Computational approaches, encompassing both physics-based and machine learning (ML) methodologies, have gained substantial traction in drug repurposing efforts targeting specific therapeutic entities. The human dopamine (DA) transporter (hDAT) is the primary therapeutic target of numerous psychiatric medications. However, traditional hDAT-targeting drugs, which interact with the primary binding site, encounter significant limitations, including addictive potential and stimulant effects. In this study, we propose an integrated workflow combining virtual screening based on weighted holistic atom localization and entity shape (WHALES) descriptors with in vitro experimental validation to repurpose novel hDAT-targeting drugs. Initially, WHALES descriptors facilitated a similarity search, employing four benztropine-like atypical inhibitors known to bind hDAT's allosteric site as templates. Consequently, from a compound library of 4,921 marketed and clinically tested drugs, we identified 27 candidate atypical inhibitors. Subsequently, ADMETlab was employed to predict the pharmacokinetic and toxicological properties of these candidates, while induced-fit docking (IFD) was performed to estimate their binding affinities. Six compounds were selected for in vitro assessments of neurotransmitter reuptake inhibitory activities. Among these, three exhibited significant inhibitory potency, with half maximal inhibitory concentration (IC₅₀) values of 0.753 μM, 0.542 μM, and 1.210 μM, respectively. Finally, molecular dynamics (MD) simulations and end-point binding free energy analyses were conducted to elucidate and confirm the inhibitory mechanisms of the repurposed drugs against hDAT in its inward-open conformation. In conclusion, our study not only identifies promising active compounds as potential atypical inhibitors for novel therapeutic drug development targeting hDAT but also validates the effectiveness of our integrated computational and experimental workflow for drug repurposing.

Ethanol (EtOH) is a common trigger for gastric mucosal diseases, and mitigating oxidative stress is essential for attenuating gastric mucosal damage. Capsaicin (CAP) has been identified as a potential agent to counteract oxidative damage in the gastric mucosa; however, its precise mechanism remains unclear. This study demonstrates that CAP alleviates EtOH-induced gastric mucosal injuries through two primary pathways: by suppressing the chemokine receptor 4 (CCR4)/Src/p47phox axis, thereby reducing oxidative stress, and by inhibiting the phosphorylation and nuclear translocation of nuclear factor-κB p65 (NF-κB) p65, resulting in diminished inflammatory responses. These findings elucidate the mechanistic pathways of CAP and provide a theoretical foundation for its potential therapeutic application in the treatment of gastric mucosal injuries.
Ethanol/toxicity* ; Animals ; Gastric Mucosa/metabolism* ; Signal Transduction/drug effects* ; Oxidative Stress/drug effects* ; Capsaicin/pharmacology* ; Male ; NADPH Oxidases/genetics* ; Mice ; Humans ; src-Family Kinases/genetics*

Computational approaches,encompassing both physics-based and machine learning(ML)methodolo-gies,have gained substantial traction in drug repurposing efforts targeting specific therapeutic entities.The human dopamine(DA)transporter(hDAT)is the primary therapeutic target of numerous psychi-atric medications.However,traditional hDAT-targeting drugs,which interact with the primary binding site,encounter significant limitations,including addictive potential and stimulant effects.In this study,we propose an integrated workflow combining virtual screening based on weighted holistic atom localization and entity shape(WHALES)descriptors with in vitro experimental validation to repurpose novel hDAT-targeting drugs.Initially,WHALES descriptors facilitated a similarity search,employing four benztropine-like atypical inhibitors known to bind hDAT's allosteric site as templates.Consequently,from a compound library of 4,921 marketed and clinically tested drugs,we identified 27 candidate atypical inhibitors.Subsequently,ADMETlab was employed to predict the pharmacokinetic and toxi-cological properties of these candidates,while induced-fit docking(IFD)was performed to estimate their binding affinities.Six compounds were selected for in vitro assessments of neurotransmitter re-uptake inhibitory activities.Among these,three exhibited significant inhibitory potency,with half maximal inhibitory concentration(IC50)values of 0.753 μM,0.542 μM,and 1.210 μM,respectively.Finally,molecular dynamics(MD)simulations and end-point binding free energy analyses were con-ducted to elucidate and confirm the inhibitory mechanisms of the repurposed drugs against hDAT in its inward-open conformation.In conclusion,our study not only identifies promising active compounds as potential atypical inhibitors for novel therapeutic drug development targeting hDAT but also validates the effectiveness of our integrated computational and experimental workflow for drug repurposing.

Objective:To explore the application effect of 5E nursing guided by empowerment theory in patients undergoing liver cancer resection.Methods:Using the purposive sampling method, a total of 88 patients who underwent liver cancer resection surgery in Zhumadian Central Hospital from July 2020 to July 2022 were selected as the research objects. They were divided into the control group ( n=44) and the observation group ( n=44) by the random number table method. The control group was given 5E nursing, while the observation group was given 5E nursing guided by empowerment theory. The improvement of gastrointestinal function between the two groups was compared by the first anal defecation time, the first anal exhaust time and the recovery time of bowel sound. Visual Analogue Scale (VAS) was used to evaluate postoperative pain, General Self-Efficacy Scale (GSES) was used to evaluate self-efficacy, and hope level was assessed by Herth Hope Index (HHI). After treatment, the compliance and occurrence of digestive tract discomfort were compared between the two groups. Results:The first anal defecation time, first anal exhaust time and bowel sound recovery time in observation group were less than those in control group ( P<0.05). Postoperative pain score of observation group was lower than that of control group 48 hours after operation ( P<0.05). After nursing, the GSES, HHI and compliance scores of the observation group were higher than those of the control group ( P<0.05), and the incidence of gastrointestinal discomfort symptoms in the observation group was lower than that in the control group ( P<0.05) . Conclusions:The 5E nursing guided by empowerment theory can effectively improve the compliance, self-efficacy and hope level of liver cancer resection patients, reduce pain, promote postoperative recovery and reduce the incidence of gastrointestinal discomfort symptoms.

Objective To explore the effects of drug therapy combined with multi-dimensional psychological intervention on the insomnia of shift medical staff in"sunshine hospital"mode,and to provide a reference for improving the physical and mental health of shift medical staff.Methods A total of 140 cases of medical staff with insomnia in shifts in Wuhan were included and divided into study group and control group by random number table method,70 cases in each group.The control group was given drug treatment,and the study group was treated combined with multi-dimensional psychological intervention.based on"sunshine hospital"model.The scale and questionnaire of PSQI,ISI,ESS and FAS were used to evaluate sleep status and HAMD,HAMA,PHQ-9 and SAS were used to evaluate psychological status,at baseline,visit 1(baseline+intervention for 1 month)and visit 2(baseline+intervention for 3 months),respectively.Results(1)Sleep status:There were differences in 7 dimensions of PSQI score,ISI,ESS,and FAS score between the study group and the control group at different periods(P<0.05);Among them,the PSQI scores of the two groups showed significant difference between the two groups at interview 2(P<0.05);There were significant differences in sleep quality,sleep efficiency scores,ESS and FAS between the two groups at visit 1 and visit 2(P<0.05).(2)Psychological status:HAMD,HAMA,PHQ-9 and SAS scores of the study group and the control group were different in different periods(P<0.05).At interview 2,there were significant differences in HAMA and SAS scores between the two groups(P<0.05).Conclusion Based on the"sunshine hospital"model of drug therapy combined with multi-dimensional psychological intervention,it can significantly improve sleepiness,fatigue symptoms,sleep quality,sleep efficiency,and anxiety and depression of first-line shift medical staff in the short term,and significantly alleviate overall insomnia and anxiety in the long term.

Early identification and intervention of high-risk factors during pregnancy is important for the prevention of maternal mortality. A certain hospital has established a management system for pregnant women undergoing first visit in non-obstetric departments and started applying it in three campus of the hospital in July 2023. Through the information management module for pregnant women undergoing first visit in non-obstetric departments that embedded in the hospital information system, abnormal pregnancy situations could be screened in a timely, comprehensive, and standardized manner, and quality control management could be carried out. At the same time, the hospital established a graded management path based on the severity of the condition of pregnant women, and provided early intervention for critically ill pregnant women reported through standardized management and multidisciplinary collaboration. From July to December 2023, a total of 5 766 pregnant women were first diagnosed and reported in 41 non-obstetric departments. Telephone follow-up showed a true reporting rate of 93.0%, and a total of 11 critical illness case were reported, including 2 cases of misoperation, with an accuracy rate of 81.8%. There were no adverse outcomes caused by failure to detect critical illness cases in a timely manner. In contrast, the relevant statistical data from January to June 2023 showed that there were 257 cases of pregnant women reported by non-obstetric departments, including 0 cases of critical illness and 1 case of missed critical illness. In addition, the time for non-obstetricians to screen for critically illness pregnant women of childbearing age has been reduced from 5-10 min per person before the system application to 15 s-1 min per person. The application of this system has reduced the missed reporting of critical illnesses, effectively ensured the safety of pregnant women, and improved work efficiency. It can provide reference for safety management of pregnant women in other medical institutions.

Objective To investigate the safety and efficacy of dorzagliatin combined with metformin in the treatment of type 2 diabetes mellitus (T2DM) patients with initially overweight/obesity. Methods Eighty T2DM patients with initially overweight/obesity diagnosed in the Department of Endocrinology of Jingzhou Central Hospital from October 2023 to April 2024 were selected. They were divided into control group and observation group with 40 cases in each group by random number table method. Control group was treated with metformin,observation group was treated with dorzagliatin combined with metformin. After 12 weeks of treatment,the therapeutic effects,and fasting blood glucose (FBG),2-h postprandial blood glucose (2hPG),glycosylated hemoglobin (HbA1c),homeostasis model assessment for β cell function (HOMA-β),homeostasis model assessment of insulin resistance (HOMA-IR) index,quality of life scale for patients with type 2 diabetes mellitus (DMQLS) scores,estimated glomerular filtration rate,liver function and lipid level before and after treatment were compared between two groups. The occurrence of adverse reactions during medication was recorded. Results The total effective rate of observation group was significantly higher than that of control group (95.00％ vs. 77.50％,x2=5.165,P=0.023). After treatment,FBG,2hPG,HbA1c,HOMA-IR index and body mass index of patients in both groups were significantly lower than before treatment,while HOMA-β and DMQLS scores were significantly higher than before treatment (P<0.05). FBG,2hPG,HbA1c,HOMA-IR index and body mass index of patients in observation group were significantly lower than those in control group,while HOMA-β and DMQLS scores were significantly higher than those in control group (P<0.05). There were no serious adverse reactions occurred during treatment in two groups (P>0.05). Conclusion The effect of dorzagliatin combined with metformin in the treatment of T2DM patients with initially overweight/obesity is remarkable. It can effectively control the level of blood glucose,improve the function of pancreatic islet cells,lose weight,and improve the life quality of patients. Its clinical application value is outstanding.

Objective To investigate the safety and efficacy of dorzagliatin combined with metformin in the treatment of type 2 diabetes mellitus (T2DM) patients with initially overweight/obesity. Methods Eighty T2DM patients with initially overweight/obesity diagnosed in the Department of Endocrinology of Jingzhou Central Hospital from October 2023 to April 2024 were selected. They were divided into control group and observation group with 40 cases in each group by random number table method. Control group was treated with metformin,observation group was treated with dorzagliatin combined with metformin. After 12 weeks of treatment,the therapeutic effects,and fasting blood glucose (FBG),2-h postprandial blood glucose (2hPG),glycosylated hemoglobin (HbA1c),homeostasis model assessment for β cell function (HOMA-β),homeostasis model assessment of insulin resistance (HOMA-IR) index,quality of life scale for patients with type 2 diabetes mellitus (DMQLS) scores,estimated glomerular filtration rate,liver function and lipid level before and after treatment were compared between two groups. The occurrence of adverse reactions during medication was recorded. Results The total effective rate of observation group was significantly higher than that of control group (95.00％ vs. 77.50％,x2=5.165,P=0.023). After treatment,FBG,2hPG,HbA1c,HOMA-IR index and body mass index of patients in both groups were significantly lower than before treatment,while HOMA-β and DMQLS scores were significantly higher than before treatment (P<0.05). FBG,2hPG,HbA1c,HOMA-IR index and body mass index of patients in observation group were significantly lower than those in control group,while HOMA-β and DMQLS scores were significantly higher than those in control group (P<0.05). There were no serious adverse reactions occurred during treatment in two groups (P>0.05). Conclusion The effect of dorzagliatin combined with metformin in the treatment of T2DM patients with initially overweight/obesity is remarkable. It can effectively control the level of blood glucose,improve the function of pancreatic islet cells,lose weight,and improve the life quality of patients. Its clinical application value is outstanding.

Theaflavins are a class of natural products extracted from black tea or green tea, with significant anti-tumor effects on gastric cancer, liver cancer, breast cancer and other tumors. Theaflavins were once considered as the new products for anticancer therapy. However, the anti-tumor mechanism of theaflavins involves a variety of biological processes, and the regulation is complex. Therefore, this article summarizes the role of theaflavins in promoting tumor cell apoptosis, inducing tumor cell mitotic arrest and regulating tumor immunity, and reviews the inhibition of tumorigenesis and growth through MAPK, PI3K/AKT, Hedgehog, NF-κB, JAK/STAT and Wnt/β-Catenin signal pathways, in order to provide new ideas for cancer treatment and anti-cancer drug development.

Objective:To investigate the relationship between serum matrix metalloproteinase-9 (MMP-9) level and the location and severity of bleeding in patients with cerebral microbleeds(CMBs).Methods:A total of 60 CMBs patients admitted to the Department of Neurology of the First Affiliated Hospital of the Xinxiang Medical University from January 2019 to August 2020 were selected as subjects as the CMBs group, and 60 healthy controls without nervous system diseases in outpatient physical examination during the same period were selected as the control group. The clinical data and biochemical indicators of the two groups were collected. Serum MMP-9 levels were measured by enzyme linked immunosorbent assay (ELISA). According to susceptibility weighted imaging (SWI), CMBs patients were divided into grade 1 group ( n=24), grade 2 group ( n=19) and grade 3 group ( n=17), and according to the micro analytical rating scale (MARS), the CMBs patients were divided into the lobar group ( n=19), the deep or infratentorial group ( n=17) and the mixed group ( n=24).The relationship between serum MMP-9 level and the location and severity of CMBs was analyzed. SPSS 19.0 software was used for data statistical analysis.One-way ANOVA, t-test and rank sum test were used for comparison. Logistic regression analysis was used to analyze the influencing factors. Pearson correlation analysis and Spearman correlation analysis were used for correlation analysis. Results:The level of MMP-9 in CMBs group was significantly higher than that in control group (208.13(142.25, 285.88) μg/L, 149.50(93.40, 186.51)μg/L), and the difference was statistically significant ( P<0.05). Serum MMP-9 level was a risk factor of CMBs ( β=1.322, OR=3.750, 95% CI=2.038-7.997, P=0.002). The difference of level of MMP-9 in different severity of CMBs was statistically significant (147.55(109.25, 266.47)μg/L, 242.12(147.55, 288.80)μg/L, 270.42(203.43, 364.27)μg/L, P=0.017). Serum MMP-9 level was positively correlated with the number of CMBs ( r=0.371, P=0.003). The difference of MMP-9 level of CMBs in different locations were statistically significant (249.77(158.43, 338.46)μg/L, 188.83(138.52, 243.15)μg/L, 210.65(144.25, 255.78)μg/L, P=0.013). The increased serum MMP-9 level was a risk factor for CMBs( β=0.401, OR=1.122, 95% CI=1.004-1.204, P=0.036). Conclusion:The increased level of serum MMP-9 may be a risk factor of CMBs, especially for CMBs in cerebral lobesand, and the level of MMP-9 is positively correlated with the severity of CMBs.