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https://www.readbyqxmd.com/read/28642588/epigenetic-targeting-drugs-potentiate-chemotherapeutic-effects-in-solid-tumor-therapy
#1
Jingjing Li, Dapeng Hao, Li Wang, Haitao Wang, Yuan Wang, Zhiqiang Zhao, Peipei Li, Chuxia Deng, Li-Jun Di
Epigenetic therapy is a novel tumor therapeutic method and refers to the targeting of the aberrant epigenetic modifications presumably at cancer-related genes by chemicals which are epigenetic targeting drugs (ETDs). Not like in treating hematopoietic cancer, the clinical trials investigating the potential use of ETDs in the solid tumor is not encouraging. Instead, the curative effects of ETD delivered together with DNA targeting chemo drugs (DTDs) are quite promising according to our meta-analysis. To investigate the synergistic mechanism of ETD and DTD drug combination, the therapeutic effect was studied using both cell lines and mouse engrafted tumors...
June 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28629431/microrna-330-3p-promotes-cell-invasion-and-metastasis-in-non-small-cell-lung-cancer-through-gria3-by-activating-mapk-erk-signaling-pathway
#2
Chun-Hua Wei, Gang Wu, Qian Cai, Xi-Can Gao, Fan Tong, Rui Zhou, Rui-Guang Zhang, Ji-Hua Dong, Yu Hu, Xiao-Rong Dong
BACKGROUND: Brain metastasis (BM) is associated with poor prognosis in patients with non-small cell lung cancer (NSCLC). Recent studies demonstrated that microRNA-330-3p (miR-330-3p) was involved in NSCLC brain metastasis (BM). However, the exact parts played by miR-330-3p in BM of NSCLC remain unknown. Discovery and development of biomarkers and elucidation of the mechanism underlying BM in NSCLC is critical for effective prophylactic interventions. Here, we evaluated the expression and biological effects of miR-330-3p in NSCLC cells and explored the underlying mechanism of miR-330-3p in promoting cell migration and invasion in NSCLC...
June 19, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28623907/dna-methylation-dysregulations-in-rheumatic-heart-valve-disease
#3
Kangjun Shen, Hui Liu, Ran Jing, Jiangfeng Yi, Xinmin Zhou
BACKGROUND: The epigenetic changes underlying the development of rheumatic heart valve disease (RHVD) remain incompletely understood. Limited evidence suggests that abnormal DNA methylation might be involved in the pathogenesis of RHVD. In the present study, we evaluated the DNA methylation dysregulations from myocardial tissue in RHVD patients systematically. METHODS: Right atrial myocardial tissue obtained from rheumatic valvular patients who had undergone valve replacements surgery (n = 73) and were compared to healthy controls (n = 4)...
June 17, 2017: BMC Cardiovascular Disorders
https://www.readbyqxmd.com/read/28622390/inhibiting-dna-methylation-activates-cancer-testis-antigens-and-expression-of-the-antigen-processing-and-presentation-machinery-in-colon-and-ovarian-cancer-cells
#4
Cornelia Siebenkäs, Katherine B Chiappinelli, Angela A Guzzetta, Anup Sharma, Jana Jeschke, Rajita Vatapalli, Stephen B Baylin, Nita Ahuja
Innovative therapies for solid tumors are urgently needed. Recently, therapies that harness the host immune system to fight cancer cells have successfully treated a subset of patients with solid tumors. These responses have been strong and durable but observed in subsets of patients. Work from our group and others has shown that epigenetic therapy, specifically inhibiting the silencing DNA methylation mark, activates immune signaling in tumor cells and can sensitize to immune therapy in murine models. Here we show that colon and ovarian cancer cell lines exhibit lower expression of transcripts involved in antigen processing and presentation to immune cells compared to normal tissues...
2017: PloS One
https://www.readbyqxmd.com/read/28614801/dna-methyltransferase-3b-regulates-articular-cartilage-homeostasis-by-altering-metabolism
#5
Jie Shen, Cuicui Wang, Daofeng Li, Taotao Xu, Jason Myers, John M Ashton, Ting Wang, Michael J Zuscik, Audrey McAlinden, Regis J O'Keefe
Osteoarthritis (OA) is the most common form of arthritis worldwide. It is a complex disease affecting the whole joint but is generally characterized by progressive degradation of articular cartilage. Recent genome-wide association screens have implicated distinct DNA methylation signatures in OA patients. We show that the de novo DNA methyltransferase (Dnmt) 3b, but not Dnmt3a, is present in healthy murine and human articular chondrocytes and its expression decreases in OA mouse models and in chondrocytes from human OA patients...
June 15, 2017: JCI Insight
https://www.readbyqxmd.com/read/28611277/association-of-rasgrf1-methylation-with-epileptic-seizures
#6
Xiaoni Chen, Xi Peng, Liang Wang, Xinwei Fu, Ji Xiu Zhou, Binglin Zhu, Jing Luo, Xuefeng Wang, Zheng Xiao
DNA methylation, one of the mechanisms of epigenetic regulation, has been suggested to be related with epilepsy. RASgrf1 is a paternally imprinted gene and has a differentially methylated region (DMR) at the promoter that can silence gene expression. We have previously observed the down-regulation of RASgrf1 in the temporal neocortex of epilepsy patients and in the hippocampus of epileptic animals. Here, we further explored the dynamic change (1-day acute period, 10-day latent period and 45-day chronic phase) of DNA methylation and RASgrf1 expression after acute epileptic seizures in kainic acid (KA)-treated mice, and we observed the impact of N-phthalyl-L-tryptophan (RG108), a DNA methyltransferase (DNMT) inhibitor, on an acute epileptic model by polymerase chain reaction (PCR), western blotting, and bisulfite sequencing PCR (BSP)...
May 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/28604729/dnmt-and-hdac-inhibitors-induce-cryptic-transcription-start-sites-encoded-in-long-terminal-repeats
#7
David Brocks, Christopher R Schmidt, Michael Daskalakis, Hyo Sik Jang, Nakul M Shah, Daofeng Li, Jing Li, Bo Zhang, Yiran Hou, Sara Laudato, Daniel B Lipka, Johanna Schott, Holger Bierhoff, Yassen Assenov, Monika Helf, Alzbeta Ressnerova, Md Saiful Islam, Anders M Lindroth, Simon Haas, Marieke Essers, Charles D Imbusch, Benedikt Brors, Ina Oehme, Olaf Witt, Michael Lübbert, Jan-Philipp Mallm, Karsten Rippe, Rainer Will, Dieter Weichenhan, Georg Stoecklin, Clarissa Gerhäuser, Christopher C Oakes, Ting Wang, Christoph Plass
Several mechanisms of action have been proposed for DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi), primarily based on candidate-gene approaches. However, less is known about their genome-wide transcriptional and epigenomic consequences. By mapping global transcription start site (TSS) and chromatin dynamics, we observed the cryptic transcription of thousands of treatment-induced non-annotated TSSs (TINATs) following DNMTi and HDACi treatment. The resulting transcripts frequently splice into protein-coding exons and encode truncated or chimeric ORFs translated into products with predicted abnormal or immunogenic functions...
June 12, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28595085/mir-152-regulated-glioma-cell-proliferation-and-apoptosis-via-runx2-mediated-by-dnmt1
#8
Peng Zhang, Hongwei Sun, Bo Yang, Wenzheng Luo, Zengjin Liu, Junkuan Wang, Yuchao Zuo
BACKGROUND: Aberrant DNA methylation is associated with tumor onset and progression. Study has verified that the DNA methylation of miR-152 was mediated in many tumors, but whether it involved in glioblastomas was still unclear. METHODS: This study enrolled 20 patients with glioma to analyze the expression pattern of miR-152. Real-time PCR and western blot were used to detect the mRNA or protein expression level, respectively. The relationship between miR-152 and runx2 was detected by Luciferase reporter assay...
June 5, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28584398/tumor-necrosis-factor-%C3%AE-decreases-ec-sod-expression-through-dna-methylation
#9
Shunpei Morisawa, Hiroyuki Yasuda, Tetsuro Kamiya, Hirokazu Hara, Tetsuo Adachi
Extracellular-superoxide dismutase (EC-SOD) is a secreted antioxidative enzyme, and its presence in vascular walls may play an important role in protecting the vascular system against oxidative stress. EC-SOD expression in cultured cell lines is regulated by various cytokines including tumor necrosis factor-α (TNF-α). TNF-α is a major mediator of pathophysiological conditions and may induce or suppress the generation of various types of mediators. Epigenetics have been defined as mitotically heritable changes in gene expression that do not affect the DNA sequence, and include DNA methylation and histone modifications...
May 2017: Journal of Clinical Biochemistry and Nutrition
https://www.readbyqxmd.com/read/28583846/epigenetic-effects-of-inhibition-of-heat-shock-protein-90-hsp90-in-human-pancreatic-and-colon-cancer
#10
Ganji Purnachandra Nagaraju, Christina Wu, Neha Merchant, Zhengjia Chen, Gregory B Lesinski, Bassel F El-Rayes
Silencing of tumor suppressor and DNA repair genes through methylation plays a role in cancer development, growth and response to therapy in colorectal and pancreatic cancers. Heat shock protein 90 (HSP90) regulates transcription of DNA methyltransferase enzymes (DNMT). In addition, DNMTs are client proteins of HSP90. The aim of this study is to evaluate the effects of HSP90 inhibition on DNA methylation in colorectal and pancreatic cancer cell lines. Our data shows that inhibition of HSP90 using ganetespib resulted in downregulation of mRNA and protein expression of DNMT1, DNMT3A, and DNMT3B in HT-29 and MIA PaCa-2 cell lines...
June 3, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28582695/identification-of-potent-inhibitors-of-dna-methyltransferase-1-dnmt1-through-a-pharmacophore-based-virtual-screening-approach
#11
Shagun Krishna, Samriddhi Shukla, Amar Deep Lakra, Syed Musthapa Meeran, Mohammad Imran Siddiqi
DNA methylation is an epigenetic change that results in the addition of a methyl group at the carbon-5 position of cytosine residues. DNA methyltransferase (DNMT) inhibitors can suppress tumour growth and have significant therapeutic value. However, the established inhibitors are limited in their application due to their substantial cytotoxicity. Additionally, the standard drugs for DNMT inhibition are non-selective cytosine analogues with considerable cytotoxic side-effects. In the present study, we have designed a workflow by integrating various ligand-based and structure-based approaches to discover new agents active against DNMT1...
May 25, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28578476/lipopolysaccharide-downregulates-kruppel-like-factor-2-klf2-via-inducing-dnmt1-mediated-hypermethylation-in-endothelial-cells
#12
Zhonghai Yan, Yan Deng, Fei Jiao, Junqi Guo, Hailong Ou
KLF2 plays a protective role in antiinflammation and endothelial function, and can be regulated by promoter methylation alteration. Lipopolysaccharide (LPS) is a mediator of inflammatory responses, which causes epigenetic change of certain genes in host cells. We thus aimed to determine whether LPS could control the KLF2 expression by inducing methylation in promoter region. DNA methylation of 16 CpG sites within KLF2 promoter region was detected by bisulfite sequencing PCR. Results showed that methylation at 12 CpG sites were significantly increased in HUVECs after exposure to LPS among the total 16 sites, and the average level was increased by 57%...
June 3, 2017: Inflammation
https://www.readbyqxmd.com/read/28561043/hsps-drive-dichotomous-t-cell-immune-responses-via-dna-methylome-remodelling-in-antigen-presenting-cells
#13
Lauren B Kinner-Bibeau, Abigail L Sedlacek, Michelle N Messmer, Simon C Watkins, Robert J Binder
Immune responses primed by endogenous heat shock proteins, specifically gp96, can be varied, and mechanisms controlling these responses have not been defined. Immunization with low doses of gp96 primes T helper type 1 (Th1) immune responses, whereas high-dose immunization primes responses characterized by regulatory T (Treg) cells and immunosuppression. Here we show gp96 preferentially engages conventional and plasmacytoid dendritic cells (pDCs) under low and high doses, respectively, through CD91. Global DNMT-dependent epigenetic modifications lead to changes in protein expression within these antigen-presenting cells...
May 31, 2017: Nature Communications
https://www.readbyqxmd.com/read/28529454/characterization-of-cytosine-methylation-and-the-dna-methyltransferases-of-toxoplasma-gondii
#14
Haixia Wei, Shichen Jiang, Longfei Chen, Cheng He, Shuizhen Wu, Hongjuan Peng
DNA methylation is a key epigenetic modification which confers phenotypic plasticity and adaptation. Cyst-forming strains of Toxoplasma gondii undergo tachyzoite to bradyzoite conversion after initial acute infection of a host, and the reverse conversion may occur in immune-suppressed hosts. The formation of m(5)C is catalyzed by DNA methyltransferase (DNMT). We identified two functional DNA methyltransferases, TgDNMTa and TgDNMTb, in T. gondii that may mediate DNA methylation. The recombinant proteins showed intrinsic methyltransferase activity; both have higher transcription levels in bradyzoites than that in tachyzoites...
2017: International Journal of Biological Sciences
https://www.readbyqxmd.com/read/28467959/zeb1-confers-stem-cell-like-properties-in-breast-cancer-by-targeting-neurogenin-3
#15
Chen Zhou, Huimin Jiang, Zhen Zhang, Guomin Zhang, Hang Wang, Quansheng Zhang, Peiqing Sun, Rong Xiang, Shuang Yang
Cancer stem cells (CSCs) are a subpopulation of cancer cells believed to be implicated in cancer initiation, progression, and recurrence. Here, we report that ectopic expression of zinc finger E-box binding homeobox 1 protein (ZEB1) results in the acquisition of CSC properties by breast cancer cells, leading to tumor initiation and progression in vitro and in vivo. The neurogenin 3 gene (Ngn3) is a bona fide target of ZEB1, and its repression is a key factor contributing to ZEB1-induced cancer cell stemness...
April 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/28447752/islet-1-induces-the-differentiation-of-mesenchymal-stem-cells-into-cardiomyocyte-like-cells-through-the-regulation-of-gcn5-and-dnmt-1
#16
Qin Yi, Hao Xu, Ke Yang, Yue Wang, Bin Tan, Jie Tian, Jing Zhu
Previous studies from this group demonstrated that insulin gene enhancer binding protein ISL-1 (Islet-1) specifically induces the differentiation of mesenchymal stem cells (MSCs) into cardiomyocyte‑like cells through histone acetylation. However, the underlying mechanisms remain unclear. In the present study, the role of the histone acetylation and DNA methylation on the regulatory mechanism of the Islet‑1 was further investigated by methylation‑specific polymerase chain reaction (PCR), chromatin immunoprecipitation quantitative PCR and western blot analysis...
May 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28433417/mechanistic-insights-into-epigenetic-modulation-of-ethanol-consumption
#17
Igor Ponomarev, Claire E Stelly, Hitoshi Morikawa, Yuri A Blednov, R Dayne Mayfield, R Adron Harris
There is growing evidence that small-molecule inhibitors of epigenetic modulators, such as histone deacetylases (HDAC) and DNA methyltransferases (DNMT), can reduce voluntary ethanol consumption in animal models, but molecular and cellular processes underlying this behavioral effect are poorly understood. We used C57BL/6J male mice to investigate the effects of two FDA-approved drugs, decitabine (a DNMT inhibitor) and SAHA (an HDAC inhibitor), on ethanol consumption using two tests: binge-like drinking in the dark (DID) and chronic intermittent every other day (EOD) drinking...
May 2017: Alcohol
https://www.readbyqxmd.com/read/28429280/synergistic-anti-cancer-effects-of-epigenetic-drugs-on-medulloblastoma-cells
#18
Juan Yuan, Núria Llamas Luceño, Bjoern Sander, Monika M Golas
PURPOSE: Medulloblastomas are aggressive brain malignancies. While considerable progress has been made in the treatment of medulloblastoma patients with respect to overall survival, these patients are still at risk of developing neurologic and cognitive deficits as a result of anti-cancer therapies. It is hypothesized that targeted molecular therapies represent a better treatment option for medulloblastoma patients. Therefore, the aim of the present study was to test a panel of epigenetic drugs for their effect on medulloblastoma cells under mild hypoxic conditions that reflect the physiological concentrations of oxygen in the brain...
April 20, 2017: Cellular Oncology (Dordrecht)
https://www.readbyqxmd.com/read/28422052/folic-acid-reduces-tau-phosphorylation-by-regulating-pp2a-methylation-in-streptozotocin-induced-diabetic-mice
#19
Miaoyan Zheng, Chen Zou, Mengyue Li, Guowei Huang, Yuxia Gao, Huan Liu
High incidence rate of Alzheimer's disease (AD) is observed in patients with type 2 diabetes. Aggregated β-amyloid (Aβ) and hyperphosphorylated tau are the hallmarks of AD. Hyperphosphorylated tau has been detected in diabetic animals as well as in diabetic patients. Folates mediate the transfer of one carbon unit, required in various biochemical reactions. The effect of folate on tau phosphorylation in diabetic models still remains unknown. In this study, we investigated the effect and mechanism of folic acid on hyperphosphorylation of tau in streptozotocin (STZ)-induced diabetic mice...
April 19, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28419930/design-synthesis-and-anticancer-potential-of-nsc-319745-hydroxamic-acid-derivatives-as-dnmt-and-hdac-inhibitors
#20
Zigao Yuan, Qinsheng Sun, Dan Li, Shuangshuang Miao, Shaopeng Chen, Lu Song, Chunmei Gao, Yuzong Chen, Chunyan Tan, Yuyang Jiang
DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) are important epigenetic targets during anticancer drug development. Recent study indicates that DNMT inhibitors and HDAC inhibitors display synergistic effects in certain cancers, therefore, development of molecules targeting both DNMT and HDAC is of therapeutic advantage against these cancers. Based on the structure of DNMT inhibitor NSC-319745 and the pharmacophore characteristics of HDAC inhibitors, a series of hydroxamic acid derivatives of NSC-319745 were designed and synthesized as DNMT and HDAC multifunctional inhibitors...
April 12, 2017: European Journal of Medicinal Chemistry
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