Identification of vilazodone as a novel plasminogen activator inhibitor to overcome Alzheimer's disease through virtual screening, molecular dynamics simulation, and biological evaluation.

Urokinase-type plasminogen activator (PLAU), a member of the S1 serine peptidase family in Clan PA, plays a crucial role in the conversion of plasminogen into active plasmin. However, the precise role of PLAU in the central nervous system remains incompletely elucidated, particularly, in relation to Alzheimer's disease (AD). In this study, we successfully identified that PLAU could promote cell senescence in neurons, indicating it as a potential target for AD treatment through a systematic approach, which included both bioinformatics analysis and experimental verification. Subsequently, a structure-based virtual screening approach was employed to identify a potential PLAU inhibitor from the Food and Drug Administration-approved drug database. After analyzing docking scores and thoroughly examining the receptor-ligand complex interaction modes, vilazodone emerges as a highly promising PLAU inhibitor. Additionally, molecular docking and molecular dynamics simulations were performed to generate a complex structure between the relatively stable inhibitor vilazodone and PLAU. Of note, vilazodone exhibited superior cytotoxicity against senescent cells, showing a senolytic activity through targeting PLAU and ultimately producing an anti-AD effect. These findings suggest that targeting PLAU could represent a promising therapeutic strategy for AD. Furthermore, investigating the inhibitory potential and structural modifications based on vilazodone may provide valuable insights for future drug development targeting PLAU in AD disorders.

Advances in the Effects of Dietary Macronutrients on the Gut Microbiota of Tilapia (Oreochromis spp.).

The homeostasis of the intestinal microbiota of fish is beneficial to fish health, while food can affect the intestinal microbiota. Tilapia (Oreochromis spp.) has great economic value and is a good model to use in studying the digestion and absorption of nutrients. Furthermore, at present, due to a high demand and high price of high-quality feed raw materials, the nutritional composition of aquafeeds has been changing dynamically. There has yet to be a comprehensive review of research conducted on the influences of dietary macronutrients (proteins, lipids, and carbohydrates) on the tilapia intestinal microbiota. Therefore, this review focuses on the effects of dietary macronutrients on the gut microbiota of tilapia. Interestingly, we found that the best growth performance might not represent the best composition or functions of the gut microbiota. Overall, the unscientific addition of macronutrients to feed is harmful to the intestinal microbiota. Therefore, both growth performance and gut microbiota should be considered when evaluating certain macronutrients. It is our hope that this review will aid in regulating the intestinal microbiota of fish through nutritional means, thereby promoting tilapia farming.

The mediating effect of self-efficacy on the relationship between diabetes self-management ability and patient activation in older adults with type 2 diabetes.

OBJECTIVE: The aim of this study was to investigate the level of diabetes self-management ability in older patients with type 2 diabetes and analyse its relationship with patient activation. Besides, the mediating effect of self-efficacy on the relationship between the two was assessed in the study. METHODS: Using a cross-sectional design, 200 elderly patients with type 2 diabetes were recruited from the community of Yangzhou, China. The Patient Activation Measure (PAM), The Self-efficacy for Diabetes (SED), and The Summary of Diabetes Self-Care Activities Measure (SDSCA) were used in the questionnaires. Data analysis was performed using SPSS 27.0 and PROCESS macro. RESULTS: Pearson correlation analysis revealed a significant positive correlation (p< 0.01) between diabetes self-management ability and patient activation (r=0.312) and self-efficacy (r=0.367). Self-efficacy partially mediated the effect between patient activation and self-management ability in older patients with type 2 diabetes, and the mediating effect accounted for 49.33% of the total effect (p< 0.001). CONCLUSIONS: Older patients with type 2 diabetes in the community have a moderate level of self-management ability. Patient activation can improve patients' self-management ability through self-efficacy.

Associations between early childhood adversity and behavioral, substance use, and academic outcomes in childhood through adolescence in a U.S. longitudinal cohort.

BACKGROUND: Childhood adversity is strongly associated with adolescent substance use, but few epidemiologic studies have investigated early childhood adversity (ECA) before age 5. This study investigated pathways by which ECA is associated with adolescent alcohol and cannabis use and high school completion through childhood behavioral and academic mediators and their reciprocal effects. METHODS: Data were from the National Longitudinal Survey of Youth 1979-Child/Young Adult Cohort which surveyed children born 1984-1999 and followed through 2016 (n = 5521). Outcomes included alcohol and cannabis use frequency at ages 15-18, and high school completion by age 19. ECA at ages 0-4 was a cumulative score of maternal heavy drinking/drug use, low emotional support, low cognitive stimulation, and household poverty. Multilevel path models were conducted with ECA, childhood mediators (behavioral (externalizing and internalizing problems) and academics (reading and math scores), accounting for demographics and confounders. RESULTS: ECA was indirectly associated with adolescent cannabis frequency through mediators of externalizing/internalizing problems, low academics, and early cannabis onset before age 14. ECA was also indirectly associated with alcohol frequency via the same mediators, but not early alcohol onset. Greater behavioral problems elevated substance use risk; whereas, low academics reduced risk. Reciprocal effects were evident between childhood behavioral problems and cannabis frequency to high school completion. CONCLUSION: Adversity from birth to age 4 is associated with childhood behavioral problems and lower academics, which increased adolescent alcohol and cannabis use and lowered high school completion. Early childhood interventions with parents and preschools/daycare may reduce early onset and adolescent substance use.

A cross-sectional observational study on the level of diabetes knowledge and related influencing factors among orthopaedic nurses.

AIM: To evaluate the level of diabetes knowledge and related influencing factors among Chinese orthopaedic nurses. DESIGN: A cross-sectional observational study. The STROBE checklist was followed. METHODS: A convenience sampling method was adopted by using the Questionnaire Star application to publish online questionnaire. The nurses' diabetes knowledge levels were assessed, including a total of 34 items from the "Orthopaedic Nurses Diabetes Knowledge Mastery Questionnaire" and the "Orthopaedic Nurses General Information Questionnaire" between July 2020 and September 2020. RESULTS: Altogether, 363 nurses participated in the survey. Their levels of diabetes-related knowledge were moderate or lower (16.51 ± 2.96 out of 25 points). The knowledge level was closely related to five factors: professional title, education level, whether the hospital employed diabetes specialist nurses or treated outpatients, type of diabetes-related training received and whether the individual was familiar with and adhered to current treatment guidelines. The knowledge level can be improved by providing additional training that accounts for these factors.

Mediation Effect of Self-Efficacy Between Health Beliefs and Glycated Haemoglobin Levels in Elderly Patients with Type 2 Diabetes Mellitus: A Cross-Sectional Study.

Purpose: To explore the mediating effect of self-efficacy in the relationship between glycated haemoglobin (HbA1c) levels and health beliefs in community elderly patients with type 2 diabetes. Patients and Methods: From January to March 2022, convenience sampling was adopted to investigate 200 elderly patients with type 2 diabetes in a community in Yangzhou, China. Data were collected using the Health Beliefs Questionnaire, Self-efficacy for Diabetes, and Medication Compliance Questionnaire. Laboratory parameters included HbA1c, fasting blood glucose, postprandial blood glucose, total cholesterol, triglyceride, high-density-lipoprotein cholesterol, and low-density-lipoprotein cholesterol levels. Correlation, linear regression, and mediation analyses were performed using SPSS 27.0. Results: HbA1c levels were higher in men (women vs men: 6.80% [6.08%, 7.73%] vs.7.30% [6.30%, 9.18%]) and employed (employed vs not employed vs retired: 7.60% [6.90%, 10.45%] vs 5.85% [5.40%, 6.95%] vs 7.10% [6.20%, 8.20%]) and low self-efficacy (low vs high: 13.1% [6.55%, 13.85%] vs 6.8% [6.10%, 7.70%]). HbA1c levels were negatively associated with health beliefs (r = -0.246) and self-efficacy (r = -0.240; p<0.01). Linear regression showed that perceived susceptibility, severity, benefit, and barriers, cues to action, and self-efficacy explained 50% of the variance in HbA1c levels after adjusting for sex and current work status. The mediation effect of self-efficacy was partial between health beliefs and HbA1c levels and accounted for 24.65% of the total effect (p < 0.001). Conclusion: Health beliefs influenced the improvement of self-efficacy in older patients with type 2 diabetes mellitus, which in turn could improve HbA1c control. Self-efficacy plays a partial mediating role between health beliefs and Hba1c levels in elderly patients with type 2 diabetes.

A Meta-Analysis of the Effectiveness of Telemedicine in Glycemic Management among Patients with Type 2 Diabetes in Primary Care.

Introduction: Telemedicine interventions are gradually being used in primary health care to help patients with type 2 diabetes receive ongoing medical guidance. The purpose of this study was to analyze the effectiveness of using telemedicine in primary health care for the management of patients with type 2 diabetes. Methods: A systematic search was conducted from database inception to August 2021 in nine databases, including PubMed, Web of Science, Cochrane Library, EMBASE, EBSCO, CNKI, Wanfang Data, VIP, and CBM. Data extraction and quality assessment were performed for studies that met the inclusion criteria. The meta-analysis was performed using Review Manager 5.4 (Cochrane) and Stata v.16.0SE (College Station, TX, USA). Results: A total of 32 articles were included in this study. Analysis showed a reduction in glycated hemoglobin, fasting glucose, and postprandial glucose after the telemedicine intervention. Systolic blood pressure and self-efficacy improved significantly, but there was no significant improvement in weight, lipid metabolism, or diabetes awareness. Subgroup analysis based on the duration of intervention showed significant improvement in glycated hemoglobin at 6 months of intervention. Conclusions: Telemedicine interventions may help patients with type 2 diabetes to effectively control blood glucose and improve self-management in primary health care. There is only moderate benefit, and the benefit may not be sustained beyond 6 months. However, the evidence for the improvement in lipid metabolism is insufficient and further studies are needed.

Breast Cancer Stem Cell-Derived ANXA6-Containing Exosomes Sustain Paclitaxel Resistance and Cancer Aggressiveness in Breast Cancer.

Continuous chemotherapy pressure-elicited annexin-A6 (ANXA6)-containing exosome (ANXA6-exo) secretion contributes to paclitaxel (PTX) resistance in breast cancer (BC), but the molecular mechanisms are not fully elucidated. The present study managed to investigate this issue and found that ANXA6-exo promoted PTX resistance and cancer progression in BC cells in a Yes-associated protein 1 (YAP1)-dependent manner. Specifically, the parental PTX-sensitive BC (PS-BC) cells were exposed to continuous low-dose PTX to generate PTX-resistant BC (PR-BC) cells, and we found that BC stem cells tended to be enriched in the descendent PR-BC cells in contrast with the PS-BC cells. In addition, PR-BC cell-derived exosomes were featured with highly expressed ANXA6, and ANXA6-exo delivered ANXA6 to promote cell migration, growth, autophagy, and stemness in PS-BC cells. Interestingly, ANXA6-exo increased PTX resistance in PS-BC cells via inducing autophagy, and the effects of ANXA6-exo on PTX resistance in PS-BC cells were abrogated by co-treating cells with the autophagy inhibitor 3-methyladenine. Moreover, the underlying mechanisms were uncovered, and we evidenced that ANXA6-exo up-regulated YAP1 to promote Hippo pathway dysregulation, and the promoting effects of ANXA6-exo on PTX resistance and cancer aggressiveness in BC cells were abrogated by silencing YAP1. Taken together, this study firstly elucidated the underlying mechanisms by which BCSC-derived ANXA6-exo facilitated BC progression and PTX resistance, which might help to develop novel treatment strategies for BC in clinic.

Omission of Chemotherapy in HR+/HER2- Early Invasive Breast Cancer Based on Combined 6-IHC Score?

PURPOSE: Current methods of judging whether HR+/HER2- breast cancer (BC) require adjuvant therapy, such as Ki67 and multigene prognostic tests, cannot balance accuracy with the price most patients can afford. METHODS: A retrospective analysis of 330 HR+/HER2- BC patients was conducted. Six BC-related genes (Cathepsin L2, MMP11, CyclinB1, Aurora A, Survivin, and Ki67) were screened using univariate and multivariate COX regression, and correlate clinical follow-up with immunohistochemical expression (designated as 6-IHC). All the included patients were divided randomly at a 7:3 ratio into training and testing cohorts. The cutoff prognosis index (PI) of 6-IHC was determined by multivariate Cox risk regression analysis after calculating the PI of each patient in training cohort and confirmed in testing cohort. Kaplan-Meier (KM) method was used to analyze Disease-free survival (DFS) and overall survival (OS). Six-IHC score and other factors associated with survival benefit of adjuvant chemotherapy were compared with Ki67 index. RESULTS: The receiver operating characteristic curve analysis showed that the patients can be divided into 6-IHC score "High" and "Low" risk groups. The 8-year DFS and OS of the KM curves showed that chemotherapy did not significantly improve the DFS in the 6-IHC score "Low" risk group (P= 0.830), but significantly improved the DFS in the 6-IHC score "High" risk group (P = 0.012). CONCLUSIONS: Combined 6-IHC score could be a reliable tool in predicting cancer-specific recurrences and survival in HR+/HER2-breast cancer patients, with additional advantages over using immunohistochemical expression of Ki67.

Identification of Aurora Kinase A as a Biomarker for Prognosis in Obesity Patients with Early Breast Cancer.

BACKGROUND: Obesity is associated both with a higher risk of developing breast cancer, particularly in postmenopausal women, and with worse disease outcome for women of all ages. Previous investigation suggested Aurora A kinase was able to partially restore the functionalities of obese adipose-derived mesenchymal stem cells by stabilizing their primary cilia and reestablishing a balance of multiple stemness-associated genes. The association between Aurora A and obesity breast cancer is still unclear. We hypothesized that overexpression of Aurora A was associated with poor survival in obesity breast cancer and the related axis mechanism was involved. METHODS: A total of 517 primary breast cancer specimens were collected from the First Affiliated Hospital of China Medical University between January 2011 and November 2016. Our independent variable was BMI at baseline, categorized as overweight (BMI ≥25 kg/m2, as obesity cohort), and normal (18.5 ≤ BMI <25 kg/m2, as non-obesity cohort). The immunohistochemical (IHC) staining was performed with Aurora A, Survivin, MMP11, Cyclin B1, and Cathepsin L. Kaplan-Meier curve was used to analyze overall survival in our cohorts and TCGA-BRCA data (GSE3494). Log rank test was used to calculate P values. Protein-protein interaction (PPI) network analysis and MCODE model were used to analyze the Aurora-altered signal pathway from GSE78958. RESULTS: Among 517 breast patients, Aurora A-positive (staining scores ≥4) was significantly higher in obesity breast carcinoma compared with non-obesity cancer carcinoma (χ 2=9.79, P=0.002), with more frequency in hormone receptor-negative (68.4% vs 77.9%, P=0.015) and HER2-positive patients (28.7% vs 17.9%, P=0.003). High Aurora A expression was remarkably and significantly associated with overall survival (OS) (8-year OS ratio: 69.5% vs 81.1%, OR=1.76, 95% CI: 1.03~3.02, P=0.041) in obesity cohort. Interestingly, higher expression of Aurora A was not associated with a shorter overall survival time among the non-obesity breast cancer (8-year OS ratio: 81.4% vs 85.8%, OR=1.40, 95% CI: 0.79~2.45, P=0.229). As for RFS, the expression levels of Aurora A expression genes have no significance with RFS statistically in non-obesity and obesity patients. Aurora A and lymph node metastases were significantly poor prognostic factors for OS, and borderline significance was noted for high BMI. Kaplan-Meier survival analysis from TCGA database confirmed that the high Aurora A expression group had worse prognosis (HR=1.47, 95% CI: 1.14-1.90, P=0.003). The KEGG pathway enrichment results were consistent with GO biological process term analysis, in which CCNB1 was enriched for upregulated Aurora A. In our samples, Aurora A level on tumor cytoplasm had broad connections with Cyclin B1 by IHC correlation analysis (correlation coefficient = 0.227, P=0.001). CONCLUSION: Our finding demonstrates here for the first time that high expression of Aurora A was notably correlated with early recurrence and poor overall survival in obesity patients with early breast cancer. The Aurora A-Cyclin B1 axis could be a potential promising therapeutic target for cancer intervention and therapy.