Increasing evidence shows that the early lesions of Parkinson's disease (PD) originate from gut, and correction of microbiota dysbiosis is a promising therapy for PD. FLZ is a neuroprotective agent on PD, which has been validated capable of alleviating microbiota dysbiosis in PD mice. However, the detailed mechanisms still need elucidated. Through metabolomics and 16S rRNA analysis, we identified glycoursodeoxycholic acid (GUDCA) was the most affected differential microbial metabolite by FLZ treatment, which was specially and negatively regulated by Clostridium innocuum, a differential microbiota with the strongest correlation to GUDCA production, through inhibiting bile salt hydrolase (BSH) enzyme. The protection of GUDCA on colon and brain were also clarified in PD models, showing that it could activate Nrf2 pathway, further validating that FLZ protected dopaminergic neurons through promoting GUDCA production. Our study uncovered that FLZ improved PD through microbiota-gut-brain axis, and also gave insights into modulation of microbial metabolites may serve as an important strategy for treating PD.

Although enteric glial cell (EGC) abnormal activation is reported to be involved in the pathogenesis of Parkinson's disease (PD), and inhibition of EGC gliosis alleviated gut and dopaminergic neuronal dysfunction was verified in our previous study, the potential role of gut microbiota on EGC function in PD still need to be addressed. In the present study, fecal microbiota transplantation revealed that EGC function was regulated by gut microbiota. By employing 16S rRNA and metabolomic analysis, we identified that 3-indolepropionic acid (IPA) was the most affected differential microbial metabolite that regulated EGC gliosis. The protective effects of IPA on PD were validated in rotenone-stimulated EGCs and rotenone (30 mg/kg i.g. for 4 weeks)-induced PD mice, as indicated by decreased inflammation, improved intestinal and brain barrier as well as dopaminergic neuronal function. Mechanistic study showed that IPA targeted pregnane X receptor (PXR) in EGCs, and inhibition of IL-13Rα1 involved cytokine-cytokine receptor interaction pathway, leading to inactivation of downstream JAK1-STAT6 pathway. Our data not only provided evidence that EGC gliosis was critical in spreading intestinal damage to brain, but also highlighted the potential role of microbial metabolite IPA in alleviating PD pathological damages through gut-brain axis.

[This corrects the article DOI: 10.1016/j.apsb.2025.02.029.].

In the century-long evolution of insulin pharmaceuticals, each transformative advancement in this drug class has been closely tied to the ability to obtain new insulin isoforms for research. Despite this, the recently discovered naturally occurring isoforms of glycosylated human insulin have remained largely unattainable for proper characterization. Herein, we demonstrate for the first time that total chemical synthesis can be used to generate all isoforms. This achievement required maintaining the correct positions of the interchain disulfide bonds while effectively removing protecting groups on complex glycans. Notably, the availability of seven glycoforms reveals the important effects of natural sialylated glycans in suppressing insulin self-association and enhancing its solubility, surpassing the performance of currently employed rapid-acting insulin drugs. This work not only offers a readily adaptable platform for exploring natural O-glycosylation in other therapeutic proteins and peptides but also lays the groundwork for further research into harnessing natural glycosylation for therapeutic applications.

BACKGROUND: The association of systemic inflammatory response index (SIRI) with prognosis of coronary artery disease (CAD) patients has never been investigated in a large sample with long-term follow-up. This study aimed to explore the association of SIRI with all-cause and cause-specific mortality in a nationally representative sample of CAD patients from United States. METHODS: A total of 3386 participants with CAD from the National Health and Nutrition Examination Survey (NHANES) 1999-2018 were included in this study. Cox proportional hazards model, restricted cubic spline (RCS), and receiver operating characteristic curve (ROC) were performed to investigate the association of SIRI with all-cause and cause-specific mortality. Piece-wise linear regression and sensitivity analyses were also performed. RESULTS: During a median follow-up of 7.7 years, 1454 all-cause mortality occurred. After adjusting for confounding factors, higher lnSIRI was significantly associated with higher risk of all-cause (HR = 1.16, 95% CI: 1.09-1.23) and CVD mortality (HR = 1.17, 95% CI: 1.05-1.30) but not cancer mortality (HR = 1.17, 95% CI: 0.99-1.38). The associations of SIRI with all-cause and CVD mortality were detected as J-shaped with threshold values of 1.05935 and 1.122946 for SIRI, respectively. ROC curves showed that lnSIRI had robust predictive effect both in short and long terms. CONCLUSIONS SIRI was independently associated with all-cause and CVD mortality, and the dose-response relationship was J-shaped. SIRI might serve as a valid predictor for all-cause and CVD mortality both in the short and long terms.

Coronavirus disease 2019 (COVID-19) is an acute infectious respiratory disease that has been prevalent since December 2019. Chinese medicine (CM) has demonstrated its unique advantages in the fight against COVID-19 in the areas of disease prevention, improvement of clinical symptoms, and control of disease progression. This review summarized the relevant material components of CM in the treatment of COVID-19 by searching the relevant literature and reports on CM in the treatment of COVID-19 and combining with the physiological and pathological characteristics of the novel coronavirus. On the basis of sorting out experimental methods in vivo and in vitro, the mechanism of herb action was further clarified in terms of inhibiting virus invasion and replication and improving related complications. The aim of the article is to explore the strengths and characteristics of CM in the treatment of COVID-19, and to provide a basis for the research and scientific, standardized treatment of COVID-19 with CM.
Humans ; Drugs, Chinese Herbal/pharmacology* ; COVID-19 Drug Treatment ; SARS-CoV-2/drug effects* ; COVID-19/therapy* ; Medicine, Chinese Traditional/methods* ; Antiviral Agents/pharmacology* ; Animals

Recent studies have shown that the physiological homeostasis of oral mucosal cells is regulated by the circadian clock.Dis-ruption or dysfunction of the circadian clock is closely associated with the development of oral squamous cell carcinoma(OSCC).Research based on the circadian clock offers a novel perspective on the pathogenesis and therapeutic strategies for OSCC.However,there is current-ly limited research on this topic,and people generally have insufficient understanding and recognition of the circadian clock.Given the complexity and challenges of circadian clock which is the fourth dimension of medical research,we organize relevant experts based on summarizing the current research results of circadian clock in the pathogenesis and precision diagnosis and treatment of OSCC,combining the scientific principles of the circadian clock's role and their long-term research experience,then summarizes and recommends the con-sensus opinions for the research of circadian clock in the pathogenesis mechanism and precision diagnosis and treatment of human OSCC,with the hope of providing guidance for the basic research and clinical application of circadian clock or circadian rhythm in the pathogene-sis mechanism and precision diagnosis and treatment of oral and maxillofacial squamous cell carcinoma.

Objective To evaluate the comprehensive value of methicillin-resistant Staphylococcus aureus(MRSA)treatment drugs in artificial joint infections from multiple perspectives and to solve the problem of MRSA infections in artificial joints.Methods Through literature research,relevant literature was retrieved and clinical studies meeting the requirements were selected and summarized.The Analytic Hierarchy Process(AHP)was applied to collect comprehensive clinical evaluation evidence and to conduct evaluations across different dimensions according to evaluation guidelines;the Delphi method combined with AHP was used for expert anonymous questionnaire evaluation,and the data was compared and analyzed.Results A clini-cal comprehensive evaluation index model for the treatment of artificial joint infections was successfully established,and the yaahp analysis software was used to score the comprehensive clinical evaluation evidence in various directions.Treatment drugs,vancomy-cin,daptomycin,and linezolid,at various levels were calculated through the software,and it was concluded that linezolid has the highest clinical comprehensive evaluation score.Conclusion Among the treatment drugs for MRSA infections in artificial joints,linezolid has a higher clinical comprehensive value and can provide a reference for the clinical treatment of MRSA infec-tions in artificial joints.

Objective:To investigate the expression of microRNA-4262 (miR-4262) and neuregulin 1 (NRG1) in non-small cell lung cancer (NSCLC) tissues and the relationship with prognosis.Methods:A total of 102 NSCLC patients who underwent surgical resection from January 2017 to February 2021 in Tongren People's Hospital of Guizhou Province were selected. The expression levels of miR-4262 and NRG1 were detected using real-time fluorescence quantitative PCR. The expression levels of miR-4262 and NRG1 in NSCLC cancer tissues and adjacent tissues, as well as NSCLC cancer tissues with different clinicopathological characteristics were analyzed. TargetScan database was used to predict the binding sites of miR-4262 and NRG1, and Pearson correlation coefficient was used to analyze the correlation between miR-4262 and NRG1 expression in NSCLC cancer tissues. Based on the mean expression levels of miR-4262 and NRG1 in NSCLC cancer tissues, the patients were divided into high miR-4262 expression group (miR-4262≥1.52, n=54) and low miR-4262 expression group (miR-4262<1.52, n=48), high NRG1 expression group (NRG1≥0.79, n=54) and low NRG1 expression group (NRG1<0.79, n=48). Kaplan-Meier survival curves were plotted to compare the 3-year overall survival (OS) rates between groups. Cox proportional risk regression model was used to analyze the influencing factors for the prognosis of NSCLC patients. Results:The expression level of miR-4262 was significantly higher in NSCLC tumor tissues compared to adjacent tissues (1.52±0.21 vs. 1.11±0.20), while NRG1 expression level was lower (0.79±0.11 vs. 1.06±0.11), there were statistically significant differences ( t=14.22, P<0.001; t=-15.13, P<0.001). The expression of miR-4262 was negatively correlated with NRG1 in cancer tissues of NSCLC patients ( r=-0.74, P<0.001). There were statistically significant differences in the expression levels of miR-4262 and NRG1 of NSCLC patients in tumor differentiation ( t=2.80, P=0.006; t=-2.80, P=0.006), TNM stage ( F=24.36, P<0.001; F=17.66, P<0.001), and lymph node metastasis ( t=4.02, P<0.001; t=-3.98, P<0.001). At the end of the follow-up period, 57 patients survived, and 45 died, with a 3-year OS rate of 55.88%. Patients with high miR-4262 expression had a significantly lower 3-year OS rate compared to those with low miR-4262 expression (35.19% vs. 79.17%), patients with high NRG1 expression had a significantly higher 3-year OS rate than those with low NRG1 expression (77.78% vs. 31.25%), there were statistically significant differences ( χ2=22.58, P<0.001; χ2=27.26, P<0.001). Univariate analysis showed that, age ( HR=2.47, 95% CI: 1.05-5.80, P=0.038), maximum tumor diameter ( HR=3.75, 95% CI: 1.61-8.74, P=0.002), differentiation degree ( HR=3.03, 95% CI: 1.32-6.96, P=0.009), TNM stage (stage Ⅱ, HR=3.45, 95% CI: 1.10-10.83, P=0.034; stage Ⅲ, HR=6.72, 95% CI: 2.03-22.26, P=0.002), lymph node metastasis ( HR=3.00, 95% CI: 1.29-6.96, P=0.010), miR-4262 expression ( HR=3.72, 95% CI: 1.48-9.35, P=0.005), and NRG1 expression ( HR=0.30, 95% CI: 0.13-0.73, P=0.008) were all influencing factors for OS in NSCLC patients. Multivariate analysis showed that, differentiation degree ( HR=5.47, 95% CI: 1.63-18.34, P=0.006), TNM stage (stage Ⅲ, HR=5.56, 95% CI: 1.23-25.14, P=0.026), lymph node metastasis ( HR=3.72, 95% CI: 1.19-11.60, P=0.024), miR-4262 expression ( HR=8.56, 95% CI: 2.26-32.41, P=0.002), and NRG1 expression ( HR=0.26, 95% CI: 0.09-0.76, P=0.014) were all independent influencing factors for OS in NSCLC patients. Conclusions:The expression of miR-4262 is high and the expression of NRG1 is low in cancer tissues of NSCLC patients. The 3-year OS rate of patients with high miR-4262 expression is lower than that of patients with low miR-4262 expression, and the 3-year OS rate of patients with high NRG1 expression is higher than that of patients with low NRG1 expression. Differentiation degree, TNM stage, lymph node metastasis, miR-4262 and NRG1 are all independent influencing factors for the prognosis of NSCLC patients.

Objective To investigate the therapeutic efficacy of Yiqi Huoxue Tongmai Decoction(a modified priscription derived from Buyang Huanwu Decoction)combined with western medicines in the treatment of patients with pulmonary hypertension due to left heart disease(PH-LHD)of qi deficiency and blood stasis syndrome,and to explore its effect on endothelial function.Methods Eighty patients with PH-LHD of qi deficiency and blood stasis syndrome who were admitted to Shangluo Central Hospital from March 2022 to December 2023 were randomly divided into a study group and a control group,with 40 patients in each group.The control group was given routine treatment with western medicine,and the study group was treated with Yiqi Huoxue Tongmai Decoction on the basis of treatment for the control group,three weeks constituting a course of treatment.Before and after intervention,the two groups of patients were observed in the changes of traditional Chinese medicine(TCM)syndrome scores,pulmonary circulation indicators[mean pulmonary arterial pressure(mPAP)and pulmonary capillary wedge pressure(PCWP)],cardiopulmonary exercise testing(CPET)indicators[peak heart rate,peak systolic blood pressure,peak diastolic blood pressure,maximal oxygen uptake(VO2max),peak oxygen pulse],vascular endothelial function indicators[serum nitric oxide(NO)and endothelin 1(ET-1)]and the scores of quality of life.After treatment,the clinical efficacy and incidence of adverse reactions of the patients between the two groups were compared.Results(1)After three-week of intervention,the total effective rate of the study group was 90.00%(36/40),while that of the control group was 72.50%(29/40),and the comparison between the two groups(tested by chi-square test)showed that the efficacy of the study group was significantly superior to that of the control group(P<0.05).(2)After intervention,the primary symptom scores,secondary symptom scores and total TCM syndrome scores of the two groups of patients were all decreased compared with those before intervention(P<0.05),and the decrease of the scores in the study group was significantly superior to that in the control group(P<0.01).(3)After intervention,the levels of pulmonary circulation indicators of mPAP and PCWP in the two groups were all decreased compared with those before intervention(P<0.05),and the decrease in the study group were significantly superior to that in the control group(P<0.01).(4)After intervention,the CPET indicators of peak heart rate,peak systolic blood pressure and peak diastolic blood pressure in the two groups were all decreased(P<0.05),while the VO2max and peak oxygen pulse rate were all increased compared with those before intervention(P<0.05),and the decrease of peak heart rate,peak systolic blood pressure and peak diastolic blood pressure as well as the increase of VO2max and peak oxygen pulse rate in the study group was significantly superior to that in the control group(P<0.05 or P<0.01).(5)After intervention,the vascular endothelial function indicator of serum ET-1 level in the two groups was decreased compared with that before intervention(P<0.05),and the serum NO level was increased compared with that before intervention(P<0.05),and the decrease of serum ET-1 level and the increase of serum NO level in the study group were significantly superior to those in the control group(P<0.01).(6)After intervention,the scores of six dimensions of 36-Item Short-Form Health Survey(SF-36),including mental health,role-emotional,social functioning,role-physical,vitality,and general health in the patients of the two groups were increased compared with those before intervention(P<0.05),and the increase in the study group was significantly superior to that of the control group(P<0.05 or P<0.01).(7)The incidence of adverse reactions in the study group was 20.00%(8/40)and that was 15.00%(6/40)in the control group,and the comparison between the two groups showed that the difference was not statistically significant(P>0.05).Conclusion Yiqi Huoxue Tongmai Decoction combined with western medicines is effective on enhancing the clinical efficacy for the intervention of patients with PH-LHD of qi deficiency and blood stasis syndrome,and can improve the patients'cardiopulmonary function,vascular endothelial function and improve the quality of life,with higher safety.