OBJECTIVE To investigate the effects and mechanism of Wenpi tongluo kaiqiao formula （WPTL） against neuronal necroptosis in Alzheimer’s disease （AD） mice based on the Z-DNA binding protein 1 （ZBP1）/mixed lineage kinase domain-like protein （MLKL） signaling pathway. METHODS Forty APP/PS1 transgenic AD mice were randomly divided into model group， WPTL low-dose （WPTL-L） group （10.4 g/kg， calculated by the raw medicine）， WPTL high-dose （WPTL-H） group （20.8 g/kg， calculated by the raw medicine） and donepezil hydrochloride group （3 mg/kg）， with 10 mice in each group； another 10 C57BL/6J mice were selected as normal control group. Intragastric administration， once a day， for 30 consecutive days. Twenty-four hours after the last administration， Morris water maze test was performed to evaluate learning and memory abilities； the pathological morphology of hippocampal tissues was observed； the serum levels of tumor necrosis factor-α （TNF-α） and interleukin-4 （IL-4） were determined； the expressions of amyloid precursor protein （APP）， Tau protein， and ZBP1/MLKL signaling pathway-related proteins in hippocampal tissues were detected； the positive expression of phosphorylated receptor-interacting protein kinase 3 （p-RIPK3） in the neurons of hippocampal tissues and mRNA expression of ZBP1 were measured in hippocampal tissues. RESULTS Compared with normal control group， the escape latency of mice in model group was prolonged significantly on day 3 to 5 （P＜0.05）， the times of crossing platform reduced significantly （P＜0.05）， and obvious pathological changes were observed in the hippocampal tissue. The level of TNF- α， the expressions of APP， p-Tau and ZBP1， the phosphorylation levels of RIPK1， RIPK3 and MLKL， the fluorescence intensity of p-RIPK3 as well as the mRNA expression of ZBP1 were significantly increased （P＜0.05）， while the serum level of IL-4 was decreased significantly （P＜0.05）. Compared with model group， above indexes were reversed significantly in administration groups （P＜0.05）， and pathological damage of hippocampal tissue was alleviated. CONCLUSIONS WPTL can inhibit the ZBP1/MLKL signaling pathway， reduce neuronal necroptosis in AD mice， and inhibit inflammatory responses， thereby improving learning and spatial memory abilities in AD mice.

OBJECTIVE To investigate the efficacy and safety of tirofiban for early neurological deterioration in patients with acute ischemic stroke. METHODS A total of 126 patients with early neurological deterioration of acute ischemic stroke who were admitted to the Department of Neurology， Heji Hospital Affiliated to Changzhi Medical College from January 2022 to December 2023 were selected and divided into observation group and control group according to random number table method， with 63 cases in each group. All patients received standardized treatment such as lipid-lowering and blood pressure-lowering therapy. Based on the standard treatment， patients in the control group additionally took Aspirin enteric-coated tablets 100 mg+Clopidogrel bisulfate tablets 75 mg orally （once a day， for 14 consecutive days）. The patients in the observation group received Tirofiban hydrochloride and sodium chloride injection based on the standardized treatment [first intravenous infusion of 0.40 μg/（kg·min） for 30 min， and then continuous intravenous infusion of 0.10 μg/（kg·min） for 47.5 h]； subsequently， patients were given Aspirin enteric-coated tablets （100 mg） and Clopidogrel bisulfate tablets （75 mg） once a day for 14 consecutive days. The clinical efficacy， the National Institutes of Health Stroke Scale （NIHSS） score， modified Rankin Scale （mRS） score， and hemorheological indexes before and after treatment were compared between the two groups， and the adverse reactions were recorded. RESULTS The total effective rate （87.30%） of the observation group was significantly higher than that of the control group （71.43%） （P＜0.05）. NIHSS scores of the two groups at 1st， 7th and 14th day after treatment， the mRS score at 90th day after treatment， and the platelet aggregation rate， whole blood viscosity， plasma viscosity and fibrinogen at 14th day after treatment were significantly lower than those before treatment in the same group， and the observation group was significantly lower than the control group at the same period （P＜0.05）. The total incidences of adverse reactions such as nausea， headache， fever， gastrointestinal bleeding， oral and nasal mucosal bleeding and thrombocytopenia in both groups of patients were 28.57% respectively， with no statistically significant difference （P＞0.05）. CONCLUSIONS For patients with early neurological deterioration in acute ischemic stroke， the addition of tirofiban can accelerate the recovery of neurological function， improve blood hyperviscosity and platelet aggregation， and improve the prognosis of patients with good safety.

OBJECTIVE To investigate the intervention effect and its potential mechanism of Yifei xuanfei jiangzhuo formula by inhibiting mitochondrial fission in a vascular dementia （VaD） model rats. METHODS VaD rat model was established by bilateral common carotid artery ligation. The experimental animals were randomly divided into sham operation group （SHAM）， model group （MOD），Yifei xuanfei jiangzhuo formula low-dose group （YFXF-L）， Yifei xuanfei jiangzhuo formula high-dose group （YFXF-H）， and Donepezil hydrochloride group （positive control）， with 9 animals in each group. After 30 days of intervention， the spatial learning memory ability was assessed by Morris water maze experiment； HE staining was used to observe histopathological changes in CA1 area of hippocampus； ELISA was used to detect the levels of serum inflammatory factors [interleukin-1β （IL-1β） and IL-4]； Western blot was used to detect the expressions of heat shock protein 90 （HSP90）/mixed lineage kinase domain-like protein （MLKL）/dynamin-related protein 1 （Drp1） pathway-related proteins， mitochondrial fusion proteins （MFN1， MFN2）， and adenosine triphosphate synthase 5A （ATP5A） in hippocampal tissues. The immunohistochemistry was used to detect the level of phosphorylated MLKL （p-MLKL）； real-time fluorescence quantitative PCR was adopted to detect mRNA expressions ofHSP90， MFN1， MFN2 and ATP5A. RESULTS Compared with SHAM group， the escape latency of rats in the MOD group was significantly prolonged， the number of crossing the platform was significantly reduced， and the hippocampal tissues showed typical neuronal damage characteristics， the positive expression level of p-MLKL and the serum level of IL-1β significantly increased， while the serum level of IL-4 significantly decreased， the protein and mRNA expression of HSP90， as well as the protein expressions of p-MLKL/MLKL and p-Drp1（Ser616）/Drp1 were all significantly increased in hippocampal tissue， the protein and mRNA expressions of MFN1， MFN2 and ATP5A， and protein expression of p-Drp1（Ser637）/Drp1 were all significantly decreased （P＜0.05）. After the intervention of Yifei xuanfei jiangzhuo formula， above indicators in each treatment group were all significantly reversed （P＜0.05）. CONCLUSIONS Yifei xuanfei jiangzhuo formula may alleviate neuronal damage and neuroinflammatory responses in VaD rats by regulating the HSP90/MLKL/Drp1 signaling pathway， inhibiting mitochondrial fission， thereby maintaining mitochondrial dynamic balance and improving mitochondrial function.

Studies on specific transient receptor potential melastatin 2 (TRPM2) channel inhibitors can deepen our understanding of the pathological mechanism of related diseases, and allow discovery of novel, effective targets and drugs for therapy. The development of TRPM2 channel inhibitors can be broadly classified into four categories with distinct characteristics: reutilization and structural modification of homologous ion channel modulators to produce a diverse array of TRPM2 channel inhibitors with strong inhibitory effects; TRPM2 channel inhibitors based on channel gating mechanism with high specificity; inhibitors identified through high-throughput screening with novel chemical structures; inhibitors developed from natural antioxidants with higher safety. In recent years, the application of computer-aided drug design has significantly accelerated the development of TRPM2 channel inhibitors. Several promising compounds such as ZA18, A1 and D9 have been discovered, and it is expected that more potent and selective TRPM2 channel inhibitor scaffolds will be discovered in the future. This article reviews the advances on the studies of TRPM2 channel inhibitors, aiming to provide insights for further research and clinical application of TRPM2 channel inhibitors.
TRPM Cation Channels/antagonists & inhibitors* ; Humans ; Drug Design

ObjectiveTo compare the development status of health facilities in different regions （non-agricultural and agricultural districts）and different types across four dimensions： organizational management， health environment， health activities， and health outcomes， to explore factors that may affect the current development status and summarize effective experiences， and to provide a foundation for the subsequent comprehensive， standardized， and effective promotion of health facility development and tiered and classified management. MethodsInvestigators conducted a health status survey based on the four dimensions for 50 health facilities in 16 districts of Shanghai， representing three types （including government agencies， enterprises， and communities）. Evaluation forms were filled out through on-site observation and document reviews， which were developed in accordance with the Shanghai Health Settings Evaluation Standards （for trial implementation in 2019）. ResultsThe average total score of health facilities in Shanghai was （88.42±11.93） points， with an overall excellence rate of 86.0%. The excellence rate of each dimension， from highest to lowest， were healthy environment （84.0%）， organizational management （82.0%）， health activities （78.0%）， and health outcomes （44.0%）. Health facilities in agricultural districts scored higher in both total score and average score on the organizational management dimension compared to non-agricultural districts. The excellence rate for the organizational management dimension was also higher in agricultural districts than in non-agricultural districts. There was no statistical significance in the total score， the score of each dimension， the overall excellence rate， and the excellence rate of each dimension among different types of health facilities （P>0.05）. ConclusionThe development of health facilities among government agencies， enterprises， and communities in Shanghai has begun to yield positive results. Health facilities in non-agricultural districts should actively draw on the experience of those in agricultural districts， particularly in organizational management， adjust development ideas and planning based on their own realities， so as to continuously improve the levels of development.

The development of health-promoting hospitals is an important part of the Healthy China Initiative， facilitating the transformation of medical institutions from a primary focus on medical and surgical treatments to a patient-centered approach prioritizing public health. To promote the scientific， standardized， and sustainable development of health-promoting hospitals， the Shanghai Municipal Center for Health Promotion， together with Shanghai General Hospital and other institutions， has jointly developed the Standards for the Development of Health⁃promoting Hospitals （Standards） in accordance with the principles of scientific rigor， feasibility， and advancing with the times. The Standards outlines the requirements for the development of health-promoting hospitals across four aspects： organizational and institutional guarantees， creation of a healthy environment， implementation of health education and promotion， and evaluation. It is applicable to all levels and types of public medical institutions in Shanghai， and can also be referred to and implemented by other medical institutions. The introduction of the Standards is of great significance for promoting the formation of a long-term mechanism in health-promoting hospitals. This paper introduces the basis， principles， main content， precautions， and implementation suggestions of the Standards. Taking into account relevant policies and standards， it interprets the technical aspects in the process of developing health-promoting hospitals， which is helpful for medical institutions and their management to better understand and apply the standards in their work.

OBJECTIVE To investigate the mechanism of Yifei xuanfei jiangzhuo formula （YFXF） against vascular dementia （VD）. METHODS The differentially expressed genes of YFXF （YDEGs） were obtained by network pharmacology. High-risk genes were screened from YDEGs by using the nomogram model. The optimal machine learning models in generalized linear， support vector machine， extreme gradient boosting and random forest models were screened based on high-risk genes. VD model rats were established by bilateral common carotid artery occlusion， and were randomly divided into model group and YFXF group （12.18 g/kg， by the total amount of crude drugs）， and sham operation group was established additionally， with 6 rats in each group. The effects of YFXF on behavior （using escape latency and times of crossing platform as indexes）， histopathologic changes of cerebral cortex， and the expression of proteins related to the secreted phosphoprotein 1 （SPP1）/phosphoinositide 3-kinase （PI3K）/protein kinase B （aka Akt） signaling pathway and the mRNA expression of SPP1 in cerebral cortex of VD rats were evaluated. RESULTS A total of 6 YDEGs were obtained， among which SPP1， CCL2， HMOX1 and HSPB1 may be high-risk genes of VD. The generalized linear model based on high-risk genes had the highest prediction accuracy （area under the curve of 0.954）. Compared with the model group， YFXF could significantly shorten the escape latency of VD rats， significantly increase the times of crossing platform （P＜0.05）； improve the pathological damage of cerebral cortex， such as neuronal shrinkage and neuronal necrosis； significantly reduce the expressions of SPP1 protein and mRNA （P＜0.05）， while significantly increase the phosphorylation levels of PI3K and Akt （P＜0.05）. CONCLUSIONS VD high-risk genes SPP1， CCL2， HMOX1 and HSPB1 may be the important targets of YFXF. YFXF may play an anti-VD role by down-regulating the protein and mRNA expressions of SPP1 and activating PI3K/Akt signaling pathway.

ObjectiveTo investigate the effects of health distress on depression and anxiety among the middle-aged and elderly hearing-impaired people, and to explore the mediating effect of social capital, so as to provide an evidence for the implementation of appropriate interventions. MethodsA face-to-face self-designed questionnaire survey was conducted on 271 middle-aged and elderly hearing-impaired people aged 50 years and above in Shanghai from September 2021 to February 2022, including the general information of the subjects, social capital scale, hospital anxiety and depression scale, and health distress scale. The higher the total scores of the social capital scale, the higher level of social capital. Higher scores on the hospital anxiety and depression scale indicate more severe anxiety and depression, and scores >7 points were used to define an anxiety or depression status. The higher scores of the health distress scale, the worse the health condition of the respondents. Univariate and multivariate linear regression models were used to investigate the effects of health distress on depression and anxiety, and the mediating effects were used to test the mediating role of social capital between health distress and depression and anxiety. ResultsThe mean scores of depression, anxiety, social capital and health distress among the middle-aged and elderly hearing-impaired people aged 50 years and above were (11.063±5.892), (58.391±15.273) and (6.384±4.787) points, respectively. Health distress scores were positively correlated with social capital scores, health distress was positively correlated with depression and anxiety, while social capital was negatively correlated with depression and anxiety (all P<0.05). Social capital had masking effects on the relationship between health distress, depression and anxiety (all P<0.05), which accounted for 24.11% and 18.93% in the effects of depression and anxiety, respectively. ConclusionThe levels of depression and anxiety are higher among the middle-aged and elderly hearing-impaired people aged 50 years and above, and health distress can affect the levels of depression and anxiety through social capital. Health workers should take measures to reduce health distress and improve social capital among the middle-aged and elderly hearing-impaired people, so as to further alleviate the occurrence and development of depression and anxiety.

Objective To investigate the risk factors of stroke in nine hospitals of six cities of Shandong,and compare the differenc-es between residents of peninsula and inland areas. Methods Stroke patients in nine hospitals belonging to the Rehabilitation Medicine Alliance of Qilu Hospital of Shan-dong Universityfrom December,2022 to October,2023 were selected as the case group.The control group con-sisted of individuals undergoing health check-ups at the same hospitals during the same period.The sample size of both groups was equal,matched by age and gender,and demographic information and medical history were collected,and the risk factors of stroke were analyzed. Results A total of 438 cases were included.Residence in the inland(OR=2.07,95%CI 1.26 to 3.40,P=0.04),smoking(P=0.007),alcohol consumption(OR=6.67,95%CI 1.16 to 38.37,P=0.019),depression(OR=2.16,95%CI 1.03 to 4.53,P=0.042)and hypertension(OR=4.15,95%CI 2.34 to 7.39,P<0.001)were possible risk factors of stroke.However,smoking(OR=3.35,95%CI 1.11 to 10.10,P=0.013)and hypertension(OR=2.79,95%CI 1.12 to 6.95,P=0.004)were possible risk factors for the prevalence of stroke among residents in peninsula ar-eas,and obesity(excess waist circumference)(OR=1.08,95%CI 1.03 to 1.13,P=0.001),depression(OR=4.27,95%CI 1.38 to 13.23,P=0.013)and hypertension(OR=4.8,95%CI 2.21 to 10.43;P<0.001)were possi-ble risk factors for the prevalence of stroke among residents in the inland areas. Conclusion Hypertension is the most likely risk factor for stroke in nine hospitals of six cities of Shandong Province.Additionally,living inland,smoking and alcohol consumption may also increase the risk of stroke.There are dif-ferences in possible risk factors for stroke between peninsula and inland residents,and targeted stroke prevention and control measures should be implemented for different regions.

Cancer cells refer to a group of malignant cells with strong division and proliferation abilities.Cancer cells rely on the unstable plunder of human nutrition to sustain the large amount of energy that they need for their own division and proliferation.The division and proliferation of cancer cells are linked to the synthesis and replication of genetic material in the nucleus.Blockage or destruction of the synthesis of genetic material in cancer cells is one of the mechanisms underlying the action of most antitumor drugs.As the key material that dominates cell division,proliferation,and death,nuclear genetic material which mainly refers to the deoxyribonucleic acid located on the chromatin in the nucleus,plays a decisive role in the final fate of cells.The final fate of cancer cells after the damage of the genetic material is worthy of investigation and analysis.In this paper,we discuss and analyze the fate of cancer cells after genetic material damage from the aspect of cellular cycle arrest,apoptosis,autophagy,and senescence to provide ideas for the mechanism research on antitumor drugs.