The clinical tumor therapy was greatly challenged due to the complex characteristics of tumor microenvironment, however, which also provide arena for novel therapeutic strategies. In this study, poly(2-ethyl-2-oxazoline)-poly(lactic acid)-SS-poly(β-amino ester (PEOz-PLA-SS-PBAE) triblock copolymers with pH and GSH double response were synthesized, polymer micelles were prepared by thin film hydration method for loading of silybin to improve its antitumor activity. The critical micelle concentration was determined by pyrene fluorescence method as 1.8 μg·mL^-1. The particle size was 155.30 ± 1.80 nm as determined by dynamic light scattering, with polydispersity index of 0.168 ± 0.004. The drug loading and entrapment efficiency of the micelles were determined by HPLC as (5.48 ± 0.04)% and (68.52 ± 0.48)%, respectively. The in vitro drug release profiles showed that the micelles have low pH sensitivity and high GSH responsiveness, and exhibited sustained release profiles. The good biocompatibility of the material was proved by measuring the hemolysis rate and cytotoxicity of the blank micelle. The cytotoxicity and apoptosis rate of tumor cells showed that the drug loaded PEOz-PLA-SS-PBAE micelles had significant inhibitory effect and apoptosis-inducing effect on MDA-MB-231 cells. The results of wounding healing assay and Transwell invasion test showed that the drug loaded PEOz-PLA-SS-PBAE micelles could significantly inhibit the metastasis of MDA-MB-231 cells. The PEOz-PLA-SS-PBAE drug-loaded micelles prepared in this study have good inhibitory effect on tumor growth and anti-tumor metastasis in vitro, which lays the foundation for the further application of silybin.

OBJECTIVE: This study investigated the effects of bis (2-butoxyethyl) phthalate (BBOP) on the onset of male puberty by affecting Leydig cell development in rats. METHODS: Thirty 35-day-old male Sprague-Dawley rats were randomly allocated to five groups mg/kg bw per day that were gavaged for 21 days with BBOP at 0, 10, 100, 250, or 500 mg/kg bw per day. The hormone profiles; Leydig cell morphological metrics; mRNA and protein levels; oxidative stress; and AKT, mTOR, ERK1/2, and GSK3β pathways were assessed. RESULTS: BBOP at 250 and/or 500 mg/kg bw per day decreased serum testosterone, luteinizing hormone, and follicle-stimulating hormone levels mg/kg bw per day (P < 0.05). BBOP at 500 mg/kg bw per day decreased Leydig cell number mg/kg bw per day and downregulated Cyp11a1, Insl3, Hsd11b1, and Dhh in the testes, and Lhb and Fshb mRNAs in the pituitary gland (P < 0.05). The malondialdehyde content in the testis significantly increased, while Sod1 and Sod2 mRNAs were markedly down-regulated, by BBOP treatment at 250-500 mg/kg bw per day (P < 0.05). Furthermore, BBOP at 500 mg/kg bw per day decreased AKT1/AKT2, mTOR, and ERK1/2 phosphorylation, and GSK3β and SIRT1 levels mg/kg bw per day (P < 0.05). Finally, BBOP at 100 or 500 μmol/L induced ROS and apoptosis in Leydig cells after 24 h of treatment in vitro (P < 0.05). CONCLUSION: BBOP delays puberty onset by increasing oxidative stress and apoptosis in Leydig cells in rats. UNLABELLED The graphical abstract is available on the website www.besjournal.com.
Rats ; Male ; Animals ; Leydig Cells/metabolism* ; Testosterone ; Glycogen Synthase Kinase 3 beta/pharmacology* ; Rats, Sprague-Dawley ; Sexual Maturation ; Testis ; Oxidative Stress ; TOR Serine-Threonine Kinases/metabolism* ; Apoptosis

Objective: To explore the short-term efficacy of fenestrated atrial septal defect (ASD) occulders in the treatment of pulmonary arterial hypertension (PAH). Methods: Thirty-six healthy dogs were divided into the balloon atrial septostomy (BAS)+fenestrated ASD occulders group (n=12), BAS group (n=12) and non-septostomy group (n=12). PAH was induced by intra-atrial injection of dehydrogenized monocrotaline (1.5 mg/kg) in all dogs. Animals in the BAS+fenestrated ASD occulders group underwent atrial septal puncture and fenestrated ASD occulders implantation. Animals in the BAS group underwent balloon atrial septostomy. The non-septostomy group received no surgical intervention. The hemodynamic indexes and blood N-terminal pro-B-type natriuretic peptide (NT-proBNP) of dogs were measured before modeling, 2 months after modeling, 1, 3, and 6 months after surgery, respectively. Echocardiography was performed to observe the patency of the shunt and atrial septostomy of the dogs in the BAS+fenestrated ASD occulders group and BAS group at 1, 3, and 6 months after surgery. Three dogs were sacrificed in each group at 1, 3, and 6 months after surgery, respectively. Atrial septal tissue and fenestrated ASD occulders were removed to observe the patency and endothelialization of the device. Lung tissues were obtained for hematoxylin-eosin (HE) staining to observe the inflammatory cells infiltration and the thickening and narrowing of the pulmonary arterials. Results: Among 36 dogs, 2 dogs died within 24 hours after modeling, and 34 dogs were assigned to BAS+fenestrated ASD occulders group (n=12), BAS group (n=11), and non-septostomy group (n=11). Compared with BAS group, the average right atrial pressure (mRAP) and NT-proBNP of dogs in the BAS+fenestrated ASD occulders group were significantly reduced at 3 months after surgery (P<0.05), and the cardiac output (CO) was significantly increased at 6 months after surgery, arterial oxygen saturation (SaO₂) was also significantly reduced (P<0.05). Compared with non-septostomy group, dogs in the BAS+fenestrated ASD occulders group had significantly lower mRAP and NT-proBNP at 1, 3, and 6 months after surgery (P<0.05), and higher CO and lower SaO₂ at 6 months after surgery (P<0.05). Compared with the non-septostomy group, the dogs in the BAS group had significantly lower mRAP and NT-proBNP at 1 month after surgery (P<0.05), and there was no significant difference on mRAP and NT-proBNP at 3 and 6 months after surgery (P>0.05). Echocardiography showed that there was a minimal right-to-left shunt in the atrial septum in the BAS group at 1 month after the surgery, and the ostomy was closed in all the dogs in the BAS group at 3 months after the surgery. There was still a clear right-to-left shunt in the dogs of BAS+fenestrated ASD occulders group. The shunt was well formed and satisfactory endothelialization was observed at 1, 3 and 6 months after surgery. The results of HE staining showed that the pulmonary arterials were significantly thickened, stenosis and collapse occurred in the non-septostomy group. Pulmonary microvascular stenosis and inflammatory cell infiltration in the pulmonary arterials were observed in the non-septostomy group. Pulmonary arterial histological results were comparable between BAS+fenestrated ASD occulders group and non-septostomy group at 6 months after surgery . Conclusions: The fenestrated ASD occulder has the advantage of maintaining the open fistula hole for a longer time compared with simple balloon dilation. The fenestrated ASD occulder can improve cardiac function, and it is safe and feasible to treat PAH in this animal model.
Animals ; Atrial Septum/surgery* ; Cardiac Catheterization/methods* ; Dogs ; Familial Primary Pulmonary Hypertension ; Heart Septal Defects, Atrial/surgery* ; Hypertension, Pulmonary ; Pulmonary Arterial Hypertension

Angelicae Sinensis Radix (Danggui) and Ligusticum Chuanxiong Rhizoma (Chuan Xiong) herb-pair (DC) have been frequently used in Traditional Chinese medicine (TCM) prescriptions for hundreds of years to prevent vascular diseases and alleviate pain. However, the mechanism of DC herb-pair in the prevention of liver fibrosis development was still unclear. In the present study, the effects and mechanisms of DC herb-pair on liver fibrosis were examined using network pharmacology and mouse fibrotic model. Based on the network pharmacological analysis of 13 bioactive ingredients found in DC, a total of 46 targets and 71 pathways related to anti-fibrosis effects were obtained, which was associated with mitogen-activated protein kinase (MAPK) signal pathway, hepatic inflammation and fibrotic response. Furthermore, this hypothesis was verified using carbon tetrachloride (CCl

Background::Accurate prediction of ischemic stroke is required for deciding anticoagulation use in patients with atrial fibrillation (AF). Even though only 6% to 8% of AF patients die from stroke, about 90% are indicated for anticoagulants according to the current AF management guidelines. Therefore, we aimed to develop an accurate and easy-to-use new risk model for 1-year thromboembolic events (TEs) in Chinese AF patients.Methods::From the prospective China Atrial Fibrillation Registry cohort study, we identified 6601 AF patients who were not treated with anticoagulation or ablation at baseline. We selected the most important variables by the extreme gradient boosting (XGBoost) algorithm and developed a simplified risk model for predicting 1-year TEs. The novel risk score was internally validated using bootstrapping with 1000 replicates and compared with the CHA 2DS 2-VA score (excluding female sex from the CHA 2DS 2-VASc score). Results::Up to the follow-up of 1 year, 163 TEs (ischemic stroke or systemic embolism) occurred. Using the XGBoost algorithm, we selected the three most important variables (congestive heart failure or left ventricular dysfunction, age, and prior stroke, abbreviated as CAS model) to predict 1-year TE risk. We trained a multivariate Cox regression model and assigned point scores proportional to model coefficients. The CAS scheme classified 30.8% (2033/6601) of the patients as low risk for TE (CAS score = 0), with a corresponding 1-year TE risk of 0.81% (95% confidence interval [CI]: 0.41%-1.19%). In our cohort, the C-statistic of CAS model was 0.69 (95% CI: 0.65-0.73), higher than that of CHA 2DS 2-VA score (0.66, 95% CI: 0.62-0.70, Z = 2.01, P = 0.045). The overall net reclassification improvement from CHA 2DS 2-VA categories (low = 0/high &ge;1) to CAS categories (low = 0/high &ge;1) was 12.2% (95% CI: 8.7%-15.7%). Conclusion::In Chinese AF patients, a novel and simple CAS risk model better predicted 1-year TEs than the widely-used CHA 2DS 2- VA risk score and identified a large proportion of patients with low risk of TEs, which could potentially improve anticoagulation decision-making. Trial Registration::www.chictr.org.cn (Unique identifier No. ChiCTR-OCH-13003729).

Paeoniae Radix Alba is the dried root of Paeonia lactiflora, which was first recorded in the Shennong's Classic of Materia Medica and listed as the top grade. It is a common blood-tonifying herb, and its chemical components are mainly monoterpenes and their glycosides, triterpenes, flavonoids and so on. Modern research has demonstrated that Paeoniae Radix Alba has the activities of anti-inflammation, pain easing, liver protection, and anti-oxidation, and thus it is widely used in clinical practice and has broad development prospects. In this paper, the research progress on the chemical composition, pharmacological effects, and quality control of Paeoniae Radix Alba were summarized. On this basis, the Q-markers of Paeoniae Radix Alba were predicted from the aspects of mass transfer and traceability, chemical composition specificity, and availability and measurability of chemical components, which will provide a scientific basis for the quality evaluation of Paeoniae Radix Alba.
Drugs, Chinese Herbal ; Medicine, Chinese Traditional ; Monoterpenes ; Paeonia ; Plant Extracts

Anticoagulants/therapeutic use* ; Atrial Fibrillation/therapy* ; China/epidemiology* ; Humans ; Registries ; Risk Factors ; Stroke

OBJECTIVE: To study the distribution and drug resistance of pathogens causing periprosthetic infections after hip and knee arthroplasty, and to formulate prevention and treatment strategies for drug-resistant bacteria. METHODS: The data of 146 cases of periprosthetic infection after primary hip and knee arthroplasty from 2010 to 2015 were collected, including 111 cases of periprosthetic infection after hip arthroplasty and 35 cases of periprosthetic infection after knee arthroplasty. The culture positive rate, pathogenic bacteria composition and drug resistance rate were counted over the years, and the change trend of pathogen distribution and drug resistance was analyzed. RESULTS: One hundredand eight strains of pathogenic bacteria were detected in 146 cases, and the positive rate of culture was 73.97%. Gram positive bacteria accounted for 55.48%, Staphylococcus epidermidis and Staphylococcus aureus accounted for 25.34% and 15.07% respectively. Gram negative bacteria accounted for 13.01%, including Enterobacter cloacae, Pseudomonas aeruginosa and Escherichia coli. There were 4 cases of Mycobacterium tuberculosis infection and mixed infection. The results of culture over the years showed that the constituent ratio of Gram positive bacteria had an increasing trend, fluctuating from 39.13% to 76.47%. The results of drug sensitivity showed that the pathogens were highly resistant to β-lactams, quinolones, clindamycin and gentamicin, and the drug resistance rate was increasing, but it was still sensitive to rifampicin, nitrofurantoin, tigecycline, linezolid and vancomycin. CONCLUSION Gram positive bacteria are the main pathogens of periprosthetic infection, and the proportion is increasing gradually.The pathogens have high resistance to many kinds of antibiotics, and the resistance rate is still increasing. To strengthen the monitoring of the distribution and drug resistance of pathogenic bacteria is helpful to grasp its change trend and formulate targeted prevention and control strategies.
Anti-Bacterial Agents/therapeutic use* ; Arthroplasty, Replacement, Knee/adverse effects* ; Drug Resistance ; Drug Resistance, Bacterial ; Gram-Positive Bacteria ; Microbial Sensitivity Tests ; Retrospective Studies

OBJECTIVE: To study the expression of multiple negative costimulatory molecules on peripheral blood T cells in patients with acute myeloid leukemia (AML) and its affection on prognosis. METHODS: The peripheral blood samples from patients with newly diagnosed AML, complete remission (CR), and no-remission (NR) were collected, the expression levels PD-1、VISTA and TIM-3 in CD4 and CD8 T cells were detected by flow cytometry , and the clinical data of patients were analyzed. RESULTS: The expression levels of PD-1、VISTA and TIM-3 of CD4 and CD8 T cells in the newly diagnosed AML patients were significantly higher than those in control group (P＜0.05). The expression levels of PD-1、TIM-3 and VISTA of CD4 and CD8 T cells in the CR group were significantly lower than those in newly diagnosed and the NR group (P＜0.05). The TIM-3 expression level positively correlated with VISTA expression level of CD4 and CD8 T cells in newly diagnosed AML patients (r=0.85 and 0.73). The VISTA and PD-1 expression level of CD4 T cells in newly diagnosed AML, NR after first induction chemotherapy and high risk patients significantly increased (P＜0.05), the TIM-3 expression level of CD8 T cells in high risk group significantly increased (P＜0.05), and the VISTA expression level of CD8 T cells in CBFβ-MYH11 mutation-positive group significantly decreased (P＜0.05). CONCLUSION The expression of PD-1、TIM-3 and VISTA in AML peripheral blood T cells may be involved in the immune escape of AML and can be the targets of treatment for acute myeloid leukemia patients.
B7 Antigens ; CD8-Positive T-Lymphocytes ; Flow Cytometry ; Hepatitis A Virus Cellular Receptor 2 ; Humans ; Leukemia, Myeloid, Acute ; Programmed Cell Death 1 Receptor

Objective: Based on the network pharmacology research method, combined with the theory of traditional Chinese medicine, to explore the mechanism of the interaction of Huobahuagen Tablets (HBHGT) for treating different diseases with same method between the lupus erythematosus (LE) and rheumatoid arthritis (RA). Methods: The components in HBHGT and their targets were collected by using TCMSP, Chinese Herb Dictionary, and other databases in combination with literature. Disease-related targets for lupus erythematosus and rheumatoid arthritis were collected using databases such as CTD, PubMed, and Drugbank in conjunction with literature. The herb-ingredient-target network and drug-target-disease interaction PPI network were constructed by Cytoscape software, and the gene function and signaling pathway of the constructed network were analyzed. ClueGO plugin in Cytoscape software was used for GO analysis and Pathway analysis. Results: The main components of torch flower roots were epicatechin, triptolide and triptonide, and 138 key targets were obtained. Through GO analysis and Pathway analysis, it was found that HBHGT for treating different diseases with same method between the lupus erythematosus and rheumatoid arthritis involved 17 common targets such as EGFR, CRK, and LCK, and its mechanism may be related to biological processes such as phosphoprotein binding, ERBB2 signaling pathway, peptidyl tyrosine autophosphorylation, and receptor tyrosine kinase signaling pathway, FGFR3 signaling pathway, Fcε receptor (FCERI) signaling pathway and other pathways. Receptor tyrosine kinase signaling pathway was the main pathway of HBHGT for treating different diseases with same method. Conclusion: This study confirmed from the two aspects of target and pathway that HBHGTs had great similarities in the treatment of RA and LE. Among them, EGFR, CBL, LCK, and other targets and EGFR-related signaling pathways were the key targets and pathways of HBHGT for "different diseases with the same treatment".