing QIANG ; Beibei ZHU ; Fangbiao TAO
Chinese Journal of Perinatal Medicine 2025;28(12):1107-1114
Objective:To determine the prevalence, risk factors, and longitudinal associations of loneliness during mid- to late pregnancy with anxiety and depressive symptoms in late pregnancy.Methods:In this prospective cohort study, 1 107 pregnant women at 24-28 weeks' gestation were enrolled between June 2021 and December 2022. Psychological status was assessed during mid-pregnancy (24-28 weeks) and late pregnancy (≥32 weeks) using standardized electronic questionnaires, including the Revised University of California Los Angeles Loneliness Scale (UCLA) Loneliness Scale-Short Form (Cronbach's α=0.82), Patient Health Questionnaire-9 ( α=0.86), and Generalized Anxiety Disorder-7 ( α=0.88). Multivariate logistic regression identified independent risk factors for loneliness. Cross-lagged path models analyzed the longitudinal predictions between loneliness and anxiety/depressive symptoms. Results:The prevalence of loneliness decreased significantly from 10.8% (120/1 107) in mid-pregnancy to 4.8% (37/777) in late pregnancy ( χ2=21.81, P<0.001). Multivariate analysis identified independent risk factors for loneliness: age <30 years ( OR=1.70, 95% CI: 1.15-2.50), annual household income <50 000 CNY ( OR=2.53, 95% CI: 1.28-5.02), unemployment during pregnancy ( OR=1.57, 95% CI: 1.03-2.39), history of alcohol consumption ( OR=1.63, 95% CI: 1.03-2.56), and the presence of mid-pregnancy depressive ( OR=2.76, 95% CI: 1.51-5.04) and anxiety symptoms ( OR=1.65, 95% CI: 1.01-2.71) (all P<0.05). Cross-lagged path models indicated bidirectional associations between loneliness and both anxiety ( β=0.32, P<0.01) and depressive symptoms ( β=0.28, P<0.01). However, the predictive effect of loneliness on subsequent depressive and anxiety symptoms ( β=0.28-0.32) was substantially stronger than the reverse prediction (mid-pregnancy anxiety on late-pregnancy loneliness: β=0.12; mid-pregnancy depression on late-pregnancy loneliness: β=0.11). Loneliness demonstrated high temporal stability (autoregressive effects β=0.29-0.32). Conclusion:Loneliness in mid-pregnancy exhibits a symmetric bidirectional association with anxiety and depressive symptoms in late pregnancy, suggesting it may be a core driver in the development of these emotional symptoms. Younger maternal age (<30 years), low household income (<50 000 CNY/year), unemployment during pregnancy, and a history of alcohol consumption were associated with a higher risk of loneliness and should be prioritized for psychological screening and intervention.
3.Clinicopathologic characteristics of patients with ovarian metastases from colorectal cancer and construction of postoperative prognostic models
Qi ZHANG ; Renshen XIANG ; Shuaibing LU ; Wenjing YANG ; Deyang KONG ; Yu SUN ; Huiru ZHANG ; Xuesi DONG ; Jialiang FAN ; Lin FENG ; Haizeng ZHANG
Chinese Journal of Surgery 2025;63(12):1137-1145
Objective:To construct and validate a prognostic prediction model for patients with ovarian metastases from colorectal cancer after radical resection.Methods:A retrospective case series analysis was conducted on the clinical and pathological data of 81 patients with colorectal cancer and ovarian metastases who underwent radical resection for ovarian metastases at the Department of Colorectal Surgery, Cancer Hospital, Chinese Academy of Medical Sciences, between January 2014 and December 2023. The patients were all female, with an age ( M(IQR)) of 49(13) years (range: 22 to 79 years). The primary tumor was located in the colon in 60 cases (74.1%) and in the rectum in 21 cases (25.9%). Univariate and multivariate Cox regression analyses were used to identify independent risk factors affecting prognosis. A risk scoring system was constructed, and patients were assigned to high-risk and low-risk groups based on their risk scores. The predictive performance of the scoring system was assessed, and 5-fold cross-validation was performed to evaluate the model′s stability on the internal dataset. Results:Among the 81 patients with ovarian metastases, a high proportion had T4 stage (58 cases, 71.6%), lymph node positivity (68 cases, 84.0%), and colon cancer (60 cases, 74.1%). Preoperative imaging suggested unilateral ovarian metastasis in 15 patients (23.4%), but pathological examination after bilateral oophorectomy confirmed bilateral ovarian metastases. Among the 17 patients who initially underwent unilateral oophorectomy, 11 developed contralateral ovarian metastases at varying times postoperatively. Univariate Cox proportional hazards regression analysis revealed that positive lymph node ratio ( HR=2.68,95% CI:1.41 to 5.09, P=0.003), N stage ( HR=2.07,95% CI:1.08 to 3.95, P=0.028),maximum diameter of metastatic tumors ( HR=2.27,95% CI:1.04 to 4.96, P=0.040),and peritoneal metastasis or ascites at the time of ovarian metastasis ( HR=2.04,95% CI:1.02 to 4.08, P=0.043) were significantly associated with overall survival in patients with ovarian metastasis from colorectal cancer. Multivariate regression analysis identified that positive lymph node ratio ( HR=3.34,95% CI:1.08 to 10.34, P=0.037) and maximum diameter of metastatic tumors ( HR=2.65,95% CI:1.19 to 5.88, P=0.017) were independent prognostic factors for overall survival following radical oophorectomy in patients with ovarian metastasis from colorectal cancer. Based on the regression coefficients from the multivariate analysis for variables (ovarian metastatic tumor diameter ≥6 cm, positive lymph node ratio ≥0.3,and presence of peritoneal metastasis or ascites), a risk scoring system was developed. Using the optimal cutoff value (154 points) for the risk score,patients were divided into high-risk (19 cases) and low-risk (62 cases) groups. Kaplan-Meier survival curves demonstrated that the high-risk group had significantly lower median overall survival (27 months) and median disease-free survival (22 months) compared to the low-risk group (median overall survival 90 months,median disease-free survival not reached; both P<0.01). Receiver operating characteristic curve analysis showed that the area under the curve(AUC) for predicting 1-,3-,and 5-year overall survival was 0.731(95% CI:0.563 to 0.899), 0.703(95% CI:0.573 to 0.833), and 0.776(95% CI: 0.657 to 0.894), respectively. The AUC for predicting 1-,3-, and 5-year disease-free survival was 0.724(95% CI:0.397 to 0.993),0.710(95% CI:0.514 to 0.906),and 0.688(95% CI:0.478 to 0.898),respectively,indicating good performance of the model.The decision curve analysis showed that the model has good clinical net benefit and the results of the 5-fold cross-validation showed that the model demonstrated stability in the internal dataset. Conclusions:When performing radical resection for ovarian metastasis from colorectal cancer,bilateral oophorectomy should be considered to minimize the risk of postoperative recurrence. Patients with ovarian metastasis from colorectal cancer,characterized by a metastatic tumor diameter ≥6 cm,a positive lymph node ratio ≥0.3,and the presence of peritoneal metastasis or ascites, tend to have a poorer prognosis. Based on these findings,a clinical prognostic scoring system for radical resection of ovarian metastasis from colorectal cancer has been developed to stratify patients into different risk groups and may assist in postoperative risk assessment and management.
4.Distribution characteristics of smoking behavior among adult twins in China
Shunkai LIU ; Wenjing GAO ; Weihua CAO ; Jun LYU ; Canqing YU ; Shengfeng WANG ; Tao HUANG ; Dianjianyi SUN ; Chunxiao LIAO ; Yuanjie PANG ; Ruqin GAO ; Min YU ; Jinyi ZHOU ; Xianping WU ; Zhong DONG ; Fan WU ; Dezheng WANG ; Zhihua XU ; Yu LIU ; Jianrui WANG ; Jie YIN ; Shengli YIN ; Liming LI
Chinese Journal of Preventive Medicine 2025;59(7):1090-1096
This study aims to describe the population and regional distribution characteristics of smoking behavior among adult twins in the China Twin Registry (CNTR), as well as the concordance rates for smoking behavior in monozygotic and dizygotic twins, and estimate the heritability. The study population included adult twins in CNTR who had smoking questionnaire data. A random-effects regression model was used to describe the distribution of smoking behavior among different subgroups based on various characteristics. The concordance of smoking behavior between different zygosity groups was calculated, and heritability was estimated. A total of 28 444 twin pairs were included in this study, with an average age of (36.6±12.0) years. Among male twins, 41.2% were current smokers, while only 1.2% of females smoked. Higher smoking rates were observed among male smokers in the 50-59 age group ( z=23.0, P<0.001), northern regions ( z=2.9, P<0.01), rural areas ( z=-5.2, P<0.001), those who were divorced/widowed ( z=3.8, P<0.001), and first-born twins ( z=-4.3, P<0.001), while lower smoking rates were found in those with higher education ( z=-16.1, P<0.001) and unmarried individuals ( z=-16.0, P<0.001). The smoking concordance rate for male monozygotic twins was 69.6%, significantly higher than the 57.3% concordance rate for dizygotic twins ( χ 2=105.0, P<0.05). The heritability of smoking behavior in male twins was estimated at 28.9% (95% CI: 24.3%-33.4%). Stratified analyses showed differences in heritability across regions and age groups: the heritability in northern regions was 32.6% (95% CI: 27.3%-38.0%), higher than the 21.0% (95% CI: 12.4%-29.5%) observed in southern regions; the highest heritability of 35.1% (95% CI: 26.3%-43.9%) was found in the 18-29 age group, with heritability decreasing with age. In conclusion, the smoking rate and influencing factors in the twin population are similar to those in the general population, with unique characteristics, such as higher smoking rates in first-born twins. Genetic factors have a significant impact on smoking behavior.
5.Study on Functional Substance Basis of Jinhong Tablet Based on GES-1 Cell Model and Mouse Gastric Organoid Model
Lihao XIAO ; Wenjing ZHAO ; Gaoshuang ZHU ; Yujiao YAN ; Xinzhuang ZHANG ; Liang CAO ; Zhenz-hong WANG ; Xiaoxue FAN ; Tong ZHANG
Journal of Nanjing University of Traditional Chinese Medicine 2025;41(7):869-880
OBJECTIVE To explore the functional substance basis of Jinhong Tablet in the treatment of chronic superficial gastri-tis(CSG).METHODS Three different models were constructed to investigate the anti-inflammatory and antioxidant effects,func-tional material basis of Jinhong Tablet:inflammatory model in human gastric epithelial cells(GES-1)induced by lipopolysaccharide(LPS),LPS-induced inflammatory model in mouse gastric organoids,and ethanol-induced oxidative damage model in GES-1 cells.MTS assay was performed to detect cell proliferation activity;qPCR was applied to measure the relative mRNA expression of tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β),interleukin-6(IL-6),and interleukin-8(IL-8)in cells and gastric organoids;and the levels of superoxide dismutase(SOD),malondialdehyde(MDA),and reactive oxygen species(ROS)in cells were detected.RESULTS Jinhong Tablet and 10 functional components significantly reduced the relative expression of inflammation-relat-ed genes TNF-α,IL-1β,IL-6,and IL-8 in LPS-induced GES-1 cells and gastric organoids,suggesting that these 10 components are the functional substance basis for the anti-inflammatory effects of Jin Hong Tablet.Jin Hong Tablet and 11 functional components markedly decreased the levels of MDA and ROS and increased the activity of SOD,indicating that these 11 components were the func-tional substance basis of the antioxidant effects of Jinhong Tablet.CONCLUSION Through in vitro cell and gastric organoid experi-ments,it has been preliminarily determined that allocryptopine,corydaline,dehydrocorydaline,palmatine hydrochloride,chlorogenic acid,costunolide,rutin,quercitrin,dehydrocostus lactone,tetrahydrocoptisine,isochlorogenic acid B,toosendanin,protopine,and quercetin are the functional material basis of Jinhong Tablet in treating CSG,accumulating scientific evidence for the enhancement of the quality standards of Jinhong Tablet.
6.Establishment of a clinical risk scoring model for patients undergoing curative resection of pulmonary metastases from colorectal cancer based on primary tumor lymph node indices
Renshen XIANG ; Qi ZHANG ; Shuaibing LU ; Wenjing YANG ; Deyang KONG ; Yu SUN ; Huiru ZHANG ; Jialiang FAN ; Lin FENG ; Haizeng ZHANG
Chinese Journal of Oncology 2025;47(10):1039-1049
Objective:To analyze the clinicopathological factors affecting the prognosis of patients after curative resection of lung metastases (LMs) from colorectal cancer (CRC) and to construct a clinical risk scoring (CRS) model.Methods:This study retrospectively collected clinicopathological data and follow-up information on 132 patients who underwent radical resection of LMs from CRC at the Cancer Hospital of the Chinese Academy of Medical Sciences between January 2010 and December 2020. We analyzed the clinicopathological factors influencing patient prognosis using univariate and multivariate Cox proportional hazards regression models, and we developed a risk stratification model for prognostic prediction.Results:The median follow-up duration for the cohort of 132 patients was 54.2 months. During this period, 61 patients (46.2%) experienced recurrence or distant metastasis, resulting in a 5-year DFS rate of 54.1%. Additionally, 33 patients (25.0%) died, corresponding to a 5-year overall survival (OS) rate of 76.7%. Univariate Cox proportional hazards regression model analysis indicated that ten clinicopathological factors were significantly associated with OS (all P<0.05). These factors include the total number of lymph nodes (LNs) dissected from the primary tumor (PT) <16, the number of negative LNs from the PT <13, pN(+) of the PT, logarithmic odds of positive lymph nodes (LODDS) of the PT ≥-1.1, lymph nodes ratio (LNR) of the PT ≥0.02, preoperative carcinoembryonic antigen (CEA) level before LMs resection ≥10 ng/ml, the presence of hilar/mediastinal LN metastasis, the number of LMs ≥2, the maximum diameter of LMs ≥2.5 cm, and the necessity for hilar/mediastinal lymphadenectomy. Multivariate Cox proportional hazards regression analysis identified the number of negative LNs <13 ( HR=3.01, 95% CI: 1.28-7.03, P=0.011), pN(+) of the PT ( HR=5.04, 95% CI: 1.51-16.84, P=0.009), preoperative CEA level before LMs resection ≥10 ng/ml ( HR=5.39, 95% CI: 1.80-16.19, P=0.003), the number of LMs ≥2 ( HR=2.47, 95% CI: 1.09-5.60, P=0.030), and the necessity for hilar/mediastinal lymphadenectomy ( HR=2.74, 95% CI: 1.15-6.52, P=0.023) as independent prognostic risk factors. Patients were categorized based on independent risk factors, revealing statistically significant differences in OS across the groups with CRS scores of ≤2, 3~4, and ≥5 ( P<0.001). Conclusions:Independent risk factors associated with LMs from CRC patients include the number of negative LNs <13, pN(+) of the PT, preoperative CEA level before LMs resection ≥10 ng/ml, the number of LMs ≥2, and the necessity for hilar/mediastinal lymphadenectomy. Patients scoring 3 or higher on the CRS model may warrant cautious assessment for the appropriateness of direct surgical treatment.
7.Establishment of real-time fluorescence quantitative PCR method for detecting the N subgenome of SARS-CoV-2
Taoli HAN ; Zhi ZHANG ; Jiaxin ZHAO ; Pan LU ; Yang JIAO ; Jianhong ZHAO ; Yan GAO ; Shiyao ZHANG ; Kuankuan LIU ; Yujie LIU ; Ru FAN ; Wenjing LI ; Lingli SUN
Chinese Journal of Experimental and Clinical Virology 2025;39(1):96-101
Objective:To establish a fluorescent quantitative RT-PCR assay based on N_sgRNA of SARS-CoV-2 and preliminarily apply it on real samples.Methods:Recombinant plasmid, specific primers and probes of N_sgRNA were designed and synthesized based on Wuhan-Hu-1/2019_MN908947 and synthesis mechanism of subgenomic RNA (sgRNA). Using recombinant plasmid as amplification templates, the optimal reaction conditions and reaction system were screened according to the Ct value, fluorescence intensity, and shape of amplification curve and was evaluated for sensitivity, reproducibility, and specificity. Meanwhile, the possibility of practical application of the method was explored by testing 172 clinical samples and 256 municipal wastewater samples. Results:A qRT-PCR assay for N_sgRNA in SARS-CoV-2 was initially established. The detection limit of the assay was 20 copies/mL, and the variation coefficients of in-batch (0.002%~0.767%) and batch to batch repetition (0.016%~0.752%) were less than 1%. Only N_sgRNA recombinant plasmid was detected in the specificity assay. So the method is more highly sensitive, specific and reproducible. The RatiosgRNA/ gRNA of clinical samples HK.3, EG.5.1, JN.1 and their sub-lineages and their corresponding urban sewage samples in epidemic period were significantly different ( P<0.05). There is a strong correlation between the median of RatiosgRNA/ gRNA in clinical samples and sewage samples in the same period (correlation coefficient r=1.000, P=0.010). Conclusions:In this study, a qRT-PCR method for detecting N_sgRNA of SARS-CoV-2 was established and the method has the characteristics of higher sensitivity, stronger specificity and better repeatability, and it can be used to detect SARS-CoV-2 infectivity.
8.Analysis of the efficacy of etoposide (Vp16) -intensified allogeneic hematopoietic stem cell transplantation in treating relapsed/refractory acute myeloid leukemia
Fan YANG ; Wenjing WANG ; Xinhong FEI ; Weijie ZHANG ; Jiangying GU ; Shuqin ZHANG ; Tingting LI ; Wenya LIU ; Jingbo WANG
Chinese Journal of Organ Transplantation 2025;46(5):375-381
Objective:To evaluate the efficacy of an etoposide (Vp16) -intensified conditioning regimen in allogeneic hematopoietic stem cell transplantation (allo-HSCT) for the treatment of relapsed/refractory acute myeloid leukemia (AML).Method:A retrospective analysis was conducted on the clinical data of 27 recipients with relapsed/refractory AML who underwent allo-HSCT using a Vp16-intensified conditioning regimen at Aerospace Center Hospital from January 2019 to January 2022. Transplantation-related complications and treatment outcomes were observed. Kaplan-Meier survival analysis was used to assess the overall survival (OS) and disease-free survival (DFS) rates.Result:Among the 27 recipients, there were 14 males and 13 females, with a median age of 41 years (range: 12~55 years). Except for one recipient who experienced primary graft failure, the remaining 26 recipients achieved hematopoietic reconstitution. The median neutrophil and platelet engraftment times were 13 days (range: 9~20 days) and 13.5 days (range: 11~33 days), respectively. Regimen-related toxicity (RRT) was mainly gastrointestinal toxicity and oral mucositis, and no deaths were attributed to RRT. A total of 12 recipients (44.44%) developed acute graft-versus-host disease (aGVHD), of whom 3 cases (11.11%) had grade III~IV aGVHD. Chronic GVHD (cGVHD) occurred in 13 recipients (48.15%), including 8 cases (29.63%) of extensive cGVHD. The median follow-up time after transplantation was 17 months (range: 1~48 months). Fifteen recipients (55.56%) survived without disease, while 12 recipients (44.44%) died— 9 due to relapse and 3 due to transplant-related complications. The 1-year overall survival and DFS rates were 74.07% and 59.26%, respectively; the 2-year overall survival and DFS rates were 59.26% and 55.56%, respectively. The 2-year relapse rate and transplant-related mortality (TRM) were 33.33% and 11.11%, respectively.Conclusion:The Vp16-intensified conditioning regimen in allo-HSCT appears to be a viable treatment option for patients with relapsed/refractory AML, offering favorable efficacy and manageable safety.
9.Distribution characteristics and heritability of alcohol consumption behavior in adult twins in China
Yuanchen LI ; Wenjing GAO ; Weihua CAO ; Jun LYU ; Canqing YU ; Shengfeng WANG ; Tao HUANG ; Dianjianyi SUN ; Chunxiao LIAO ; Yuanjie PANG ; Ruqin GAO ; Min YU ; Jinyi ZHOU ; Xianping WU ; Zhong DONG ; Fan WU ; Dezheng WANG ; Zhihua XU ; Yu LIU ; Yanxia MA ; Jie YIN ; Shengli YIN ; Liming LI
Chinese Journal of Epidemiology 2025;46(1):73-80
Objective:To describe the distribution characteristics of alcohol consumption in adult twins in the Chinese National Twin Registry (CNTR), and further explore the influence of genetic factors on alcohol consumption in adult twins.Methods:The subjects of the study were twins registered by CNTR in 11 project areas across China from 2010 to 2018. A total of 56 966 twins (28 483 pairs) aged 18 years and above who answered questions about drinking behavior were included, and the random effect model was used to describe the population and regional distribution characteristics of alcohol consumption. Intra-pair analysis was performed to calculate the concordance rate and heritability of their alcohol consumption.Results:The age of all subjects was (36.6±12.0) years, and current drinkers accounted for 16.6% (9 461/56 966) of all subjects. In men, those aged 50-59 years, those in northern China, those living in rural area, those with low education level and those with high BMI, the proportions of current drinkers were higher. After excluding 468 pairs of twins who had stopped alcohol use and 21 764 pairs of twins who had no drink or had small amount drink, an intra-pair analysis was conducted in 4 929 pairs of same-sex twins, and found that the concordance rate of alcohol consumption was 64.0% (2 059/3 215) in monozygotic twins, and 52.6% (902/1 714) in dizygotic twins, the difference was significant ( P<0.001), and the heritability of alcohol consumption was 24.1% (95% CI: 18.9%- 29.3%). The further stratified analysis found that in southern men, the heritability was highest in those aged 40-49 years (36.1%, 95% CI: 21.6%-50.7%), while in northern men, the heritability was highest in those aged 50-59 years (34.2%, 95% CI: 18.1%-50.3%). Conclusions:In adult twins in China, there were population and regional differences in the distribution of alcohol consumption behavior, and alcohol consumption was influenced by genetic factors, and gender, age and region had potential modifying effects.
10.Discovery and proof-of-concept study of a novel highly selective sigma-1 receptor agonist for antipsychotic drug development.
Wanyu TANG ; Zhixue MA ; Bang LI ; Zhexiang YU ; Xiaobao ZHAO ; Huicui YANG ; Jian HU ; Sheng TIAN ; Linghan GU ; Jiaojiao CHEN ; Xing ZOU ; Qi WANG ; Fan CHEN ; Guangying LI ; Chaonan ZHENG ; Shuliu GAO ; Wenjing LIU ; Yue LI ; Wenhua ZHENG ; Mingmei WANG ; Na YE ; Xuechu ZHEN
Acta Pharmaceutica Sinica B 2025;15(10):5346-5365
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.

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