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Wei Jia, Yi-Fu He, Xiao-Jun Qian, Jian Chen Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, People’s Republic of ChinaCorrespondence: Jian ChenDepartment of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, No. 17 Lujiang Road, Luyang District, Hefei, 230001, People’s Republic of ChinaTel/Fax +86-551-62283411Email woxinxiang2020@sina.comBackground: To explore the clinicopathological significance and prognostic value of thiopurine methyltransferase (TPMT) in patients with colon cancer by bioinformatics analysis.Materials and Methods: The clinicopathological information and TPMT expression data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Wilcoxon signed-rank test was used to evaluate the relationship between TPMT mRNA expression levels and clinicopathological characteristics in patients with colon cancer. Then, the prognostic value of TPMT mRNA expression for disease-free survival (DFS) and overall survival (OS) in patients with colon cancer was assessed by Kaplan–Meier and Cox regression analyses. Additionally, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to explore potential functions of TPMT in patients with colon cancer.Results: TPMT mRNA was significantly downregulated in colon cancer compared with normal tissues (P < 0.05). Wilcoxon analysis revealed that lower TPMT mRNA expression was remarkably associated with lymph node metastasis (P = 0.008), distant metastasis (P = 0.012) and advanced pathological stage (P = 0.010). Besides, the high TPMT mRNA level was also correlated with a favorable DFS and OS in colon cancer patients (both P < 0.05). Moreover, GO enrichment analysis indicated that the co-expressed genes of TPMT function as extracellular matrix (ECM) structural constituent, insulin-like growth factor binding, cell adhesion molecule binding and growth factor binding. KEGG enrichment analysis suggested that the co-expressed genes of TPMT were particularly enriched in amino sugar and nucleotide sugar metabolism, ECM-receptor interaction and focal adhesion.Conclusion: TPMT mRNA level might be a novel prognostic biomarker for patients with colon cancer.Keywords: colon cancer, thiopurine methyltransferase, bioinformatics analysis, prognosis

Objective: We analyzed the impact of different inhalant allergens on T-lymphocyte subsets in patients diagnosed with bronchial asthma., Methods: The study included 57 bronchial asthma patients and 22 healthy controls. Asthma patients were categorized into dust mite, animal hair, pollen, and mold groups. Flow cytometry was used to measure the cells in the case group and control group. These T-lymphocyte subset markers were evaluated among patients with bronchial asthma caused by different allergens as well as between the case group and control group., Results: Peripheral blood CD4 + T-cells, CD8 + T-cells, CD4/CD8 ratio, and Th17/Treg ratios were all higher in the case group than in the control group ( p  < 0.05). Peripheral blood T-lymphocyte subsets were compared among the four groups, and it was found that there were statistical differences in the Th17/Treg ratio among the four groups ( p  < 0.05). There were no significant differences observed among the four groups in terms of CD3+ cells, CD4+ cells, CD8+ cells, Th1 cells, Th2 cells, Th17 cells, Treg cells, Th9 cells, and Th22 cells. Further pairwise comparison was made, and the results suggested that the peripheral blood Th17/Treg ratio in the pollen mixed group was lower than that in the dust mite mixed group, animal hair mixed group, and mold mixed group ( p  < 0.05)., Conclusion: Patients with bronchial asthma show varied T-lymphocyte subset responses to different inhalant allergens. Elevated CD4+ T cells and Th17 cells in peripheral blood could indicate asthma risk. However, small sample size may introduce bias to these findings.

Glycerophosphocholine (GPC) is a water-soluble small molecule found naturally in humans and foods such as milk and soybeans. It can activate the IIS pathway by regulating the expression of daf-2 , ins-18 and daf-16 genes, sek-1 and skn-1 genes of MAPK pathway, sod-3 , ctl-1 , gst-4 and other antioxidant genes. GPC can relieve symptoms related to aging in organisms. The aim of this study was to probe the effects of GPC on the longevity and stress resistance of the entomopathogenic nematode (EPN) Steinernema kraussei 0657L strain. The results showed that the lifespan of S. kraussei 0657L was significantly prolonged by 50 mM GPC treatment, which was 54.55% longer than that of the control (0 mM GPC). GPC significantly inhibited reactive oxygen species (ROS) and lipofuscin accumulation, but the body size and fecundity of S. kraussei 0657L had little changed. At the same time, the longevity of S. kraussei 0657L exposed to heat shock and UV-B radiation was significantly prolonged than that with no external stress. GPC supplementation increased the activity of antioxidant enzymes and corresponding gene expression. Under treatment with 50 mM GPC, the activities of superoxide dismutase and catalase were increased by 1.90- and 4.13-fold, respectively, the expression of the sod-3 and ctl-1 genes was increased by 3.60- and 0.60-fold, respectively, and harmful reactive oxygen species were removed. In addition, the expression levels of the ins-18 , skn-1 , sek-1 and gst-4 genes related to the insulin/IGF-1 signaling pathway were upregulated 1.04-, 1.84-, 2.21- and 1.24-fold, respectively. These results indicate that GPC is mainly involved in the lifespan regulation of S. kraussei 0657L and plays an important role in resistance to external stress by activating the insulin/IGF-1 signaling pathway and downstream PI3K/MAPK kinase, creating a new idea for improving the commercial efficacy of S. kraussei . It also laid a theoretical foundation for its further efficient development and utilization in the field of biological control., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Qian, Chen, Wang and Wu.)

Background: Lung cancer is a leading cause of cancer mortality. It is one of the most abundant cancer types clinically, with 2 million new cases diagnosed yearly., Aims: Using clinically collected non-small cell lung cancer (NSCLC) samples, we sought to hypothesize an innovative intact signaling cascade for the disorder., Methods: We dissected snap-frozen NSCLC tissues along with sibling-paired nearby non-tumorous tissues from 108 NSCLC patients. We measured the expression levels of miR-451/ETV4/MMP13 using qRT-PCR and did a thorough investigation of the molecular mechanism for the signaling axis in NSCLC cell line A549. We also studied the epithelial-mesenchymal transition (EMT) process., Results: The activity of miR-451 was significantly decreased in NSCLC tissues, while the expression levels of ETV4 and MMP13 were remarkably increased. At the same time, miR-451 levels maintained a declining trend across TNM stage I-III. Inversely, ETV4 and MMP13 increased as the TNM stage increased. The miR-451/ETV4/MMP13 signaling axis was closely associated with prognosis in NSCLC patients. Based on in vitro experiments, ETV4 was a direct targeting factor for miRNA-451. Meanwhile, ETV4 promoted the tumor properties of NSCLC cells by directly activating MMP13. Silencing MMP13 blocked the EMT progress of NSCLC cells., Conclusion: Overall, we hypothesized an impeccable signaling pathway for NSCLC from a new aspect, and this can offer alternative insights for a better understanding of the disorder., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

This study investigated the mechanism of action of Scutellariae Radix-Coptidis Rhizoma(SR-CR) in intervening in non-alcoholic fatty liver disease(NAFLD) in rats based on lipidomics. Thirty-six SD rats were divided into a control group, a model group, SR-CR groups of different doses, and a simvastatin group, with six rats in each group. Rats in the control group were fed on a normal diet, while those in the remaining groups were fed on a high-lipid diet. After four weeks of feeding, drug treatment was carried out and rats were sacrificed after 12 weeks. Serum liver function and lipid indexes were detected using kits, and the pathomorphology of liver tissues was evaluated by hematoxylin-eosin(HE) staining and oil red O staining. Changes in lipid levels in rats were detected using the LC-MS technique. Differential lipid metabolites were screened by multivariate statistical analysis, and lipid metabolic pathways were plotted. The changes in lipid-related protein levels were further verified by Western blot. The results showed that compared with the control group, the model group showed increased levels of alanine aminotransferase(ALT), aspartate aminotransferase(AST), total cholesterol(TC), triglyceride(TG), and low-density lipoprotein cholesterol(LDL-c)(P&lt;0.01), and decreased levels of γ-glutamyl transferase(γ-GT) and high-density lipoprotein cholesterol(HDL-c)(P&lt;0.01), which were significantly recovered by the intervention of SR-CR. HE staining and oil red O staining showed that different doses of SR-CR could reverse the steatosis in the rat liver in a dose-dependent manner. After lipidomics analysis, there were significant differences in lipid metabolism between the model group and the control group, with 54 lipids significantly altered, mainly including glycerolipids, phosphatidylcholine, and sphingolipids. After administration, 44 differential lipids tended to normal levels, which indicated that SR-CR groups of different doses significantly improved the lipid metabolism level in NAFLD rats. Western blot showed that SR-CR significantly decreased TG-synthesis enzyme 1(DGAT1), recombinant lipin 1(LPIN1), fatty acid synthase(FASN), acetyl-CoA carboxylase 1(ACC1), and increased the phosphorylation level of ACC1. These changes significantly decreased the synthesis of TG and increased the rate of its decomposition, which enhanced the level of lipid metabolism in the body and finally achieved the lipid-lowering effect. SR-CR can improve NAFLD by inhibiting the synthesis of fatty acids and TG.

Background: Patients undergoing laparoscopic resection of liver metastases of colorectal cancer are prone to negative emotions and decrease of digestive function. Early nursing and psychological intervention are necessary., Aim: To observe the effect of enhanced recovery nursing combined with mental health education on postoperative recovery and mental health of patients undergoing laparoscopic resection of liver metastases of colorectal cancer., Methods: One hundred and twenty patients who underwent laparoscopic resection of liver metastases of colorectal cancer at our hospital between March 2021 and March 2023, were selected as participants. The patients admitted from March 1, 2021 to February 28, 2022 were set as the control group, and they were given routine nursing combined with mental health education intervention. While the patients admitted from March 1, 2022 to March 31, 2023 were set as the observation group, they were given accelerated rehabilitation surgical nursing combined with mental health education intervention. The differences in postoperative recovery-related indices, complications and pain degrees, and mental health-related scores were compared between groups. The T lymphocyte subset levels of the two groups were also compared., Results: The postoperative exhaust, defecation, eating and drainage time of the observation group were shorter than those of the control group. The pain scores of the observation group were lower than those of the control group at 6, 12, 24, 48, and 72 h after surgery. The cumulative complication rate of the observation group was lower than that of the control group ( P < 0.05). The CD4+/CD8+ in the observation group was higher than that in the control group 3 d after surgery ( P < 0.05). After intervention, the self-rating depression scale, self-rating anxiety scale, avoidance dimension, and yielding dimension in Medical coping style (MCMQ) scores of the two groups were lower than those prior to intervention, and the scores in the observation group were lower than those in the control group ( P < 0.05). The face dimension score in the MCMQ score was higher than that before intervention, and that of the observation group was higher than that of the control group ( P < 0.05). After intervention, the total scores of the life function index scale (FLIC) and psychological well-being scores of cancer patients in the two groups, and the physical and social well-being scores in the observation group, were higher than those before intervention. The nursing satisfaction of the observation group was higher than that of the control group ( P < 0.05). The physical, psychological, and social well-being, and the total FLIC scores of the observation group were higher than those in the control group after surgery ( P < 0.05)., Conclusion: Enhanced recovery nursing combined with mental health education can promote the recovery of gastrointestinal function, improve the mental health and quality of life of patients after laparoscopic resection of colorectal cancer liver metastases, and reduce the incidence of complications., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background and Purpose: Cerebrovascular parenchymal damage is prevalent in ageing brains; however, its vascular aetiology has not been fully elucidated. In addition to the underlying role of sclerotic arterioles, the correlation between collagenised venules has not been clarified. Here, we aimed to investigate the associations between microvascular injuries, including arteriolosclerosis and venular collagenosis, and related parenchymal damages in ageing brains, to investigate the underlying correlations., Methods: We evaluated arteriolosclerosis and venular collagenosis in 7 regions from 27 autopsy cases with no history of stroke or brain tumour. The correlations between the ratio of arteriolosclerosis, venular collagenosis and the severity of cerebrovascular parenchymal damage, including lacunes, microinfarcts, myelin loss, and parenchymal and perivascular haemosiderin deposits, were assessed., Results: Arteriolosclerosis and venular collagenosis became more evident with age. Arteriolosclerosis was associated with lacunes (p=0.004) and brain parenchymal haemosiderin deposits in the superior frontal cortex (p=0.024) but not with leukoaraiosis severity. Venular collagenosis was not associated with the number of lacunes or haemosiderin, while white matter generally became paler with severe venular collagenosis in the periventricular (β=-0.430, p=0.028) and deep white matter (β=-0.437, p=0.025)., Conclusion: Our findings imply an important role for venular lesions in relation to microvessel-related parenchymal damage which is different from that for arteriolosclerosis. Different underlying mechanisms of both cerebral arterioles and venules require further investigation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The present study aims to evaluate the efficacy of an anti-immunoglobulin E monoclonal antibody (omalizumab) in the treatment of allergic asthma (AS). A total of 34 patients with moderate-to-severe bronchial asthma admitted to the Respiratory Department of Tianjin First Central Hospital between September 2019 and September 2021 were enrolled in this study. The patients were treated with omalizumab in addition to conventional inhaled corticosteroids + long-acting β2 agonist treatment. The therapeutic effects before and after the addition of omalizumab were compared. The lung function indicators (ratio of the forced expiratory volume [FEV] in the first second to the forced vital capacity, FEV in the first second, forced expiratory flow [FEF] at 50% of vital capacity, FEF at 75% of vital capacity, and maximum mid-expiratory flow), fractionated exhaled nitric oxide values, asthma control test scores, rhinoconjunctivitis quality of life questionnaire scores, and urticaria control test scores were significantly different after 4 months of the regular administration of omalizumab (p < 0.05) compared with before administration. The use of omalizumab had a significant efficacy in the treatment of patients with AS, and the effects were obvious in the subgroups of patients with a combination of AS and atopic dermatitis, chronic urticaria, and allergic rhinitis. These results indicate that the treatment is worthy of clinical promotion., (© 2022 John Wiley & Sons Ltd.)

Background: Serum protein induced by vitamin K absence or antagonist-II (PIVKA-II) is a promising biomarker for hepatocellular carcinoma (HCC) surveillance., Aim: To identify the contributing factors related to the abnormal elevation of PIVKA-II level and assess their potential influence on the performance of PIVKA-II in detecting HCC., Methods: This study retrospectively enrolled in 784 chronic liver disease (CLD) patients and 267 HCC patients in Mengchao Hepatobiliary Hospital of Fujian Medical University from April 2016 to December 2019. Logistic regression and the area under the receiver operating characteristic curve (AUC) were used to evaluate the influencing factors and diagnostic performance of PIVKA-II for HCC, respectively., Results: Elevated PIVKA-II levels were independently positively associated with alcohol-related liver disease, serum alkaline phosphatase (ALP), and total bilirubin (TBIL) for CLD patients and aspartate aminotransferase (AST) and tumor size for HCC patients (all P < 0.05). Serum PIVKA-II were significantly lower in patients with viral etiology, ALP ≤ 1 × upper limit of normal (ULN), TBIL ≤ 1 × ULN, and AST ≤ 1 × ULN than in those with nonviral disease and abnormal ALP, TBIL, or AST (all P < 0.05), but the differences disappeared in patients with early-stage HCC. For patients with TBIL ≤ 1 × ULN, the AUC of PIVKA-II was significantly higher compared to that in patients with TBIL > 1 × ULN (0.817 vs 0.669, P = 0.015), while the difference between ALP ≤ 1 × ULN and ALP > 1 × ULN was not statistically significant (0.783 vs 0.729, P = 0.398). These trends were then more prominently perceived in subgroups of patients with viral etiology and HBV alone., Conclusion: Serum PIVKA-II has better performance in detecting HCC at an early stage for CLD patients with normal serum TBIL., Competing Interests: Conflict-of-interest statement: The authors declare no conflicts of interest., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Purpose: Noninvasively assessing the tumor biology and microenvironment before treatment is greatly important, and glypican-3 (GPC-3) is a new-generation immunotherapy target for hepatocellular carcinoma (HCC). This study investigated the application value of a nomogram based on LI-RADS features, quantitative contrast-enhanced MRI parameters and clinical indicators in the noninvasive preoperative prediction of GPC-3 expression in HCC., Methods and Materials: We retrospectively reviewed 127 patients with pathologically confirmed solitary HCC who underwent Gd-EOB-DTPA MRI examinations and related laboratory tests. Quantitative contrast-enhanced MRI parameters and clinical indicators were collected by an abdominal radiologist, and LI-RADS features were independently assessed and recorded by three trained intermediate- and senior-level radiologists. The pathological and immunohistochemical results of HCC were determined by two senior pathologists. All patients were divided into a training cohort (88 cases) and validation cohort (39 cases). Univariate analysis and multivariate logistic regression were performed to identify independent predictors of GPC-3 expression in HCC, and a nomogram model was established in the training cohort. The performance of the nomogram was assessed by the area under the receiver operating characteristic curve (AUC) and the calibration curve in the training cohort and validation cohort, respectively., Results: Blood products in mass, nodule-in-nodule architecture, mosaic architecture, contrast enhancement ratio (CER), transition phase lesion-liver parenchyma signal ratio (TP-LNR), and serum ferritin (Fer) were independent predictors of GPC-3 expression, with odds ratios (ORs) of 5.437, 10.682, 5.477, 11.788, 0.028, and 1.005, respectively. Nomogram based on LI-RADS features (blood products in mass, nodule-in-nodule architecture and mosaic architecture), quantitative contrast-enhanced MRI parameters (CER and TP-LNR) and clinical indicators (Fer) for predicting GPC-3 expression in HCC was established successfully. The nomogram showed good discrimination (AUC of 0.925 in the training cohort and 0.908 in the validation cohort) and favorable calibration. The diagnostic sensitivity and specificity were 76.9% and 92.3% in the training cohort, 76.8% and 93.8% in the validation cohort respectively., Conclusion: The nomogram constructed from LI-RADS features, quantitative contrast-enhanced MRI parameters and clinical indicators has high application value, can accurately predict GPC-3 expression in HCC and may help noninvasively identify potential patients for GPC-3 immunotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Song, Zhang, Yu, Chen, Wei, Zhang, Hu, Qian, Zhu, Zhang and Shen.)

Background: Bacterial infection is an important cause of cholelithiasis or gallstones and interferes with its treatment. There is no consensus on bile microbial culture profiles in previous studies, and identified microbial spectrum and drug resistance is helpful for targeted preventive and therapeutic drugs in the perioperative period., Aim: To analyze the bile microbial spectrum of patients with cholelithiasis and the drug susceptibility patterns in order to establish an empirical antibiotic treatment for cholelithiasis-associated infection., Methods: A retrospective single-center study was conducted on patients diagnosed with cholelithiasis between May 2013 and December 2018., Results: This study included 185 patients, of whom 163 (88.1%) were diagnosed with gallstones and 22 (11.9%) were diagnosed with gallstones and common bile duct stones (CBDSs). Bile culture in 38 cases (20.5%) was positive. The presence of CBDSs (OR = 5.4, 95%CI: 1.3-21.9, P = 0.03) and longer operation time (> 80 min) (OR = 4.3, 95%CI: 1.4-13.1, P = 0.01) were identified as independent risk factors for positive bile culture. Gram-negative bacteria were detected in 28 positive bile specimens, and Escherichia coli ( E. coli ) (19/28) and Klebsiella pneumoniae (5/28) were the most frequently identified species. Gram-positive bacteria were present in 10 specimens. The resistance rate to cephalosporin in E. coli was above 42% and varied across generations. All the isolated E. coli strains were sensitive to carbapenems, with the exception of one imipenem-resistant strain. K. pneumoniae showed a similar resistance spectrum to E. coli . Enterococcus spp. was largely sensitive to glycopeptides and penicillin, except for a few strains of E. faecium ., Conclusion: The presence of common bile duct stones and longer operation time were identified as independent risk factors for positive bile culture in patients with cholelithiasis. The most commonly detected bacterium was E. coli . The combination of β-lactam antibiotics and β-lactamase inhibitors prescribed perioperatively appears to be effective against bile pathogens and is recommended. Additionally, regular monitoring of emerging resistance patterns is required in the future., Competing Interests: Conflict-of-interest statement: There are no conflicts of interest to report., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Natural plant-derived baicalein which is extracted from Chinese herb Scutellaria baicalensis Georgi belongs to the flavonoid compounds and possesses multiple pharmacological activities. In this study, we designed and synthesized new series of derivatives of baicalein (BE) through catalytic coupling reactions, and screened for their antiviral activity against arboviruses including Chikungunya virus (CHIKV), West Nile virus (WNV) or Zika virus (ZIKV). Our results revealed for the first time that BE and its derivatives had potent anti-CHIKV, anti-WNV and anti-ZIKV effects. And modification of 8 or 4' position could lead to obtain potent antiviral compounds against CHIKV, WNV and ZIKV with lower cytotoxicity. Among the baicalein derivatives, C3 and F3 showed the most potent antiviral activities against CHIKV, WNV and ZIKV, which were 5-10 times more potent than baicalein. Our findings will provide research basis for the development of baicalein derivatives as effective antiviral agents., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: To explore the diagnostic value and model of serum Golgi protein 73 (GP73) in patients with hepatitis C cirrhosis. Methods: 271 cases with chronic hepatitis C virus infection who were treated in the Fifth Medical Center of PLA General Hospital from January 2010 to December 2017 were retrospectively collected as the research objects, including 126 cases with hepatitis and 145 cases with liver cirrhosis. Serum GP73 and liver stiffness measurement (LSM) based on transient elastography test were performed in all patients. Simultaneously, blood routine, liver function, coagulation function and other related indicators were collected. GP73 diagnostic efficiency for liver cirrhosis was evaluated by receiver operating characteristic curve (ROC). GP73 diagnostic value was clarified after comparison with aspartate aminotransferase/platelet ratio index (APRI), FIB-4 index (FIB-4) and LSM. Compensated hepatitis C virus-related cirrhosis diagnostic model based on serological index was established by logistic regression analysis. Results: The area under the receiver operating characteristic curve (AUC) of GP73, LSM, FIB-4 and APRI in the diagnosis of compensated hepatitis C virus-related cirrhosis were 0.923, 0.839, 0.836 and 0.800 respectively, and GP73 had the best diagnostic efficiency (P <0.001). LSM and GP73 combined use had improved the diagnostic sensitivity of cirrhosis to 97.24%. Multivariate logistic regression analysis revealed that GP73, age, and platelets were independent predictors of cirrhosis.Compensated hepatitis C virus-related cirrhosis diagnostic model (GAP) was established based on the result: LogitP=1/[1+exp(6.145+0.013×platelet-0.059×age-0.059×GP73)].AUC model for diagnosing compensated liver cirrhosis was 0.944, and the optimal cut-off value was 0.56, with sensitivity and specificity of 84.03% and 92.06%, respectively, and the diagnostic efficiency of this model was better than that of APRI, FIB-4, LSM and GP73 alone ( P <0.05). Conclusion: GP73 is a reliable serum biomarker for the diagnosis of compensated hepatitis C virus-related cirrhosis. The GAP diagnostic model based on GP73, platelet count, and age can further improve the diagnostic efficiency and help to diagnose patients with compensated hepatitis C virus-related cirrhosis.

Background: Pneumocystis pneumonia (PCP) is a common medical issue in immunosuppressive patients. Increasing evidence supports that B cells may play an essential role in PCP individuals. The present study aims to integrate lncRNA and mRNA expression profiles and further investigate the molecular function of mature B cells in PCP., Methods: The lung tissue of wild-type (WT) mice and B-cell-activating factor receptor-deficient (mature B-cell deficiency, BAFF-R -/- ) mice were harvested at 3 weeks after being infected with pneumocystis. After total RNAs were extracted, transcriptome profiling was performed following the Illumina HiSeq 3000 protocol. lncRNA-targeted miRNA pairs were predicted using the online databases. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment pathways were analyzed to functionally annotate these differentially expressed genes. Additionally, the immune-related lncRNA-miRNA-mRNA-ceRNA network was subsequently performed. The quantitative real-time PCR (RT-PCR) analysis was conducted to evaluate the lncRNA and mRNA expression profiles in WT-PCP mice and BAFF-R -/- PCP mice., Results: Compared with the control group, 166 mRNAs were observed to be aberrantly expressed (fold change value ≥2; P < 0.05) in the BAFF-R -/- PCP group, including 39 upregulated and 127 downregulated genes, while there were 69 lncRNAs differently expressed in the BAFF-R -/- PCP group, including 15 upregulated and 54 downregulated genes. In addition, GO and KEGG pathway analyses showed that BAFF-R deficiency played an important role in the primary and adaptive immune responses in PCP. Furthermore, the lncRNA and mRNA co-expression network was established. We noted that the core network of lncRNA-TF (transcription factor) pairs could be classified into the categories including infection and immunity pathways., Conclusion: In summary, in this study, we further explored the role of mature B cells in the pathogenesis and progression of PCP and the data demonstrated that BAFF-R deficiency could play a significant role in immune regulation in the PCP population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rong, Zhang, Rong, Li, Qian, Wang and Tong.)

Oxypeucedanin, a furanocoumarin extracted from many traditional Chinese herbal medicines, has a variety of pharmacological effects. However, the independent pharmacokinetic characteristics and bioavailability of this compound remains elusive. In this study, a rapid, sensitive, and selective method using ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC/MS/MS) was developed for evaluating the intravenous and oral pharmacokinetics of oxypeucedanin. After intravenous administration of oxypeucedanin (2.5, 5, and 10 mg/kg), and intragastric administration of oxypeucedanin (20 mg/kg), blood samples were collected periodically from the tail vein. The plasma concentration-time curves were plotted, and the pharmacokinetic parameters were calculated using a non-compartmental model analysis. After intravenous administration of oxypeucedanin (single dosing at 2.5, 5, and 10 mg/kg) to rats, the pharmacokinetics fit the linear kinetics characteristics, which showed that some parameters including average elimination half-life (T 1/2Z of 0.61~0.66 h), mean residence time (MRT of 0.62~0.80 h), apparent volume of distribution (V Z of 4.98~7.50 L/kg), and systemic clearance (CL Z of 5.64~8.55 L/kg/h) are dose-independent and the area under concentration-time curve (AUC) increased in a dose-proportional manner. Single oral administration of oxypeucedanin (20 mg/kg) showed poor and slow absorption with the mean time to reach the peak concentration (T max ) of 3.38 h, MRT of 5.86 h, T 1/2Z of 2.94 h, and a mean absolute bioavailability of 10.26% in rats. These results provide critical information for a better understanding of the pharmacological effect of oxypeucedanin, which will facilitate its research and development.

Hepatitis C virus (HCV) infection affects approximately 1% of the world's population and is a major cause of chronic liver diseases. Although antiviral therapy consisting of direct-acting antivirals (DAAs) can cure the majority of HCV patients, it is still limited by viral resistances, drug-drug interactions, and high costs. Moreover, the role of DAAs in the prevention of occurrences of graft reinfection in HCV patients who receive liver transplantations is still under comprehensive clinical investigation, bringing the risk of recipient reinfection. HCV entry is composed of initial non-specific attachment and binding, post-binding interactions with essential host factors, internalization, and virion-cell membrane fusion to release viral RNA to cytosol. Thus, a number of novel and promising targets from either virion or cellular factors of these processes become optimal interfering elements for antiviral therapy, eliminating viral infection at the very beginning. Therefore, entry inhibitors can be supplemented into the future treatment regimens to optimize and widen the prevention and therapeutics of HCV infection. This chapter introduces the basic HCV entry processes and summarizes molecular mechanisms and research status of the current antiviral agents targeting HCV entry in preclinical and clinical study., (© 2022. Springer Nature Singapore Pte Ltd.)

Met tyrosine kinase, a receptor for a hepatocyte growth factor (HGF), plays a critical role in tumor growth, metastasis, and drug resistance. Mitochondria are highly dynamic and undergo fission and fusion to maintain a functional mitochondrial network. Dysregulated mitochondrial dynamics are responsible for the progression and metastasis of many cancers. Here, using structured illumination microscopy (SIM) and high spatial and temporal resolution live cell imaging, we identified mitochondrial trafficking of receptor tyrosine kinase Met. The contacts between activated Met kinase and mitochondria formed dramatically, and an intact HGF/Met axis was necessary for dysregulated mitochondrial fission and cancer cell movements. Mechanically, we found that Met directly phosphorylated outer mitochondrial membrane protein Fis1 at Tyr38 (Fis1 pY38). Fis1 pY38 promoted mitochondrial fission by recruiting the mitochondrial fission GTPase dynamin-related protein-1 (Drp1) to mitochondria. Fragmented mitochondria fueled actin filament remodeling and lamellipodia or invadopodia formation to facilitate cell metastasis in hepatocellular carcinoma (HCC) cells both in vitro and in vivo. These findings reveal a novel and noncanonical pathway of Met receptor tyrosine kinase in the regulation of mitochondrial activities, which may provide a therapeutic target for metastatic HCC., (© 2021. The Author(s).)

Objective: To explored the effect of preoperative antiviral therapy on the prognosis of microvascular tumor thrombi patients, and to established a prognostic prediction model for these patients after radical resection of liver cancer. Methods: The clinicopathological and survival data of hepatocellular carcinoma patients with microvascular tumor thrombus who underwent radical resection in the Third Affiliated Hospital of Sun Yat-sen University from January 1, 2013 to December 31, 2015 were retrospectively collected. Kaplan-Meier method was used to calculate the survival curve, and log-rank test was used to compare the prognosis of patients with and without antiviral treatment before operation. Univariate and multivariate Cox proportional hazard regression model was used to screen predictive factors. R software was used to make predictive nomogram, and discrimination and calibration degree were used to evaluate the prediction model. Results: Among all 153 patients, 22 were female and 131 were male, aged (51.3±11.7) years. The preoperative antiviral therapy significantly improved overall survival and recurrence-free survival (χ 2 =41.423, 54.389; both P <0.001). According to the results of multivariate and regression analysis, preoperative antiviral therapy ( HR =0.301,95% CI :0.171-0.532, P <0.001), alpha fetoprotein ( HR =1.226,95% CI :1.157-1.776, P =0.032) and tumor size ( HR =1.008,95% CI :1.001-1.016, P =0.02) were important prognostic factors for overall survival. The area under curve value of 3-year survival prediction model was 0.749(95% CI : 0.712-0.782), and that of 5-year survival prediction model was 0.755(95% CI : 0.724-0.793), with good calibration. Conclusions: Preoperative anti hepatitis B virus(HBV) therapy can significantly improve the prognosis of patients with hepatocellular carcinoma complicated with microvascular tumor thrombus, we develope the prediction models of 3-year and 5-year survival rate that can improve the reference for clinical work and benefit patients.

Background: Licorice is widely used as a hepatoprotective herb for thousands of years in Traditional Chinese Medicine, and its main chemical constituent glycyrrhizin (GL) is used as a treatment for chronic hepatitis in Japan for over 20 years. 18β-Glycyrrhetinic acid (GA) is the main active metabolite of GL., Objective: Series of GA derivatives were designed and synthesized, and their anti-HCV activities were screened to investigate the structure-activity relationship (SAR). Besides, their in-silico ADMET properties were analyzed to search for a promising lead compound for further identification of anti-HCV terpenoid candidates., Methods: GA derivatives were synthesized via reactions of oxidation, oxime, rearrangement, esterification and acylation. In vitro anti-HCV activity of derivatives was tested on the HCV cell culture (HCVcc) system. In-silico ADMET properties analysis was performed via "pkCSM" and "SwissADME" platforms., Results: Eighteen GA derivatives were synthesized, and their structures were confirmed by MS and NMR spectrums. All compounds exhibited superior HCV inhibitory activity to that of GA. Compound 2 possessed the most potent anti-HCV activity with an IC50 value of 0.79 μM, which is nearly 58 times potent than SA (a previously reported potent anti-HCV terpenoids) and >200 times than GA. SAR revealed that the introduction of 3-oxo, short-chain (C1-C3) aliphatic alcohols or cyclic aliphatic amines is conducive to improving anti-HCV activity. In-silico ADMET prediction demonstrated most of the potent compounds possessed favorable ADMET properties., Conclusion: Structural modification of GA at 3-position and 30-position is an effective approach to searching for potent anti-HCV agents. Compound 2, with the most potent anti-HCV activity and favorable in-silico ADMET properties, is a promising lead compound for further identification of anti-HCV terpenoid candidates., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Schisandronic acid (SA), a triterpenoid from fruits of Schisandra sphenanthera, inhibited pan-genotypic HCV entry into human hepatocytes by interfering with virion-cell membrane fusion. It was a promising lead compound for the development of novel HCV entry inhibition agents., Objective: The aim of the present study is to search for compounds with more potent anti-HCV and antitumor activities and explore SARs. A series of novel derivatives of SA were designed and synthesized and evaluated for in vitro, their anti-HCV and antitumor activities., Methods: SA derivatives were synthesized by reduction, condensation, esterification or amidation. The anti-HCV activity of title compounds was tested by inhibition on HCVcc infection of Huh7 cells, and a preliminary MOA study was conducted by determining inhibition on HCVpp entry into Huh7 cells. The antitumor activity in vitro was determined by MTT methods., Results: In total, 24 novel derivatives were synthesized. Most of the compounds inhibited HCVcc infection. Compounds 5h and 6 showed the most potent anti-HCVcc activities and inhibition of HCVpp entry into Huh7 cells without obvious cytotoxicity. Most of the title compounds showed potent in vitro antitumor activities against Bel7404 and SMMC7721 tumor cell lines. Compounds 5j and 6 exhibited more potent antitumor activity than positive control SA and DOX., Conclusion: Structural modification of SA could lead to the discovery of potent anti-HCV or antitumor agents. Compounds 5h, 5j and 6 were promising lead compounds for development of novel HCV entry inhibition or antitumor agents., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: To evaluate the efficacy and safety of local application of tranexamic acid (TXA) in reducing perioperative blood loss in total hip arthroplasty via direct anterior approach (DAA)., Methods: From July 2013 to September 2018, 46 patients with avascular necrosis of the femoral head were divided into tranexamic acid group ( n =23) and saline group ( n =23). In the tranexamic acid group, there were 14 males and 9 females, aged 52 to 72(63.70±5.34) years old. They were diluted with 3 g tranexamic acid in 50 ml normal saline and immersed in the joint cavity for 3 min after prosthesis replacement;in the normal saline group, there were 13 males and 10 females, aged 55 to 73 (61.26±5.78) years, who were treated with the sameamount of normal saline. The blood loss, hemoglobin value, number of blood transfusion cases, the time of first landing after operation, the incidence of thrombosis and incision adverse events were compared between the two groups. Harris score was used to evaluate hip joint function at 1 and 3 months after operation., Results: The incision healed well and no obvious complications occurred in the two groups. All patients were followed up for 12 to 59 months(averaged 31.11 months). No hip pain was found in the follow-up patients. Hip joint function was improved effectively and no prosthesis loosening occurred. The total perioperative blood loss in tranexamic acid group and normal saline group was(740.09±77.14) ml and (1 069.07±113.53) ml respectively, 24 hours after operation, the drainage volume was (87.61±9.28) ml, (233.83±25.62) ml, the hidden blood loss was (409.65±38.01) ml and (588.33±57.16) ml. the difference of hemoglobin before and after operation was (24.78±2.19) g / L and (33.57±2.95) g / L, the difference was statistically significant ( P <0.05). There was no significant difference in blood loss, incidence of deep vein thrombosis and pulmonary embolism, and Harris score of hip joint between the two groups ( P >0.05)., Conclusion: local application of tranexamic acid in total hip arthroplasty through direct anterior approach can safely and effectively reduce perioperative blood loss, and does not increase the risk of thrombosis, and does not affect the normal recovery of joint function.

Objective: To analyze the level and trend of respiratory disease mortality in China from 2002 to 2016. Methods: The standardized mortality rates were calculated based on the China health statistics yearbook (2003-2012) and China statistical yearbook of health and family planning (2013-2017) data released by the statistical information center of National health Commission of the People's Republic of China. Joinpoint model was used to calculate the standardized mortality rates (SMR), Annual percentage change (APC) and the average annual percentage change (AAPC) for standardized mortality rates. Results: The SMR of respiratory diseases and chronic lower respiratory diseases were decreased significantly in 2002 to 2016 (AAPC=-3.6%, AAPC=-6.4%, P< 0.001, respectively). The SMR of lung cancer showed a significant increase trend (AAPC=1.6%, P= 0.001). There were no significant differences in the SMR of pneumonia and pneumonoconiosis (APCC=1.0%, P= 0.242; APCC=-0.2%, P= 0.905). Both urban and rural SMR of respiratory diseases were declining significantly (AAPC=-2.9%, P= 0.001; AAPC=-4.2%, P< 0.001). Both urban and rural SMR of lung cancer showed an increasing trend (AAPC=0.6%, P= 0.022; AAPC=2.1%, P= 0.003, respectively). The SMR of pneumonia in urban areas showed an upward trend (AAPC=2.7%, P= 0.017). The SMR of respiratory disease of all age groups (<35 years old, 35-65 years old and ≥65 years old) showed a downward trend (AAPC=-3.8%, P= 0.001; AAPC=-2.6%, P< 0.001; AAPC=-3.9%, P< 0.001). The SMR of pneumonia between 35 and 65 years old and SMR of lung cancer over 65 years old showed an increasing trend (AAPC=2.8%, P= 0.001; AAPC=2.4%, P< 0.001). The SMR of respiratory diseases among males and females showed a downtrend (AAPC=-3.1%, P< 0.001; AAPC=-4.3%, P< 0.001). However, the SMR of lung cancer in males and females increased significantly (AAPC=1.2%, P< 0.001; AAPC=2.5%, P< 0.001, respectively). There were no significant trends in the SMR of pneumonia and pneumoconiosis in males (AAPC=1.5%, P= 0.096; AAPC=-1.6%, P= 0.218). There was no obvious trend in the SMR of pneumonia in females (AAPC=-0.1%, P= 0.872). Conclusions: The SMR of respiratory diseases in China generally shows a downward trend. The overall SMR and SMR of major respiratory diseases varies among different regions, genders and age groups.

Objectives: There is currently no effective salvage therapeutic modality that improves the survival outcomes of patients with recurrent or metastatic nasopharyngeal carcinoma. However, the programmed cell death protein 1 (PD-1) and its ligand (PD-L1) inhibitors may provide clinical benefit for these advanced patients., Materials and Methods: The databases, including PubMed, Web of Science, EMBASE and Cochrane Library, were systematically searched up to Nov 5, 2019. Data of objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) rate, overall survival (OS) rate, and drug-related adverse events were extracted and pooled meta-analyzed., Results: From 71 search records, eight studies were included in the systematic review, of which three were eligible for final meta-analysis. In recurrent or metastatic nasopharyngeal carcinoma patients treated with anti-PD-1 therapy, the pooled ORR was 27% (95% confidence interval [CI] 19-36%), DCR was 63% (95% CI 50-75%), 6 months PFS rate was 49% (95% CI 40-58%), 1-year PFS rate was 25% (95% CI 19-32%), 1-year OS rate was 61% (95% CI 49-72%). The pooled incidences of any grade and grade ≥ 3 drug-related adverse events were 94% and 20% respectively., Conclusion: We present the aggregate response rates, survival rates and incidences of drug-related adverse events for recurrent or metastatic nasopharyngeal carcinoma patients receiving PD-1/PD-L1 blockage treatment, which could provide useful information for future design of clinical studies. There is a need for more randomized controlled studies with head-to-head comparison of PD-1/PD-L1 inhibitors and traditional chemotherapeutic strategies to enable better recommendations for optimal advanced nasopharyngeal carcinoma treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Mucins are major macromolecular components of lung mucus that are mainly responsible for the viscoelastic property of mucus. MUC5AC is a major mucin glycoprotein that is hypersecreted in asthmatic individuals. Vascular endothelial growth factor (VEGF) has been implicated in inflammatory and airway blood vessel remodeling in asthmatics. Our previous studies indicate that VEGF upregulates MUC5AC expression by interacting with VEGF receptor 2 (VEGFR2). It has been shown that dexamethasone (Dex) downregulates MUC5AC expression; however, the underlying mechanisms have not been completely elucidated. Therefore, we sought to investigate the effect of Dex on MUC5AC expression induced by VEGF and study the underlying mechanisms. We tested the effects of Dex on VEGFR2 and RhoA activation, caveolin-1 expression, and the association of caveolin-1 and VEGFR2 in primary bronchial epithelial cells. Dex downregulated MUC5AC mRNA and protein levels in a dose- and time-dependent manner, and suppressed the activation of VEGFR2 and RhoA induced by VEGF. Additionally, Dex upregulated caveolin-1 protein levels in a dose- and time-dependent manner. Furthermore, phospho-VEGFR2 expression was decreased through overexpression of caveolin-1 and increased after caveolin-1 knockdown. Dex treatment attenuated the VEGF-decreased association of caveolin-1 and VEGFR2. Collectively, our findings suggest that Dex downregulates VEGF-induced MUC5AC expression by inactivating VEGFR2 and RhoA. Furthermore, decreased MUC5AC expression by Dex was related to the increased association of caveolin-1 with VEGFR2. Further studies characterizing these mechanisms are required to facilitate the development of improved treatment strategies for asthma., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To establish and evaluate diagnostic efficacy and applicability of serum Golgi protein (GP) 73 based non-invasive diagnostic model with other conventional serological indicators for compensated stage hepatitis B cirrhosis. Methods: 666 cases with chronic hepatitis B (CHB) who had visited to the Fifth Medical Center of People's Liberation Army General Hospital from January 2010 to December 2017 were selected as the study subjects, and were classified according to compensated stage cirrhosis into clinical and pathological diagnosis group based on whether or not the liver histological examination was performed. A diagnostic model of compensated stage hepatitis B cirrhosis in the clinical diagnosis group was established. The current clinically used diagnostic model of liver cirrhosis, aspartate aminotransferase/platelet ratio index (APRI), fibrosis index (FIB)-4 and liver stiffness measurement (LSM) were compared. Eventually, the diagnostic model was verified step by step by pathological diagnosis group. Results: The area under the receiver operating characteristic curve (AUC) of GP73 and APRI, FIB-4, and LSM for cirrhosis patients in the clinical diagnosis group were 0.842, 0.857, 0.864, and 0.832, respectively. The diagnostic efficiency of the four indicators were of similar ( P value > 0.05). A diagnostic model of compensated stage hepatitis B cirrhosis (GAPA) using logistic regression analysis was established: LogitP = 1/ [1 + exp (1.614-0.054 × GP73-0.045 × Age + 0.030 × PLT-0.015 × ALP)]. The AUC of the model was as high as 0.940 and the optimal cut-off value were 0.41. The corresponding diagnostic sensitivity and specificity were 0.92 and 0.82, respectively. The diagnostic efficiency was better than that of APRI, FIB-4, LSM and GP73 alone ( P < 0.05). The AUC of GAPA was 0.877 in the pathological diagnosis group, which was similar to the diagnostic efficacy of LSM (0.891) and FIB-4 (0.847) ( P > 0.1), but still superior to that of APRI (0.811) and GP73 alone (0.780) ( P < 0.001). Conclusion: GAPA, a diagnostic model for compensated stage hepatitis B cirrhosis established in this study, has a good diagnostic efficacy in both the clinical and pathological diagnosis group, and has certain auxiliary diagnostic value in the areas where resources are relatively scarce or where LSM has not been developed.

Background: Airway mucus hypersecretion is an important pathophysiological feature in asthma. Mucins are glycoproteins that are mainly responsible for the viscoelastic property of mucus, and MUC5AC is a major mucin glycoprotein that is overproduced in asthma. Vascular endothelial growth factor (VEGF) has been implicated in inflammatory and airway blood vessel remodeling in asthmatics. Therefore, we sought to investigate the effect of VEGF on MUC5AC expression and study the underlying mechanisms., Methods: In order to elucidate the precise mechanism underlying the effect of VEGF on MUC5AC expression, we tested the effects of VEGF on RhoA activation and the association of caveolin-1 and VEGFR2 in Primary Bronchial Epithelial Cells., Results: VEGF up-regulated MUC5AC mRNA and protein levels in a dose- and time-dependent manner, and activated RhoA. Additionally, VEGF-induced MUC5AC expression and RhoA activation were enhanced by disrupting caveolae with cholesterol depletion and reversed by cholesterol repletion, and inhibited by a selective VEGF receptor 2 (VEGFR2) inhibitor SU1498. Furthermore, phospho-VEGFR2 expression was decreased via overexpression of caveolin-1. VEGF treatment reduced the association of caveolin-1 and VEGFR2., Conclusion: Collectively, our findings suggest that VEGF up-regulates MUC5AC expression and RhoA activation by interaction with VEGFR2, and this phenomenon was related with the association of caveolin-1 and VEGFR2. Further studies on these mechanisms are needed to facilitate the development of treatments for asthma.

Background: Pneumocystis pneumonia (PCP) remains a common opportunistic infection in immunosuppressed individuals. Current studies showed that multiple immune cells and cytokines took part in the host defense against Pneumocystis (PC). However, the roles of IL-17 and IL-10 in the development of PCP have not been elucidated., Methods: IL-10 and IL-17 levels in serum from PCP mice were detected via ELISA. The percentages of B10 cells, IL-10 + macrophages, and IL-10 + T cells in the lung from IL-17 -/- PCP mice and Th17 cells and IL-17 + γδ T cells in IL-10 -/- PCP mice were examined via flow cytometry. Also, antibody neutralization examination was also performed to elucidate the relationship of IL-17 and IL-10 in the PCP model., Results: We noted the increase of IL-17 and IL-10 levels in serum from mice infected with Pneumocystis . Furthermore, deficiency of IL-17 or IL-10 could lead to the delayed clearance of Pneumocystis and more severed lung damage. Our data also demonstrated that IL-17 deficiency enhanced the serum IL-10 level and the percentages of B10 cells, IL-10 + macrophages, and IL-10 + T cells in the lung from PCP mice. Interestingly, we also noted an increase of the IL-17 level in serum and Th17 cell and IL-17 + γδ T cell percentages in the lung from IL-10 -/- PCP mice. Using antibody neutralization experiments, we found that the STAT3 gene might play a critical role in the interplay of IL-17 and IL-10 in PCP., Conclusion: Taken together, our results demonstrated that IL-17 and IL-10 could play the protective roles in the progression of PCP and the inverse correlation of them might be mediated by STAT3., Competing Interests: The authors have declared no conflict of interest., (Copyright © 2019 Heng-Mo Rong et al.)

Objective: The aim of this study was to observe the influence of micro ribonucleic acid (miR)-124 on neuronal apoptosis in rats with cerebral infarction (CI), and to further investigate the underlying mechanism of miR-124 in CI occurrence and development., Materials and Methods: A total of 60 adult male Wistar rats were randomly divided into the Sham group, the CI group and the CI + miR-124 mimics group using a random number table. The focal CI model was established using the suture-occluded method. After successful modeling, miR-124 mimics were stereotactically injected into the lateral ventricle of rats. 24 h after operation, the neurological function of rats in each group was scored using modified neurological severity score (mNSS). Meanwhile, the infarction area of brain tissues was evaluated by the triphenyl tetrazolium chloride (TTC) method. The protein expression levels of apoptosis-related genes, including B-cell lymphoma-2 (Bcl-2), Bcl-2 associated X protein (Bax), C-Caspase and T-Caspase, were detected via Western blotting. The expression and location of caspase-3 in brain tissues were detected via immunofluorescence staining. Moreover, the level of apoptosis in each group was detected via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. In addition, the expression levels of the Wnt/β-catenin signaling pathway-related proteins were detected via Western blotting., Results: Polymerase Chain Reaction (PCR) results revealed that the expression level of miR-124 in the CI group was significantly decreased when compared with that of the Sham group (p<0.05). The mNSS and TTC staining results manifested that injection of miR-124 mimics could significantly reduce the CI-induced neurological deficits and CI area (p<0.05). At the same time, the levels of Bax and C-caspase/T-Caspase were significantly decreased, whereas the expression of Bcl-2 was remarkably increased after the injection of miR-124 mimics (p<0.05). Besides, the number of apoptotic cells in the CI + miR-124 mimic group was remarkably decreased (p<0.05). In addition, miR-124 mimics significantly activated the expression levels of Wnt and β-catenin (p<0.05)., Conclusions: The inhibitory effect of miR-124 on neuronal apoptosis in CI rats is probably related to the activation of the Wnt/β-catenin signaling pathway. Furthermore, miR-124 is expected to be a target drug for the clinical treatment of CI.

Gastric cancer (GC) is a common gastrointestinal tumor with poor prognosis. However, conventional prognostic factors cannot accurately predict the outcomes of GC patients. Therefore, there remains a need to identify novel predictive markers to improve prognosis. In this study, we obtained microRNA expression profiles of 385 GC patients from The Cancer Genome Atlas. We performed Cox regression analysis to identify overall survival-related microRNA and then constructed a microRNA signature-based prognostic model. The accuracy of the model was evaluated and validated through Kaplan-Meier survival analysis and time-dependent receiver operating characteristic (ROC) curve analysis. The independent prognostic value of the model was assessed by multivariate Cox regression analysis. Enrichment analysis was performed to explore potential functions of the prognostic microRNA. Finally, a prognostic model based on a six-microRNA (miRNA-100, miRNA-374a, miRNA-509-3, miRNA-668, miRNA-549, and miRNA-653) signature was developed. Further analysis in the training, test, and complete The Cancer Genome Atlas set showed the model can distinguish between high-risk and low-risk patients and predict 3-year and 5-year survival. The six-microRNA signature was also an independent prognostic marker, and enrichment analysis suggested that the microRNA may be involved in cell cycle and mitosis. These results demonstrated that the model based on the six-microRNA signature can be used to accurately predict the prognosis of GC patients., Competing Interests: The authors declare no conflict of interest.

Objective: To investigate the prognostic value of albumin/globulin ratio on postoperative survival outcomes in patients with hepatocellular carcinoma. Methods: Data of 630 patients with HCC, who underwent surgical resection from February 2009 to July 2013, were retrospectively analyzed. Patients were divided into low-value group (A/G < 1.5, defined as L group) and high-value group (A/G≥1.5, defined as H group), and their distribution characteristics were observed with the normal A/G threshold value. Independent risk factors' affecting survival and prognosis was analyzed with univariate and multivariate Cox's regression model. Survival trend of all patients with low-value and high-value groups in A, B and C of Barcelona stage (BCLC stage) were analyzed using the Kaplan-Meier method. Results: Multivariate analysis showed that preoperative A/G ratio ( P = 0.007), alpha-fetoprotein ( P < 0.001), gamma-glutamyltransferase ( P = 0.006), RBC ( P = 0.014), international normalized ratio ( P = 0.009), preoperative BCLC staging ( P < 0.001) and number of tumors ( P = 0.003), and intraoperative blood transfusion ( P < 0.001) were independent prognostic factors affecting long-term survival in HCC patients. The median overall survival time in-group L was 15 months, significantly lower than that in group H of 42 months ( P < 0.001). Stratified analysis showed that the short-term survival advantage of patients with high A / G value was limited to those with Barcelona stage A ( P < 0.001), and disappeared in patients with Barcelona stage B and C ( P > 0.05). The long-term survival advantage existed in patients with Barcelona stage A ( P < 0.001), B ( P < 0.05), and disappeared in C ( P > 0.05). Conclusion: Preoperative albumin/globulin ratio can predict postoperative prognosis and survival, and direct towards the treatment for early stage of HCC and thus representing as an indicator of high clinical value.

Brassinosteroids (BRs) regulate plant development and stress response. Although much has been learned about their roles in plant development, the mechanisms by which BRs regulate plant stress tolerance remain unclear. Chilling is a major stress that adversely affects plant growth. Here, we report that BR positively regulates chilling tolerance in tomato. BR partial deficiency aggravated chilling-induced oxidized protein accumulation, membrane lipid peroxidation, and decrease of maximum quantum efficiency of photosystem II (Fv/Fm). By contrast, overexpression of BR biosynthetic gene Dwarf or treatment with 24-epibrassinolide (EBR) attenuated chilling-induced oxidative damages and resulted in an increase of Fv/Fm. BR increased transcripts of RESPIRATORY BURST OXIDASE HOMOLOG1 (RBOH1) and GLUTAREDOXIN (GRX) genes, and BR-induced chilling tolerance was associated with an increase in the ratio of reduced/oxidized 2-cysteine peroxiredoxin (2-Cys Prx) and activation of antioxidant enzymes. However, RBOH1-RNAi plants failed to respond to EBR as regards to the induction of GRX genes, activation of antioxidant capacity, and attenuation of chilling-induced oxidative damages. Furthermore, silencing of GRXS12 and S14 compromised EBR-induced increases in the ratio of reduced/oxidized 2-Cys Prx and activities of antioxidant enzymes. Our study suggests that BR enhances chilling tolerance through a signalling cascade involving RBOH1, GRXs, and 2-Cys Prx in tomato., (© 2017 John Wiley & Sons Ltd.)

Environmental pollution by organic pollutants (OPs) has become a global concern due to its detrimental effects on the environment and human health. As plants are used to remediate contaminated sites, understanding the responses of plants to various OPs and fortification of plant tolerance are of great significance. In this work, we studied the biochemical and molecular responses of cucumber plants to three well-known OPs, 2,4,6-trichlorophenol, chlorpyrifos and oxytetracycline in the absence or presence of 24-epibrassinolide (EBR), a potent regulator of plant growth and stress tolerance. The results showed that the selected three OPs retarded root elongation; however, the phytotoxic effects of OPs were attenuated by exogenous EBR. OPs induced accumulations of both hydrogen peroxide (H 2 O 2 ) and nitric oxide (NO) in root tips and resulted in an increased malondialdehyde (MDA) content, an indicator of membrane lipid peroxidation. Exogenous EBR reduced accumulations of H 2 O 2 , NO and MDA in the roots by increasing the expression of antioxidant and detoxification genes and the activities of the corresponding enzymes. Intriguingly, EBR not only promoted the activities of glutathione S-transferase and glutathione reductase, but also increased the content of reduced glutathione without altering the content of oxidized glutathione, which resulted in a reduced redox state under OPs stress. Furthermore, EBR increased the free radical scavenging capacity, flavonoid content and the activity and transcription of secondary metabolism related enzymes. Our results suggest that EBR treatment may fortify secondary metabolism to enhance antioxidant capacity in response to OPs treatment, which might have potential implication in phytoremediation of OPs., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Wee1 kinase is a crucial negative regulator of Cdk1/cyclin B1 activity and is required for normal entry into and exit from mitosis. Wee1 activity can be chemically inhibited by the small molecule MK-1775, which is currently being tested in phase I/II clinical trials in combination with other anti-cancer drugs. MK-1775 promotes cancer cells to bypass the cell-cycle checkpoints and prematurely enter mitosis. In our study, we show premature mitotic cells that arise from MK-1775 treatment exhibited centromere fragmentation, a morphological feature of mitotic catastrophe that is characterized by centromeres and kinetochore proteins that co-cluster away from the condensed chromosomes. In addition to stimulating early mitotic entry, MK-1775 treatment also delayed mitotic exit. Specifically, cells treated with MK-1775 following release from G1/S or prometaphase arrested in mitosis. MK-1775 induced arrest occurred at metaphase and thus, cells required 12 times longer to transition into anaphase compared to controls. Consistent with an arrest in mitosis, MK-1775 treated prometaphase cells maintained high cyclin B1 and low phospho-tyrosine 15 Cdk1. Importantly, MK-1775 induced mitotic arrest resulted in cell death regardless the of cell-cycle phase prior to treatment suggesting that Wee1 inhibitors are also anti-mitotic agents. We found that paclitaxel enhances MK-1775 mediated cell killing. HeLa and different breast cancer cell lines (T-47D, MCF7, MDA-MB-468 and MDA-MB-231) treated with different concentrations of MK-1775 and low dose paclitaxel exhibited reduced cell survival compared to mono-treatments. Our data highlight a new potential strategy for enhancing MK-1775 mediated cell killing in breast cancer cells., Competing Interests: CONFLICTS OF INTEREST None.

Objective: To explore the effect of carbon monoxide (CO) and ozone (O(3)) in the air on the myocardial infarction mortality in Ningbo, Zhejiang province, from 2011 to 2015. Methods: The data of daily air quality surveillance and the causes of deaths in Ningbo from January 1, 2011 to December 31, 2015 were collected and the time series study using a generalized additive model was conducted to evaluate the relationship between the mortality of myocardial infarction and the air pollutants after adjustment for the long-term trend of death, weather conditions," days of the week" and other confounding factors. Results: The daily average concentrations of CO and O(3) in Ningbo during 2011-2015 were 0.90 (0.02-3.31) mg/m(3) and 82.78 (4-236) μg/m(3), respectively. A total of 5 388 myocardial infarction deaths occurred, with a daily average of 3 deaths. In single-pollutant model, an increase of 0.1 mg/m(3) in average concentration of CO could increase the risk of myocardial infarction mortality by 1.06% (95 % CI : 0.29%-1.93%) in general population, and by 1.26% (95 % CI :0.28%-2.24%) in aged people aged ≥65 years in lagged 6 days, but the influence was not significant in people aged <65 years. The influence had no significant difference in males, but it increased the risk of myocardial infarction mortality by 1.77% in females (95 % CI : 0.44%-3.13%). In multi-pollutant model, CO did remain robust after adjusting for other co-pollutants. Whereas the effect of O(3) had no significant influence. Conclusion: These findings suggested that the increased risk of daily myocardial infarction mortality was associated with the increase of CO concentration, but no such association was found for O(3) in Ningbo.

Asthma is a chronic respiratory disease characterized by reversible airway obstruction with persistent airway inflammation and airway remodeling, which is associated with increased airway smooth muscle (ASM) mass. Licochalcone A is the predominant characteristic chalcone in licorice root. We found that licochalcone A inhibited vascular endothelial growth factor (VEGF)-induced ASM cell proliferation and induced cell cycle arrest. Additionally, VEGF-induced ASM cell proliferation was suppressed via inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) activity, but not that of Akt. Furthermore, licochalcone A treatment inhibited VEGF-induced activation of VEGF receptor 2 (VEGFR2) and ERK and blocked the downregulation of caveolin-1 in a concentration-dependent manner. Collectively, our findings suggested that licochalcone A inhibited VEGF-induced ASM cell proliferation by suppressing VEGFR2 and ERK1/2 activation and downregulating caveolin-1. Further studies of these mechanisms are needed to facilitate the development of treatments for smooth muscle hyperplasia-associated diseases of the airway, such as asthma.

Background: Asthma is a chronic respiratory disease characterized by reversible airway obstruction with persistent airway inflammation and airway remodeling, which is associated with increased airway smooth muscle (ASM) mass. Vascular endothelial growth factor (VEGF) has been implicated in inflammatory and airway blood vessel remodeling in asthma. Recent evidence indicates that a deficiency of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) may influence asthma pathogenesis. A disintegrin and metalloproteinase (ADAM)33 has been identified as playing a role in the pathophysiology of asthma. ADAM33, which is expressed in ASM cells, is suggested to play a role in the function of these cells. Recent studies show that 1,25-(OH)2D3 exerts direct inhibitory effects on passively sensitized human ASM cells in vitro, including inhibition of ADAM33 expression and cell proliferation; however, the mechanism has not been fully understood., Methods: In order to elucidate the precise mechanism underlying the effect of 1,25(OH)2D3 on VEGF-induced ADAM33 expression and ASM cell proliferation, we tested the effects of 1,25(OH)2D3 on cell cycle progression and evaluated the levels of phospho-VEGF receptor 2 (VEGFR2), phospho-extracellular signal-regulated kinase 1/2 (ERK1/2), and phospho-Akt in VEGF-stimulated ASM cells., Results: We found that 1,25(OH)2D3 inhibited VEGF-induced ADAM33 expression and ASM cell proliferation, as well as cell cycle arrest. Additionally, VEGF-induced ADAM33 expression and ASM cell proliferation was suppressed via inhibition of ERK1/2 activity, but not that of Akt. Furthermore, 1,25(OH)2D3 treatment inhibited VEGF-induced activation of VEGFR2 as well as that of ERK and Akt in a concentration-dependent manner. 1,25(OH)2D3 also inhibited transforming growth factor (TGF)-β-induced VEGF secretion by ASM cells., Conclusions: Collectively, our findings suggest that 1,25(OH)2D3 inhibits VEGF-induced ASM cell proliferation by suppressing VEGFR2 and ERK1/2 activation and downregulating ADAM33. Further studies of these mechanisms are needed to facilitate the development of treatments for smooth muscle hyperplasia-associated diseases of the airway such as asthma.

Asthma is a chronic respiratory disease characterized by reversible airway obstruction with persistent airway inflammation and airway remodeling. Features of airway remodeling include increased airway smooth muscle (ASM) mass. A disintegrin and metalloproteinase (ADAM)-33 has been identified as playing a role in the pathophysiology of asthma. ADAM-33 is expressed in ASM cells and is suggested to play a role in the function of these cells. However, the regulation of ADAM-33 is not fully understood. Vascular endothelial growth factor (VEGF) has been implicated in inflammatory and airway blood vessel remodeling in asthmatics. Although VEGF was initially thought of as an endothelial-specific growth factor, recent reports have found that VEGF can promote proliferation of other cell types, including ASM cells. To investigate the precise mechanism of VEGF's effect on ASM cell proliferation, we tested the expression of ADAM-33, phospho-extracellularsignal-regulated kinase 1/2 (ERK1/2), and phospho-Akt in VEGF-stimulated ASM cells. We found that VEGF up-regulates ADAM-33 mRNA and protein levels in a dose- and time-dependent manner as well as phosphorylation of ERK1/2 and Akt. We also found that VEGF-induced ASM cell proliferation is inhibited by both ADAM-33 knockdown and a selective VEGF receptor 2 (VEGFR2) inhibitor (SU1498). Furthermore, VEGF-induced ADAM-33 expression and ASM cell proliferation were suppressed by inhibiting ERK1/2 activity, but not by inhibiting Akt activity. Collectively, our findings suggest that VEGF enhances ADAM-33 expression and ASM cell proliferation by activating the VEGFR2/ERK1/2 signaling pathway, which might be involved in the pathogenesis of airway remodeling. Further elucidation of the mechanisms underlying these observations might help develop therapeutic strategies for airway diseases associated with smooth muscle hyperplasia such as asthma.

Asthma is a chronic respiratory disease characterized by reversible airway obstruction with persistent airway inflammation and airway remodelling, which is associated with increased airway smooth muscle (ASM) mass. Roxithromycin (RXM) has been widely used in asthma treatment; however, its mechanism of action is poorly understood. Vascular endothelial growth factor (VEGF) has been implicated in inflammatory and airway blood vessel remodelling in patients with asthma, and shown to promote ASM cell proliferation. Here, we investigated the effect of RXM on VEGF-induced ASM cell proliferation and attempted to elucidate the underlying mechanisms of action. We tested the effect of RXM on proliferation and cell cycle progression, as well as on the expression of phospho-VEGF receptor 2 (VEGFR2), phospho-extracellular signal-regulated kinase 1/2 (ERK1/2), phospho-Akt, and caveolin-1 in VEGF-stimulated ASM cells. RXM inhibited VEGF-induced ASM cell proliferation and induced cell cycle arrest. Additionally, VEGF-induced ASM cell proliferation was suppressed by inhibiting the activity of ERK1/2, but not that of Akt. Furthermore, RXM treatment inhibits VEGF-induced activation of VEGFR2 and ERK and downregulation of caveolin-1 in a dose-dependent manner. RXM also inhibited TGF-β-induced VEGF secretion by ASM cells and BEAS-2B cells. Collectively, our findings suggest that RXM inhibits VEGF-induced ASM cell proliferation by suppression of VEGFR2 and ERK1/2 activation and caveolin-1 down-regulation, which may be involved in airway remodelling. Further elucidation of the mechanisms underlying these observations should enable the development of treatments for smooth muscle hyperplasia-associated diseases of the airway such as asthma., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Despite recent progress in the development of hepatitis C virus (HCV) inhibitors, cost-effective antiviral drugs, especially among the patients receiving liver transplantations, are still awaited. Schisandra is a traditional medicinal herb used to treat a range of liver disorders including hepatitis for thousands of years in China. To isolate the bioactive compounds of schisandra for the treatment of HCV infection, we screened a schisandra-extracts library and identified a tetracyclic triterpenoid, schizandronic acid (SZA), as a novel HCV entry inhibitor. Our findings suggested that SZA potently inhibited pan-HCV genotype entry into hepatoma cells and primary human hepatocytes without interfering virus binding on cell surface or internalization. However, virion-cell fusion process was impaired in the presence of SZA, along with the increased host membrane fluidity. We also found that SZA inhibited the spread of HCV to the neighboring cells, and combinations of SZA with interferon or telaprevir resulted in additive synergistic effect against HCV. Additionally, SZA diminished the establishment of HCV infection in vivo. The SZA target is different from conventional direct-acting antiviral agents, therefore, SZA is a potential therapeutic compound for the development of effective HCV entry inhibitors, especially for patients who need to prevent HCV reinfection during the course of liver transplantations.

Objective: To explore the short-term effect of particulate matters with an aerodynamic diameter of less than or equal to 10 μg (PM10) and aerodynamic diameter of less than or equal to 2.5 μg (PM2.5) on cardio-cerebrovascular mortality in Ningbo city., Methods: Daily cardio-cerebrovascular mortality data from 2011 to 2014 in Ningbo city were collected and the time series study using a semi-parametric generalized additive model were used to evaluate the relationship between the mortality of cardio-cerebrovascular disease and particulate matters after adjustment for the long-term trend of death,weather conditions, "days of the week" and other confounding factors., Results: In single-pollutant model, the short-term effects of particulate matter on cardio-cerebrovascular mortality was strongest in lagged 2 days in Ningbo city, and an increase of 10 μg/m(3) in moving average concentrations (lagged 2-3 days and lagged 2-4 days) of PM2.5 and PM10 could increase the cardio-cerebrovascular mortality by 0.55% (0.23%-0.87%) and 0.53% (0.28%-0.78%), respectively. In multi-pollutant models, PM10 did remain robust after being adjusted for PM2.5 with 0.58% (0.09%-1.07%) increase in cardio-cerebrovascular mortality. The effect of PM2.5 had no statistical significantce after being adjusted for other co-pollutants., Conclusion: These findings suggested that the concentrations of ambient particulate matters were associated with an increased risk of daily cardio-cerebrovascular mortality in Ningbo city.

Objective: To investigate the serum levels of Interleukin (IL)-17 and eotaxin levels and the relationship between serum IL-17, eotaxin and pulmonary function in asthmatic patients with allergic rhinitis., Methods: Serum IL-17 and eotaxin levels in asthmatic patients with allergic rhinitis during attacking and remission and in healthy control subjects were measured using enzyme-linked immunosorbent assay (ELISA) kits. Then we studied the correlation between the serum IL-17, eotaxin levels and pulmonary function in patients., Results: Serum IL-17 and eotaxin levels were significantly elevated in patients during asthma attack and remission compared with healthy control subjects. These levels in patients during asthma attack were much higher than those during remission. Furthermore, serum IL-17 and eotaxin levels were negatively correlated with pulmonary function in asthmatic patients with allergic rhinitis, respectively., Conclusion: Our findings suggest that IL-17 and eotaxin are important factors in asthma with allergic rhinitis, and the correlation between serum IL-17, eotaxin and lung function possibly lead to improvements in the diagnosis and treatment of asthma with allergic rhinitis and related diseases.

Although much progress has been made in antiviral agents against hepatitis C virus (HCV) in recent years, novel HCV inhibitors with improved efficacy, optimized treatment duration and more affordable prices are still urgently needed. Here, we report the identification of a natural plant-derived lignan, trachelogenin (TGN), as a potent entry inhibitor of HCV without genotype specificity, and with low cytotoxicity. TGN was extracted and purified from Caulis trachelospermi, a traditional Chinese herb with anti-inflammatory and analgesic effects. A crucial function of TGN was the inhibition of HCV entry during a post-binding step without affecting virus replication, translation, assembly and release. TGN blocked virus infection by interfering with the normal interactions between HCV glycoprotein E2 and the host entry factor CD81, which are key processes for valid virus entry. In addition, TGN diminished HCV cell-to-cell spread and exhibited additional synergistic effects when combined with IFN or telaprevir. In conclusion, this study highlights the effect of a novel HCV entry inhibitor, TGN, which has a target that differs from those of the current antiviral agents. Therefore, TGN is a potential candidate for future cocktail therapies to treat HCV-infected patients.

Hepatitis C virus (HCV) infection affects approximately 3% of the world's population and causes chronic liver diseases, including liver fibrosis, cirrhosis, and hepatocellular carcinoma. Although current antiviral therapy comprising direct-acting antivirals (DAAs) can achieve a quite satisfying sustained virological response (SVR) rate, it is still limited by viral resistance, long treatment duration, combined adverse reactions, and high costs. Moreover, the currently marketed antivirals fail to prevent graft reinfections in HCV patients who receive liver transplantations, probably due to the cell-to-cell transmission of the virus, which is also one of the main reasons behind treatment failure. HCV entry is a highly orchestrated process involving initial attachment and binding, post-binding interactions with host cell factors, internalization, and fusion between the virion and the host cell membrane. Together, these processes provide multiple novel and promising targets for antiviral therapy. Most entry inhibitors target host cell components with high genetic barriers and eliminate viral infection from the very beginning of the viral life cycle. In future, the addition of entry inhibitors to a combination of treatment regimens might optimize and widen the prevention and treatment of HCV infection. This review summarizes the molecular mechanisms and prospects of the current preclinical and clinical development of antiviral agents targeting HCV entry.

The combination of time and order-dependent chemotherapeutic strategies has demonstrated enhanced efficacy in killing cancer cells while minimizing adverse effects. However, the precise mechanism remains elusive. Our results showed that pre-treatment of MCF-7 and MDA-MB-468 cells with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib or lapatinib significantly enhanced the cytotoxic effects of DNA-damaging agents compared to coadministration of the EGFR inhibitor and DNA-damaging agent. Sequential application of erlotinib and doxorubicin increased activated caspase-8 by promoting pro-caspase-8 homodimerization and autocatalytical cleavage, whereas coadministration did not. We found that EGFR inhibitors promoted pro-caspase-8 homodimerization by inhibiting ERK pathway signaling, while doxorubicin promoted it. Our data highlight that ERK has the potential to inhibit the formation of pro-caspase-8 homodimers by phosphorylating pro-caspase-8 at S387. In conclusion, the pretreatment of EGFR tyrosine kinase inhibitors promote pro-caspase-8 dimerization that sensitizes cancer cells to DNA-damaging agents. Our findings provide rationale for novel strategies for the implementation of combined targeted and cytotoxic chemotherapy within a new framework of time and order-dependent therapy.

Beclin 1, a protein essential for autophagy, regulates autophagy by interacting with Vps34 and other cofactors to form the Beclin 1 complex. Modifications of Beclin 1 may lead to the induction, inhibition or fine-tuning of the autophagic response under a variety of conditions. Here we show that Beclin 1 is acetylated by p300 and deacetylated by SIRT1 at lysine residues 430 and 437. In addition, the phosphorylation of Beclin 1 at S409 by CK1 is required for the subsequent p300 binding and Beclin 1 acetylation. Beclin 1 acetylation inhibits autophagosome maturation and endocytic trafficking by promoting the recruitment of Rubicon. In tumour xenografts, the expression of 2KR mutant Beclin 1 (substitution of K430 and K437 to arginines) leads to enhanced autophagosome maturation and tumour growth suppression. Therefore, our study identifies an acetylation-dependent regulatory mechanism governing Beclin 1 function in autophagosome maturation and tumour growth.

The phosphoinositide-3 kinase (PI3K) - phosphoinositide-dependent protein kinase 1 (PDK1)-Akt/protein kinase B (PKB) cascade plays a critical role in cardiovascular development and tumor genesis. But the role of PDK1 in the microenvironment of heart and tumor remains unknown. To clarify the effects of PDK1 on tissue microenvironment in vivo, here, we created α-SMA-Cre-mediated excision of PDK1 mice. And the mice were injected subcutaneously with Lewis lung carcinoma (LLC) cells. We found PDK1-deficient mice had post-natal praecox dilated cardiomyopathy, decelerated tumor growth and severe tumor metastasis. Histopathological analysis revealed abnormality of vascular microenvironment in heart and primary tumor. In conclusion, PDK1 plays a pivotal role in regulating cardiac function and tumor metastasis by interfering with microenvironment., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Side population (SP) contains cancer stem-like cells (CSLCs). In this study, we characterized SP cells from nasopharyngeal carcinoma (NPC) cell lines and found that SP cells had a higher self-renewal ability in vitro and greater tumorigenicity in vivo. The AKT pathway was activated in NPC SP cells. DC120, a 2-pyrimidyl-5-amidothiazole inhibitor of the ATP binding site of AKT, inhibited phosphorylation of FKHRL1 and GSK-3β. DC120 inhibited SP fraction, the sphere-forming ability in vitro and growth of primary xenografts as well as secondary xenografts' tumor recurrence. This inhibition was accompanied by reduced expression of stem-related gene Sox2 due to induction of p27 and miR-30a. A combination of DC120 and CDDP more effectively inhibited NPC cells compared with monotherapy in vitro and in vivo. Clinical evaluation of DC120 is warranted.