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Search Results: 1 - 10 of 12485 matches for " DNA methyltransferase inhibition "
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Epigenetic modulation in the treatment of atherosclerotic disease
Mikaela M. Byrne,Anthony W. Ryan
Frontiers in Genetics , 2014, DOI: 10.3389/fgene.2014.00364
Abstract: Cardiovascular disease is the single largest cause of death in the western world and its incidence is on the rise globally. Atherosclerosis, characterized by the development of atheromatus plaque, can trigger luminal narrowing and upon rupture result in myocardial infarction or ischemic stroke. Epigenetic phenomena are a focus of considerable research interest due to the role they play in gene regulation. Epigenetic mechanisms such as DNA methylation and histone acetylation have been identified as potential drug targets in the treatment of cardiovascular disease. miRNAs are known to play a role in gene silencing, which has been widely investigated in cancer. In comparison, the role they play in cardiovascular disease and plaque rupture is not well understood. Nutritional epigenetic modifiers from dietary components, for instance sulforaphane found in broccoli, have been shown to suppress the pro-inflammatory response through transcription factor activation. This review will discuss current and potential epigenetic therapeutics for the treatment of cardiovascular disease, focusing on the use of miRNAs and dietary supplements such as sulforaphane and protocatechuic aldehyde.
O 6 -methylguanine DNA methyltransferase gene promoter methylation in high-grade gliomas: A review of current status
Suri Vaishali,Jha Prerana,Sharma Mehar,Sarkar Chitra
Neurology India , 2011,
Abstract: Assessment of promoter methylation of the O 6 -methylguanine DNA methyltransferase (MGMT) gene has recently gained importance in molecular profiling of high-grade gliomas. It has emerged not only as an important prognostic marker but also as a predictive marker for response to temozolomide in patients with newly diagnosed glioblastoma. Further, recent studies indicate that MGMT promoter methylation has strong prognostic relevance even in anaplastic (grade III) gliomas, irrespective of therapy (chemotherapy or radiotherapy). This article provides an overview of its use as a predictive and prognostic biomarker, as well as the methods employed for its assessment and use in therapeutic decision making.
High Expression of DNMT1 was Correlated with beta-catenin Accumulation and Malignant Phynotype of Lung Squamous Cell Carcinoma and Adenocarcinoma
Hongtao XU,Zuozhou WANG,Di LIU,Qingchang LI
Chinese Journal of Lung Cancer , 2010,
Abstract: Background and objective DNA methyltransferase 1 (DNMT1) is one of the important molecules regulating DNA methylation. The abnormal expression of DNMT1 was associated with the methylation and inactivation of tumor suppressor gene and tumorigenesis. The aim of this study is to clarify the difference of DNMT1 expression between lung cancer tissues and corresponding normal lung tissues, to analyze the relationships between DNMT1 expression and clinicopathologic characteristics of lung squamous cell carcinoma and adenocarcinoma, and to investigate the correlation between the expressions of DNMT1 and β-catenin. Methods The expressions of DNMT1 and β-catenin were examined in 84 lung squamous cell carcinoma and adenocarcinoma tissues and corresponding normal lung tissues using tissue microarray and immunohistochemistry. Results The average positive rate of DNMT1 was significantly higher in 84 lung cancer tissues [(58.04±35.07)%] than that in corresponding normal lung tissues [(6.88±10.26)%](t=12.835, P < 0.001). The high expression of DNMT1 was positively correlated with adenocarcinoma histological type (r=0.365, P=0.001), poor differentiation (r=0.253, P=0.021) and lymph node metastasis (r=0.246, P=0.024) in lung cancer. The expression of DNMT1 was significantly correlated with the cytoplasmic expression of β-catenin (r=0.571, P < 0.001). Conclusion The high expression of DNMT1 was a common phenomenon in lung squamous cell carcinoma and adenocarcinoma. The high expression of DNMT1 was correlated with the malignant phynotype of lung cancer. DNMT1 may express coordinately with β-catenin in lung cancer.
Thymidine Glycol: The Effect on DNA Structure and DNA Binding by Site-Specific Proteins  [PDF]
Elena A. Kubareva, Fan Yang, Alexandra Yu. Ryazanova, Nina G. Dolinnaya, Andrei V. Golovin, Nikolai V. Molochkov, Elena A. Romanova, Elizaveta A. Karpova, Timofei S. Zatsepin, Tatiana S. Oretskaya
Natural Science (NS) , 2015, DOI: 10.4236/ns.2015.711051
Abstract: Thymidine glycol (5,6-dihydroxy-5,6-dihydrothymidine, Tg) is a major type of oxidative damage in DNA. During chemical oligonucleotide synthesis, Tg residue was incorporated in the different positions of 17 b.p. DNA duplexes, which differ in one base pair in the internal part. According to UV-melting curves, Tg destabilizes the double helix in a sequence independent manner. In contrast, the localized alterations in duplex structure were shown by CD spectroscopy to depend on the type of base pairs flanking the Tg lesion. Molecular dynamics simulations demonstrate that Tg is partially out of the double helix. For the first time, Tg impact on several site-specific DNA-binding proteins is studied, namely p50 and p65 subunits of nuclear factor kappa-B (NF-κB) and DNA methyltransferase SsoII (M.SsoII). Our results show that p50/p50 and p65/p65 homodimers of NF-κB can tolerate a single Tg residue in the binding site quite well. Nevertheless the homodimers have different affinities to the oxidized κB site depending on the Tg position. M.SsoII can act as a transcription repressor when bound to the regulatory site. M.SsoII demonstrates decreased affinity and lowered methylation efficiency when its methylation site contains Tg in the central position. Single Tg in one half of the regulatory site decreases M.SsoII affinity to the oxidized DNA, whereas Tg presence in both half-sites prevents M.SsoII binding to such ligand.
DNMT (DNA methyltransferase) inhibitors radiosensitize human cancer cells by suppressing DNA repair activity
Hak Jae Kim, Jin Ho Kim, Eui Kyu Chie, Park Da Young, In Ah Kim, Il Han Kim
Radiation Oncology , 2012, DOI: 10.1186/1748-717x-7-39
Abstract: A549 (lung cancer) and U373MG (glioblastoma) cells were exposed to radiation with or without six DNMT inhibitors (5-azacytidine, 5-aza-2'-deoxycytidine, zebularine, hydralazine, epigallocatechin gallate, and psammaplin A) for 18 hours prior to radiation, after which cell survival was evaluated via clonogenic assays. Cell cycle and apoptosis were analyzed via flow cytometry. Expressions of DNMT1, 3A/3B, and cleaved caspase-3 were detected via Western blotting. Expression of γH2AX, a marker of radiation-induced DNA double-strand break, was examined by immunocytochemistry.Pretreatment with psammaplin A, 5-aza-2'-deoxycytidine, and zebularine radiosensitized both A549 and U373MG cells. Pretreatment with psammaplin A increased the sub-G1 fraction of A549 cells, as compared to cells exposed to radiation alone. Prolongation of γH2AX expression was observed in the cells treated with DNMT inhibitors prior to radiation as compared with those treated by radiation alone.Psammaplin A, 5-aza-2'-deoxycytidine, and zebularine induce radiosensitivity in both A549 and U373MG cell lines, and suggest that this effect might be associated with the inhibition of DNA repair.Epigenetic alteration is one of the most important gene regulatory mechanisms. Unlike genetic alterations, epigenetic events are not changes in gene function that occur in conjunction with DNA sequence changes. Recently, epigenetic studies have been conducted in many different aspects of biology, and particularly in the cancer field. DNA methylation and histone modifications are two principal factors in epigenetic phenomena. These two mechanisms perform a crucial function in carcinogenesis and tumor progression.DNA methylation is controlled by DNA methyltransferase (DNMT), an enzyme that catalyzes the transfer of a methyl moiety from S-adenosyl-l-methionine to the 5-postion of cytosines in the CpG dinucleotide [1]. DNMT overexpression has been detected in a variety of malignancies, including lung, prostate, and colorect
Inhibition of DNA methyltransferase activity and expression by treatment with the pan-deacetylase inhibitor panobinostat in hepatocellular carcinoma cell lines
Zopf Steffen,Ocker Matthias,Neureiter Daniel,Alinger Beate
BMC Cancer , 2012, DOI: 10.1186/1471-2407-12-386
Abstract: Background Hepatocellular carcinoma (HCC) still represents an unmet medical need. Epigenetic inactivation of tumor suppressor genes like RASSF1A or APC by overexpression of DNA methyltransferases (DNMTs) has been shown to be common in HCC and to be linked to the overall prognosis of patients. Inhibitors of protein and histone deacetylases (DACi) have been demonstrated to possess strong anti-tumor effects in HCC models. Methods We therefore investigated whether DACi also has any influence on the expression and activity of DNMTs and methylated target genes in HepG2 and Hep3B cell culture systems and in a xenograft model by immunohistochemistry, westernblotting, RT-qPCR and methylation-specific PCR. Results Our findings demonstrate a rapid inhibition of DNMT activity 6 h after treatment with 0.1 μM of the pan-DACi panobinostat. A downregulation of DNMT mRNAs and protein were also observed at later points in time. This loss of DNMT activity and expression was paralleled by a diminished methylation of the target genes RASSF1A and APC and a concomitant re-expression of APC mRNA and protein. Analysis of HepG2 xenograft specimens confirmed these results in vivo. Conclusion We suggest a dual mode of action of DACi on DNA methylation status: a rapid inhibition of enzyme activity due to interference with posttranslational acetylation and a delayed effect on transcriptional control of DNMT genes by HDAC or miRNA mechanisms.
Epigenetic Modulating Agents as a New Therapeutic Approach in Multiple Myeloma
Ken Maes,Eline Menu,Els Van Valckenborgh,Ivan Van Riet,Karin Vanderkerken,Elke De Bruyne
Cancers , 2013, DOI: 10.3390/cancers5020430
Abstract: Multiple myeloma (MM) is an incurable B-cell malignancy. Therefore, new targets and drugs are urgently needed to improve patient outcome. Epigenetic aberrations play a crucial role in development and progression in cancer, including MM. To target these aberrations, epigenetic modulating agents, such as DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi), are under intense investigation in solid and hematological cancers. A clinical benefit of the use of these agents as single agents and in combination regimens has been suggested based on numerous studies in pre-clinical tumor models, including MM models. The mechanisms of action are not yet fully understood but appear to involve a combination of true epigenetic changes and cytotoxic actions. In addition, the interactions with the BM niche are also affected by epigenetic modulating agents that will further determine the in vivo efficacy and thus patient outcome. A better understanding of the molecular events underlying the anti-tumor activity of the epigenetic drugs will lead to more rational drug combinations. This review focuses on the involvement of epigenetic changes in MM pathogenesis and how the use of DNMTi and HDACi affect the myeloma tumor itself and its interactions with the microenvironment.
Dietary Conjugated Linoleic Acids Arrest Cell Cycle Progression and Prevent Ovarian Cancer Xenografts Growth Suggesting a Trans-10 Cis-12 Isoform Specific Activity  [PDF]
Philippe Thuillier, Nupur T. Pande, Andrea Ghena, Shuang Song, Yancey Lawrence, Vidya Shridhar, Yasmine Akkari, Tanja Pejovic, Susan Olson
Journal of Cancer Therapy (JCT) , 2013, DOI: 10.4236/jct.2013.45A006
Abstract:

Therapies for treating ovarian cancer (OvCa) successfully are largely inadequate. Alternative therapies and diet(s) with preventive potential to debilitated onset, and reduced OvCa tumor burden in situ, have not been systematically studied. Preventive role of conjugated linoleic acids (CLAs) has been reported in many other cancers. We report the first systematic in vitro and in vivo study modeling potential preventive mechanism(s) of CLA, an octadecadienolic fatty acid in clear cell OvCa cell line TOV-21G. We demonstrate that a dose and time-dependent down-regulation of cyclin E and A proteins (p < 0.05) by CLA (t10,c12) was concomitant with cell cycle arrest of TOV-21G cell lines in S phase. To understand the molecular mechanism underlying CLA (t10,c12) induced S phase arrest, levels of cell cycle regulatory proteins were determined by western blot analyses. Exposure to CLA (t10,c12) increased p21(CIP1/WAF1), and p27(KIP1) protein levels in a time and dose-dependent manner. Interestingly CLA (t10,c12) did not significantly affect protein levels of cyclin-dependent kinase (cdk) 2, and p53, however, hyperphosphorylated form of pRb (p < 0.05) was abrogated. Exposure to CLA (c9,t11) indicated a modest increase in p21(CIP1/WAF1) and p27(KIP1)

Sensitivity of Planktonic Aquatic Bacteria to Ciprofloxacin  [PDF]
Brij Verma, David Verma
Advances in Microbiology (AiM) , 2016, DOI: 10.4236/aim.2016.610074
Abstract: Many anthropogenic compounds, such as antibiotics, are found at trace levels (<μg·L-1) in aquatic and terrestrial systems. The effect of these compounds on the metabolism and function of microbes are difficult to assess because the assays used, such as the minimum inhibitory concentration (MIC) and the disk diffusion methods, lack the sensitivities to measure bacterial response to these very low levels of antibiotics on bacterial populations. Therefore, we theorized that the [3H] thymidine incorporation into DNA method might be sensitive in determining the effect of DNA inhibiting antibiotics on DNA production in planktonic bacteria in aquatic systems. Utilizing the 3H thymidine method, we measured the effects of ciprofloxacin on DNA production on planktonic bacteria in river and pond waters. Ciprofloxacin significantly (P < 0.02) inhibited river water bacteria at a concentration of 25 μg·L-1 but significant inhibition (P < 0.01) occurred at 1000 μg·L-1in pond water. The very low concentration required to inhibit DNA production in river water bacteria indicates that bacteria are extremely sensitive to antibiotics at very low concentrations. A likely reason for the differences in inhibition between the two waters is due to ciprofloxacin becoming bound, and possibly becoming biologically inactive, in the pond water due to higher dissolved organic carbon content. This work demonstrates that bacteria in some aquatic systems can be significantly impacted by low concentrations of anthropogenic antibiotics finding their way into these systems and that our assumptions as to the concentrations at which antibiotics affect microbes are highly underestimated.
DNA-Like Duplex Structures Derived from Chemistry Based on 2’-Deoxy-Cytidine: A New Model for Base-Specific Inhibition of G and C on DNA and RNA Level  [PDF]
Henk M. Buck
Journal of Biophysical Chemistry (JBPC) , 2018, DOI: 10.4236/jbpc.2018.93003
Abstract: The new epigenetic elements 5-hydroxymethyl-dC, 5-formyl-dC, and 5-car- boxy-dC may be considered as intermediates of an active demethylation process. A comprehensive mechanistic model is given for the C-C bond cleavage focused on the chemistry within the DNA duplex structure. In addition we register spin-off chemistry of this process in evaluating new duplex systems closely related to natural DNA and RNA concerning their hydrogen-bond symmetrization. A model is composed for a base-specific inhibition of G and C on the DNA and RNA level. C-G combinations are of general importance in controlling the dynamics of gene expression. In some way the suggested model systems are related to antisense oligonucleotides (ASOs).
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