Computational study of novel natural inhibitors targeting Kirsten rat sarcoma viral oncogene homolog G12C.

Lung adenocarcinoma is one of the most aggressive and rapidly fatal types of malignant lung tumor. Molecular docking and virtual screening were effectively and systematically used to identify specific targets in malignant tumors and screen potential drugs. Here, we screen perfect leading compounds from a medicate library (ZINC15 database) and analyze their properties (conveyance, absorption, metabolism, excretion, and harmless forecasts) with potential inhibition of Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) G12C. Further results demonstrated that ZINC000013817014 and ZINC000004098458 were screened out from the ZINC15 database and were identified to have a much better binding affinity and more favorable interaction vitality binding with KRAS G12C and less rat carcinogenicity, Ames mutagenicity, way better dissolvability in water and noninhibition with cytochrome P-450 2D6. Molecular dynamics simulation analysis indicated that the binding capacity of these two compounds and KRAS G12C, ZINC000013817014-KRAS G12C, and ZINC000004098458-KRAS G12C is stable in the natural environment. Our findings reveal that ZINC000013817014 and ZINC000004098458 were perfect leading compounds to be inhibitors binding with KRAS G12C, which were selected as safe drug candidates and a cornerstone for KRAS G12C-related medicine plan and improvement. What is more, we have conducted a Cell Counting Kit-8 to verify the exactly inhibitory effects of the two selected drugs on Lung adenocarcinoma. This study establishes a solid framework for systematic anticancer medication research and development.

Identification of novel natural inhibitors targeting AKT Serine/Threonine Kinase 1 (AKT1) by computational study.

Despite great progress, the current cancer treatments often have obvious toxicity and side effects. and a poor prognosis (some patients). One of the reasons for the poor prognosis is that certain enzymes prevent anticancer drugs from killing tumor cells. AKT1 is involved in regulating PI3K/AKT/mTOR, a tumor-generating pathway. Ipatasertib, a highly selective inhibitor of AKT1, is widely used in the treatment of tumors. In this study, many structural and biochemical methodswere used to find better AKT1(Threonine Kinase 1) inhibitors, which laid a foundation for the further development of AKT1 inhibitors and provided new drugs for the treatment of tumors. ZINC15 database and Discovery Studio 4.5, a computer-aided drug screening software with many modules (LibDock for virtual screening, ADME (Absorption, Distribution, Metabolism, Excretion) and TOPKAT (toxicity prediction module) for the toxicity and properties analysis, and MD simulation for stability prediction), were employed. CCK8 assay, ELISA assay genicity and higher tolerance to cytochrome P4502D6. MD simulations indicated they could bind with AKT1 stably in the natural environment. The cell experiment and specific assay for AKT1 inhibition showed they could inhibit the proliferation and AKT1 expression of MG63 cells (Osteosarcoma cells). Moreover, these novel compounds with structural modifications can be potential contributors that lead to further rational drug design for targeting AKT1.AbbreviationAKT1, AKT Serine/Threonine Kinase 1; ADME, absorption, distribution, metabolism, excretion; TOPKAT, toxicity prediction by Computer assisted technology; CCK8, Cell Counting Kit 8; ELISA, Enzyme-linked immunosorbent assay; CYP2D6, cytochrome P4502D6 inhibition; GBM, Glioblastoma; AGC kinase, protein kinase A, G, and C families (PKA, PKC, PKG); PKB, protein kinase B; PAM pathway, PI3K/AKT/mTOR pathway; OS, overall survival; PFS, progression-free survival; LD50, lethal dose half in rats; LOAEL, lowest observed adverse effect level; NPT, normal pressure and temperature; PME, particle mesh Ewald; LINCS, linear constraint solver; RMSD, root-mean-square deviation; BBB, blood-brain barrier; DS, Discovery Studio; DTP, Developmental toxicity potential; PPB, Plasma protein binding; MTD, Maximum Tolerated Dosage; AB, Aerobic Biodegradability; NTP, US. National Toxicology Program; DTP, developmental toxicity potential.

An interrelated CataFlower enzyme system for sensitively monitoring sweat glucose.

An accurate measurement of sweat glucose is a promising alternative to invasive finger prick blood test, and may provide effective self-monitoring of blood glucose with good patient compliance. Herein, an interrelated catalytic enzyme system has been developed, termed as CataFlower, which is composed of nanoflower MoS2 (peroxidase) decorated with GOx (glucose oxidase) and MnO2 (oxygen generator), and exhibits synergistic oxidative capability for sensitively monitoring sweat glucose. CataFlower can not only generate oxygen in situ to maximize GOx activity, but promote peroxidase-triggered H2O2 oxidation of methylene blue, resulting in sensitive colorimetric detection of glucose. We identify that CataFlower can precisely detect glucose with a detection limit of 10 µM, allowing for measuring glucose levels in different biological samples, such as blood and urine. Particularly, CataFlower is capable of monitoring dynamic changes in sweat glucose with high sensitivity and accuracy during exercise. Therefore, CataFlower provides a stepping stone to eliminate invasive blood tests, significantly improving the diagnosis and management of diabetes mellitus.

Computational study on novel natural inhibitors targeting c-MET.

ABSTRACT: This study was designed to select ideal lead compounds and preclinical drug candidates http://dict.youdao.com/w/eng/preclinical_drug_candidate/javascript:void (0); with inhibitory effect on c-MET from the drug library (ZINC database).A battery of computer-aided virtual techniques was used to identify possible inhibitors of c-MET. A total of 17,931 ligands were screened from the ZINC15 database. LibDock is applied for structure-based screening followed by absorption, distribution, metabolic, and excretion, and toxicity prediction. Molecular docking was conducted to confirm the binding affinity mechanism between the ligand and c-MET. Molecular dynamics simulations were used to assess the stability of ligand-c-MET complexes.Two new natural compounds ZINC000005879645 and ZINC000002528509 were found to bind to c-MET in the ZINC database, showing higher binding affinity. In addition, they were predicted to have lower rodent carcinogenicity, Ames mutagenicity, developmental toxicity potential, and high tolerance to cytochrome P4502D6. Molecular dynamics simulation shows that ZINC000005879645 and ZINC000002528509 have more favorable potential energies with c-MET, which could exist stably in the natural environment.This study suggests that ZINC000005879645 and ZINC000002528509 are ideal latent inhibitors of c-MET targeting. As drug candidates, these 2 compounds have low cytotoxicity and hepatotoxicity as well as important implications for the design and improvement of c-MET target drugs.

Novel natural inhibitors targeting B-RAF(V600E) by computational study.

The aim of this research was to screen the ZINC15 database to select lead compounds and drug candidates which can inhibit B-RAF (V600E). In order to identify drugs potentially inhibited B-RAF (V600E), numerous modules of Discovery Studio 4.5 were employed. Structure-based screening using LibDock was carried out followed by ADME (absorption, distribution, metabolism, excretion) and toxicity prediction. CDOCKER was performed to demonstrate the binding affinity and mechanism between ligands and B-RAF(V600E). To evaluate whether ligand-receptor complexes were stable, molecular dynamics were employed. Two novel natural compounds (ZINC000100168592 and ZINC000049784088) from ZINC15 database were found binding to B-RAF(V600E) with more favorable interaction energy in comparison with the reference drug Vemurafenib. Also, they were predicted with less ames mutagenicity, rodent carcinogenicity, non-developmental toxic potential and tolerance to cytochrome P450 2D6 (CYP2D6). The molecular dynamics simulation analysis indicated that the compound-B-RAF(V600E) complexes had more favorable potential energy compared with Vemurafenib and they can exist in natural environments stably. The result of this study shows that ZINC000100168592 and ZINC000049784088 are ideal leading potential compounds to inhibit B-RAF(V600E). The findings of this study and these selected drug candidates greatly contributed to the medication design and improvement of B-RAF(V600E) and other proteins.

Selected using bioinformatics and molecular docking analyses, PHA-793887 is effective against osteosarcoma.

To identify novel prognostic and therapeutic targets for osteosarcoma patients, we compared the gene expression profiles of osteosarcoma and control tissues from the GSE42352 dataset in the Gene Expression Omnibus. Differentially expressed genes were subjected to Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, Gene Set Enrichment and protein-protein interaction network analyses. Survival curve analyses indicated that osteosarcoma patients with lower mRNA levels of cyclin-dependent kinase 1 (CDK1) and topoisomerase II alpha had better prognoses. Various computer-aided techniques were used to identify potential CDK1 inhibitors for osteosarcoma patients, and PHA-793887 was predicted to be a safe drug with a high binding affinity for CDK1. In vitro, MTT and colony formation assays demonstrated that PHA-793887 reduced the viability and clonogenicity of osteosarcoma cells, while a scratch assay suggested that PHA-793887 impaired the migration of these cells. Flow cytometry experiments revealed that PHA-793887 dose-dependently induced apoptosis in osteosarcoma cells. Western blotting and enzyme-linked immunosorbent assays indicated that CDK1 expression in osteosarcoma cells declined with increasing PHA-793887 concentrations. These results suggest that PHA-793887 could be a promising new treatment for osteosarcoma.

Effective natural inhibitors targeting poly ADP-ribose polymerase by computational study.

OBJECT: This study was designed to screen ideal lead compounds and drug candidates with an inhibitory effect on PARP from the drug library (ZINC database). RESULTS: Two effective natural compounds ZINC000003938684 and ZINC000014811844 were found to bind to PARP in the ZINC database, showing a higher binding affinity. Also, they were predicted to have lower rodent carcinogenicity, Ames mutagenicity, developmental toxicity potential, and high tolerance to cytochrome P4502D6. Molecular dynamics simulation showed that ZINC000003938684 and ZINC000014811844 had a more favorable potential energies with PARP, which could exist stably in natural circumstances. CONCLUSION: This study suggested that ZINC000003938684 and ZINC000014811844 were ideal potential inhibitors of PARP targeting. These compounds were safe drug candidates and had important implications for the design and improvement of CMET target drugs. METHODS: A battery of computer-aided virtual techniques were used to identify potential inhibitors of PARP. LibDock is used for structure-based screening followed by ADME (absorption distribution, metabolic excretion) and toxicity prediction. Molecular docking was performed to demonstrate the binding affinity mechanism between the ligand and PARP. Molecular dynamics simulations were used to evaluate the stability of ligand-receptor complexes.

Computational study on natural compounds inhibitor of c-Myc.

To screen and identify ideal leading compounds from a drug library (ZINC15 database) with potential inhibition effect against c-Myc to contribute to medication design and development.A series of computer-aided virtual screening techniques were performed to identify potential inhibitors of c-Myc. LibDock from the software Discovery Studio was used to do a structure-based screening after ADME (absorption, distribution, metabolism, excretion) and toxicity prediction. Molecular docking was utilized to show the binding affinity and potential mechanism between ligands and c-Myc. Stability of the ligand-receptor complex was analyzed by molecular dynamic simulation at the end of the research.Compounds with more interactive energy which are confirmed to be the potential inhibitors for c-Myc were identified from the ZINC15 databases. Additionally, those compounds are also anticipated with fewer ames mutagenicity, rodent carcinogenicity, nondevelopmental toxic potential, and tolerant with cytochrome p450 2D6(CYP2D6). Dynamic simulation analysis also revealed that the very compounds had more favorable potential energy compared with 10058-F4(ZINC12406714). Furthermore, we prove that those compounds are stable and can exist in natural conditions.This study demonstrates that the compounds are potential therapeutic inhibitors for c-Myc. These compounds are safe and stable for drug candidates and may play a critical role in c-Myc inhibitor development.

Bioactive multi-engineered hydrogel offers simultaneous promise against antibiotic resistance and wound damage.

Wound healing is a complex process involved in repairing tissue damage and preventing infection. However, there is a lack of appropriate treatment solutions that can simultaneously promote tissue repair and protect againstbacteria, especially antibiotic-resistant bacteria. In this study, we have developed an injectable hydrogel encapsulating acidic fibroblast growth factor (aFGF) and bacteriophage, termed as ABgel, for combating antibiotic-resistant bacteria and enhancing wound regeneration. ABgel is composed of oxidized sodium alginate (OSA), gelatin and hyaluronic acid (HA), and can rapidly form hydrogel with an elastic modulus of 13 kPa, which mimics the skin tissues. In addition, ABgel can effectively load and stabilize bacteriophage and aFGF, allowing for preventing bacterial infections and improving regeneration of damaged dermal tissues. In vitro studies demonstrate that ABgel exhibits enormous antibacterial activity against antibiotic-resistant E. coli and enhanced angiogenetic activity. Importantly, ABgel can promote skin regeneration and prevent bacterial infections in mice, thereby promoting wound healing process. Therefore, ABgel represents a decent bioactive engineered hydrogel dressing with a broad application potential.

Computational study of novel natural inhibitors targeting aminopeptidase N(CD13).

OBJECTIVES: To screen and identify ideal leading compounds from a drug library (ZINC15 database) with potential inhibition of aminopeptidase N(CD13) to contribute to medication design and development. RESULTS: Two novel natural compounds, ZINC000000895551 and ZINC000014820583, from the ZINC15 database were found to have a higher binding affinity and more favorable interaction energy binding with CD13 with less rodent carcinogenicity, Ames mutagenicity, and non-inhibition with cytochrome P-450 2D6. Molecular dynamics simulation analysis suggested that the 2 complexes, ZINC000000895551-CD13 and ZINC000014820583-CD13, have favorable potential energy, and exist stably in the natural circumstances. CONCLUSION: This study discovered that ZINC000000895551 and ZINC000014820583 were ideal leading compounds to be inhibitions targeting to CD13. These compounds were selected as safe drug candidates as CD13 target medication design and improvement. MATERIALS AND METHOD: Potential inhibitors of CD13 were identified using a series of computer-aided structural and chemical virtual screening techniques. Structure-based virtual screening was carried out to calculate LibDock scores, followed by analyzing their absorption, distribution, metabolism, and excretion and toxicity predictions. Molecule docking was employed to reveal binding affinity between the selected compounds and CD13. Molecular dynamics simulation was applied to evaluate stability of the ligand-CD13 complex under natural environment.

A stimuli-responsive combination therapy for recovering p53-inactivation associated drug resistance.

Drug resistance is a major hindrance in the anticancer treatment, which encourages the development of effective therapeutic strategies. For the first time, MDM2-mediated p53 degradation was identified as a critical factor for developing acquired resistance of doxorubicin (DOX) in HepG2 tumor spheroids, which could be effectively reversed by MDM2 inhibitor MI-773, thereby improving anticancer effects. Therefore, a pH-sensitive liposomal formulation of DOX and MI-773 (LipD/M@CMCS) were developed for recovering p53-mediated DOX resistance in hepatocellular carcinoma. LipD/M@CMCS were composed of cationic liposomes covered with carboxymethyl chitosan (pI = 6.8), and were stable in the physiological condition (pH 7.4), but rapidly converted to cationic liposomes in tumor acidic microenvironment (pH 6.5), endowing them with tumor specificity and enhanced cellular uptake. We showed that LipD/M@CMCS could not only effectively induce cell apoptosis in HepG2 tumor spheroids, but significantly inhibit tumor growth with minimal adverse effects. In summary, selective regulation of MDM2 in cancer cells is a promising strategy to overcome DOX resistance, and may provide a perspective on the management of malignant tumors.

Selected by gene co-expression network and molecular docking analyses, ENMD-2076 is highly effective in glioblastoma-bearing rats.

BACKGROUND: Glioblastoma is the most common type of malignant brain tumor. Bioinformatics technology and structure biology were effectively and systematically used to identify specific targets in malignant tumors and screen potential drugs. RESULTS: GBM patients have higher AURKA and KDR mRNA expression compared with normal samples. Then, we identified a small molecular compound, ENMD-2076, could effectively inhibit Aurora kinase A and VEGFR-2 (encoded by KDR) activities. ENMD-2076 is predicted without toxic properties and also has absorption and gratifying brain/blood barrier penetration ability. Further results demonstrated that ENMD-2076 could significantly inhibit GBM cell lines proliferation and vitality, it also suppressed GBM cells migration and invasion. ENMD-2076 induced glioblastoma cell cycle arrest in G2-M phase and apoptosis by inhibiting PI3K/AKT/mTOR signaling pathways. Additionally, ENMD-2076 prolonged the median survival time of tumor-bearing rats and restrained growth rate of tumor volume in vivo. CONCLUSIONS: Our findings reveal that ENMD-2076 is a promising drug in dealing with glioblastoma and have a perspective application. METHODS: We show that AURKA and KDR genes are hub driver genes in glioblastoma with bioinformatics technology including WGCNA analysis, PPI network, GO, KEGG analysis and GSEA analysis. After identifying a compound via virtual screening analysis, further experiments were carried out to examine the anti-glioblastoma activities of the compound in vivo and in vitro.

Identification of driver genes and key pathways of prolactinoma predicts the therapeutic effect of genipin.

The purpose of the present study was to identify the potential targets and markers for diagnosis, therapy and prognosis in patients with prolactinoma at the molecular level and to determine the therapeutic effects of genipin in prolactinoma. The gene expression profiles of GSE2175, GSE26966 and GSE36314 were obtained from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) were identified after comparing between gene expression profiles of the prolactinoma tissues and normal tissues. Then, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and protein­protein interaction (PPI) network analysis were conducted. In addition, in vitro, scratch assay, colony­forming assay, Cell Counting Kit 8 (CCK8) assay and flow cytometry were performed to verify the functional effects of genipin. An aggregate of 12,695, 3,847 and 5,310 DEGs were identified from GSE2175, GSE26966 and GSE36314, respectively. The results of GO and KEGG analysis showed that the DEGs significant and important for prolactinoma were mostly involved with 'spindle pole' and 'oocyte meiosis'. A total of 20 genes were selected as hub genes with high degrees after PPI network analysis, including mitogen­activated protein kinase 1 (MAPK1), MYC, early growth response 1 (EGR1), Bcl2 and calmodulin 1 (CALM1). CCK8 assay, colony­forming assay and scratch assay were performed to verify the anti­prolactinoma effect of genipin. The results of flow cytometry showed that apoptosis was increased by genipin. MAPK1, MYC, EGR1, Bcl2 and CALM1 were screened as main hub genes. Genipin upregulated the expression level of EGR1 and p21 (downstream mediator of EGR1) and EGR1, inhibited the proliferation and migration of prolactinoma cells. Genipin is a promising drug for treatment of patients with prolactinoma.

A potent free fatty acid receptor 1 agonist with a glucose-dependent antihyperglycemic effect.

We present a novel free fatty acid receptor 1 (FFA1) agonist, named PAFA, with a strong agonist potency (EC50 = 6.04 nM) and good serum stability. PAFA significantly stimulates insulin secretion in INS-1 cells in a glucose-dependent manner and exhibits high antihyperglycemic effects in db/db mice without adverse effects.

Novel Gold Nanorod-Based HR1 Peptide Inhibitor for Middle East Respiratory Syndrome Coronavirus.

Middle East respiratory syndrome coronavirus (MERS-CoV) causes a severe acute respiratory syndrome-like illness with high pathogenicity and mortality due to the lack of effective therapeutics. Currently, only few antiviral agents are available for the treatment of MERS, but their effects have been greatly impaired by low antiviral activity, poor metabolic stability, and serious adverse effects. Therefore, the development of effective treatment for MERS is urgently needed. In this study, a series of heptad repeat 1 (HR1) peptide inhibitors have been developed to inhibit HR1/HR2-mediated membrane fusion between MERS-CoV and host cells, which is the major pathway of MERS-CoV-induced host infections. Particularly, peptide pregnancy-induced hypertension (PIH) exhibits potent inhibitory activity with IC50 of 1.171 µM, and its inhibitory effects can be further increased to 10-fold by forming a gold nanorod complex (PIH-AuNRs). In addition, PIH-AuNRs display enhanced metabolic stability and biocompatibility in vitro and in vivo and, therefore, effectively prevent MERS-CoV-associated membrane fusion. In summary, PIH-AuNRs represent a novel class of antiviral agents and have a great potential in treating MERS in the clinic.

Synergistic Amplification of Oxidative Stress-Mediated Antitumor Activity via Liposomal Dichloroacetic Acid and MOF-Fe2.

Cancer cells are susceptible to oxidative stress; therefore, selective elevation of intracellular reactive oxygen species (ROS) is considered as an effective antitumor treatment. Here, a liposomal formulation of dichloroacetic acid (DCA) and metal-organic framework (MOF)-Fe2+ (MD@Lip) has been developed, which can efficiently stimulate ROS-mediated cancer cell apoptosis in vitro and in vivo. MD@Lip can not only improve aqueous solubility of octahedral MOF-Fe2+ , but also generate an acidic microenvironment to activate a MOF-Fe2+ -based Fenton reaction. Importantly, MD@Lip promotes DCA-mediated mitochondrial aerobic oxidation to increase intracellular hydrogen peroxide (H2 O2 ), which can be consequently converted to highly cytotoxic hydroxyl radicals (•OH) via MOF-Fe2+ , leading to amplification of cancer cell apoptosis. Particularly, MD@Lip can selectively accumulate in tumors, and efficiently inhibit tumor growth with minimal systemic adverse effects. Therefore, liposome-based combination therapy of DCA and MOF-Fe2+ provides a promising oxidative stress-associated antitumor strategy for the management of malignant tumors.

An elegant nitroreductase responsive fluorescent probe for selective detection of pathogenic Listeria in vitro and in vivo.

Listeria monocytogenes (Listeria) is a facultative pathogenic bacterium, and a sensitive method for specific detection of Listeria is considered of clinically significant. However, current approaches for identifying Listeria are time consuming or tentative, and especially, cannot identify bacterial viability and antibiotic efficacy, which are critical in establishing a treatment recipe. Herein, we have developed a nitroreductase (NTR) responsive fluorescent probe (NRFP) with a fluorescence off-on feature, which could rapidly detect Listeria in vitro and in vivo with high specificity and sensitivity. NRFP showed a selective response to NTRs over other biological reductants, and could detect NTRs as low as 12.5 ng/mL. Furthermore, NRFP responded rapidly to NTRs within 10 min, enabling it real-time monitoring NTR production. Most importantly, NRFP could not only distinguish Listeria from other bacteria in vitro and in vivo for the first time, but could provide valuable information about Listeria desired for healthcare professionals, such as the presence and viability. Particularly, NRFP could real-time monitor antimicrobial effects in vivo, thereby identifying effective antibiotics for Listeria infections. Overall, NRFP appears to be an ideal imaging probe for Listeria, and possesses great potentials in diagnostic and therapeutic applications.

A sensitive and fast responsive fluorescent probe for imaging hypoxic tumors.

Nitroreductase activities are positively associated with the hypoxic level of tumors, making it an attractive target for tumor detection. Herein, we have developed a 2,5-bis(methylsulfinyl)-1,4-diaminobenzene based probe (BBP), which is a nitroreductase (NTR) responsive fluorescent probe and can rapidly detect NTRs with high sensitivity and specificity. The BBP showed not only a selective response to NTRs over other biological reductants, but also high sensitivity to NTRs and could detect as low as 20 ng mL-1 NTRs. Furthermore, the BBP responded rapidly to NTRs in as fast as 10 minutes, enabling real-time monitoring of the production levels of NTRs. Most importantly, the BBP could identify NTR activities in 2D cell monolayers, 3D tumor spheroids, and even solid tumors in mice. Particularly, the BBP could monitor the early tumor formation and treatment response via measuring NTR activities. Overall, the BBP appears to be an ideal imaging probe for the detection of solid tumors, and possesses great potential in a broad range of diagnostic and therapeutic applications in the clinic.

HDAC3 Expression Correlates with the Prognosis and Grade of Patients with Glioma: A Diversification Analysis Based on Transcriptome and Clinical Evidence.

OBJECTIVE: This study aimed to clarify the relationship between histone deacetylase 3 (HDAC3) expression and the prognosis as well as the grade of patients with glioma. METHODS: The quantitative real-time polymerase chain reaction was profiled to examine the HDAC3 expression in glioma and normal glial cell lines. An Oncomine database analysis and prognosis analysis were performed. The correlation between World Health Organization (WHO) grade and HDAC3 was analyzed by Spearman rank correlation test. A meta-analysis was performed to confirm the conclusion. RESULTS: HDAC3 RNA overexpression in glioma cell lines was detected (P < 0.05). Four data sets were screened from the Oncomine database and showed that the expression level of HDAC3 was consistently higher in glioma than in normal tissue (P < 0.001). The prognostic analysis of 325 glioma samples from the Chinese Glioma Genome Atlas showed that patients with low HDAC3 expression had significantly better overall survival (OS) and progression-free survival (PFS) than did patients with high HDAC3 expression [hazard ratio [HR], 1.992; 95% confidence interval [CI], 1.490-2.662; P < 0.0001 and HR, 1.874; 95% CI, 1.412-2.487; P < 0.0001, respectively]. Both the WHO grade III group and the WHO grade IV group expressed significantly higher messenger RNA (mRNA) level than did the WHO grade II group (P < 0.05). Four cohort studies consisting of 490 patients were included in the meta-analysis. The pooled data of subgroup analysis showed significantly longer OS in low HDAC3 mRNA level [HR, 3.38; 95% CI, 1.80-6.37; P = 0.0002]. CONCLUSIONS: HDAC3 mRNA was expressed more in glioma than in the normal glial cell line. Low HDAC3 mRNA expression levels predicted better OS. HDAC3 expression could be a biomarker to discriminate glioma grade.