Overexpression of miR-506-3p reversed doxorubicin resistance in drug-resistant osteosarcoma cells.

Background and objective: Osteosarcoma is a common primary malignant tumor of bone, and doxorubicin is one of the most widely used therapeutic drugs. While the problem of doxorubicin resistance limits the long-term treatment benefits in osteosarcoma patients. The role of miRNAs and their target genes in osteosarcoma have become increasingly prominent. Currently, there is no report on miR-506-3p reversing doxorubicin resistance by targeting STAT3 in osteosarcoma. The purpose of this study was to investigate the molecular mechanism that overexpression of miR-506-3p reverses doxorubicin resistance in drug-resistant osteosarcoma cells. Methods: Doxorubicin-resistant osteosarcoma cells (U-2OS/Dox) were constructed by intermittent stepwise increasing stoichiometry. The target genes of miR-506-3p were predicted by bioinformatics approach and the targeting relationship between miR-506-3p and STAT3 was detected using dual luciferase reporter assay. U-2OS/Dox cells were treated with miR-506-3p overexpression and STAT3 silencing respectively. Then Western blot and RT-qPCR were used to detect the protein and mRNA expression levels of JAK2/STAT3 signaling pathway, drug-resistant and apoptotic associated molecules. The migration and invasion were assessed by cell scratch assay and transwell assay. The cell proliferative viability and apoptosis were investigated by CCK8 assay and flow cytometry assay. Results: U-2OS/Dox cells were successfully constructed with a 14.4-fold resistance. MiR-506-3p is directly bound to the 3'-UTR of STAT3 mRNA. Compared with U-2OS cells, the mRNA expression of miR-506-3p was reduced in U-2OS/Dox cells. Overexpression of miR-506-3p decreased the mRNA expression levels of JAK2, STAT3, MDR1/ABCB1, MRP1/ABCC1, Survivin and Bcl-2, and decreased the protein expression levels of p-JAK2, STAT3, MDR1/ABCB1, MRP1/ABCC1, Survivin and Bcl-2, and conversely increased Bax expression. It also inhibited the proliferation, migration and invasion of U-2OS/Dox cells and promoted cells apoptosis. The results of STAT3 silencing experiments in the above indicators were consistent with that of miR-506-3p overexpression. Conclusion: Overexpression of miR-506-3p could inhibit the JAK2/STAT3 pathway and the malignant biological behaviors, then further reverse doxorubicin resistance in drug-resistant osteosarcoma cells. The study reported a new molecular mechanism for reversing the resistance of osteosarcoma to doxorubicin chemotherapy and provided theoretical support for solving the clinical problems of doxorubicin resistance in osteosarcoma.

Lipidomics Analysis Reveals a Protective Effect of Myriocin on Cerebral Ischemia/Reperfusion Model Rats.

Ceramide accumulation has been associated with ischemic stroke. Myriocin is an effective serine palmitoyltransferase (SPT) inhibitor that reduces ceramide levels by inhibiting the de novo synthesis pathway. However, the role of myriocin in cerebral ischemia/reperfusion (I/R) injury and its underlying mechanism remain unknown. The present study established an experimental rat model of middle cerebral artery occlusion (MCAO). We employed ultra-performance liquid chromatograph quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS)-based lipidomic analysis to identify the disordered lipid metabolites and the effects of myriocin in cerebral cortical tissues of rats. In this study, we found 15 characterized lipid metabolites involved in sphingolipid and glycerophospholipid metabolism in cerebral I/R-injured rats, and these alterations were significantly alleviated by myriocin. Specifically, the mRNA expression of metabolism-related enzyme genes was detected by real-time quantitative polymerase chain reaction (RT-qPCR). We demonstrated that myriocin could regulate the mRNA expression of ASMase, NSMase, SGMS1, SGMS2, ASAH1, ACER2, and ACER3, which are involved in sphingolipid metabolism and PLA2, which is involved in glycerophospholipid metabolism. Moreover, TUNEL and Western blot assays showed that myriocin plays a key role in regulating neuronal cell apoptosis. In summary, the present work provides a new perspective for the systematic study of metabolic changes in ischemic stroke and the therapeutic applications of myriocin.

Quantitative Trait Locus Mapping and Identification of Candidate Genes for Resistance to Fusarium Wilt Race 7 Using a Resequencing-Based High Density Genetic Bin Map in a Recombinant Inbred Line Population of Gossypium barbadense.

Fusarium wilt caused by Fusarium oxysporum f. sp. vasinfectum (FOV) is one of the most destructive diseases in cotton (Gossypium spp.) production, and use of resistant cultivars is the most cost-effective method managing the disease. To understand the genetic basis of cotton resistance to FOV race 7 (FOV7), this study evaluated a recombinant inbred line (RIL) population of 110 lines of G. barbadense from a cross between susceptible Xinhai 14 and resistant 06-146 in eight tests and constructed a high-density genetic linkage map with resequencing-based 933,845 single-nucleotide polymorphism (SNP) markers covering a total genetic distance of 2483.17 cM. Nine quantitative trait loci (QTLs) for FOV7 resistance were identified, including qFOV7-D03-1 on chromosome D03 in two tests. Through a comparative analysis of gene expression and DNA sequence for predicted genes within the QTL region between the two parents and selected lines inoculated with FOV7, GB_D03G0217 encoding for a calmodulin (CaM)-like (CML) protein was identified as a candidate gene. A further analysis confirmed that the expression of GB_D03G0217 was suppressed, leading to increased disease severity in plants of the resistant parent with virus induced gene silencing (VIGS).

MiR-93-5p regulates tumorigenesis and tumor immunity by targeting PD-L1/CCND1 in breast cancer.

Background: Challenges in medical care posed by rapid tumor progression, individualized responses to therapy, and the heterogeneous characteristics of breast cancer (BRCA) highlight the urgent need for new treatment strategies, as well as therapeutic and prognostic markers. Accumulating evidence has revealed that microRNAs broadly participate in carcinogenesis, but our understanding of the role of miR-93-5p in BRCA remains limited. Methods: The prognosis of miR-93-5p, programmed cell death-ligand 1 (PD-L1) and CCND1 were analyzed by datasets. Freshly excised breast cancer tissues (N=33) and adjacent noncancerous tissues (N=18) were collected to detect the expression of CCND1 and PD-L1 by immunohistochemistry (IHC). Quantitative real-time PCR (qRT-PCR) and Western blot were used to test the expression of miR-93-5p, PD-L1 and CCND1 after transfected mimics or inhibitors. Dual-luciferase reporter assay indicates the direct targeting between miR-93-5p and PD-L1. Results: Bioinformatics analysis demonstrated that miR-93-5p plays differential roles in various tumors, and further verification using qRT-PCR revealed that the expression levels of miR-93-5p were lower in MDA-MB-231 cells than in noncancerous breast cells. In addition, we confirmed that PD-L1 and CCND1 generated mutual effects, and miR-93-5p directly targets the PD-L1/CCND1 signaling pathway to influence their accumulation and distribution in the cell membrane, nucleus, and cytoplasm, mediating tumor progression and immune regulation in BRCA. Conclusions: Taken together, miR-93-5p could regulate tumorigenesis and tumor immunity by targeting PD-L1/CCND1 in BRCA and our research provides a rationale for therapy with miR-93-5p to overcome immune escape and improve risk stratification.

High miR-3609 expression is associated with better prognosis in TNBC based on mining using systematic integrated public sequencing data.

MicroRNAs (miRNAs/miRs) are small endogenous RNAs that regulate gene expression post-transcriptionally. Abnormal miR-3609 expression is associated with the occurrence of pancreatic cancer, glioma and other diseases, such as polycystic ovary syndrome. However, the prognostic potential of miR-3609 has been reported in breast cancer. Thus, the present study aimed to investigate the differential expression and prognostic value of miR-3609 in patients with breast cancer from the UALCAN, cBioportal and Kaplan-Meier Plotter databases, respectively. Furthermore, the co-expression genes of miR-3609 in breast cancer were investigated using data from the LinkedOmics database, and functional enrichment analysis was performed using the LinkInterpreter module in LinkedOmics. The co-expression gene network was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins database, and the cytoHubba plug-in was used to identify the hub genes, which were visualized using Cytoscape software. The prognoses of the hub genes were performed using the Kaplan-Meier Plotter database. The Cell Counting Kit-8 and cell cycle assays were performed to confirm the functions of miR-3609 mimics transfection in MDA-MB-231 cells. Survival analysis using the Kaplan-Meier Plotter database demonstrated that high miR-3609 expression in triple-negative breast cancer (TNBC) was associated with a better prognosis. Furthermore, the experimental results indicated that high miR-3609 expression inhibited the proliferation of TNBC cells and induced cell cycle arrest of TNBC cells in the G0/G1 phase. Taken together, the results of the present study suggest that miR-3609 plays a vital role in mediating cell cycle arrest and inhibiting the proliferation of TNBC cells.

Identification and potential functions of tRNA-derived small RNAs (tsRNAs) in irritable bowel syndrome with diarrhea.

IBS-D is a functional bowel disease without clear diagnostic markers and exact pathogenesis. Studies have proved that non-coding RNAs participate in IBS-D. However, tRNA-derived small RNAs (tsRNAs), as a new type of non-coding RNAs that are more suitable as markers, remain to be clarified in IBS-D. Hence, we focused on the identification and potential functions of tsRNAs in IBS-D. Intestinal biopsies were obtained from IBS-D patients and healthy volunteers, and twenty-eight differential tsRNAs were screened by high-throughput sequencing. The changes of tiRNA-His-GTG-001, tRF-Ser-GCT-113, and tRF-Gln-TTG-035 by q-PCR in expanded samples were consistent with the sequencing results. Meanwhile, target gene prediction and bioinformatics showed that the three differential tsRNAs may be involved in some key signal pathways, such as GABAergic synapse, tumor necrosis factor-α (TNF-α), etc. Their regulation on target genes were demonstrated through cell experiments and luciferase reporter assays. In addition, the receiver-operating characteristic (ROC) analysis showed that the three tsRNAs all could be used as candidate markers of IBS-D. The correlation analysis indicated they were related to the degree of abdominal pain, abdominal distension, and stool morphology. So, we believe that the abnormal tiRNA-His-GTG-001, tRF-Ser-GCT-113, and tRF-Gln-TTG-035 are related to the clinical symptoms of IBS-D, and can target regulate the important molecules of the brain-gut axis, even could be expected as potential biomarkers for the diagnosis and treatment of IBS-D.

Genetic landscape of 125 pharmacogenes in Chinese from the Chinese Millionome Database.

Inter-individual differences of drug responses could be attributed to genetic variants of pharmacogenes such as cytochrome P450 (CYP), phase 2 enzymes, and transporters. In contrast to extensive studies on the genetic polymorphisms of CYP gene, genetic mutation spectrum of other pharmacogenes was under-representative in the pharmacogenetics investigations. Here we studied the genetic variations of 125 pharmacogenes including drug transporters, non-CYP phase 1 enzymes, phase 2 enzymes, nuclear receptors and others in Chinese from the Chinese Millionome Database (CMDB), of which 38,188 variants were identified. Computational analyses of the 2554 exonic variants found 617 deleterious missense variants, 91.1% of which were rare, and of the 54 loss-of-function (splice acceptor, splice donor, start lost, and stop gained) variants, 53 (98.1%) were rare. These results suggested an enrichment of rare variants in functional ones for pharmacogenes. Certain common functional variants including NUDT15 13:48611934 G/A (rs186364861), UGT1A1 2:234676872 C/T (rs34946978), and ALDH2 12:112241766 G/A (rs671) were population-specific for CMDB Chinese because they were absent (with a zero of variant allele frequency) or very rare in other gnomAD populations. These findings might be useful for the further pharmacogenomics research and clinical application in Chinese.

The safety and effectiveness of salvianolate in preventing perioperative venous thromboembolism in China: A PRISMA-compliant meta-analysis based on RCTs.

BACKGROUND: Salvianolate, a common drug for stabilizing heart disease and Angina Pectoris, is considered to be off-label for preventing venous thromboembolism (VTE) or anticoagulation at present. However, many clinical studies have showed that salvianolate can effectively inhibit the deep-vein thrombosis (DVT) incidence, and prevent VTE of perioperative patients in the real world in China. OBJECTIVE: This analysis aimed to evaluate the effectiveness and safety of salvianolate in preventing VTE in perioperative patients. METHODS: Databases of PubMed, Cochrane Library, Embase, CNKI, Wanfang and VIP were searched until July 2019. Literature retrieval, data extraction and quality assessment were independently completed by two researchers and checked with each other. Review Manager 5.2 software was applied for meta-analysis. RESULTS: A total of 429 studies were retrieved, including 11 randomized controlled trials (RCTs) with a total of 1149 subjects. Compared with low molecular weight heparin (LMWH) group alone, salvianolate combined LMWH group had lower DVT incidence in preventing perioperative thrombosis (2.75% and 14.23%, OR: 0.21, 95% CI:[0.08,0.53]; P = .0009). The incidence of adverse reactions of experimental group was similar to that of control group (1.79% and 2.31%, OR: 0.65, 95% CI:[0.18,2.35]. P = .51). Compared with the control group, D-dimer level (D-D), platelet count (PLT), fibrinogen (FIB), whole blood high shear viscosity (WBHSV), and whole blood low shear viscosity (WBLSV) were all significantly decreased (P < .01), and prothrombin time (PT) was significantly increased (P < .05). CONCLUSION: Salvianolate combined LMWH has better effectiveness and the same safety in preventing venous thromboembolism in perioperative patients. However, due to the small number of included literatures, large sample studies are still needed to further verify this conclusion.

Identification of Five Immune-Related lncRNAs Predicting Survival and Tumor Microenvironment Characteristics in Breast Cancer.

A common cancer in females, breast cancer (BRCA) mortality has been recently reduced; however, the prognosis of BRCA patients remains poor. This study attempted to develop prognostic immune-related long noncoding RNAs (lncRNAs) for BRCA and identify the effects of these lncRNAs on the tumor microenvironment (TME). Gene expression data from The Cancer Genome Atlas (TCGA) database were collected in order to select differentially expressed lncRNAs. Immune-related lncRNAs were downloaded from the ImmLnc database, where 316 immune-related lncRNAs were identified, 12 of which were found to be significantly related to the prognosis of BRCA patients. Multivariate cox regression analysis was then applied to construct prognostic immune-related lncRNAs as the risk model, including C6orf99, LINC00987, SIAH2-AS1, LINC01010, and ELOVL2-AS1. High-risk and low-risk groups were distinguished according to the median of immune-related risk scores. Accordingly, the overall survival (OS) in the high-risk group was observed to be shorter than that in the low-risk group. qRT-PCR analysis demonstrated that lncRNA expression levels in BRCA cell lines were in basic agreement with predictions except for LINC00987. By validating numerous clinical samples, lncRNA C6orf99 was shown to be highly expressed in the advanced stage, while LINC01010 and SIAH2-AS1 decreased in the advanced T-stage and M-stage. Moreover, the expression of LINC0098 was found to be significantly decreased among the groups (>50 years old). Gene set enrichment analysis (GSEA) was applied to analyze the cancer hallmarks and immunological characteristics of the high-risk and low-risk groups. Importantly, the TIMER database demonstrated that this immune-related lncRNA risk model for breast cancer is related to the infiltration of immune cells. In conclusion, the results indicated that five immune-related lncRNAs could be used as a prognostic model and may even accelerate immunotherapy for BRCA patients.

Near-infrared fluorescent probe with large stokes shift for detecting Human Neutrophil elastase in living cells.

Human Neutrophil elastase (HNE) plays a great role in immune responses and inflammation, and is associated closely with lung cancer and acute lung injury (ALI). Accurate detection of its activity is imperative to understand its biological function and diagnosing the disease states through monitoring the dynamic changes. Herein, we report a new NIR fluorescent probe (F-1) with large Stokes shift (182 nm). Probe F-1 featured high sensitivity (LOD ~ 5.6 ng/mL), good selectivity, low toxicity and a bright NIR emission triggered by HNE. Moreover, F-1 was successfully applied as an indicator to track the HNE in the A549 cells. Thus, F-1 may be an excellent tool for detecting enzymatic activity for preclinical applications and NE related diseases.

Improved Neuroprotective Effects of Gallic Acid-Loaded Chitosan Nanoparticles Against Ischemic Stroke.

Ischemic stroke is a typical cerebrovascular illness with high morbidity and mortality worldwide. Nevertheless, strategies for the prevention and treatment of cerebral ischemia/reperfusion injury (CIRI) are limited. Gallic acid (GA) is a plant polyphenol that has been used against CIRI. However, the pharmacokinetic (PK) properties of GA, such as its low absorption, poor bioavailability, and quick elimination, have negative effects on its application. To strengthen its effectiveness, a delivery system of GA-loaded o-carboxymethyl chitosan nanoparticles (GA-NPs) was synthesized in our study. In PKs study, GA-NPs apparently increases the area under the curve of plasma concentration-time and prolonged half-life of GA. Then, we measured the in vitro and in vivo effects of the GA-NPs in the oxygen glucose deprivation model and the middle cerebral artery occlusion model. The results from our pharmacodynamic studies, including assessment of neurological deficit, cerebral infarction, levels of inflammation, and oxidative stress, showed that GA-NPs possess better neuroprotection compared with GA. In conclusion, GA-NPs may be used as an efficacious delivery vehicle for GA in the treatment of CIRI.

miR3609 sensitizes breast cancer cells to adriamycin by blocking the programmed death-ligand 1 immune checkpoint.

Chemoresistance is the leading cause of breast cancer therapy failure, and studies of the mechanisms underlying chemoresistance and the treatment of drug-resistant tumors remain challenging. In the present study, we discovered a novel microRNA, miR3609, that influences the malignancy of breast cancer. Our results showed miR-3609 expression was lower in resistant breast cancer cells than in sensitive breast cancer cells (MCF-7), while PD-L1 expression was higher in resistant breast cancer cells than in sensitive breast cancer cells. Co-transfection of a miR-3609 plasmid with a luciferase construct containing the PD-L1 3'-untranslated region suppressed luciferase activity. Transfection of a miR-3609 mimic markedly suppressed PD-L1 protein expression in MDA-MB-231 and MDA-MB-468 cells in a dose-dependent manner and increased the sensitivity of MCF7/ADR cells to adriamycin, whereas transfection of a miR-3609 inhibitor enhanced PD-L1 protein expression in HBL-100 and MCF-7 cells. In addition, knockdown of PD-L1 by siRNA restored the sensitivity of MCF7/ADR cells to adriamycin. Mice injected with breast cancer cells stably overexpressing miR3609 survived markedly longer and had fewer tumors than mice injected with control miRNA (miR-sc)-transfected cells. Treatment with a CD8+ blocking antibody (anti-CD8) eliminated these effects, suggesting that CD8+ T cells are required for the efficacy of miR3609 in breast cancer. Further, low miR-3609 expression and high PD-L1 expression were correlated with poor prognosis in breast cancer patients. Therefore, restoration of miR-3609 expression may sensitize breast cancer to adriamycin by blocking PD-L1 expression.

Walnut (Juglans regia L.) Kernel Extracts Protect Against Isoproterenol-Induced Myocardial Infarction in Rats.

Walnuts kernels (Juglans regia L.) have rich antioxidants content and have been used in both cosmetic and pharmaceutical industry. This study dealt with the protective role of walnut kernels extracts (WK) on isoproterenol (ISO)-induced myocardial infarction (MI) in rats. Rats were pretreated with WK extracts (300 mg/kg) daily for 35 days. Then, ISO (100 mg/kg) was injected subcutaneously into rats to induce MI. Cardiac diagnostic markers (LDH and CPK), cardiac troponin, heart lipid peroxidation (TBARS and hydroperoxide), antioxidant system (CAT, SOD, GPx, GST, GSH, and GSSG) and the levels of lipid profile were evaluated in rats, and the results revealed WK significantly prevented myocardial injury induced by ISO (p < 0.05). WK significantly alleviated the oxidative damage and dyslipidemia in ISO-induced MI rats (p < 0.05). The effect produced by WK was compared with α-tocopherol. The mechanisms for the protective effects of WK could be attributed to its antilipid peroxidative, antioxidant, and antilipidemic properties. In conclusion, we demonstrated that WK has a significant protective effect against ISO-induced MI.

A novel liquid chromatography Orbitrap mass spectrometry method with full scan for simultaneous determination of multiple bioactive constituents of Shenkang injection in rat tissues: Application to tissue distribution and pharmacokinetic studies.

Shenkang injection is a traditional Chinese formula with good curative effect on chronic renal failure. In this paper, a novel, rapid and sensitive ultra-high-performance liquid chromatography coupled with Q Exactive hybrid quadrupole Orbitrap high-resolution accurate mass spectrometry was developed and validated for simultaneous determination of seven bioactive constituents of Shenkang injection in rat plasma and tissues after intravenous administration. Acetonitrile was used as a protein precipitation agent in biological samples disposal with carbamazepine as internal standard. The chromatographic separation was carried out on a C18 column with a gradient mobile phase consisting of acetonitrile and water (containing 0.1% formic acid). The MS analysis was performed in the full-scan positive and negative ion mode. The lower limits of quantification for the seven analytes in rat plasma and tissues were 0.1-10 ng/mL. The validated method was successfully applied to tissue distribution and pharmacokinetic studies of Shenkang injection after intravenous administration. The results of the tissue distribution study showed that the high concentrations of seven constituents were primarily in the kidney tract. This is the first report of the application of Q-Orbitrap with full-scan mass spectrometry in tissue distribution and pharmacokinetic studies of Shenkang injection.

Genetic variation of cytochrome P450 in Uyghur Chinese population.

Interindividual and interethnic variability of drug responses could be attributed to the differences of genetic polymorphisms in the drug metabolizing enzymes and transporters genes among the populations. Here we reviewed the studies of genetic variations in Uyghur Chinese of fifteen CYP450 genes including CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP2J2, CYP2W1, CYP3A4, CYP3A5, CYP4A11, and CYP17A1, which totally covered 277 variants. We also collected the data of 277 variants covered in our study in two extensive population sequencing projects, the International HapMap Project (Hap-Map) and the 1000 Genomes Project and compared them with the data of Uyghur Chinese. The results suggested that remarkable differences of variants allele frequencies of CYP450 genes were existed among Uyghur Chinese and other world populations and drug doses should be adjusted clinically in Uyghur in contrast to Han Chinese and Caucasians.

BTG3 Overexpression Suppresses the Proliferation and Invasion in Epithelial Ovarian Cancer Cell by Regulating AKT/GSK3ß/ß-Catenin Signaling.

Epithelial ovarian cancer (EOC) is the leading cause of cancer-related death among all the gynecological malignancies of the female genital system, and its incidence and mortality rates continue to rise. B-cell translocation gene 3 (BTG3) plays an important role in the occurrence and development of numerous cancers. However, the role of BTG3 in EOC remains poorly understood. In this study, we aimed to investigate the biological role and potential molecular mechanism of BTG3 in EOC. We found that BTG3 protein expression was significantly lower in human EOC cell lines. Next, BTG3 upregulation by transfection with pcDNA3.1-BTG inhibited cell proliferation and invasion but promoted cell apoptosis in 2 human EOC cell lines, SKOV-3 and HO-8910 cells. In addition, BTG3 knockdown by small interfering RNA promoted cell proliferation and invasion, but inhibited cell apoptosis in 2 human EOC cell lines, SKOV-3 and HO-8910 cells. Importantly, several proteins, including phosphorylation serine/threonine kinase (p-AKT), phosphorylated glycogen synthase kinase 3ß (p-GSK3ß), and ß-catenin, were markedly decreased by BTG3 upregulation, whereas increased by BTG3 knockdown. Taken together, the results of our study suggest that BTG3 overexpression could inhibit cell proliferation and invasion and promotes cell apoptosis in EOC cell, possibly by regulating the AKT/GSK3ß/ß-catenin signaling pathway, providing novel insights into the treatment of EOC through BTG3 overexpression.

Matrine induces cell cycle arrest and apoptosis with recovery of the expression of miR-126 in the A549 non-small cell lung cancer cell line.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-associated mortality in the United States. Chemotherapy prolongs survival rates among patients with advanced disease, however, this is at the cost of clinically significant adverse effects. Matrine is an active component of traditional Chinese medicine and is a promising alternative drug for the treatment of NSCLC. In the present study, the therapeutic effects and the underlying molecular mechanisms of matrine on the A549 NSCLC cell line were investigated. A high concentration of matrine (1.0 mg/ml) significantly (P<0.05) inhibited cell proliferation, by 52.68±3.32%, under which cell shrinkage and disruption were observed. Flow cytometric analysis showed that the proportion of G1/G0 cells was significantly increased, whereas the proportions of S and G2/M cells were significantly decreased (P<0.05) following treatment with matrine for 48 h. These results indicated that cell arrest was induced by matrine. Upregulation of the expression of microRNA (miR)­126, followed by downregulation of the expression of its target gene, vascular endothelial growth factor, were detected following treatment with a low concentration of matrine (0.2 mg/ml) using reverse transcription­quantitative polymerase chain reaction analysis, immunohistochemistry and western blot analysis. In conclusion, matrine induced cell cycle arrest and apoptosis, and recovered the expression of miR­126 in the A549 NSCLC cell line.

-141C insertion/deletion polymorphism of the dopamine D2 receptor gene is associated with schizophrenia in Chinese Han population: Evidence from an ethnic group-specific meta-analysis.

Accumulate evidence has implicated dopamine D2 receptor gene polymorphisms in the etiology of schizophrenia. A single nucleotide polymorphism, -141C insertion/deletion (Ins/Del) (rs1799732), in the promoter region of the dopamine D2 receptor gene has been linked to schizophrenia; however, the data are inconclusive. This study investigated whether the -141C polymorphism is associated with the risk of schizophrenia in different ethnic groups by performing a meta-analysis. A total of 24 case-control studies examining the association between -141C Ins/Del polymorphism and schizophrenia were identified according to established inclusion criteria. Significant association was revealed between -141C Ins/Del polymorphism and schizophrenia risk in dominant genetic model (Ins/Ins + Ins/Del versus Del/Del) (odds ratio = 0.33, 95% confidence interval = 0.14-0.81, z = 2.41, P = 0.02) in Chinese Han but not in Caucasian, Japanese or India populations. Our results indicate that -141C Ins/Del polymorphism might be a susceptibility factor for schizophrenia in Chinese Han population.

Cyclin-dependent kinase 11(p110) (CDK11(p110)) is crucial for human breast cancer cell proliferation and growth.

Cyclin-dependent kinases (CDKs) play important roles in the development of many types of cancers by binding with their paired cyclins. However, the function of CDK11 larger protein isomer, CDK11(p110), in the tumorigenesis of human breast cancer remains unclear. In the present study, we explored the effects and molecular mechanisms of CDK11(p110) in the proliferation and growth of breast cancer cells by determining the expression of CDK11(p110) in breast tumor tissues and examining the phenotypic changes of breast cancer cells after CDK11(p110) knockdown. We found that CDK11(p110) was highly expressed in breast tumor tissues and cell lines. Tissue microarray analysis showed that elevated CDK11(p110) expression in breast cancer tissues significantly correlated with poor differentiation, and was also associated with advanced TNM stage and poor clinical prognosis for breast cancer patients. In vitro knockdown of CDK11(p110) by siRNA significantly inhibited cell growth and migration, and dramatically induced apoptosis in breast cancer cells. Flow cytometry demonstrated that cells were markedly arrested in G1 phase of the cell cycle after CDK11(p110) downregulation. These findings suggest that CDK11(p110) is critical for the proliferation and growth of breast cancer cells, which highlights CDK11(p110) may be a promising therapeutic target for the treatment of breast cancer.

MicroRNA-1 (miR-1) inhibits gastric cancer cell proliferation and migration by targeting MET.

MicroRNAs (miRs) are short endogenous non-coding RNAs that act as posttranscriptional regulatory factors of gene expression. Downregulation of miR-1 has been reported in gastric cancer; however, the mechanisms underlying its functions via target genes in gastric cancer remain largely unknown. The purpose of this study was to investigate the mechanism by which miR-1 inhibits gastric cancer cell proliferation and migration. The effects of miR-1 on gastric cancer cell proliferation and migration were determined by MTT and wound-healing assays. Cell protein expression of the miR-1 target gene MET was analyzed by Western blotting. Finally, MET expression was evaluated by immunohistochemistry in a stomach tumor tissue microarray (TMA). Ectopic expression of miR-1 inhibited proliferation and migration in both AGS and SGC-7901 gastric cancer cell lines. miR-1 directly targets the MET gene and downregulates its expression. MET siRNA also inhibited proliferation and migration in both cell lines. Immunohistochemistry revealed significantly higher MET expression levels in gastric cancer tissues compared with matched adjacent non-cancer tissues. These findings indicate that the miR-1/MET pathway is a potential therapeutic target due to its crucial role in gastric cancer cell proliferation and migration.