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 explore the clinical efficacy of Gandou decoction in treating Wilson's disease （WD） with dampness heat accumulation accompanied by rapid eye movement （REM） sleep behavior disorder （RBD）. MethodFrom April 2019 to August 2023，62 patients with dampness heat accumulation type WD accompanied by RBD who met the inclusion criteria were selected from the Department of Encephalopathy at the First Affiliated Hospital of Anhui University of Chinese Medicine. They were randomly divided into a control group and an observation group with 31 cases each using a computer distributor. The control group received routine copper removal treatment，while the observation group received additional treatment with Gandou decoction on the basis of the control group. Eight days was one course of treatment，totaling three courses. The scores of traditional Chinese medicine syndromes，RBD screening questionnaire （RBDSQ） scores，RBD questionnaire-Hong Kong （RBDQ-HK） scores，polysomnography （PSG） parameters，24-hour urine copper （24 h U-Cu） levels，and non-ceruloplasmin-bound copper （NCC） levels between the two groups before and after treatment were compared，and adverse reactions were observed. ResultSixty trial cases were ultimately completed，with 30 cases in each group. Before treatment，there was no statistically significant difference in various indicators between the two groups， and thus they were comparable. Compared with those before treatment，the traditional Chinese medicine syndrome scores，RBDSQ scores and RBDQ-HK scores of the two groups were significantly reduced，the 24 h U-Cu levels were significantly increased，and the NCC levels were significantly reduced （P<0.05，P<0.01）. Compared with the control group， the observation group showed better improvement in traditional Chinese medicine syndrome scores， RBDSQ scores， RBDQ-HK scores， and NCC levels （P<0.05，P<0.01）. Compared with those before treatment，the total sleep time （TST），sleep efficiency （SE），sleep/REM latency，the proportion of N1/N2/REM stages，arousal index （ARI），and proportion of phasic electromyographic activity （P-EMG-A） were significantly improved in both groups （P<0.05）. Compared with the control group after treatment，the observation group showed more significant improvements in the proportion of TST，SE，REM stages，ARI，and P-EMG-A proportion （P<0.05）. ConclusionGandou decoction can not only improve the traditional Chinese medicine syndrome of WD patients with dampness heat accumulation accompanied by RBD but also alleviate their RBD symptoms.

Objective To summarize and explore the individualized surgical treatment strategy and prognosis of anomalous aortic origin of coronary artery (AAOCA). Methods The clinical data of children with AAOCA admitted to Shanghai Children's Medical Center from March 2018 to August 2021 were retrospectively analyzed. Results A total of 17 children were enrolled, including 13 males and 4 females, with a median age of 88 (44, 138) months and a median weight of 25 (18, 29) kg. All patients received operations. The methods of coronary artery management included coronary artery decapitation in 9 patients, coronary artery transplantation in 5 patients and coronary artery perforation in 3 patients. One patient with severe cardiac insufficiency (left ventricular ejection fraction 15%) received mechanical circulatory assistance after the operation for 12 days. No death occurred in the early postoperative period, the average ICU stay time was 4.3±3.0 d, and the total hospital stay was 14.4±6.1 d. All the children received regular anticoagulation therapy for 3 months after discharge. The median follow-up time was 15 (13, 24) months. All patients received regular anticoagulation therapy for 3 months after discharge. No clinical symptoms such as chest pain and syncope occurred again. The cardiac function grade was significantly improved compared with that before operation. Imaging examination showed that the coronary artery blood flow on the operation side was unobstructed, and no restenosis occurred. Conclusion AAOCA is easy to induce myocardial ischemia and even sudden cardiac death. Once diagnosed, operation should be carried out as soon as possible. According to the anatomic characteristics of coronary artery, the early effect of individualized surgery is satisfactory, and the symptoms of the children are significantly improved and the cardiac function recovers well in the mid-term follow-up.

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.

OBJECTIVE To optimize the pre-audit rules for anesthesia prescriptions， improve the audit quality and rational drug use. METHODS The inpatient medical orders of anesthesia department from prescription pre-audit system of the Affiliated Hospital of Qingdao University （hereinafter referred to as “our hospital”） were analyzed from April 1 to 30， 2023. The classification statistics and evidence-based inquiry were carried out for irrational drug use issues； combined with our hospital’s current implementation of the Anesthesiology Clinical Pathway Medication Standards， the audit rules were set in details， and audit management and communication feedback processes were established. The total number of monthly audited orders， the number of pre-audit pop ups， system interception rate， physician modification rate after system audit， pharmacist audit rate， and reasonable rate of medical orders after refined setting of rules （May-December in 2023） were compared with before setting （April in 2023）； the average medication cost per anesthesia session after refined setting of rules was also compared with before setting （May- December in 2022）. RESULTS Irrational drug use in the anesthesia department mainly included inappropriate indications， inappropriate administration routes， inappropriate usage and dosage， inappropriate compatibility， medication problems in special populations， and improper medication during the perioperative period. After the refinement of the rules， the number of pre-audit pop ups in the anesthesia department significantly decreased over time， and gradually reached a stable state after continuous improvement. Compared with before setting， the system interception rate after the refinement of rules （P＜0.001）， physician modification rate after system audit （P＜0.001） both increased significantly， while the pharmacist audit rate significantly decreased （P＜0.001）. There was a linear trend between the reasonable rate of medical orders and the month from May to December in 2023 （P＜0.05）. Compared with before the setting， the average medication cost of anesthesia per session decreased from 720.72 yuan to 528.21 yuan， with a decrease of 26.71%. CONCLUSIONS Based on evidence-based reference， refining pre-audit rules for anesthesia prescriptions can significantly improve the quality of prescription examination， promote rational drug use， and save patient’s medical expenses.

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.