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Himanshu Sankrityayan, Yogesh A Kulkarni, Anil Bhanudas Gaikwad
Diabetic nephropathy (DN) is still one of the leading causes of end-stage renal disease despite the emergence of different therapies to counter the metabolic, hemodynamic and fibrotic pathways, implicating a prominent role of genetic and epigenetic factors in its progression. Epigenetics is the study of changes in the expression of genes which may be inheritable and does not involve a change in the genome sequence. Thrust areas of epigenetic research are DNA methylation and histone modifications. Noncoding RNAs (ncRNAs), particularly microRNAs (miRNAs) control the expression of genes via post-transcriptional mechanisms...
January 26, 2019: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Edgar López-López, Fernando D Prieto-Martínez, José L Medina-Franco
In this work we discuss the insights from activity landscape, docking and molecular dynamics towards the understanding of the structure-activity relationships of dual inhibitors of major epigenetic targets: lysine methyltransferase (G9a) and DNA methyltranferase 1 (DNMT1). The study was based on a novel data set of 50 published compounds with reported experimental activity for both targets. The activity landscape analysis revealed the presence of activity cliffs, e.g., pairs of compounds with high structure similarity but large activity differences...
December 11, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Dandara Cassu-Corsi, Willames Mbs Martins, Adriana G Nicoletti, Luiz Gp Almeida, Ana Tr Vasconcelos, Ana C Gales
OBJECTIVES The emergence of 16S rRNA methyltranferases (16 RMTAses) has jeopardised the clinical use of aminoglycosides. RmtB is one of the most frequently reported in Gram-negatives worldwide. In this study, we aimed to estimate the frequency of 16S RMTAses encoding genes in Enterobacteriaceae isolated in a three-month period from a tertiary Brazilian hospital. METHODS All Gram-negatives classified as resistant to amikacin, gentamicin, and tobramycin by agar screening were selected for analysis. The presence of 16SRMTases encoding genes was verified by polymerase chain reaction (PCR)...
December 10, 2018: Memórias do Instituto Oswaldo Cruz
Ghazal Aarabi, Tanja Zeller, Guido Heydecke, Matthias Munz, Arne Schäfer, Udo Seedorf
Periodontitis (PD) is a common gingival infectious disease caused by an over-aggressive inflammatory reaction to dysbiosis of the oral microbiome. The disease induces a profound systemic inflammatory host response, that triggers endothelial dysfunction and pro-thrombosis and thus may aggravate atherosclerotic vascular disease and its clinical complications. Recently, a risk haplotype at the ANRIL / CDKN2B-AS1 locus on chromosome 9p21.3, that is not only associated with coronary artery disease / myocardial infarction (CAD/MI) but also with PD, could be identified by genome-wide association studies...
2018: Frontiers in Cardiovascular Medicine
Ranjan Kumar Singh, André Feller, Martine Roovers, Dany Van Elder, Lina Wauters, Louis Droogmans, Wim Versées
tRNA molecules get heavily modified post-transcriptionally. The N-1 methylation of purines at position 9 of eukaryal and archaeal tRNA is catalyzed by the SPOUT methyltranferase Trm10. Remarkably, while certain Trm10 orthologs are specific for either guanosine or adenosine, others show a dual specificity. Structural and functional studies have been performed on guanosine- and adenosine-specific enzymes. Here we report the structure and biochemical analysis of the dual-specificity enzyme from Thermococcus kodakaraensis (Tk Trm10)...
August 2018: RNA
Rajnish Kumar Singh, Fengchao Lang, Yonggang Pei, Hem Chandra Jha, Erle S Robertson
Kaposi's sarcoma associated herpesvirus (KSHV) infection stabilizes hypoxia inducible factors (HIFs). The interaction between KSHV encoded factors and HIFs plays a critical role in KSHV latency, reactivation and associated disease phenotypes. Besides modulation of large-scale signaling, KSHV infection also reprograms the metabolic activity of infected cells. However, the mechanism and cellular pathways modulated during these changes are poorly understood. We performed comparative RNA sequencing analysis on cells with stabilized hypoxia inducible factor 1 alpha (HIF1α) of KSHV negative or positive background to identify changes in global and metabolic gene expression...
May 2018: PLoS Pathogens
Ângela Marques-Magalhães, Inês Graça, Rui Henrique, Carmen Jerónimo
Urological cancers are a heterogeneous group of malignancies accounting for a considerable proportion of cancer-related morbidity and mortality worldwide. Aberrant epigenetic traits, especially altered DNA methylation patterns constitute a hallmark of these tumors. Nonetheless, these alterations are reversible, and several efforts have been carried out to design and test several epigenetic compounds that might reprogram tumor cell phenotype back to a normal state. Indeed, several DNMT inhibitors are currently under evaluation for therapeutic efficacy in clinical trials...
2018: Frontiers in Pharmacology
Christian L Lino Cardenas, Chase W Kessinger, Carolyn MacDonald, Arminder S Jassar, Eric M Isselbacher, Farouc A Jaffer, Mark E Lindsay
Loss-of-function mutations in genes encoding contractile proteins have been observed in thoracic aortic aneurysms (TAA). To gain insight into the contribution of contractile protein deficiency in the pathogenesis of TAA, we examined human aneurysm samples. We found multiple contractile gene products deficient in TAA samples, and in particular, expression of SM22α was inversely correlated with aneurysm size. SM22α-deficient mice demonstrated pregnancy-induced aortic dissection, and SM22α deficiency worsened aortic aneurysm in Fbn1C1039G/+ (Marfan) mice, validating this gene product as a TAA effector...
March 8, 2018: JCI Insight
Shiyu Chen, Yanqin Lv, Yanfei Shen, Jingjing Ji, Qing Zhou, Songqin Liu, Yuanjian Zhang
DNA methylation catalyzed by methylase plays a key role in many biological activities. However, developing a highly sensitive, simple, and reliable way for evaluation of DNA methyltransferase (MTase) activity is still a challenge. Here, we report a sandwich-assembled electrochemiluminescence (ECL) biosensor using multifunctional carbon nitride nanosheets (CNNS) to evaluate the Dam MTase activity. The CNNS could not only be used as an excellent substrate to conjugate a large amount of hairpin probe DNA to improve the sensitivity but also be utilized as an internal reliability checker and an analyte reporter in the bottom and top layers of the biosensor, respectively...
February 28, 2018: ACS Applied Materials & Interfaces
Radovan Murín, Eva Vidomanová, Bhavani S Kowtharapu, Jozef Hatok, Dušan Dobrota
Alterations in enzymatic activities underlying the cellular capacity to maintain functional S-adenosylmethionine (SAM) cycle are associated with modified levels of its constituents. Since SAM is the most prominent donor of methyl group for sustaining the methylation pattern of macromolecules by methyltransferases, its availability is an essential prerequisite for sustaining the methylation pattern of nucleic acids and proteins. In addition, increased intracellular concentrations of S-adenosylhomocysteine and homocysteine, another two constituents of SAM cycle, exerts an inhibitory effect on the enzymatic activity of methyltranferases...
December 2017: General Physiology and Biophysics
Jeongyoon Choi, Andreas Linus Bachmann, Katharina Tauscher, Christian Benda, Beat Fierz, Jürg Müller
Polycomb repressive complex 2 (PRC2) trimethylates histone H3 at lysine 27 to mark genes for repression. We measured the dynamics of PRC2 binding on recombinant chromatin and free DNA at the single-molecule level using total internal reflection fluorescence (TIRF) microscopy. PRC2 preferentially binds free DNA with multisecond residence time and midnanomolar affinity. PHF1, a PRC2 accessory protein of the Polycomblike family, extends PRC2 residence time on DNA and chromatin. Crystallographic and functional studies reveal that Polycomblike proteins contain a winged-helix domain that binds DNA in a sequence-nonspecific fashion...
December 2017: Nature Structural & Molecular Biology
Ching-Fen Yang, Hsiang-Ling Ho, Shih-Chieh Lin, Chih-Yi Hsu, Donald Ming-Tak Ho
The relationship between human cytomegalovirus (HCMV) and glioblastoma (GBM) has been debated for more than a decade. We investigated the presence of HCMV genes, RNA and protein in GBMs and their relationships with tumor progression. Results of quantitative PCR for HCMV UL73, nested PCR for HCMV UL144, in situ hybridization (ISH) for RNA transcript, and immunohistochemistry (IHC) for protein expression and their relationship to the prognosis of 116 patients with GBM were evaluated. Nine (7.8%) cases revealed a low concentration of HCMV UL73, and only 2 of the 9 (1...
2017: PloS One
Xiao-Qing Zeng, Jian Wang, Shi-Yao Chen
Gastric cancer (GC) is one of the most common cancers and the second leading cause of cancer-related mortality. Increasing discoveries have highlighted aberrant epigetic modifications actively contribute to the pathogenesis of this fatal disease. Among these epigenetic events, dysregulated methylation is particularly associated with GC progression. Importantly, these aberrant methylation modifications caused by the misregulation of methyltranferases are frequently reversible, which provides opportunities for targeted treatment using specific molecular inhibitors...
June 2017: International Journal of Oncology
Hong Fan, Jian Cheng, Zhu Jiang Zhao
BACKGROUND: Aberrant epigenetic patterns, including inactivation of tumor suppressor genes due to DNA methylation, have been described in many human cancers. Epigenetic therapeutic is a new and rapidly developing area of tumor treatment because DNA methyltransferase (DNMT) inhibitors can reverse its changes. We attempted to identify potential approach for epigenetic therapy of hepatocellular carcinoma. METHODS: We knocked down the expression of DNMT 1 or DNMT 3B by siRNA, and inhibited DNA methyltranferases by 5-Aza-2'-deoxycytidine...
December 2008: Gastroenterology Research
Shannon F Manzi, Vincent A Fusaro, Laura Chadwick, Catherine Brownstein, Catherine Clinton, Kenneth D Mandl, Wendy A Wolf, Jared B Hawkins
OBJECTIVE: This paper outlines the implementation of a comprehensive clinical pharmacogenomics (PGx) service within a pediatric teaching hospital and the integration of clinical decision support in the electronic health record (EHR). MATERIALS AND METHODS: An approach to clinical decision support for medication ordering and dispensing driven by documented PGx variant status in an EHR is described. A web-based platform was created to automatically generate a clinical report from either raw assay results or specified diplotypes, able to parse and combine haplotypes into an interpretation for each individual and compared to the reference lab call for accuracy...
January 2017: Journal of the American Medical Informatics Association: JAMIA
Yi Qu, Danyu Lu, Hao Jiang, Xiaochun Chi, Hongquan Zhang
Enhancer of zeste homolog 2 (EZH2) trimethylates histone H3 Lys 27 and plays key roles in a variety of biological processes. Stability of spindle assembly checkpoint protein BubR1 is essential for mitosis in somatic cells and for meiosis in oocytes. However, the role of EZH2 in oocyte meiotic maturation was unknown. Here, we presented a mechanism underlying EZH2 control of BubR1 stability in the meiosis of mouse oocytes. We identified a methyltransferase activity-independent function of EZH2 by demonstrating that EZH2 regulates spindle assembly and the polar body I extrusion...
September 19, 2016: Nucleic Acids Research
Chih-Yi Hsu, Hsiang-Ling Ho, Shih-Chieh Lin, Ming-Hsiung Chen, Sanford P-C Hsu, Yu-Shu Yen, Wan-Yuo Guo, Donald Ming-Tak Ho
The O-methylguanine-DNA-methyltranferase (MGMT) status is a powerful predictor of response to temozolomide for newly diagnosed glioblastoma (GBM) patients, and it is commonly assessed by immunohistochemistry (IHC), methylation-specific polymerase chain reaction (MSP), quantitative real-time MSP (qMSP), and/or pyrosequencing (PSQ). This study was to compare their predictive power of prognosis in 121 newly diagnosed GBM patients using multivariate Cox regression with bootstrapping. MGMT status tested by IHC, MSP, qMSP, or PSQ all showed significant correlation with the progression-free survival and overall survival of GBM patients...
August 2017: Applied Immunohistochemistry & Molecular Morphology: AIMM
Yuan Sun, Peyman Sahbaie, DeYong Liang, Wenwu Li, Xiaoyou Shi, Paige Kingery, J David Clark
DNA methylation is a key epigenetic mechanism controlling DNA accessibility and gene expression. Blockade of DNA methylation can significantly affect pain behaviors implicated in neuropathic and inflammatory pain. However, the role of DNA methylation with regard to postoperative pain has not yet been explored. In this study we sought to investigate the role of DNA methylation in modulating incisional pain and identify possible targets under DNA methylation and contributing to incisional pain. DNA methyltranferase (DNMT) inhibitor 5-Aza-2'-deoxycytidine significantly reduced incision-induced mechanical allodynia and thermal sensitivity...
2015: PloS One
Gabrielle Bourgeois, Michel Ney, Imre Gaspar, Christelle Aigueperse, Matthias Schaefer, Stefanie Kellner, Mark Helm, Yuri Motorin
Modified nucleotide 5-methylcytosine (m5C) is frequently present in various eukaryotic RNAs, including tRNAs, rRNAs and in other non-coding RNAs, as well as in mRNAs. RNA:m5C-methyltranferases (MTases) Nop2 from S. cerevisiae and human proliferation-associated nucleolar antigen p120 are both members of a protein family called Nop2/NSUN/NOL1. Protein p120 is well-known as a tumor marker which is over-expressed in various cancer tissues. Using a combination of RNA bisulfite sequencing and HPLC-MS/MS analysis, we demonstrated here that p120 displays an RNA:m5C- MTase activity, which restores m5C formation at position 2870 in domain V of 25S rRNA in a nop2Δ yeast strain...
2015: PloS One
Giulia Malacarne, Laura Costantini, Emanuela Coller, Juri Battilana, Riccardo Velasco, Urska Vrhovsek, Maria Stella Grando, Claudio Moser
Flavonols are a ubiquitous class of flavonoids that accumulate preferentially in flowers and mature berries. Besides their photo-protective function, they play a fundamental role during winemaking, stabilizing the colour by co-pigmentation with anthocyanins and contributing to organoleptic characteristics. Although the general flavonol pathway has been genetically and biochemically elucidated, the genetic control of flavonol content and composition at harvest is still not clear. To this purpose, the grapes of 170 segregating F1 individuals from a 'Syrah'×'Pinot Noir' population were evaluated at the mature stage for the content of six flavonol aglycons in four seasons...
August 2015: Journal of Experimental Botany
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