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https://www.readbyqxmd.com/read/28527406/the-relevance-of-ki-calculation-for-bi-substrate-enzymes-illustrated-by-kinetic-evaluation-of-a-novel-lysine-k-acetyltransferase-8-inhibitor
#1
Hannah Wapenaar, Thea van den Bosch, Niek G J Leus, Petra E van der Wouden, Nikolaos Eleftheriadis, Jos Hermans, Gebremedhin Solomon Hailu, Dante Rotili, Antonello Mai, Alexander Dömling, Rainer Bischoff, Hidde J Haisma, Frank J Dekker
Histone acetyltransferases (HATs) are important mediators of epigenetic post-translational modifications of histones that play important roles in health and disease. A disturbance of these modifications can result in disease states, such as cancer or inflammatory diseases. Inhibitors of HATs (HATi) such as lysine (K) acetyltransferase 8 (KAT8), could be used to study the epigenetic processes in diseases related to these enzymes or to investigate HATs as therapeutic targets. However, the development of HATi is challenged by the difficulties in kinetic characterization of HAT enzymes and their inhibitors to enable calculation of a reproducible inhibitory potency...
May 5, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28527212/apolipoprotein-e4-gender-body-mass-index-inflammation-insulin-resistance-and-air-pollution-interactions-recipe-for-alzheimer-s-disease-development-in-mexico-city-young-females
#2
Lilian Calderón-Garcidueñas, Suzanne M de la Monte
Given the epidemiological trends of increasing Alzheimer's disease (AD) and growing evidence that exposure and lifestyle factors contribute to AD risk and pathogenesis, attention should be paid to variables such as air pollution, in order to reduce rates of cognitive decline and dementia. Exposure to fine particulate matter (PM2.5) and ozone (O3) above the US EPA standards is associated with AD risk. Mexico City children experienced pre- and postnatal high exposures to PM2.5, O3, combustion-derived iron-rich nanoparticles, metals, polycyclic aromatic hydrocarbons, and endotoxins...
May 17, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28526930/micrornas-in-parkinson-s-disease
#3
REVIEW
Abhishek Singh, Dwaipayan Sen
Parkinson's disease is the second most common neurodegenerative disease commonly affecting the older population. Loss of dopaminergic neurons in the substantia nigra of brain leads to impairment of motor activities as well as cognitive defects. There are many underlying causes to this disease, both genetic and epigenetic, which are yet to be fully explored. Non-coding RNAs are significant part of our genome and are involved in various cellular processes. MicroRNAs, which are small non-coding RNAs having 20-22 nucleotides, are involved in many underlying mechanisms of pathogenesis of several neurodegenerative diseases including Parkinson's...
May 19, 2017: Experimental Brain Research. Experimentelle Hirnforschung. Expérimentation Cérébrale
https://www.readbyqxmd.com/read/28526736/chd4-mediated-dna-hypermethylation-promotes-colorectal-cancer
#4
(no author information available yet)
CHD4 maintains epigenetic silencing of tumor suppressor genes to promote tumorigenesis.
May 19, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28526543/thyroid-hormone-biosynthesis-machinery-is-altered-in-the-ischemic-myocardium-an-epigenomic-study
#5
Carolina Gil-Cayuela, Esther Roselló-LLetí, Estefanía Tarazón, Ana Ortega, Juan Sandoval, Luis Martínez-Dolz, Juan Cinca, Esther Jorge, José Ramón González-Juanatey, Francisca Lago, Miguel Rivera, Manuel Portolés
BACKGROUND: Abnormal thyroid hormone (TH) metabolism is significantly associated with impaired left ventricular (LV) function and death. Although TH was traditionally thought to be produced exclusively by the thyroid gland, an increasing number of studies report TH production in other tissues. Based on these findings, we evaluated whether the genes required for TH biosynthesis are expressed in the human heart, and whether their expression is altered in patients with ischemic cardiomyopathy (ICM) and is related to epigenetic variations...
May 11, 2017: International Journal of Cardiology
https://www.readbyqxmd.com/read/28526414/a-novel-sirt1-inhibitor-4bb-induces-apoptosis-in-hct116-human-colon-carcinoma-cells-partially-by-activating-p53
#6
Ananga Ghosh, Amrita Sengupta, Guru Pavan Kumar Seerapu, Ali Nakhi, E V Venkat Shivaji Ramarao, Navneet Bung, Gopalakrishnan Bulusu, Manojit Pal, Devyani Haldar
The NAD+-dependent protein deacetylase SIRT1 has emerged as an important target for epigenetic therapeutics of colon cancer as its increased expression is associated with cancer progression. Additionally, SIRT1 represses p53 function via deacetylation, promoting tumor growth. Therefore, inhibition of SIRT1 is of great therapeutic interest for the treatment of colon cancer. Here, we report discovery of a novel quinoxaline based small molecule inhibitor of human SIRT1, 4bb, investigated its effect on viability of colon cancer cells and molecular mechanism of action...
May 16, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28526412/adaptor-proteins-gir1-and-gir2-ii-interaction-with-the-co-repressor-topless-and-promotion-of-histone-deacetylation-of-target-chromatin
#7
Renhong Wu, Vitaly Citovsky
Understanding how root hair development is controlled is important for understanding of many fundamental aspects of plant biology. Previously, we identified two plant-specific adaptor proteins GIR1 and GIR2 that interact with the major regulator of root hair development GL2 and suppress formation of root hair. Here, we show that GIR1 and GIR2 also interact with the co-repressor TOPLESS (TPL). This interaction required the GIR1 protein EAR motif, and was essential for the transcriptional repressor activity of GIR1...
May 16, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28526340/unfolding-the-pathogenesis-of-scleroderma-through-genomics-and-epigenomics
#8
REVIEW
Pei-Suen Tsou, Amr H Sawalha
With unknown etiology, scleroderma (SSc) is a multifaceted disease characterized by immune activation, vascular complications, and excessive fibrosis in internal organs. Genetic studies, including candidate gene association studies, genome-wide association studies, and whole-exome sequencing have supported the notion that while genetic susceptibility to SSc appears to be modest, SSc patients are genetically predisposed to this disease. The strongest genetic association for SSc lies within the MHC region, with loci in HLA-DRB1, HLA-DQB1, HLA-DPB1, and HLA-DOA1 being the most replicated...
May 16, 2017: Journal of Autoimmunity
https://www.readbyqxmd.com/read/28526334/regulatory-cis-and-trans-elements-of-mitochondrial-d-loop-driven-reporter-genes-in-budding-tunicates
#9
Kaz Kawamura, Yuhya Saitoh, Loriano Ballarin, Takeshi Sunanaga
To unveil the underlying mechanism of mitochondrial gene regulation associated with ageing and budding in the tunicate Polyandrocarpa misakiensis, mitochondrial non-coding-region (NCR)-containing reporter genes were constructed. PmNCR2.3K/GFP was expressed spatiotemporally in a pattern quite similar to mitochondrial 16SrRNA. The reporter gene expression was sensitive to high dose of rifampicin similar to mitochondrial genes, suggesting that the transcription indeed occurs in mitochondria. However, the gene expression also occurred in vivo in the cell nucleus and in vitro in the nuclear extracts...
May 16, 2017: Mitochondrion
https://www.readbyqxmd.com/read/28526320/mercury-exposure-induces-cytoskeleton-disruption-and-loss-of-renal-function-through-epigenetic-modulation-of-mmp9-expression
#10
Hafizurrahman Khan, Radha Dutt Singh, Ratnakar Tiwari, Siddhartha Gangopadhyay, Somendu Kumar Roy, Dhirendra Singh, Vikas Srivastava
Mercury is one of the major heavy metal pollutants occurring in elemental, inorganic and organic forms. Due to ban on most inorganic mercury containing products, human exposure to mercury generally occurs as methylmercury (MeHg) by consumption of contaminated fish and other sea food. Animal and epidemiological studies indicate that MeHg affects neural and renal function. Our study is focused on nephrotoxic potential of MeHg. In this study, we have shown for the first time how MeHg could epigenetically modulate matrix metalloproteinase 9(MMP9) to promote nephrotoxicity using an animal model of sub chronic MeHg exposure...
May 16, 2017: Toxicology
https://www.readbyqxmd.com/read/28526299/mir-200a-regulates-cdk4-6-inhibitor-effect-by-targeting-cdk6-in-metastatic-melanoma
#11
Matias A Bustos, Shigeshi Ono, Diego M Marzese, Takashi Oyama, Yuuki Iida, Garrett Cheung, Nellie Nelson, Sandy C Hsu, Qiang Yu, Dave S B Hoon
Cyclin-dependent kinase (CDK) 4 and 6 pathway is frequently dysregulated in cutaneous melanoma. Recently, CDK4/6 inhibitors have shown promising clinical activity against several cancer types, including melanoma. Here, we demonstrate that miR-200a decreases CDK6 expression and thus reduces the response of CDK4/6 inhibitor in highly proliferative metastatic melanoma. Down-regulation of miR-200a expression in melanoma cells is associated with disease progression and a higher number of lymph node metastases. Furthermore, miR-200a expression is epigenetically modulated by both DNA methylation at the promoter region and chromatin accessibility of an upstream genomic region with enhancer activity...
May 16, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28526137/cellular-and-molecular-mechanisms-of-autoimmunity-and-lupus-nephritis
#12
S K Devarapu, G Lorenz, O P Kulkarni, H-J Anders, S R Mulay
Autoimmunity involves immune responses directed against self, which are a result of defective self/foreign distinction of the immune system, leading to proliferation of self-reactive lymphocytes, and is characterized by systemic, as well as tissue-specific, inflammation. Numerous mechanisms operate to ensure the immune tolerance to self-antigens. However, monogenetic defects or genetic variants that weaken immune tolerance render susceptibility to the loss of immune tolerance, which is further triggered by environmental factors...
2017: International Review of Cell and Molecular Biology
https://www.readbyqxmd.com/read/28525852/absolute-quantification-of-dna-methylation-using-microfluidic-chip-based-digital-pcr
#13
Zhenhua Wu, Yanan Bai, Zule Cheng, Fangming Liu, Ping Wang, Dawei Yang, Gang Li, Qinghui Jin, Hongju Mao, Jianlong Zhao
Hypermethylation of CpG islands in the promoter region of many tumor suppressor genes downregulates their expression and in a result promotes tumorigenesis. Therefore, detection of DNA methylation status is a convenient diagnostic tool for cancer detection. Here, we reported a novel method for the integrative detection of methylation by the microfluidic chip-based digital PCR. This method relies on methylation-sensitive restriction enzyme HpaII, which cleaves the unmethylated DNA strands while keeping the methylated ones intact...
May 12, 2017: Biosensors & Bioelectronics
https://www.readbyqxmd.com/read/28525743/bromodomain-protein-brd4-is-a-transcriptional-repressor-of-autophagy-and-lysosomal-function
#14
Jun-Ichi Sakamaki, Simon Wilkinson, Marcel Hahn, Nilgun Tasdemir, Jim O'Prey, William Clark, Ann Hedley, Colin Nixon, Jaclyn S Long, Maria New, Tim Van Acker, Sharon A Tooze, Scott W Lowe, Ivan Dikic, Kevin M Ryan
Autophagy is a membrane-trafficking process that directs degradation of cytoplasmic material in lysosomes. The process promotes cellular fidelity, and while the core machinery of autophagy is known, the mechanisms that promote and sustain autophagy are less well defined. Here we report that the epigenetic reader BRD4 and the methyltransferase G9a repress a TFEB/TFE3/MITF-independent transcriptional program that promotes autophagy and lysosome biogenesis. We show that BRD4 knockdown induces autophagy in vitro and in vivo in response to some, but not all, situations...
May 18, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28524856/histone-variant-h3-3-orchestrates-neural-stem-cell-differentiation-in-the-developing-brain
#15
Wenlong Xia, Jianwei Jiao
During the brain development, the process of neural stem cells (NSCs) proliferation and differentiation is precisely regulated. The deficiency in the embryonic brain development will cause serious developmental disorders. Epigenetic modifications play critical roles in controlling proliferation and differentiation in different types of stem cells. Histone variants, as one of epigenetic regulators, have been reported to be associated with many bioprocesses. Among different variants, H3.3 is one of the important epigenetic regulators, but its role in embryonic NSCs remains unclear...
May 19, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28524836/effect-of-histone-deacetylase-inhibition-on-the-expression-of-multidrug-resistance-associated-protein-2-in-a-human-placental-trophoblast-cell-line
#16
Hong-Yu Duan, Dan Ma, Kai-Yu Zhou, Tao Wang, Yi Zhang, Yi-Fei Li, Jin-Lin Wu, Yi-Min Hua, Chuan Wang
BACKGROUND: Placental multidrug resistance-associated protein 2 (MRP2), encoded by ABCC2 gene in human, plays a significant role in regulating drugs' transplacental transfer rates. Studies on placental MRP2 regulation could provide more therapeutic targets for individualized and safe pharmacotherapy during pregnancy. Currently, the roles of epigenetic mechanisms in regulating placental drug transporters are still unclear. This study aimed to investigate the effect of histone deacetylases (HDACs) inhibition on MRP2 expression in the placental trophoblast cell line and to explore whether HDAC1/2/3 are preliminarily involved in this process...
June 5, 2017: Chinese Medical Journal
https://www.readbyqxmd.com/read/28524769/machine-learning-for-epigenetics-and-future-medical-applications
#17
Lawrence B Holder, M Muksitul Haque, Michael K Skinner
Understanding epigenetic processes holds immense promise for medical applications. Advances in Machine Learning (ML) are critical to realize this promise. Previous studies used epigenetic data sets associated with the germline transmission of epigenetic transgenerational inheritance of disease and novel ML approaches to predict genome-wide locations of critical epimutations. A combination of Active Learning (ACL) and Imbalanced Class Learning (ICL) was used to address past problems with ML to develop a more efficient feature selection process and address the imbalance problem in all genomic data sets...
May 19, 2017: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/28524743/nanoparticle-exposures-from-nano-enabled-toner-based-printing-equipment-and-human-health-state-of-science-and-future-research-needs
#18
Sandra Vanessa Pirela, John Martin, Dhimiter Bello, Philip Demokritou
Toner formulations used by laser printers (LP) and photocopiers (PC), collectively called "toner-based printing equipment" (TPE), are nano-enabled products (NEP) because they contain several engineered nanomaterials (ENM) that improve toner performance. It has been shown that during consumer use (printing), these ENM are released in the air, together with other semi-volatile organic nanoparticles, and newly formed gaseous co-pollutants such as volatile organic compounds (VOC). The aim of this review is to detail and analyze physico-chemical and morphological (PCM), as well as the toxicological properties of particulate matter (PM) emissions from TPE...
May 19, 2017: Critical Reviews in Toxicology
https://www.readbyqxmd.com/read/28524214/-possible-treatments-for-infantile-spinal-atrophy
#19
S I Pascual-Pascual, M Garcia-Romero
The new treatments of spinal muscular atrophy (SMA) due by SMN1 gene deletions are reviewed. There are several ways to increase the protein SMN, its activity and persistence in the tissues. Neuroprotective drugs as olesoxime or riluzole, and drugs acting by epigenetic mechanisms, as histone deacetylase inhibitors, have shown positive effects in preclinical studies but no clear efficacy in clinical trials. They might give in the future added benefits when used associated to other genetic modifying drugs. The best improvements in murine models of SMA and in clinical trials have been reached with antisense oligonucleotides, drugs that modify the splicing of SMN2, and they are expected to get better in the near future...
May 17, 2017: Revista de Neurologia
https://www.readbyqxmd.com/read/28524180/aberrant-epigenetic-regulation-of-gabrp-associates-with-aggressive-phenotype-of-ovarian-cancer
#20
Hye Youn Sung, San-Duk Yang, Woong Ju, Jung-Hyuck Ahn
Metastasis is a major cause of therapeutic failure in ovarian cancer. To elucidate molecular mechanisms of ovarian cancer metastasis, we previously established a metastatic xenograft mouse model using human ovarian carcinoma SK-OV-3 cells. Using gene expression profiling, we found that γ-aminobutyric acid (GABA)A receptor π subunit (GABRP) expression was upregulated (>4-fold) in metastatic tissues from our xenograft mice compared with SK-OV-3 cells. Importantly, GABRP knockdown diminished the migration and invasion of SK-OV-3 cells, and reduced extracellular signal-regulated kinase (ERK) activation while overexpression of GABRP exhibited significantly increased cell migration, invasion and ERK activation...
May 19, 2017: Experimental & Molecular Medicine
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