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(Epigenetic) and (mitochondrial dysfunction)

Valentina Medici, Dorothy A Kieffer, Noreene M Shibata, Harpreet Chima, Kyoungmi Kim, Angela Canovas, Juan F Medrano, Alma D Islas-Trejo, Kusum K Kharbanda, Kristin Olson, Ruijun J Su, Mohammad S Islam, Raisa Syed, Carl L Keen, Amy Y Miller, John C Rutledge, Charles H Halsted, Janine M LaSalle
Wilson disease (WD), a genetic disorder affecting copper transport, is characterized by hepatic and neurological manifestations with variable and often unpredictable presentation. Global DNA methylation in liver was previously modified by dietary choline in tx-j mice, a spontaneous mutant model of WD. We therefore hypothesized that the WD phenotype and hepatic gene expression of tx-j offspring could be modified by maternal methyl supplementation during pregnancy. In an initial experiment, female tx-j mice or wild type mice were fed control or choline-supplemented diets two weeks prior to mating through embryonic day 17...
September 9, 2016: Epigenetics: Official Journal of the DNA Methylation Society
Gael L M Cagnone, Marc-Andre Sirard
Recent genomic studies have shed light on the impact of in vitro culture (IVC) on embryonic homeostasis and the differential gene expression profiles associated with lower developmental competence. Consistently, the embryonic stress responses to IVC conditions correlate with transcriptomic changes in pathways related to energetic metabolism, extracellular matrix remodelling and inflammatory signalling. These changes appear to result from a developmental adaptation that enhances a Warburg-like effect known to occur naturally during blastulation...
September 6, 2016: Reproduction: the Official Journal of the Society for the Study of Fertility
Thangavel Samikkannu, Venkata S R Atluri, Madhavan P N Nair
HIV infection and cocaine use have been identified as risk factors for triggering neuronal dysfunction. In the central nervous system (CNS), energy resource and metabolic function are regulated by astroglia. Glia is the major reservoir of HIV infection and disease progression in CNS. However, the role of cocaine in accelerating HIV associated energy deficit and its impact on neuronal dysfunction has not been elucidated yet. The aim of this study is to elucidate the molecular mechanism of HIV associated neuropathogenesis in cocaine abuse and how it accelerates the energy sensor AMPKs and its subsequent effect on mitochondrial oxidative phosphorylation (OXPHOS), BRSKs, CDC25B/C, MAP/Tau, Wee1 and epigenetics remodeling complex SWI/SNF...
2016: Scientific Reports
Sanne A M van Lith, Anna C Navis, Krissie Lenting, Kiek Verrijp, Jan T G Schepens, Wiljan J A J Hendriks, Nil A Schubert, Hanka Venselaar, Ron A Wevers, Arno van Rooij, Pieter Wesseling, Remco J Molenaar, Cornelis J F van Noorden, Stefan Pusch, Bastiaan Tops, William P J Leenders
The majority of low-grade and secondary high-grade gliomas carry heterozygous hotspot mutations in cytosolic isocitrate dehydrogenase 1 (IDH1) or the mitochondrial variant IDH2. These mutations mostly involve Arg132 in IDH1, and Arg172 or Arg140 in IDH2. Whereas IDHs convert isocitrate to alpha-ketoglutarate (α-KG) with simultaneous reduction of NADP(+) to NADPH, these IDH mutants reduce α-KG to D-2-hydroxyglutarate (D-2-HG) while oxidizing NADPH. D-2-HG is a proposed oncometabolite, acting via competitive inhibition of α-KG-dependent enzymes that are involved in metabolism and epigenetic regulation...
2016: Scientific Reports
Toke Bek
Mitochondrial dysfunction may predispose to the development of diabetes mellitus with the accompanying risk for developing diabetic retinopathy or may contribute directly to the diabetic metabolic dysregulation and thereby increase the risk of diabetic late complications including retinopathy. Diabetes mellitus in mitochondrial disease can lead to the development of vision threatening retinopathy, but visual acuity is often reduced secondary to neurological deficits resulting from the mitochondrial dysfunction...
July 22, 2016: Mitochondrion
Mohammad Hossein Asghari, Milad Moloudizargari, Haji Bahadar, Mohammad Abdollahi
INTRODUCTION: Pesticides are among the most important chemicals used in agriculture sector. However, their extensive use has polluted the environment and increased human vulnerability to various chronic diseases. Pesticide exposure causes genetic and epigenetic modifications, endocrine disruption, mitochondrial dysfunction and oxidative stress. AREAS COVERED: This review is based on the literature studies currently reported on pesticide-induced toxicity and the protective role of melatonin...
July 19, 2016: Expert Opinion on Drug Metabolism & Toxicology
Satish Srinivasan, Manti Guha, Narayan G Avadhani
In the past decade mitochondria have emerged as an important cellular signaling hub controlling metabolism, epigenetics, and cell fate. Dysfunctional mitochondria initiate a retrograde nuclear response that influences the cellular reprograming observed in various human pathologies, including cancer. New data suggest that loss of cytochrome c oxidase function promotes the Warburg effect and upregulates several genes with roles in tumor development.
March 2016: Molecular & Cellular Oncology
Elisiário J Tavares-da-Silva, Carla L Varela, Ana S Pires, João C Encarnação, Ana M Abrantes, Maria F Botelho, Rui A Carvalho, Carina Proença, Marisa Freitas, Eduarda Fernandes, Fernanda M F Roleira
Colon cancer is one of the most incident cancers in the Western World. While both genetic and epigenetic factors may contribute to the development of colon cancer, it is known that chronic inflammation associated to excessive production of reactive oxygen and nitrogen species by phagocytes may ultimately initiate the multistep process of colon cancer development. Phenolic compounds, which reveal antioxidant and antiproliferative activities in colon cancer cells, can be a good approach to surpass this problem...
August 15, 2016: Bioorganic & Medicinal Chemistry
Catherine Cherry, Brian Thompson, Neil Saptarshi, Jianyu Wu, Josephine Hoh
The integration of the many roles of mitochondria in cellular function and the contribution of mitochondrial dysfunction to disease are major areas of research. Within this realm, the roles of mitochondria in immune defense, epigenetics, and stem cell (SC) development have recently come into the spotlight. With new understanding, mitochondria may bring together these seemingly unrelated fields, a crucial process in treatment and prevention for various diseases. In this review we describe novel findings in these three arenas, discussing the significance of the interplay between mitochondria and the cell nucleus in response to environmental cues...
April 14, 2016: Trends in Molecular Medicine
Carsten Merkwirth, Virginija Jovaisaite, Jenni Durieux, Olli Matilainen, Sabine D Jordan, Pedro M Quiros, Kristan K Steffen, Evan G Williams, Laurent Mouchiroud, Sarah U Tronnes, Virginia Murillo, Suzanne C Wolff, Reuben J Shaw, Johan Auwerx, Andrew Dillin
Across eukaryotic species, mild mitochondrial stress can have beneficial effects on the lifespan of organisms. Mitochondrial dysfunction activates an unfolded protein response (UPR(mt)), a stress signaling mechanism designed to ensure mitochondrial homeostasis. Perturbation of mitochondria during larval development in C. elegans not only delays aging but also maintains UPR(mt) signaling, suggesting an epigenetic mechanism that modulates both longevity and mitochondrial proteostasis throughout life. We identify the conserved histone lysine demethylases jmjd-1...
May 19, 2016: Cell
Ye Tian, Gilberto Garcia, Qian Bian, Kristan K Steffen, Larry Joe, Suzanne Wolff, Barbara J Meyer, Andrew Dillin
Organisms respond to mitochondrial stress through the upregulation of an array of protective genes, often perpetuating an early response to metabolic dysfunction across a lifetime. We find that mitochondrial stress causes widespread changes in chromatin structure through histone H3K9 di-methylation marks traditionally associated with gene silencing. Mitochondrial stress response activation requires the di-methylation of histone H3K9 through the activity of the histone methyltransferase met-2 and the nuclear co-factor lin-65...
May 19, 2016: Cell
Julia Yue Cui, Curtis D Klaassen
The pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are well-known xenobiotic-sensing nuclear receptors with overlapping functions. However, there lacks a quantitative characterization to distinguish between the PXR and CAR target genes and signaling pathways in the liver. The present study performed a transcriptomic comparison of the PXR- and CAR-targets using RNA-Seq in livers of adult wild-type mice that were treated with the prototypical PXR ligand PCN (200mg/kg, i.p. once daily for 4days in corn oil) or the prototypical CAR ligand TCPOBOP (3mg/kg, i...
September 2016: Biochimica et Biophysica Acta
Carrie C Hoefer, Rachael Hageman Blair, Javier G Blanco
Daunorubicin (DAUN) and doxorubicin (DOX) are used to treat a variety of cancers. The use of DAUN and DOX is hampered by the development of cardiotoxicity. Clinical evidence suggests that patients with leukemia and Down syndrome are at increased risk for anthracycline-related cardiotoxicity. Carbonyl reductases and aldo-keto reductases (AKRs) catalyze the reduction of DAUN and DOX into cardiotoxic C-13 alcohol metabolites. Anthracyclines also exert cardiotoxicity by triggering mitochondrial dysfunction. In recent studies, a collection of heart samples from donors with and without Down syndrome was used to investigate determinants for anthracycline-related cardiotoxicity including cardiac daunorubicin reductase activity (DA), carbonyl reductase/AKRs protein expression, mitochondrial DNA content (mtDNA), and AKR7A2 DNA methylation status...
June 2016: Journal of Pharmaceutical Sciences
Hyang-Min Byun, Elena Colicino, Letizia Trevisi, Tianteng Fan, David C Christiani, Andrea A Baccarelli
BACKGROUND: The mitochondrion is the primary target of oxidative stress in response to exogenous environments. Mitochondrial DNA (mtDNA) is independent from nuclear DNA and uses separate epigenetic machinery to regulate mtDNA methylation. The mtDNA damage induced by oxidative stress can cause mitochondrial dysfunction and is implicated in human diseases; however, mtDNA methylation has been largely overlooked in environmental studies relating to human disease. The purpose of this study was to examine the association between exposure to fine metal-rich particulates (particulate matter <2...
April 2016: Journal of the American Heart Association
Moisés Selman, Ivette Buendía-Roldán, Annie Pardo
Idiopathic pulmonary fibrosis is a chronic, progressive, and usually fatal lung disorder of unknown etiology. The disease likely results from the interaction of genetic susceptibility architecture, environmental factors such as smoking, and an abnormal epigenetic reprogramming that leads to a complex pathogenesis. Idiopathic pulmonary fibrosis occurs in middle-aged and mainly elderly adults, and in this context age has emerged as its strongest risk factor. However, the mechanisms linking it to aging are uncertain...
March 2016: Revista de Investigación Clínica; Organo del Hospital de Enfermedades de la Nutrición
Hua Liu, Paul Talalay, Jed W Fahey
Autism spectrum disorder (ASD) is a complex, life-long neurodevelopmental disorder currently affecting an estimated 1 out of 68 among children aged 8 y in the United States. ASD has complex genetic and epigenetic features that lead to the phenotype and there is no single genetic marker for the diagnosis. Therefore, the diagnosis for ASD is phenotype- based with no validated or credible laboratory tests available. Evidence-based treatments for ASD are limited. There is no FDA approved medical therapy that addresses either core ASD symptoms or pathophysiological processes associated with ASD...
2016: CNS & Neurological Disorders Drug Targets
H Wesseling, B Xu, E J Want, E Holmes, P C Guest, M Karayiorgou, J A Gogos, S Bahn
Deletions on chromosome 22q11.2 are a strong genetic risk factor for development of schizophrenia and cognitive dysfunction. We employed shotgun liquid chromatography-mass spectrometry (LC-MS) proteomic and metabonomic profiling approaches on prefrontal cortex (PFC) and hippocampal (HPC) tissue from Df(16)A(+/-) mice, a model of the 22q11.2 deletion syndrome. Proteomic results were compared with previous transcriptomic profiling studies of the same brain regions. The aim was to investigate how the combined effect of the 22q11...
March 22, 2016: Molecular Psychiatry
Walter H Moos, Eleni Maneta, Carl A Pinkert, Michael H Irwin, Michelle E Hoffman, Douglas V Faller, Kosta Steliou
Neuropsychiatric disorders are a heterogeneous group of conditions that often share underlying mitochondrial dysfunction and biological pathways implicated in their pathogenesis, progression, and treatment. To date, these disorders have proven notoriously resistant to molecular-targeted therapies, and clinical options are relegated to interventional types, which do not address the core symptoms of the disease. In this review, we discuss emerging epigenetic-driven approaches using novel acylcarnitine esters (carnitinoids) that act on master regulators of antioxidant and cytoprotective genes and mitophagic pathways...
March 2016: Drug Development Research
Michael H Irwin, Walter H Moos, Douglas V Faller, Kosta Steliou, Carl A Pinkert
Preclinical Research In this review, we discuss epigenetic-driven methods for treating neurodegenerative disorders associated with mitochondrial dysfunction, focusing on carnitinoid antioxidant-histone deacetylase inhibitors that show an ability to reinvigorate synaptic plasticity and protect against neuromotor decline in vivo. Aging remains a major risk factor in patients who progress to dementia, a clinical syndrome typified by decreased mental capacity, including impairments in memory, language skills, and executive function...
May 2016: Drug Development Research
Anna Egresi, Gabriella Lengyel, Anikó Somogyi, Anna Blázovics, Krisztina Hagymási
As the result of various effects (viruses, metabolic diseases, nutritional factors, toxic agents, autoimmune processes) abnormal liver function, liver steatosis and connective tissue remodeling may develop. Progression of this process is complex including various pathways and a number of factors. The authors summarize the factors involved in the progression of chronic liver disease. They describe the role of cells and the produced inflammatory mediators and cytokines, as well as the relationship between the disease and the intestinal flora...
February 21, 2016: Orvosi Hetilap
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