DOCSLIB.ORG

Pyrroloquinoline Quinone Increases the Expression and Activity of Sirt1

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Pyrroloquinoline Quinone Increases the Expression and Activity of Sirt1 NUTRITION RESEARCH 35 (2015) 844– 849 Available online at www.sciencedirect.com ScienceDirect www.nrjournal.com Communication Pyrroloquinoline quinone increases the expression ☆ and activity of Sirt1 and -3 genes in HepG2 cells Jian Zhang a, Sunitha Meruvu a, Yudhishtar Singh Bedi a, Jason Chau a, Andrix Arguelles a, Robert Rucker b, Mahua Choudhury a,⁎ a Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Kingsville, TX, USA b Department of Nutrition, University of California, Davis, CA, USA ARTICLE INFO ABSTRACT Article history: Sirtuin (Sirt) 1 and Sirt 3 are nicotinamide adenine dinucleotide (+)-dependent protein Received 24 March 2015 deacetylases that are important to a number of mitochondrial-related functions; thus, Revised 24 June 2015 identification of sirtuin activators is important. Herein, we hypothesize that pyrroloquinoline Accepted 30 June 2015 quinone (PQQ) can act as a Sirt1/Sirt3 activator. In HepG2 cell cultures, PQQ increased the expression of Sirt1 and Sirt3 gene, protein, and activity levels (P < .05). We also observed a Keywords: significant increase in nicotinamide phosphoribosyltransferase gene expression (as early as 18 Sirtuins hours) and increased NAD+ activity at 24 hours. In addition, targets of Sirt1 and Sirt3 Pyrroloquinoline quinone (peroxisome proliferator–activated receptor γ coactivator 1α, nuclear respiratory factor 1 and 2, Metabolic syndrome and mitochondrial transcription factor A) were increased at 48 hours. This is the first report Mitochondria that demonstrates PQQ as an activator of Sirt1 and Sirt3 expression and activity, making it an Aging attractive therapeutic agent for the treatment of metabolic diseases and for healthy aging. Mitochondrial biogenesis regulators Based on our study and the available data in vivo, PQQ has the potential to serve as a therapeutic nutraceutical, when enhancing mitochondrial function. © 2015 Elsevier Inc. All rights reserved. 1. Introduction has emerged as a new frontier for the discovery of how networks of modified genes contribute to major pathologies. Recent evidence suggests that environmental factors (eg, In this regard, the sirtuins have emerged as a group of chemicals, physiologic stress, and nutrition) are important mitochondrial nicotinamide adenine dinucleotide (NAD)+- in the epigenetic regulation of metabolically active tissues. dependent protein deacetylases that act as cellular sensors Indeed, the interaction between genes and the environment in the regulation of a wide range of cellular processes [1]. Abbreviations: CR, caloric restriction; mRNA, messenger RNA; NAMPT, nicotinamide phosphoribosyltransferase; NRF-1, nuclear respiratory factor 1; NRF-2, nuclear respiratory factor 2; PGC-1α, peroxisome proliferator–activated receptor γ coactivator 1α; PQQ, pyrroloquinoline quinone; qRT-PCR, quantitative real-time reverse transcription–polymerase chain reaction; Tfam, mitochondrial transcription factor A. ☆ Competing financial interests: The authors have declared that no conflict of interest exists. ⁎ Corresponding author. Morris L Lichtenstein Jr, Medical Research Scientist, Assistant Professor I, Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center; Assistant Professor, Nutrition and Food Science, Texas A&M University, MS 131, 1010 West Ave B, Kingsville, TX, 78363 USA. Tel.: +1 361 221 0753; fax: +1 361 221 0793. E-mail address: [email protected] (M. Choudhury). URL: http://pharmacy.tamhsc.edu/labs/choudhury/ (M. Choudhury). http://dx.doi.org/10.1016/j.nutres.2015.06.014 0271-5317/© 2015 Elsevier Inc. All rights reserved. NUTRITION RESEARCH 35 (2015) 844– 849 845 Among the 7 types of sirtuins, Sirt1 and Sirt3 have been most DNA was generated from 1 μg of RNA by reverse transcription extensively investigated. (Applied Biosystems, Foster City, CA) Primer sequences are listed Our focus on Sirt1 and Sirt3 is fueled in part by the finding in the Supplementary Table 1. Relative gene expression was that Sirt3 activity is down-regulated upon exposure to a high-fat determined by quantitative real-time reverse transcription– diet [1] and that Sirt1 plays a role in whole-body energy polymerase chain reaction (qRT-PCR) and expressed relative metabolism [2]. As specific examples, Sirt3-deficient mice to 18S. display augmented mitochondrial protein hyperacetylation For the immunoblotting, 1 × 106 cells were plated in 6 well and accelerated development of the metabolic syndrome when plates. Twenty-four hours later, cells were incubated with fed a high-fat diet [1,3]. In addition to whole-body metabolism, either control Dulbecco's Modified Eagle's Medium or media Sirt1 appears important to pancreatic β-cell integrity and supplemented with PQQ for 48 hours. Cells were washed with function [4], reducing myocardial hypertrophy [5] and neuropro- ice-cold phosphate-buffered saline and scraped into ice-cold tection [6].Furthermore,bothSirt1and Sirt3 are involved in radioimmunoprecipitation assay buffer lysis buffer or high- the regulation of mitochondrial biogenesis [7] (Supplementary salt buffer [1] containing protease inhibitors (Sigma). The Fig. 2). Because sirtuins play beneficial roles in a number of protein concentration in the cell lysate was determined using a pathophysiologic conditions, there is an increasing interest in Bradford assay. Total cell lysate (30 μg) was separated by identifying compounds, especially natural products that can sodium dodecyl sulfate polyacrylamide gel electrophoresis modulate the activity of sirtuins or increase their expression (Bio-Rad Ready Gels) under reducing conditions and transferred levels [8]. To date, only few natural compounds (eg, resveratrol) to nitrocellulose membrane. Bands were visualized by chemi- have been found to activate Sirt1 [9]. luminescence using WesternSure ECL chemiluminescent sub- Pyrroloquinoline quinone is an aromatic heterocyclic strate (LI-COR). Membranes were imaged using a LiCor C-digit anionic orthoquinone found in plant foods, especially effec- Blot scanner, and blots were analyzed by ImageStudio software tive in neutralizing superoxide and hydroxyl radicals, two (LI-COR). Both actin and GAPDH were used as loading controls. prominent causes of mitochondrial dysfunction. Most signif- icantly, PQQ not only protects mitochondria from oxidative 2.4. Sirtuin and NAD+/nicotinamide adenine dinucleotide stress; it also promotes mitochondrial biogenesis [10]. Varying (NADH) activity assays PQQ in the diets of mice and rats also results in changes in mitochondrial content and altered lipid metabolism [11]. Sirt1andSirt3activityassayswere performed with slight However, many aspects of its mechanism of action remain modifications [1] using kits from Cayman Chemical Company unclear. Here, we hypothesize that PQQ can act as a Sirt1/Sirt3 (SIRT1 Direct Fluorescent Screening Assay Kit, catalog no. activator. Thus, in the present study, we investigated whether 10010401; SIRT3 Direct Fluorescent Screening Assay Kit, catalog PQQ has an effect on Sirt1/Sirt3 expression and activities. no. 10011566). The NAD+/NADH assay was performed according Using a HepG2 cell line, we also investigated whether the to the manufacturer's protocol using NAD/NADH Cell Based stimulation of the sirtuin pathway increased the mitochon- Assay Kit (catalog no. 600480) from Cayman Chemical Company. drial function and biogenesis in the treated cells. 2.5. Statistical analyses 2. Methods and materials All data are presented as the means ± SE. Statistical significance was determined by Student t test (α = .05) or 2.1. Reagents one-way analysis of variance using Tukey test (α = .05). Pyrroloquinoline quinone disodium salt was a gift from Mitsubishi Gas and Chemical (Tokyo, Japan). Antibodies 3. Results and discussion were purchased from Santa Cruz Biotechnology or Cell Signaling Technology. The present study is the first report to identify the effects of PQQ on sirtuins. Pyrroloquinoline quinone exposure (10-30 μM) 2.2. Cell culture significantly increased Sirt1 and Sirt3 gene and protein expres- sion as well as activity and decreased overall protein acetyla- Cells were cultured in Dulbecco's Modified Eagle's Medium tion in the human hepatocyte cell line, HepG2 (Fig. 1). The PQQ media supplemented with 10% fetal bovine serum, 100 U/mL concentrations that were used were based on our previous penicillin, and 100 mg/mL streptomycin. The cells were observations [10]. Pyrroloquinoline quinone treatment did maintained in a humidified incubator at 37°C under 5% CO2. not alter membrane potential or cell viability (Supplementary Figs. 3 and 4). For comparison, to obtain similar results 2.3. Quantitative real-time reverse transcription–polymerase using resveratrol or piceatannol (a resveratrol metabolite) chain reaction and immunoblotting and a hepatocyte culture system, somewhat higher concentra- tions (>50 μM) are often needed [12]. With regard to PQQ, HepG2 cells (2.5 × 105 per well) were plated in 24 well plates. the need for micromolar amounts is most likely due to Twenty-four hours later, cells were incubated in control or PQQ- the reaction of PQQ with amino acids and proteins to supplemented media for 48 hours, and total RNA was isolated form derivatives, primarily imidazolopyrroquinoline [13]. from cells using E.Z.N.A Total RNA kit I (Omega Bio-Tek) Imidazolopyrroquinoline does not influence mitochondrio- according to the manufacturer's instructions. Complementary genesis [10] but appears to be the dominant form of PQQ in 846 NUTRITION RESEARCH
Load more

Recommended publications
  • Understanding the Potential Role of Sirtuin 2 on Aging: Consequences of SIRT2.3 Overexpression in Senescence
    International Journal of Molecular Sciences Article Understanding the Potential Role of Sirtuin 2 on Aging: Consequences of SIRT2.3 Overexpression in Senescence Noemi Sola-Sevilla 1, Ana Ricobaraza 2, Ruben Hernandez-Alcoceba 2 , Maria S. Aymerich 3,4, Rosa M. Tordera 1 and Elena Puerta 1,* 1 Pharmacology and Toxicology Department, Faculty of Pharmacy, University of Navarra, Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain; [email protected] (N.S.-S.); [email protected] (R.M.T.) 2 Gene Therapy Program CIMA, University of Navarra, Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain; [email protected] (A.R.); [email protected] (R.H.-A.) 3 Departamento de Bioquímica y Genética, Facultad de Ciencias, Universidad de Navarra, 31008 Pamplona, Spain; [email protected] 4 Neuroscience Program CIMA, University of Navarra, Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain * Correspondence: [email protected] Abstract: Sirtuin 2 (SIRT2) has been associated to aging and age-related pathologies. Specifically, an age-dependent accumulation of isoform 3 of SIRT2 in the CNS has been demonstrated; however, no study has addressed the behavioral or molecular consequences that this could have on aging. In the present study, we have designed an adeno-associated virus vector (AAV-CAG-Sirt2.3-eGFP) for the overexpression of SIRT2.3 in the hippocampus of 2 month-old SAMR1 and SAMP8 mice. Our Citation: Sola-Sevilla, N.; results show that the specific overexpression of this isoform does not induce significant behavioral or Ricobaraza, A.; Hernandez-Alcoceba, molecular effects at short or long term in the control strain. Only a tendency towards a worsening in R.; Aymerich, M.S.; Tordera, R.M.; the performance in acquisition phase of the Morris Water Maze was found in SAMP8 mice, together Puerta, E.
    [Show full text]
  • Effect of Pyrroloquinoline Quinone Disodium in Female Rats During
    Downloaded from British Journal of Nutrition (2019), 121, 818–830 doi:10.1017/S0007114519000047 © The Authors 2019 https://www.cambridge.org/core Effect of pyrroloquinoline quinone disodium in female rats during gestating and lactating on reproductive performance and the intestinal barrier functions in the progeny . IP address: Boru Zhang, Wei Yang, Hongyun Zhang, Shiqi He, Qingwei Meng, Zhihui Chen and Anshan Shan* Institute of Animal Nutrition, Northeast Agricultural University, Harbin 150030, People’s Republic of China 170.106.202.226 (Submitted 26 September 2018 – Final revision received 21 December 2018 – Accepted 28 December 2018 – First published online 28 January 2019) , on Abstract 30 Sep 2021 at 19:42:41 The objective of this study was to investigate the effects of dietary pyrroloquinoline quinone disodium (PQQ·Na2) supplementation on the reproductive performance and intestinal barrier functions of gestating and lactating female Sprague–Dawley (SD) rats and their offspring. Dietary supplementation with PQQ·Na2 increased the number of implanted embryos per litter during gestation and lactation at GD 20 and increased the number of viable fetuses per litter, and the weight of uterine horns with fetuses increased at 1 d of newborn. The mRNA expression levels of catalase (CAT), glutathione peroxidase (GPx2), superoxide dismutase (SOD1), solute carrier family 2 member 1 (Slc2a1) · and solute carrier family 2 member 3 (Slc2a3) in the placenta were increased with dietary PQQ Na2 supplementation. Dietary , subject to the Cambridge Core terms of use, available at supplementation with PQQ·Na2 in gestating and lactating rats increased the CAT, SOD and GPx activities of the jejunal mucosa of weaned rats on PD 21.
    [Show full text]
  • Annotation Guidelines for Experimental Procedures
    Annotation Guidelines for Experimental Procedures Developed By Mohammed Alliheedi Robert Mercer Version 1 April 14th, 2018 1- Introduction and background information What is rhetorical move? A rhetorical move can be defined as a text fragment that conveys a distinct communicative goal, in other words, a sentence that implies an author’s specific purpose to readers. What are the types of rhetorical moves? There are several types of rhetorical moves. However, we are interested in 4 rhetorical moves that are common in the method section of a scientific article that follows the Introduction Methods Results and Discussion (IMRaD) structure. 1- Description of a method: It is concerned with a sentence(s) that describes experimental events (e.g., “Beads with bound proteins were washed six times (for 10 min under rotation at 4°C) with pulldown buffer and proteins harvested in SDS-sample buffer, separated by SDS-PAGE, and analyzed by autoradiography.” (Ester & Uetz, 2008)). 2- Appeal to authority: It is concerned with a sentence(s) that discusses the use of standard methods, protocols, and procedures. There are two types of this move: - A reference to a well-established “standard” method (e.g., the use of a method like “PCR” or “electrophoresis”). - A reference to a method that was previously described in the literature (e.g., “Protein was determined using fluorescamine assay [41].” (Larsen, Frandesn and Treiman, 2001)). 3- Source of materials: It is concerned with a sentence(s) that lists the source of biological materials that are used in the experiment (e.g., “All microalgal strains used in this study are available at the Elizabeth Aidar Microalgae Culture Collection, Department of Marine Biology, Federal Fluminense University, Brazil.” (Larsen, Frandesn and Treiman, 2001)).
    [Show full text]
  • Mechanism of Reconstitution/Activation of the Soluble PQQ-Dependent Glucose Dehydrogenase from Acinetobacter Calcoaceticus
    Mechanism of reconstitution/activation of the soluble PQQ-dependent glucose dehydrogenase from Acinetobacter calcoaceticus: a comprehensive study Claire Stines-Chaumeil, François Mavré, Brice Kauffmann, Nicolas Mano, Benoit Limoges To cite this version: Claire Stines-Chaumeil, François Mavré, Brice Kauffmann, Nicolas Mano, Benoit Limoges. Mecha- nism of reconstitution/activation of the soluble PQQ-dependent glucose dehydrogenase from Acine- tobacter calcoaceticus: a comprehensive study. ACS Omega, ACS Publications, 2020, 10.1021/ac- somega.9b04034. hal-02457126 HAL Id: hal-02457126 https://hal.archives-ouvertes.fr/hal-02457126 Submitted on 27 Jan 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Mechanism of reconstitution/activation of the soluble PQQ-dependent glucose dehydrogenase from Acinetobacter calcoaceticus: a comprehensive study Claire Stines-Chaumeil,*,a Francois Mavré,b Brice Kauffmann,c Nicolas Mano,a and Benoit Limoges*,b a CNRS, Université de Bordeaux, CRPP, UMR5031, 115 Avenue Schweitzer, F-33600 Pessac, France. b Université de Paris, Laboratoire d'Electrochimie Moléculaire, UMR 7591, CNRS, F-75013 Paris, France. c CNRS UMS3033, INSERM US001, Université de Bordeaux, IECB, 2, Rue Robert Escarpit, F- 33607 Pessac, France. KEYWORDS: pyrroloquinoline quinone, enzyme reconstitution, enzyme cofactor, apoenzyme, glucose dehydrogenase.
    [Show full text]
  • Prolonging Healthy Aging: Longevity Vitamins and Proteins PERSPECTIVE Bruce N
    PERSPECTIVE Prolonging healthy aging: Longevity vitamins and proteins PERSPECTIVE Bruce N. Amesa,1 Edited by Cynthia Kenyon, Calico Labs, San Francisco, CA, and approved September 13, 2018 (received for review May 30, 2018) It is proposed that proteins/enzymes be classified into two classes according to their essentiality for immediate survival/reproduction and their function in long-term health: that is, survival proteins versus longevity proteins. As proposed by the triage theory, a modest deficiency of one of the nutrients/cofactors triggers a built-in rationing mechanism that favors the proteins needed for immediate survival and reproduction (survival proteins) while sacrificing those needed to protect against future damage (longevity proteins). Impairment of the function of longevity proteins results in an insidious acceleration of the risk of diseases associated with aging. I also propose that nutrients required for the function of longevity proteins constitute a class of vitamins that are here named “longevity vitamins.” I suggest that many such nutrients play a dual role for both survival and longevity. The evidence for classifying taurine as a conditional vitamin, and the following 10 compounds as putative longevity vitamins, is reviewed: the fungal antioxidant ergo- thioneine; the bacterial metabolites pyrroloquinoline quinone (PQQ) and queuine; and the plant antioxidant carotenoids lutein, zeaxanthin, lycopene, α-andβ-carotene, β-cryptoxanthin, and the marine carotenoid astaxanthin. Because nutrient deficiencies are highly prevalent in the United States (and elsewhere), appro- priate supplementation and/or an improved diet could reduce much of the consequent risk of chronic disease and premature aging. vitamins | essential minerals | aging | nutrition I propose that an optimal level of many of the known adverse health effects.
    [Show full text]
  • PQQ —— a Novel Human Essential Nutrient General Information of PQQ
    PQQ —— A Novel Human Essential Nutrient General Information of PQQ Stable small molecular Chemical Name: Pyrroloquinoline Quinone Disodium Salt (PQQ●Na2) Molecular Formula: C14H4N2Na2O8 Molecular Weight: 374.17 CAS Number: 122628-50-6 Appearance: Reddish brown powder Melting Point: >300℃ (decomposed during the assay) Solubility: Water-soluble (3g/L at 25℃) Stability: Stable for at least 24 months. 50+ Years of Research 1964 1979 1989 2003 2008 2010 2012 2016 Discovered Extracted Identified Kasahara MGC’s UC Davis ZCHT ZCHT as the third from as an and Kato NDI filing published completed PQQ redox methanol essential stated that accepted PQQ developme obtained cofactor after dehydrogen nutrients PQQ was a by FDA promotes nt via US FDA nicotinamide ase and in animal. new mitochondrial chemical GRAS and flavin in identified vitamin in biogenesis synthesis bacteria its Nature LE introduced molecular Magazine the 1st PQQ structure Supplement More than 800 studies on PQQ published (by July 2016) 55 41 39 37 33 32 32 30 30 27 26 25 25 24 24 23 22 22 21 21 20 20 19 19 19 19 19 18 17 16 11 6 4 4 2 3 2 2016 2015 2014 2013 2012 2011 2010 2009 2008 2007 2006 2005 2004 2003 2002 2001 2000 1999 1998 1997 1996 1995 1994 1993 1992 1991 1990 1989 1988 1987 1986 1985 1984 1983 1982 1981 1980 The Discovery of PQQ Produced by Bacteria Plants Growth Factor PQQ is Widely Distributed in Nature Playing important roles in Mammals Nature 1979；280(5725), 843-844 PQQ is Widely Distributed in Daily Life The PQQ Food PQQ(ng/g) Food PQQ(ng/g or ml) content of food products
    [Show full text]
  • Why Are You So
    September is here, and for WHY many of us, the rat race picks up in speed, leading us to feel ARE drained. Yes, our adrenals are being affected; we’ve written often on how to address YOU stress and the resulting adrenal exhaustion. In this article, however, we address SO how to conquer energy drain at the cellular level. We also provide tips for better sleep, which is critical in giving DRAINED? you the energy boost you so By Carol Blair, BS, DiHom, CNC, Laurel Sterling, RD, desperately desire! and Shannon Morehouse, MA, CHHC Feed the mitochondria in your cells! at the very least, because the mitochondria the balance to our cells and even help make new Mitochondria is a big word with a big meaning! power up those cells to give you the energy you mitochondria. need. The mitochondria generate ATP, the main Resveratrol, another powerful antioxidant, energy for the body. You might call them Even a mild form of mitochondrial dysfunction can play an indirect role in AMPK by activating the energy powerhouses. Mitochondrial can lead to low energy, poor stamina, increased SIRT-1, an enzyme involved in longevity. insufficiency can tip the delicate balance in our fat storage, insulin resistance, and the SIRT-1 quiets the genes that cause unhealthy cells. accumulation of toxins inside the cells. responses to inflammation, stress, and fat storage. Resveratrol has gained much attention When most physicians think of mitochondrial Fortunately, today we know several ways to in recent years as a longevity factor; it is dysfunction, they think of major diseases like optimize mitochondrial function and revitalize thought to help reduce the effects of aging in Parkinson’s, MS, autism, or myasthenia gravis.
    [Show full text]
  • Protective Effects of Pyrroloquinoline Quinone Against Oxidative Stress
    International Immunopharmacology 72 (2019) 445–453 Contents lists available at ScienceDirect International Immunopharmacology journal homepage: www.elsevier.com/locate/intimp Protective effects of pyrroloquinoline quinone against oxidative T stress-induced cellular senescence and inflammation in human renal tubular epithelial cells via Keap1/Nrf2 signaling pathway ⁎ Ziqiang Wanga,b, Ning Hana, Kunxiao Zhaoa, Ying Lia, , Yanqing Chia, Baoxing Wanga a Department of Nephrology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei Province 050051, China b Department of Nephrology, Cangzhou People's Hospital, Cangzhou, Hebei Province 061000, China ARTICLE INFO ABSTRACT Keywords: Oxidative stress-induced cellular senescence and inflammation are important biological events in diabetic ne- Pyrroloquinoline quinone phropathy (DN). Our recent studies have found that pyrroloquinoline quinone (PQQ) has protective effects Cellular senescence against HG-induced oxidative stress damage and apoptosis in HK-2 cells. Nevertheless, whether PQQ has the Inflammation effect of anti-inflammation and anti-senescence in HK-2 cells remains unclear. Here, we showed thatlow-dose High glucose PQQ treatment (100 nM) downregulates the expression of P16, P21, IL-1β, TNF-α and NF-κB in HG cultured HK- Keap1/Nrf2 signaling pathway 2 cells. A low dose of PQQ also upregulated the protein expression of SOD2, CAT and inhibited the generation of Renal tubular epithelial cells ROS. We also indicated that PQQ affected the activity of Keap1/Nrf2 pathway, increased the nuclear accumu- lation of Nrf2 and the downstream pathway protein expression of Keap1/Nrf2 signaling pathway (HO-1, NQO-1, GST and GPx-3). When ML385 was added to inhibit the activity of Keap1/Nrf2 signaling pathway, the effects of PQQ on anti-oxidative stress, anti-inflammation and anti-senescence in HK-2 cells under HG condition were weakened.
    [Show full text]
  • Pan-Histone Deacetylase Inhibitors Regulate Signaling Pathways
    Majumdar et al. BMC Genomics 2012, 13:709 http://www.biomedcentral.com/1471-2164/13/709 RESEARCH ARTICLE Open Access Pan-histone deacetylase inhibitors regulate signaling pathways involved in proliferative and pro-inflammatory mechanisms in H9c2 cells Gipsy Majumdar1, Piyatilake Adris1, Neha Bhargava1, Hao Chen2 and Rajendra Raghow1,2* Abstract Background: We have shown previously that pan-HDAC inhibitors (HDACIs) m-carboxycinnamic acid bis-hydroxamide (CBHA) and trichostatin A (TSA) attenuated cardiac hypertrophy in BALB/c mice by inducing hyper-acetylation of cardiac chromatin that was accompanied by suppression of pro-inflammatory gene networks. However, it was not feasible to determine the precise contribution of the myocytes- and non-myocytes to HDACI-induced gene expression in the intact heart. Therefore, the current study was undertaken with a primary goal of elucidating temporal changes in the transcriptomes of cardiac myocytes exposed to CBHA and TSA. Results: We incubated H9c2 cardiac myocytes in growth medium containing either of the two HDACIs for 6h and 24h and analyzed changes in gene expression using Illumina microarrays. H9c2 cells exposed to TSA for 6h and 24h led to differential expression of 468 and 231 genes, respectively. In contrast, cardiac myocytes incubated with CBHA for 6h and 24h elicited differential expression of 768 and 999 genes, respectively. We analyzed CBHA- and TSA-induced differentially expressed genes by Ingenuity Pathway (IPA), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Core_TF programs and discovered that CBHA and TSA impinged on several common gene networks. Thus, both HDACIs induced a repertoire of signaling kinases (PTEN-PI3K-AKT and MAPK) and transcription factors (Myc, p53, NFkB and HNF4A) representing canonical TGFβ, TNF-α, IFNγ and IL-6 specific networks.
    [Show full text]
  • Flawed Phospholipid Formation Or Faulty Fatty Acid Oxidation: Determining the Cause of Mitochondrial Dysfunction in Hearts Lacking Acsl1
    FLAWED PHOSPHOLIPID FORMATION OR FAULTY FATTY ACID OXIDATION: DETERMINING THE CAUSE OF MITOCHONDRIAL DYSFUNCTION IN HEARTS LACKING ACSL1 Trisha J. Grevengoed A dissertation submitted to the faculty at the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Nutrition (Biochemistry) in the School of Public Health. Chapel Hill 2015 Approved by: Rosalind A. Coleman Stephen D. Hursting Liza Makowski Leslie V. Parise Steven H. Zeisel © 2015 Trisha J. Grevengoed ALL RIGHTS RESERVED ii ABSTRACT Trisha J. Grevengoed: Fatty acid activation in cardiac mitochondria: The role of ACSL1 in phospholipid formation and remodeling, substrate switching, and autophagic flux (Under the direction of Rosalind A. Coleman) Cardiovascular disease is the number one cause of death worldwide. In the heart, mitochondria provide up to 95% of energy, with most of this energy coming from metabolism of fatty acids (FA). FA must be converted to acyl-CoAs by acyl-CoA synthetases (ACS) before entry into pathways of β- oxidation or glycerolipid synthesis. ACSL1 contributes more than 90% of total cardiac ACSL activity, and mice with an inducible knockout of ACSL1 (Acsl1T-/-) have impaired cardiac FA oxidation. The effects of loss of ACSL1 on mitochondrial respiratory function, phospholipid formation, or autophagic flux have not yet been studied. Acsl1T-/- hearts contained 3-fold more mitochondria with abnormal structure and displayed lower respiratory function. Because ACSL1 exhibited a strong substrate preference for linoleate (18:2), we investigated the composition of mitochondrial phospholipids. Acsl1T-/- hearts contained 83% less tetralinoleoyl-cardiolipin (CL), the major form present in control hearts.
    [Show full text]
  • GRAS Notice 709, Pyrroloquinoline Quinone Disodium Salt
    GRAS Notice (GRN) No. 709 https://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/NoticeInventory/default.htm GENERALLY RECOGNIZED AS SAFE (GRAS) NOTICE OF PYRROLOQUINOLINE QUINONE DISODIUM SALT AS A FOOD INGREDIENT Prepared for: Shangdong JinCheng Bio-Pharmaceutical Co., Ltd. Prepared by: NutraSource, Inc. 6309 Morning Dew Court Clarksville, MD 21029 Tel: 410-531-3336; [email protected] PQQ Disodium Salt Produced by JinCheng 1 GENERALLY RECOGNIZED AS SAFE (GRAS) STATUS OF Pyrroloquinoline quinone (PQQ) AS A FOOD INGREDIENT PART 1. SIGNED STATEMENTS AND A CERTIFICATION 5 1.A. Name and Address of the Notifier 5 1.B. Common or Trade Name 5 1.C. Applicable Conditions of Use of the Notified Substance 5 1.C.1. Foods in Which the Substance is to be Used 5 1.C.2. Levels of Use in Such Foods 5 1.C.3. Purpose for Which the Substance is Used 6 1.C.4. Description of the Potential Population Expected to Consume the Substance 6 1.D. Basis for the GRAS Determination 6 1.E. Availability of Information 6 1.F. Availability of FOIA Exemption 6 1.G. Certification 6 1.H. Name, Position/Title of Responsible Person Who Signs Dossier and Signature 6 1.I. FSIS/USDA Statement 7 PART 2. IDENTITY, MANUFACTURING, SPECIFICATION, TECHNICAL 8 EFFECTS OF PYRROLOQUINONE QUINONE (PQQ) DISODIUM SALT 2.A.1. Identity of the Notified Substance 8 2.A.1.1. Common Name 8 2.A.1.2. Chemical Names 8 2.A.1.3. Chemical Abstract Service (CAS) Registry Number 8 2.A.1.4. Empirical Formula 8 2.A.1.5.
    [Show full text]
  • Effects of Pyrroloquinoline Quinone and Vitamin C on Diabetes
    www.symbiosisonline.org Symbiosis www.symbiosisonlinepublishing.com Research article SOJ Pharmacy & Pharmaceutical Sciences Open Access Effects of Pyrroloquinoline Quinone and Vitamin C on Diabetes Associated Testicular Dysfunction and Oxidative Damages in Testis of Streptozotocin-Induced Diabetic Mice: Histopathological Study Narendra Kumar* and Anand Kar School of life Sciences, Devi Ahilya University, Takshashila Campus, Indore, India Received: October 02, 2017; Accepted: November 03, 2017; Published: November 10, 2017 *Corresponding author: Narendra Kumar, School of Life Sciences, Devi Ahilya University, Takshashila Campus, Indore, Madhya Pradesh, India, Tel: +91 9425481242; Fax +91 731 2360026; E-mail: [email protected] fertility through hyperglycemia-induced testicular dysfunctions Abstract leading to atrophy of sex organs; decrease in testosterone level; The aim of this study was to investigate the hitherto unknown loss in libido and in sperm count and motility [4, 5]. Agbaje, et potential of Pyrroloquinoline Quinone (PQQ) in regulating diabetes al. [6] also reported that streptozotocin (STZ)-induced diabetic associated testicular dysfunctions and oxidative damages in testis of adult mice. Seven groups such as normoglycemic and PQQ treated DNA in sperms. These adverse effects are thought to be due to controls; STZ-treated and STZ + PQQ treated (5, 10 and 20 mg/ animals show a significant increase in the level of fragmented kg/day, separately) and STZ + Vit.C (50 mg/kg) were established. DM associated oxidative stress [7-9]. These observations led us to After 18 days of experimentation, alterations in the markers of assume that a potent antioxidant is crucial in reducing the damage caused by oxidative stress. Some experimental, epidemiological testosterone and testicular histology were evaluated.
    [Show full text]