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 systematically review and synthesize the psychological experience of kinesiophobia in patients with cardiac rehabilitation.Methods PubMed,Web of science,Journals@Ovid,Embase,CINAHL,PsycINFO,Cochrane Library,CNKI,SinoMed,WanFang Database,Vip Database,American Heart Association,European Society of Cardiology and American Association of Cardiovascular and Pulmonary Rehabilitation were searched to collect qualitative research on the psychological experience of cardiac rehabilitation patients with kinesiophobia.The retrieval time was from the establishment of the databases to Jun 2023.The literature was evaluated using the Australian JBI Quality Evaluation Criteria for Qualitative Research in Evidence-based Health Care Centres(2016),and the results were consolidated using an aggregative integration approach.Results A total of 45 results were extracted from 14 studies.Similar results were summarized into 10 groups,and 3 integrated results were synthesized as followed.Kinesiophobia was influenced by many factors;kinesiophobia affects the life experience of patients;strategies to reduce the level of kinesiophobia.Conclusion Nurses should pay more attention to psychological experience of kinesiophobia,and take the corresponding intervention measures to help patients overcome the psychological barriers of kinesiophobia,perfect personalized exercise programs,and improve the level of physical activity.

Platycodonis Radix is the dry root of Platycodon grandiflorum of Campanulaceae, which has a variety of pharmacological effects and is a commonly used bulk Chinese medicine. In this study, the chloroplast genome sequences of six P. grandiflorum from different producing areas has been sequenced with Illumina HiSeq X Ten platform. The specific DNA barcodes were screened, and the germplasm resources and genetic diversity were analyzed according to the specific barcodes. The total length of the chloroplast genome of 6 P. grandiflorum samples was 172 260-172 275 bp, and all chloroplast genomes showed a typical circular tetrad structure and encoded 141 genes. The comparative genomics analysis and results of amplification efficiency demonstrated that trnG-UCC and ndhG_ndhF were the potential specific DNA barcodes for identification the germplasm resources of P. grandiflorum. A total of 305 P. grandiflorum samples were collected from 15 production areas in 9 provinces, for which the fragments of trnG-UCC and ndhG_ndhF were amplificated and the sequences were analyzed. The results showed that trnG-UCC and ndhG_ndhF have 5 and 11 mutation sites, respectively, and 5 and 7 haplotypes were identified, respectively. The combined analysis of the two sequences formed 13 haplotypes (named Hap1-Hap13), and Hap4 is the main genotype, followed by Hap1. The unique haplotypes possessed by the three producing areas can be used as DNA molecular tags in this area to distinguish from the germplasm resources of P. grandiflorum from other areas. The haplotype diversity, nucleotide diversity and genetic distance were 0.94, 4.79×10^-3 and 0.000 0-0.020 3, respectively, suggesting that the genetic diversity was abundant and intraspecific kinship was relatively close. This study laid a foundation for the identification of P. grandiflorum, the protection and utilization of germplasm resources, and molecular breeding.

Objective To investigate the predictive value of morphology-voltage-P wave duration(MVP)electrocardiogram(ECG)score for major adverse cardiovascular events(MACE)in elder-ly patients with coronary heart disease(CHD)and atrial fibrillation(AF)within 1 year after treatment.Methods A total of 122 elderly CHD patients with concomitant AF admitted to our department from August 2020 to June 2023 were enrolled,and divided into MACE group(n=31)and non-MACE group(n=91)according to whether MACE occurred within 1 year after treat-ment.Their clinical data,treatment,laboratory indicators and ECG data were collected and ana-lyzed.Multivariate logistic regression analysis was used to identify the risk factors of MACE,and ROC curve was drawn to calculate the AUC value of MVP ECG score in the prediction of MACE occurrence.Results The MACE group had significantly higher Gensini score,C-reactive protein(CRP)level and MVP ECG score,and lower LVEF value than the non-MACE group(P＜0.01).Multivariate logistic regression analysis showed that Gensini score,CRP,LVEF and MVP ECG score were the influencing factors for MACE in elderly CHD patients complicated with AF within 1 year after treatment(OR=4.562,95％CI:1.881-11.064,P=0.001;OR=5.127,95％CI:1.865-14.096,P=0.001;OR=0.998,95％CI:0.687-0.959,P=0.012;OR=4.829,95％CI:2.343-9.953,P=0.001).ROC curve analysis indicated that the AUC value of MVP ECG score in predic-ting MACE within 1 year after treatment in these patients was 0.820,and the optimal cut-off val-ue was 3,the sensitivity was 77.78％and the specificity was 61.00％.Conclusion MVP ECG score has a good predictive value for MACE in elderly CHD patients with concomitant AF within 1 year after treatment.

Humans ; Child ; Vertigo/therapy* ; Diagnosis, Differential

Nuclear transporter importin-β1 is emerging as an attractive target by virtue of its prevalence in many cancers. However, the lack of druggable inhibitors restricts its therapeutic proof of concept. In the present work, we optimized a natural importin-β1 inhibitor DD1 to afford an improved analog DD1-Br with better tolerability (>25 folds) and oral bioavailability. DD1-Br inhibited the survival of castration-resistant prostate cancer (CRPC) cells with sub-nanomolar potency and completely prevented tumor growth in resistant CRPC models both in monotherapy (0.5 mg/kg) and in enzalutamide-combination therapy. Mechanistic study revealed that by targeting importin-β1, DD1-Br markedly inhibited the nuclear accumulation of multiple CRPC drivers, particularly AR-V7, a main contributor to enzalutamide resistance, leading to the integral suppression of downstream oncogenic signaling. This study provides a promising lead for CRPC and demonstrates the potential of overcoming drug resistance in advanced CRPC via targeting importin-β1.

Objective To observe the potential mechanism of electroacupuncture regulating the erythropoietin-producing hepatocellular receptor B2/erythropoietin-producing hepatocellular receptor-interacting B2/big mitogen-activated protein kinase 1(EphB2/EphrinB2/BMK1) signaling pathway to improve neural damage in vascular dementia rats. Methods Eighty SD male adult rats were randomly divided into a sham surgery group, a model group, a non acupoint electroacupuncture group, a nimodipine group, and an electroacupuncture three needle group. The vascular dementia rat model was made by the modified Pulsinelli four vessel occlusion method. After grouping, the rats in each group were subjected to water maze test, HE staining, Nissl staining, and transmission electron microscopy(TEM) to observe the pathological changes in the hippocampal CA1 area, and the expression of EphB2 and BMK1 in the hippocampal CA1 area was detected by immunohistochemistry; Detection of EphB2 and BMK1 protein expression in rat hippocampal CA1 region was detected by Western blotting. Results Compared with the model group, the escape latency of vascular dementia rats treated with electroacupuncture and nimodipine decreased (P<0.05), while the number of crossing platforms significantly increased (P<0.05); The result of HE staining, Nissl staining and TEM showed that compared with the model group, the neurons in hippocampal CA1 area of rats in the EA Zhisanzhen group and nimodipine group were arranged orderly, and the morphology and structure of cells and organelle were complete; Immunohistochemical method and Western blotting showed that the expression of EphB2 and BMK1 in the CA1 region of hippocampus in the model group was significantly lower than that in the sham surgery group (P<0.05); Compared with the model group, the expression of EphB2 and BMK1 in the hippocampal CA1 region of rats in the electroacupuncture Zhisanzhen group significantly increased (P<0.05), while the expression of EphB2 and BMK1 in the hippocampal CA1 region of rats in the non acupoint electroacupuncture group was not statistically significant (P>0.05). Compared with the nimodipine group, the expression of EphB2 and BMK1 in the hippocampal CA1 region of rats in the electroacupuncture Zhisanzhen group significantly increased (P<0.05). Conclusion Electroacupuncture may improve the damage of hippocampal neurons in vascular dementia rats by increasing the expression of EphB2 and BMK1 in the CA1 region of the hippocampus, thereby improving the learning and memory of vascular dementia rats.

Small ubiquitin-related modifier(SUMOylation)is a dynamic post-translational modification that maintains cardiac function and can protect against a hypertrophic response to cardiac pressure overload.However,the function of SUMOylation after myocardial infarction(MI)and the molecular details of heart cell responses to SUMO1 deficiency have not been determined.In this study,we demonstrated that SUMO1 protein was inconsistently abundant in different cell types and heart regions after MI.However,SUMO1 knockout significantly exacerbated systolic dysfunction and infarct size after myocardial injury.Single-nucleus RNA sequencing revealed the differential role of SUMO1 in regulating heart cells.Among cardiomyocytes,SUMO1 deletion increased the Nppa+Nppb+Ankrd1+cardiomyocyte subcluster pro-portion after MI.In addition,the conversion of fibroblasts to myofibroblasts subclusters was inhibited in SUMO1 knockout mice.Importantly,SUMO1 loss promoted proliferation of endothelial cell subsets with the ability to reconstitute neovascularization and expressed angiogenesis-related genes.Computational analysis of ligand/receptor interactions suggested putative pathways that mediate cardiomyocytes to endothelial cell communication in the myocardium.Mice preinjected with cardiomyocyte-specific AAV-SUMO1,but not the endothelial cell-specific form,and exhibited ameliorated cardiac remodeling following MI.Collectively,our results identified the role of SUMO1 in cardiomyocytes,fibroblasts,and endothelial cells after Ml.These findings provide new insights into SUMO1 involvement in the patho-genesis of MI and reveal novel therapeutic targets.

Background The safety of drinking water is closely related to people's health. In recent years, relevant studies have identified some health related problems with drinking water in Inner Mongolia Autonomous Region. The complex and diverse natural environment embraced by the vast jurisdiction of the region may lead to uneven drinking water quality across the region. Objective To evaluate eight chemicals including arsenic, cadmium, chromium (hexavalent), lead, mercury, fluoride, trichloromethane, and carbon tetrachloride in urban drinking water in Inner Mongolia Autonomous Region in 2021, and to provide reference for optimizing urban water supply system and ideas for further developing strategies to promote population health. Methods A total of 1228 monitoring sites were set up in urban areas of Inner Mongolia, and water samples were collected once in dry season (May) and once in wet season (August−September). Eight chemicals of interest in drinking water were detected according to the Standard examination methods for drinking water, and assessed for health risks using the health risk assessment model recommended by the United States Environmental Protection Agency (USEPA) and following the Technical guide for environmental health risk assessment of chemical exposure. Mann-Whitney U test was used to compare the concentrations of eight chemicals in urban drinking water by water seasons and water sample types. Results In 2021, a total of 2381 samples of urban drinking water were tested in the Inner Mongolia Autonomous Region, including 1195 samples in wet season and 1186 samples in dry season; 389 samples of finished water and 1992 samples of tap water. The positive rates of arsenic and fluoride were 26.25% and 96.77%, respectively. The positive rates of cadmium, chromium (hexavalent), lead, mercury, trichloromethane, and carbon tetrachloride were 6.22%, 16.63%, 6.09%, 16.67%, 18.98%, and 8.36%, respectively. The exceeding standard rate of fluoride was 4.87%. Trichloromethane and carbon tetrachloride were qualified in all samples. There were statistical differences in the concentrations of arsenic, cadmium, chromium (hexavalent), lead, and carbon tetrachloride in urban drinking water between water seasons (Z=−3.847, P<0.05; Z=2.464, P=0.014; Z=−3.129, P=0.002; Z=4.341, P<0.05; Z=4.342, P<0.05). Only fluoride concentration was found statistically different among different water sample types (Z=−2.287, P=0.022). The non-carcinogenic risks of ingestion and dermal exposure to each chemical in drinking water by water seasons and water sample types were all less than 1, but the P₉₅ total non-carcinogenic risks of oral exposure were greater than 1. The P₉₅ carcinogenic risks of oral exposure to some chemicals in drinking water by water seasons and water sample types were>10⁻⁴, which suggested carcinogenic risks, while the carcinogenic risks of dermal explore to chemicals were all less than 10⁻⁶. Conclusion In 2021, urban drinking water in Inner Mongolia Autonomous Region is generally safe, but arsenic, cadmium, chromium (hexavalent), lead, mercury, and fluoride still exceed the national limits, posing certain health risks.

The aim of this study was to investigate the effect of baicalein on a Drosophila model of hereditary Parkinson's disease caused by gene mutations and to preliminarily elucidate the mechanism of baicalein in delaying hereditary Parkinson's disease. In this paper, PTEN-induced putative kinase 1 (PINK1)-RNAi Parkinson's Drosophila were used as the model group and wild-type Drosophila w¹¹¹⁸ were used as the control group. Different doses of baicalein and Madopa were administered to the model group to observe their effects on the life span, motor ability, the abnormal rate of wings, dopamine content and dopaminergic neurons of PINK1-RNAi Parkinson's Drosophila and their effects on mitochondrial dysfunction including adenosine triphosphate (ATP), mitochondrial DNA (mtDNA) and reactive oxygen species (ROS) content. The results showed that the effective administration doses of baicalein were 0.8 mg·mL^-1 for low concentration, 1.6 mg·mL^-1 for medium concentration and 3.2 mg·mL^-1 for high concentration, and the optimal administration dose of the positive drug Madopa was 0.1 μg·mL^-1. Baicalein and Madopa could significantly improve the life span, exercise ability and reduce the abnormal rate of wings of PINK1-RNAi male Drosophila (P < 0.05), and low dose baicalein showed the best effect; baicalein could improve the loss of dopaminergic neurons, and the effects of low dose and high dose were the best, but Madopa showed no significant effect; baicalein and Madopa had no significant effect on dopamine content (P > 0.05). Baicalein and Madopa could increase the ATP content of PINK1-RNAi male Drosophila (P < 0.05), and low dose baicalein showed the best effect; middle dose baicalein could significantly increase the mtDNA content of PINK1-RNAi male Drosophila (P < 0.05), but Madopa had no significant effect; baicalein and Madopa had no significant effect on ROS content (P > 0.05).