Estrogen Status Influences Whole-Body Vibration Training-Induced Improvements on Muscle Mass and Strength in Female Ovariectomized Mice.

Estradiol (E2) deficiency arising from menopause is closely related to changes in body composition and declines of muscle mass and strength in elderly women. Whole-body vibration training (WBV) is an emerging approach expected to improve muscle mass and strength of older person, but the underlying mechanisms remain unclear. The balance between protein synthesis and degradation is a determining factor for muscle mass and strength, which is regulated by Akt-mTOR and FoxO1 signal pathway, respectively. In the present study, we firstly determined whether the effects of WBV on muscle mass and strength in ovariectomized female mice was affected by estrogen level, then investigated whether this was associated with Akt-mTOR and FoxO1 signal pathways. We found that (1) WBV, E2 supplementation (E) and WBV combined with E2 supplementation (WBV+E) significantly increased serum estradiol content, quadriceps muscle mass and grip strength in ovariectomized mice, accompanied with alterations of body composition (reducing fat content, increasing lean body mass and lean percent), furthermore, the altered degrees of these indicators by WBV+E were greater than WBV alone; (2) WBV, E and WBV+E remarkably increased the activities of Akt and mTOR and decreased FoxO1 activity, and the changed degrees by WBV+E were greater than WBV alone; (3) Pearson correlation coefficient revealed that serum estradiol content was positively correlated with Akt and mTOR activities, while inversely associated with FoxO1 activity. We concluded that WBV could significantly increase muscle mass and strength in ovariectomized mice, which might achieve through activating Akt-mTOR and suppressing FoxO1 signal pathways, and the improving effect of WBV on muscle mass and strength was better when in the presence of estrogen.

Selection and Mechanism Study of Q-Markers for Xanthocerais lignum Anti-Rheumatoid Arthritis Based on Serum Spectrum-Effect Correlation Analysis.

OBJECTIVE: To elucidate the chemical profile of Xanthocerais lignum's extracts of different polarities and their impact on rheumatoid arthritis (RA), we identified anti-RA markers and predicted their action mechanisms. METHODS: A collagen-induced arthritis rat model was established, and UPLC-Q-Exactive Orbitrap MS technology was employed to analyze and identify the chemical constituents within the alcohol extract of Xanthocerais lignum and its various extraction fractions, as well as their translocation into the bloodstream. Serum spectrum-effect correlation analysis was utilized to elucidate the pharmacodynamic material basis of Xanthocerais lignum against RA and to screen for Q-Markers. Finally, the potential anti-RA mechanisms of the Q-Markers were predicted through compound-target interaction data and validated using molecular docking techniques. RESULTS: We identified 71 compounds, with flavan-3-ols and flavanones as key components. Of these, 36 were detected in the bloodstream, including 17 original and 19 metabolized forms. Proanthocyanidin A2, dihydroquercetin, catechin, and epicatechin (plus glucuronides) showed potential anti-RA activity. These compounds, acting as Q-Markers, may modulate ERK, NF-κB, HIF-1α, and VEGF in the HIF-1 pathway. CONCLUSIONS: This research clarifies Xanthocerais lignum's pharmacodynamic material basis against RA, identifies 4 Q-Markers, and offers insights into their mechanisms, aiding quality assessment and lead compound development for RA treatment.

Lifestyle behaviors and stress are risk factors for overweight and obesity in healthcare workers: a cross-sectional survey.

BACKGROUND: Overweight and obesity have become major public health concerns worldwide. Persistent stress can activate the human hypothalamic‒pituitary‒adrenal axis (HPA) and increase the intake of "self-rewarding food", thereby raising the incidence of obesity. Health care workers (HCWs) experience higher workloads and mental stress than workers in many other industries, which may put them at increased risk for overweight/obesity. However, few studies have been carried out on overweight and obesity among HCWs in China, and the overall scenario and behind-the-scenes factors of their overweight and obesity are unknown. The aim of this study is to understand the epidemic of overweight and obesity and risk factors among Chinese HCWs. METHODS: Based on a cross-sectional web survey design, 23,234 HCWs from 100 health institutions in 5 provinces/autonomous regions/municipalities across China were sampled to answer a self-administered questionnaire that was purposely developed using a multi-staged clustered random-sampling method. Chi-square test and ANOVA were performed to compare variables between two or more groups. Univariate analyses were conducted to identify the influence of self-reported persistent stress and/or recurrent anxiety/depressed mood on lifestyle behaviors. A multivariate binary logistic regression model was used to analyse the risk factors of overweight/obesity. RESULTS: Among the respondents, 34.26% were overweight, and 11.22% were obese. Most of the respondents had regular exercise habits (68.17%), had habitually stayed-up late (65.06%) and had been affected by persistent stress and/or recurrent anxiety/depressed mood (62.04%). A higher proportion of those with persistent stress and/or recurrent anxiety/depressed mood than those without habitually staying-up late (76.18%); consumed take-out food (54.92%), fried food (49.93%), snacks or desserts (50.51%); drank sugary drinks (46.57%); smoked (14.27%); and drank alcohol (23.34%). Gender (Female) (OR: 0.314, 95%CI: 0.292-0.336), age (OR: 1.742-2.334, 95%CI: 1.544-2.858), education (OR: 0.620-0.728, 95%CI: 0.445-0.973), living and working area (OR: 1.271, 95%CI: 1.192-1.355), breakfast (OR: 0.898, 95%CI: 0.839-0.960), fried food (OR: 1.133, 95%CI: 1.048-1.224), and alcohol consumption (OR: 1.111, 95%CI: 1.017-1.214) were factors for overweight/obesity. All of the aforementioned results were significant (P < 0.05). CONCLUSIONS: The overweight/obesity rate of Chinese HCWs is rather high, which might be directly associated with lifestyle behaviors. However, these behaviors fundamentally originated from persistent stress and/or recurrent anxiety/depression, mediated by lifestyle behaviors. Substantial measures should be taken for stress reduction and mental health promotion for overweight/obesity prevention and control among HCWs.

Mechanical stretch activates glycometabolism-related enzymes via estrogen in C2 C12 myoblasts.

Moderate exercise improves glycometabolic disorder and type 2 diabetes mellitus in menopausal females. So far, the effect of exercise-induced estrogen on muscular glycometabolism is not well defined. The current study was designed to explore the effect of mechanical stretch-induced estrogen on glycometabolism in mouse C2 C12 myoblasts. The mouse C2 C12 myoblasts in vitro were assigned randomly to the control (C), stretch (S), and stretch plus aromatase inhibitor anastrozole (SA) groups. Cells in the S group were stretched by the Flexcell FX-5000™ system (15% magnitude, 1 Hz frequency, and 6-hr duration) whereas those in the SA group were treated with 400 µg/ml anastrozole before the same stretching. Glucose uptake, estradiol levels, PFK-1 levels, and oxygen consumption rate were determined, and the expression of HK, PI3K, p-AKT, AKT, and GLUT4 proteins were semiquantified with western blot analysis. Compared to the control, the estradiol level, oxygen consumption rate, expression of HK, PI3K, and PFK-1 proteins, the ratio of p-AKT to AKT, and the ratio of GLUT4 in the cell membrane to that in the whole cell were higher in the S group. On the other hand, the estradiol level, glucose uptake, expression of PFK-1 and GLUT4 proteins, oxygen consumption rate, expression of HK protein, and the ratio of p-AKT/AKT were lower in the myoblasts in the SA group than those in the S group. The level of estradiol was positively correlated with glucose uptake (p < .01, r = .818). Therefore, mechanical stretch-induced estrogen increased the expression of glycometabolism-related enzymes and proteins in the mouse C2 C12 myoblasts.

Simultaneous Study of Mechanical Stretch-Induced Cell Proliferation and Apoptosis on C2C12 Myoblasts.

Mechanical stretch may cause myoblasts to either proliferate or undergo apoptosis. Identifying the molecular events that switch the fate of a stretched cell from proliferation to apoptosis is practically important in the field of regenerative medicine. A recent study on vascular smooth muscle cells illustrated that identification of these events may be achieved by addressing the stretch-induced opposite cellular outcomes simultaneously within a single investigation. To define conditions or a model in which both proliferation and apoptosis can be studied at the same time, we exposed in vitro cultured C2C12 myoblasts to a cyclic mechanical stretch regimen of 15% elongation at a stretching frequency of 1 Hz for 0, 2, 4, 6, or 8 h every day, consecutively, for 3 days. Both proliferation and apoptosis were observed. Moreover, as the duration of the stretch was prolonged, cell proliferation increased until it peaked at the optimal stretching duration. Afterwards, apoptosis gradually prevailed. Therefore, we established a model in which stretch-induced cell proliferation and apoptosis can be studied simultaneously.

The effect of downregulation of Stathmin gene on biological behaviors of U373 and U87-MG glioblastoma cells.

BACKGROUND: Stathmin as a critical protein involved in microtubule polymerization, is necessary for survival of cancer cells. However, extremely little is known about Stathmin in glioblastoma. So, this study was designed to elucidate the function of Stathmin gene in the tumorigenesis and progression of glioblastoma cells. METHOD: The lentiviral interference vector pLV3-si-Stathmin targeting Stathmin gene and the control vector pLV3-NC were established for the co-transfection of 293T cells together with the helper plasmids. Viral titer was determined via limiting dilution assay. Then pLV3-si-Stathmin and pLV3-NC were stably co-transfected into U373 and U87-MG glioblastoma cells. Expression levels of Stathmin protein in each group were determined by using Western Blot, and the proliferation and migration ability of the cells with downregulated Stathmin were evaluated through CCK8 assay and transwell invasion assay, respectively. Cell cycles and cell apoptosis were detected with flow cytometry. Finally, the effect of Stathmin in tumor formation was determined in nude mice. RESULT: DNA sequencing and viral titer assay indicated that the lentiviral interference vector was successfully established with a viral titer of 4 × 108 TU/ml. According to the results from Western Blotting, Stathmin protein expression level decreased significantly in the U373 and U87-MG cells after transfected with pLV3-si-Stathmin, respectively, compared with those transfected with pLV3-NC. In glioblastoma cells, the cell proliferation and migration were greatly inhibited after the downregulation of Stathmin protein. Flow cytometry showed that much more cells were arrested in G2/M phasein Stathmin downregulated group, compared with the non-transfection group and NC group. But Stathmin downregulation did not induce significant cell apoptosis. Tumor formation assay in nude mice showed that tumor formation was delayed after Stathmin downregulation, with a reduction in both tumor formation rate and tumor growth velocity. CONCLUSION: Stathmin downregulation affected the biological behaviors of U373 and U87-MG glioblastoma cells, inhibiting the proliferation and migration of tumor cells. Stathmin gene may serve as a potential target in gene therapy for glioblastoma.

[Effects of LncRNA H19 on Proliferation of Human Colorectal Cancer SW620 Cells].

OBJECTIVE: To determine the expression level of long non-coding RNA (lncRNA) imprinted maternallyexpressed transcript (H19) in colorectal cancer tissues and its effect on proliferation of colorectal cancer SW620 cells. METHODS: Real-time quantitative PCR (qRT-PCR) was applied to detect the expression of H19 in 20 paired tumor tissues and adjacent normal tissues,and in normal NCM460 cells and colorectal cancer SW480,HCT116 and SW620 cells. The specific small interfering RNA for H19 (si-H19 group) or negative control sequence (si-NC group) were transfected into SW620 cells. Proliferation of the transfected cells was detected using flow cytometry,CCK8 assay and clone formation experiment. The expressions of CyclinD1 and cyclin dependent kinase 4 (CDK4) were detected by qRT-PCR and Western blot. RESULTS: The expression levels of H19 in colorectal cancer tissues and cells were higher compared with those in adjacent normal tissues and normal NCM460 cells. Lower H19 level,cell activities and cell clone numbers were found in si-H19 transfected cells compared with those in si-NC transfected cells ( P<0.05). si-H19transfected cells had decreased expression of CyclinD1 and CDK4 ( P<0.05). CONCLUSION: H19expression in colorectal cancer is high. Knock-down H19 expression can inhibit proliferation of colorectal cancer cells,which provides a potential strategy for targeted therapy of colorectal cancer.

Prediction of Anti-rheumatoid Arthritis Natural Products of Xanthocerais Lignum Based on LC-MS and Artificial Intelligence.

AIMS: Employing the technique of liquid chromatography-mass spectrometry (LCMS) in conjunction with artificial intelligence (AI) technology to predict and screen for antirheumatoid arthritis (RA) active compounds in Xanthocerais lignum. BACKGROUND: Natural products have become an important source of new drug discovery. RA is a chronic autoimmune disease characterized by joint inflammation and systemic inflammation. Although there are many drugs available for the treatment of RA, they still have many side effects and limitations. Therefore, finding more effective and safer natural products for the treatment of RA has become an important issue. METHODS: In this study, a collection of inhibitors targeting RA-related specific targets was gathered. Machine learning models and deep learning models were constructed using these inhibitors. The performance of the models was evaluated using a test set and ten-fold cross-validation, and the most optimal model was selected for integration. A total of five commonly used machine learning algorithms (logistic regression, k-nearest neighbors, support vector machines, random forest, XGBoost) and one deep learning algorithm (GCN) were employed in this research. Subsequently, a Xanthocerais lignum compound library was established through HPLC-Q-Exactive- MS analysis and relevant literature. The integrated model was utilized to predict and screen for anti-RA active compounds in Xanthocerais lignum. RESULTS: The integrated model exhibited an AUC greater than 0.94 for all target datasets, demonstrating improved stability and accuracy compared to individual models. This enhancement enables better activity prediction for unknown compounds. By employing the integrated model, the activity of 69 identified compounds in Xanthocerais lignum was predicted. The results indicated that isorhamnetin-3-O-glucoside, myricetin, rutinum, cinnamtannin B1, and dihydromyricetin exhibited inhibitory effects on multiple targets. Furthermore, myricetin and dihydromyricetin were found to have relatively higher relative abundances in Xanthocerais lignum, suggesting that they may serve as the primary active components contributing to its anti-RA effects. CONCLUSION: In this study, we utilized AI technology to learn from a large number of compounds and predict the activity of natural products from Xanthocerais lignum on specific targets. By combining AI technology and the LC-MS approach, rapid screening and prediction of the activity of natural products based on specific targets can be achieved, significantly enhancing the efficiency of discovering new bioactive molecules from medicinal plants.

Prognostic significance of programmed cell death ligand 1 blood markers in non-small cell lung cancer treated with immune checkpoint inhibitors: a systematic review and meta-analysis.

Background: Immune checkpoint inhibitors (ICIs) are effective for non-small cell lung cancer (NSCLC) treatment, but the response rate remains low. Programmed cell death ligand 1 (PD-L1) in peripheral blood, including soluble form (sPD-L1), expression on circulating tumor cells (CTCs PD-L1) and exosomes (exoPD-L1), are minimally invasive and promising markers for patient selection and management, but their prognostic significance remains inconclusive. Here, we performed a meta-analysis for the prognostic value of PD-L1 blood markers in NSCLC patients treated with ICIs. Methods: Eligible studies were obtained by searching PubMed, EMBAS, Web of Science, and Cochrane Library prior to November 30, 2023. The associations between pre-treatment, post-treatment and dynamic changes of blood PD-L1 levels and progression-free survival (PFS)/over survival (OS) were analyzed by estimating hazard ratio (HR) and 95% confidence interval (CI). Results: A total of 26 studies comprising 1606 patients were included. High pre- or post-treatment sPD-L1 levels were significantly associated with worse PFS (pre-treatment: HR=1.49, 95%CI 1.13-1.95; post-treatment: HR=2.09, 95%CI 1.40-3.12) and OS (pre-treatment: HR=1.83, 95%CI 1.25-2.67; post-treatment: HR=2.60, 95%CI 1.09-6.20, P=0.032). High pre-treatment exoPD-L1 levels predicted a worse PFS (HR=4.24, 95%CI 2.82-6.38, P<0.001). Pre-treatment PD-L1+ CTCs tended to be correlated with prolonged PFS (HR=0.63, 95%CI 0.39-1.02) and OS (HR=0.58, 95%CI 0.36-0.93). Patients with up-regulated exoPD-L1 levels, but not sPD-L1, after ICIs treatment had significantly favorable PFS (HR=0.36, 95%CI 0.23-0.55) and OS (HR=0.24, 95%CI 0.08-0.68). Conclusion: PD-L1 blood markers, including sPD-L1, CTCs PD-L1 and exoPD-L1, can effectively predict prognosis, and may be potentially utilized for patient selection and treatment management for NSCLC patients receiving ICIs.

Correlation between lipoprotein-associated phospholipase A2 and poststroke mild cognitive impairment.

OBJECTIVES: This study aimed to investigate the correlation between serum lipoprotein-associated phospholipase A2 (Lp-PLA2) and poststroke mild cognitive impairment (PSMCI). METHODS: The patients included in the study were divided into PSMCI (68 cases) and cognitively normal (CN) (218 cases) groups and followed up for six months. Demographic and clinical data were collected. A logistic regression analysis was performed to determine whether Lp-PLA2 is an independent risk factor for PSMCI. Spearman's correlation analysis was used to examine the correlation between Lp-PLA2 levels and Montreal Cognitive Assessment (MoCA) scores. A receiver operating characteristic (ROC) curve analysis was performed to determine the diagnostic threshold value of Lp-PLA2 for PSMCI. RESULTS: Serum Lp-PLA2 levels were significantly higher in the PSMCI group than in the CN group. The logistic regression analysis showed that Lp-PLA2 was an independent risk factor for PSMCI (OR = 1.05, 95% CI = 1.03-1.07). Spearman's correlation analysis revealed a significant correlation between the Lp-PLA2 levels and MoCA scores (R = -0.49). The area under the ROC curve for Lp-PLA2 was 0.849, and the threshold value for PSMCI occurrence was 236.8 ng/ml. CONCLUSIONS: Elevated serum Lp-PLA2 is an independent risk factor for PSMCI and may serve as a potential biomarker for PSMCI.

A comparison of the efficacy of computed tomography-guided minimally invasive puncture and drainage and craniotomy for hematoma evacuation in the treatment of cerebellar hemorrhage.

OBJECTIVE: This study aimed to compare the efficacy of computed tomography (CT)-guided minimally invasive puncture and drainage (MIPD) and craniotomy for hematoma evacuation in the treatment of cerebellar hemorrhage. METHODS: This single-center prospective cohort study was conducted from January 2020 to February 2023. During the study period, 40 patients with cerebellar hemorrhage who underwent CT-guided MIPD treatment were enrolled in the CT-guided MIPD (CTGMIPD) group, and 40 patients with the cerebellar hemorrhage who had a propensity score matching that of the CTGMIPD group and who underwent craniotomy for hematoma evacuation were enrolled in the standard craniotomy (SC) group. The primary outcome indicators were the 6-month mortality of the patients and the proportion of survivors with a modified Rankin Scale (mRS) scores of 1 or 2. The secondary outcome indicators were the cerebellar hematoma volume, National Institutes of Health Stroke Scale (NIHSS) score, Glasgow Coma Scale (GCS) score, incidence of postoperative complications, length of hospital stay, and medical costs. In addition, data concerning the patients who died during the study period were further analyzed. RESULTS: At the 6-month follow-up, there was no significant difference in mortality between the two groups, although the proportion of patients with an mRS scores of 1 or 2 was significantly higher in the CTGMIPD group when compared with the SC group (P = 0.015). No significant differences were observed in the hematoma volume, NIHSS score, and GCS score between the two groups. By contrast, the incidence of postoperative complications, length of hospital stay, and medical costs were significantly lower in the CTGMIPD group than in the SC group (all P < 0.05). When compared with the SC group, the proportion of dead patients with a hematoma volume greater than 30 ml was higher in the CTGMIPD group (P = 0.03). Moreover, after stratification of the patients with a preoperative GCS score ≤8, the CTGMIPD group had a significantly higher mortality rate than the SC group (P = 0.04). CONCLUSION: The efficacy of CT-guided MIPD in the treatment of cerebellar hemorrhage is close to that of craniotomy for hematoma excavation, although the complication and disability rates of the former are significantly lower than those of the latter. When the preoperative hematoma volume is less than 30 mL or the preoperative GCS score is greater than 8, CT-guided MIPD represents a better choice for the treatment of cerebellar hemorrhage than craniotomy for hematoma evacuation.

Passive exercise is an effective alternative to HRT for restoring OVX induced mitochondrial dysfunction in skeletal muscle.

Background: Postmenopausal women are more prone to develop muscle weakness, which is strongly associated with impairment of mitochondrial function in skeletal muscle. This study aimed to examine the impact of a passive exercise modality, whole-body vibration training (WBVT), on muscle mitochondrial function in ovariectomized (OVX) mice, in comparison with 17ß-estradiol (E2) replacement. Methods: Female C57BL/6J mice were assigned to four groups: sham operation control group (Sham), ovariectomized group (OVX), OVX with E2 supplement group (OVX+E), and OVX with WBVT group (OVX+W). The estrous cycle, body weight, body composition, and muscle strength of the mice were monitored after the operation. Serum E2 level was assessed by enzyme-linked immunosorbent assay (ELISA). The ATP levels were determined using a luciferase-catalyzed bioluminescence assay. The activity of mitochondrial respiration chain complexes was evaluated using high-resolution respirometry (O2K). Expression levels of oxidative phosphorylation (OXPHOS), peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), and mitochondrial transcription factor A (TFAM) were detected using western blotting. Results: We observed decreased muscle strength and impaired mitochondrial function in the skeletal muscle of OVX mice. The vibration training alleviated these impairments as much as the E2 supplement. In addition, the vibration training was superior to the ovariectomy and the estradiol replacement regarding the protein expression of PGC-1α and TFAM. Conclusion: WBVT improves the OVX-induced decline in muscle strength and impairment of mitochondrial function in the skeletal muscle. This passive exercise strategy may be useful as an alternative to E2 replacement for preventing menopausal muscular weakness. Further studies are needed to understand the effects of WBVT on various physiological systems, and precautions should be taken when implementing it in patient treatment.

Red blood cell distribution width combined with age as a predictor of acute ischemic stroke in stable COPD patients.

Aim: This retrospective study aimed to investigate the independent clinical variables associated with the onset of acute cerebral ischemic stroke (AIS) in patients with stable chronic obstructive pulmonary disease (COPD). Method: A total of 244 patients with COPD who had not experienced a relapse within 6 months were included in this retrospective study. Of these, 94 patients hospitalized with AIS were enrolled in the study group, and the remaining 150 were enrolled in the control group. Clinical data and laboratory parameters were collected for both groups within 24 h after hospitalization, and the data of the two groups were statistically analyzed. Results: The levels of age, white blood cell (WBC), neutrophil (NEUT), glucose (GLU), prothrombin time (PT), albumin (ALB), and red blood cell distribution width (RDW) were different in the two groups (P < 0.01). Logistic regression analysis showed that age, WBC, RDW, PT, and GLU were independent risk factors for the occurrence of AIS in patients with stable COPD. Age and RDW were selected as new predictors, and the receiver operating characteristic curves (ROC) were plotted accordingly. The areas under the ROC curves of age, RDW, and age + RDW were 0.7122, 0.7184, and 0.7852, respectively. The sensitivity was 60.5, 59.6, and 70.2%, and the specificity was 72.4, 86.0, and 60.0%, respectively. Conclusion: The combination of RDW and age in patients with stable COPD might be a potential predictor for the onset of AIS.

Community Efficacy for Non-Communicable Disease Management and Medication Adherence: The Sequential Mediating Role of Self-Efficacy and Depressive Symptoms.

Purpose: We assess whether the sequential mediating effects of self-efficacy and depressive symptoms on the relationship between community efficacy for non-communicable disease management (COEN) and medication adherence and whether these relationships differed by sex and age. Patients and Methods: Overall, 662 individuals from 12 communities in China were interviewed twice 1 year apart. Serial mediation analysis examined whether the relationship between COEN and medication adherence was mediated by self-efficacy and depressive symptoms. Model invariance across sex and age groups was assessed using multi-group analysis. Results: Serial mediation analysis indicated that self-efficacy and depressive symptoms sequentially mediated relationship between COEN and medication adherence. Multi-group analysis by sex showed that the path from self-efficacy to medication adherence was significant only for females and from depressive symptoms to medication adherence was significant only for males. Conclusion: Interventions that enhance individual self-efficacy may be beneficial in decreasing depressive symptoms and improving medication adherence.

[Status of knowledge and behavior of drug use among residents in 5 provinces in China in 2011].

OBJECTIVE: To understand the status of knowledge and behavior of drug use among urban and rural residents in 5 provinces in China to suggest priority intervention strategies and measures for drug use health education. METHODS: From March to May of 2011, 6159 urban and rural residents were selected from Beijing, Liaoning, Zhejiang, Yunnan, Shaanxi provinces by the multistage stratified sampling method and were investigated by the questionnaires on drug use knowledge and behavior. RESULTS: The residents' average awareness rate for 11 pieces of basic drug use information was 48.3% (32,750/67,749). The residents' average awareness rate in the rural (40.3%, 9189/22 792) was lower than that in metropolitan (51.9%, 11 483/22 110) and small and middle-sized cities (52.9%, 12,078/22,847) and the differences had statistical significance (χ2=889.30, P<0.01). Overall, 77.0% (4742/6159) of residents purchased drug according to the doctors' prescription; 36.9% (2271/6159) of residents bought by their experiences; 33.3% (2049/6159) of residents did not know whether they had bought faked drugs; 32.7% (2016/6159) of residents did not read instructions carefully before using drug; 83.4% (5134/6159) of residents stored drugs in their house and only 29.2% (1798/6159) of residents would check up expired drugs regularly; 59.6% (3673/6159) of residents changed drug by themselves after suspected adverse reaction of drugs. CONCLUSION: Chinese urban and rural residents' knowledge level of drug use is inadequate and drug use behaviors are not optimistic. Drug use health education should be enhanced among urban and rural residents.

Botulinum toxin A improves psychological distress in patients with hemifacial spasm.

OBJECTIVE: This study aimed at assessing mental health in patients with hemifacial spasm (HFS) and determined the effect of botulinum toxin type A (BTX-A) on psychological distress in patients with HFS. METHODS: Ninety-five HFS patients and 95 age- and sex-matched healthy controls were enrolled. Symptom checklist-90 (SCL-90) scores were used to measure psychological distress in HFS patients and healthy controls. The mental health status of HFS patients was also evaluated by SCL-90, before and after the injection of BTX-A. Moreover, for those patients with abnormal mental health, efficacy outcomes after treatment with BTX-A were compared with a propensity score-matched historical cohort without BTX-A treatment. RESULTS: The mean scores for interpersonal sensitivity, phobia, anxiety, depression, and somatization were significantly higher among HFS patients than healthy people (P < 0.05). There was no significant difference between female patients and male patients in HFS group (P > 0.05). There were significant improvements in somatization, interpersonal sensitivity, depression, anxiety, and phobia scores before and after treatment (P < 0.05). At 2 months, more patients experienced an improvement in psychological distress in the BTX-A group (61.29% versus 38.71%; P = 0.03). CONCLUSION: Patients with HFS are often accompanied by somatization, interpersonal sensitivity, depression, anxiety, and phobia. Our findings suggest that BTX-A can improve these symptoms. However, further well-designed prospective studies are warranted to validate our findings.

Efficacy and Safety of Recombinant Human Prourokinase in Acute Ischemic Stroke: A Phase IIa Randomized Clinical Trial.

Recombinant human prourokinase (rhPro-UK) is a novel thrombolytic that has been approved to treat patients with acute myocardial infarction. However, the safety and efficacy of intravenous rhPro-UK in patients with acute ischemic stroke (AIS) has not been well established. We aimed to investigate the safety and preliminary efficacy of rhPro-UK in patients with AIS in a multi-center phase IIa trial setting. One hundred nineteen patients within 4.5 h of AIS onset were enrolled in this randomized, open-label, 23-center phase IIa clinical trial. Patients were randomly assigned to 35 mg (n = 40) or 50 mg (n = 39) intravenous rhPro-UK or 0.9 mg/kg recombinant tissue plasminogen activator (r-tPA; n = 40). The primary endpoint was functional independence defined as a modified Rankin scale (mRS) score of 0 or 1 at 90 days. The secondary outcome was early neurological improvement defined as a reduction of ≥ 4 points on the National Institutes of Health Stroke Scale (NIHSS) score from baseline to 24 h after drug administration. Safety endpoints included death due to any cause, symptomatic intracerebral hemorrhage (sICH), and other serious adverse events (SAEs). The proportion of patients with an mRS score of ≤ 1 at 90 days did not differ significantly among three groups (35 mg rhPro-UK: 55.56% vs. 50 mg rhPro-UK: 57.89% vs. vs. r-tPA: 52.63%; P = 0.92). The rates of treatment response, referring to early neurological improvement, were similar among these three groups (36.11% vs. 31.58% vs. 28.95%, respectively; P = 0.85). There was no difference in mortality at 90 days or in the rate of other SAEs among the three groups. One patient in the 50 mg rhPro-UK group suffered sICH. While neither the primary efficacy outcomes nor safety profile differed significantly among the low, high rhPro-UK and control groups, it is a logical step to further test the low-dose rhPro-UK group versus the control group in a well-powered phase III study.Trial Registration: http://www.chictr.org.cn . Identifier: ChiCTR1800016519. Date of registration: June 6 2018.

Apatinib Promotes Ferroptosis in Colorectal Cancer Cells by Targeting ELOVL6/ACSL4 Signaling.

BACKGROUND: Colorectal cancer (CRC) is a common digestive system malignancy. Ferroptosis, a new form of regulated cell death, plays a vital role in the pathogenesis and therapy of cancers. OBJECTIVE: We aimed to study the role of apatinib in ferroptosis of CRC cells and its potential mechanisms. MATERIALS AND METHODS: Human CRC HCT116 cells were exposed to apatinib. Cell viability was examined using a CCK-8 kit. The concentrations of intracellular iron and reactive oxygen species (ROS) were detected using kits. Additionally, Western blot analysis was used to determine the expression of ferroptosis-related proteins. Elongation of very long-chain fatty acids family member 6 (ELOVL6) was one of the targets of apatinib predicted by SwissTargetPrediction. Therefore, ELOVL6 expression was evaluated after treatment with apatinib. Subsequently, the effects of ELOVL6 overexpression on ferroptosis of HCT116 cells were investigated. Finally, STRING database was applied to predict the potential proteins interacting with ELOVL6, and co-immunoprecipitation (co-IP) assay was applied for confirmation. RESULTS: Results indicated that apatinib decreased cell viability and increased the contents of intracellular iron ROS. Moreover, significantly upregulated ACSL4 expression was observed, accompanied by notable downregulation of GPx4 and FTH1 expression after apatinib exposure. Furthermore, ELOVL6 expression was remarkably enhanced in HCT116 cells, which was dramatically inhibited under apatinib intervention. ELOVL6 overexpression reversed the effects of apatinib on cell viability and ferroptosis of HCT116 cells. Moreover, ACSL4, a vital regulator of ferroptosis, could interact with ELOVL6 directly, which was confirmed by the result of co-IP. CONCLUSION: These findings demonstrated that apatinib promoted ferroptosis in CRC cells by targeting ELOVL6/ACSL4, providing a new mechanism support for apatinib application in the clinical treatment of CRC.

MicroRNA-429 acts as a tumor suppressor in colorectal cancer by targeting high mobility group box 3.

Colorectal cancer (CRC) is one of the most common solid tumors worldwide and has an extremely poor prognosis. MicroRNA-429 (miR-429) has been reported to participate in the progression of CRC. However, the pathological mechanisms require further investigation. The aim of the present study was to investigate the association between miR-429 and high mobility group box 3 (HMGB3) in CRC and the associated mechanism. The mRNA expression levels of miR-429 and HMGB3 in 65 paired CRC and adjacent tissues were examined by reverse transcription-quantitative PCR. Furthermore, a dual-luciferase reporter assay was performed to identify the association between miR-429 and HMGB3. Finally, the effects of miR-429 and HMGB3 on the proliferation and apoptosis of CRC cells were detected. As a result, it was identified that miR-429 expression was downregulated and HMGB3 expression was upregulated in CRC tissues compared with in adjacent non-cancer tissues, and the expression levels of miR-429 were negatively associated with those of HMGB3. Notably, HMGB3 was demonstrated to be a direct target of miR-429 by dual-luciferase reporter assay. Furthermore, transfection with a miR-429 mimic significantly inhibited HMGB3 expression and led to decreased proliferation and increased apoptosis of CRC cells. On the other hand, transient overexpression of HMGB3 partially inhibited the antitumor effects of miR-429. To the best of our knowledge, the present study demonstrated for the first time that miR-429 regulated the proliferation and apoptosis of CRC cells via HMGB3, suggesting a specific tumor suppressive function of the miR-429/HMGB3 signaling pathway in CRC.

Pharmacogenetic Association between XRCC1 Polymorphisms and Response to Platinum-Based Chemotherapy in Asian Patients with NSCLC: A Meta-Analysis.

BACKGROUND: Platinum-based chemotherapy plays an antitumor role by damaging DNA. X-ray repair crosscomplementing protein 1 (XRCC1) participates in DNA repair and thus affects the sensitivity to platinum drugs. Two polymorphisms of XRCC1, rs25487 (Arg399Gln) and rs1799782 (Arg194Trp), have been widely studied for the association with clinical outcomes of platinum-based chemotherapy in Asian patients with non-small-cell lung cancer (NSCLC), but the results remain inconclusive. Thus, we performed the present meta-analysis. METHODS: Literature search was performed in PubMed, Web of Science, and EMBASE up to June 2019. Odds ratios (ORs) for objective response ratio (ORR), Cox proportional hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS), and the corresponding 95% confidence intervals (95% CIs) were calculated to assess the association strengths between XRCC1 polymorphisms and clinical outcomes. Comparisons were performed in homozygous, heterozygous, dominant, and recessive models. RESULTS: Finally, a total of 23 studies involving 5567 patients were included in the meta-analysis. Compared to ArgArg of rs25487, GlnGln (OR = 1.71, 95% CI: 1.16-2.52, p = .007, I 2 = 56.8%) and GlnArg (OR = 1.23, 95% CI: 1.07-1.40, p = .003, I 2 = 29.0%) were associated with higher ORR. Meanwhile, GlnGln indicated a favorable OS (HR = 0.60, 95% CI: 0.40-0.88) and PFS (HR = 0.64, 95% CI: 0.46-0.90). We also found positive associations between rs1799782 and ORR in all comparison models with low between-study heterogeneity. The association strength increased with the number of variant alleles (TrpTrp vs. ArgArg: OR = 1.73, 95% CI:1.31-2.27; TrpArg vs. ArgArg: OR = 1.28, 95% CI: 1.06-1.55), suggesting a gene dosage effect. In addition, TrpTrp predicted a longer OS. CONCLUSION: Our results showed that rs25487 and rs1799782 of XRCC1 are potential markers to predict clinical outcomes of platinum-based chemotherapy in Asian patients with NSCLC.