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Special Report

Anti-Fibrotic Effects of Valproic Acid: Role of HDAC Inhibition and Associated Mechanisms

, &
Pages 1087-1101 | Received 24 Mar 2016, Accepted 13 May 2016, Published online: 14 Jul 2016

References

  • Wynn TA . Cellular and molecular mechanisms of fibrosis . J. Pathol.214 ( 2 ), 199 – 210 ( 2008 ).
  • Nikolic-Paterson DJ , WangS , LanHY . Macrophages promote renal fibrosis through direct and indirect mechanisms . Kidney Int. Suppl. (2011)4 ( 1 ), 34 – 38 ( 2014 ).
  • Verma RP , HanschC . Matrix metalloproteinases (MMPs): chemical-biological functions and (Q)SARs . Bioorg. Med. Chem.15 ( 6 ), 2223 – 2268 ( 2007 ).
  • Duarte S , BaberJ , FujiiT , CoitoAJ . Matrix metalloproteinases in liver injury, repair and fibrosis . Matrix Biol.44–46 , 147 – 156 ( 2015 ).
  • Aher JS , KhanS , JainS , TikooK , JenaG . Valproate ameliorates thioacetamide-induced fibrosis by hepatic stellate cell inactivation . Hum. Exp. Toxicol.34 ( 1 ), 44 – 55 ( 2015 ).
  • Benyon RC , ArthurMJ . Extracellular matrix degradation and the role of hepatic stellate cells . Semin. Liver Dis.21 ( 3 ), 373 – 384 ( 2001 ).
  • Hemmann S , GrafJ , RoderfeldM , RoebE . Expression of MMPs and TIMPs in liver fibrosis – a systematic review with special emphasis on anti-fibrotic strategies . J. Hepatol.46 ( 5 ), 955 – 975 ( 2007 ).
  • Xu CJ , MikamiT , NakamuraTet al. Tumor budding, myofibroblast proliferation, and fibrosis in obstructing colon carcinoma: the roles of Hsp47 and basic fibroblast growth factor . Pathol. Res. Pract.209 ( 2 ), 69 – 74 ( 2013 ).
  • Xu J , KisselevaT . Bone marrow-derived fibrocytes contribute to liver fibrosis . Exp. Biol. Med. (Maywood)240 ( 6 ), 691 – 700 ( 2015 ).
  • Murphy AM , WongAL , BezuhlyM . Modulation of angiotensin II signaling in the prevention of fibrosis . Fibrogenesis Tissue Repair8 , 7 ( 2015 ).
  • Borthwick LA , BarronL , HartKMet al. Macrophages are critical to the maintenance of IL-13-dependent lung inflammation and fibrosis . Mucosal Immunol.9 ( 1 ), 38 – 55 ( 2015 ).
  • Kok HM , FalkeLL , GoldschmedingR , NguyenTQ . Targeting CTGF, EGF and PDGF pathways to prevent progression of kidney disease . Nat. Rev. Nephrol.10 ( 12 ), 700 – 711 ( 2014 ).
  • Lv LL , LiuBC . Role of non-classical renin–angiotensin system axis in renal fibrosis . Front. Physiol.6 , 117 ( 2015 ).
  • Gu H , MicklerEA , CummingsOWet al. Crosstalk between TGF-beta1 and complement activation augments epithelial injury in pulmonary fibrosis . FASEB J.28 ( 10 ), 4223 – 4234 ( 2014 ).
  • Okada Y , ShiraiK , ReinachPSet al. TRPA1 is required for TGF-beta signaling and its loss blocks inflammatory fibrosis in mouse corneal stroma . Lab. Invest.94 ( 9 ), 1030 – 1041 ( 2014 ).
  • Wynn TA , RamalingamTR . Mechanisms of fibrosis: therapeutic translation for fibrotic disease . Nat. Med.18 ( 7 ), 1028 – 1040 ( 2012 ).
  • Mann J , MannDA . Epigenetic regulation of wound healing and fibrosis . Curr. Opin. Rheumatol.25 ( 1 ), 101 – 107 ( 2013 ).
  • Chen PJ , HuangC , MengXM , LiJ . Epigenetic modifications by histone deacetylases: biological implications and therapeutic potential in liver fibrosis . Biochimie116 , 61 – 69 ( 2015 ).
  • Schuetze KB , MckinseyTA , LongCS . Targeting cardiac fibroblasts to treat fibrosis of the heart: focus on HDACs . J. Mol. Cell. Cardiol.70 , 100 – 107 ( 2014 ).
  • Wagner FF , Wesmall YiUM , LewisMC , HolsonEB . Small molecule inhibitors of zinc-dependent histone deacetylases . Neurotherapeutics10 ( 4 ), 589 – 604 ( 2013 ).
  • Hess-Stumpp H . Histone deacetylase inhibitors and cancer: from cell biology to the clinic . Eur. J. Cell Biol.84 ( 2–3 ), 109 – 121 ( 2005 ).
  • Khan S , JenaGB . Effect of sodium valproate on the toxicity of cyclophosphamide in the testes of mice: influence of pre- and post-treatment schedule . Toxicol. Int.20 ( 1 ), 68 – 76 ( 2013 ).
  • Khan S , JenaG . Sodium valproate, a histone deacetylase inhibitor ameliorates cyclophosphamide-induced genotoxicity and cytotoxicity in the colon of mice . J. Basic Clin. Physiol. Pharmacol.27 , 1 – 11 ( 2014 ).
  • Mannaerts I , NuyttenNR , RogiersV , VanderkerkenK , Van GrunsvenLA , GeertsA . Chronic administration of valproic acid inhibits activation of mouse hepatic stellate cells in vitro and in vivo . Hepatology51 ( 2 ), 603 – 614 ( 2010 ).
  • Van Beneden K , GeersC , PauwelsMet al. Comparison of trichostatin A and valproic acid treatment regimens in a mouse model of kidney fibrosis . Toxicol. Appl. Pharmacol.271 ( 2 ), 276 – 284 ( 2013 ).
  • Cetinkaya M , CansevM , CekmezFet al. Protective effects of valproic acid, a histone deacetylase inhibitor, against hyperoxic lung injury in a neonatal rat model . PLoS ONE10 ( 5 ), e0126028 ( 2015 ).
  • Kang SH , SeokYM , SongMJ , LeeHA , KurzT , KimI . Histone deacetylase inhibition attenuates cardiac hypertrophy and fibrosis through acetylation of mineralocorticoid receptor in spontaneously hypertensive rats . Mol. Pharmacol.87 ( 5 ), 782 – 791 ( 2015 ).
  • Khan S , JenaG , TikooK . Sodium valproate ameliorates diabetes-induced fibrosis and renal damage by the inhibition of histone deacetylases in diabetic rat . Exp. Mol. Pathol.98 ( 2 ), 230 – 239 ( 2015 ).
  • Hannan JL , KutluO , StopakBLet al. Valproic acid prevents penile fibrosis and erectile dysfunction in cavernous nerve-injured rats . J. Sex. Med.11 ( 6 ), 1442 – 1451 ( 2014 ).
  • Khan S , JenaG , TikooK , KumarV . Valproate attenuates the proteinuria, podocyte and renal injury by facilitating autophagy and inactivation of NF-kappaB/iNOS signaling in diabetic rat . Biochimie110 , 1 – 16 ( 2015 ).
  • Patel BM , RaghunathanS , PorwalU . Cardioprotective effects of magnesium valproate in type 2 diabetes mellitus . Eur. J. Pharmacol.728 , 128 – 134 ( 2014 ).
  • Cho YK , EomGH , KeeHJet al. Sodium valproate, a histone deacetylase inhibitor, but not captopril, prevents right ventricular hypertrophy in rats . Circ. J.74 ( 4 ), 760 – 770 ( 2010 ).
  • Goldberg AD , AllisCD , BernsteinE . Epigenetics: a landscape takes shape . Cell128 ( 4 ), 635 – 638 ( 2007 ).
  • Berger SL , KouzaridesT , ShiekhattarR , ShilatifardA . An operational definition of epigenetics . Genes Dev.23 ( 7 ), 781 – 783 ( 2009 ).
  • Handel AE , EbersGC , RamagopalanSV . Epigenetics: molecular mechanisms and implications for disease . Trends Mol. Med.16 ( 1 ), 7 – 16 ( 2010 ).
  • Chandler VL . Paramutation: from maize to mice . Cell128 ( 4 ), 641 – 645 ( 2007 ).
  • Egger G , LiangG , AparicioA , JonesPA . Epigenetics in human disease and prospects for epigenetic therapy . Nature429 ( 6990 ), 457 – 463 ( 2004 ).
  • Thiagalingam S , ChengKH , LeeHJ , MinevaN , ThiagalingamA , PonteJF . Histone deacetylases: unique players in shaping the epigenetic histone code . Ann. NY Acad. Sci.983 , 84 – 100 ( 2003 ).
  • Delcuve GP , KhanDH , DavieJR . Roles of histone deacetylases in epigenetic regulation: emerging paradigms from studies with inhibitors . Clin. Epigenetics4 ( 1 ), 5 ( 2012 ).
  • Khan S , KumarS , JenaG . Valproic acid reduces insulin-resistance, fat deposition and FOXO1-mediated gluconeogenesis in type-2 diabetic rat . Biochimie125 , 42 – 52 ( 2016 ).
  • Marmorstein R , TrievelRC . Histone modifying enzymes: structures, mechanisms, and specificities . Biochim. Biophys. Acta1789 ( 1 ), 58 – 68 ( 2009 ).
  • Levine MH , WangZ , BhattiTRet al. Class-specific histone/protein deacetylase inhibition protects against renal ischemia reperfusion injury and fibrosis formation . Am. J. Transplant.15 ( 4 ), 965 – 973 ( 2015 ).
  • Van Beneden K , MannaertsI , PauwelsM , Van Den BrandenC , Van GrunsvenLA . HDAC inhibitors in experimental liver and kidney fibrosis . Fibrogenesis Tissue Repair6 ( 1 ), 1 ( 2013 ).
  • Marks PA . Histone deacetylase inhibitors: a chemical genetics approach to understanding cellular functions . Biochim. Biophys. Acta1799 ( 10–12 ), 717 – 725 ( 2010 ).
  • Khan S , JenaG . Valproic Acid Improves Glucose Homeostasis by Increasing Beta-Cell Proliferation, Function, and Reducing its Apoptosis through HDAC Inhibition in Juvenile Diabetic Rat . J. Biochem. Mol. Toxicol. doi:10.1002/jbt.21807 ( 2016 ) ( Epub ahead of print ).
  • Yoon S , EomGH . HDAC and HDAC inhibitor: from cancer to cardiovascular diseases . Chonnam Med. J.52 ( 1 ), 1 – 11 ( 2016 ).
  • Rafehi H , KhanAW , El-OstaA . Improving understanding of chromatin regulatory proteins and potential implications for drug discovery . Expert Rev. Proteomics13 ( 4 ), 435 – 445 ( 2016 ).
  • Pang M , ZhuangS . Histone deacetylase: a potential therapeutic target for fibrotic disorders . J. Pharmacol. Exp. Ther.355 ( 2 ), 266 – 272 ( 2010 ).
  • Kanika G , KhanS , JenaG . Sodium Butyrate Ameliorates l-Arginine-Induced Pancreatitis and Associated Fibrosis in Wistar Rat: Role of Inflammation and Nitrosative Stress . J. Biochem. Mol. Toxicol.29 ( 8 ), 349 – 359 ( 2015 ).
  • Khan S , JenaGB . Protective role of sodium butyrate, a HDAC inhibitor on beta-cell proliferation, function and glucose homeostasis through modulation of p38/ERK MAPK and apoptotic pathways: study in juvenile diabetic rat . Chem. Biol. Interact.213 , 1 – 12 ( 2014 ).
  • Atmaca A , Al-BatranSE , MaurerAet al. Valproic acid (VPA) in patients with refractory advanced cancer: a dose escalating Phase I clinical trial . Br. J. Cancer97 ( 2 ), 177 – 182 ( 2007 ).
  • Friedman SL . Liver fibrosis- from bench to bedside . J. Hepatol.38 , 38 – 53 ( 2003 ).
  • Dooley S , Ten DijkeP . TGF-beta in progression of liver disease . Cell Tissue Res.347 ( 1 ), 245 – 256 ( 2012 ).
  • Friedman SL . Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury . J. Biol. Chem.275 ( 4 ), 2247 – 2250 ( 2000 ).
  • Westra IM , OosterhuisD , GroothuisGM , OlingaP . The effect of antifibrotic drugs in rat precision-cut fibrotic liver slices . PLoS ONE9 ( 4 ), e95462 ( 2014 ).
  • Mezaki Y , MoriiM , YoshikawaKet al. Elevated expression of transforming growth factor beta3 in carbon tetrachloride-treated rat liver and involvement of retinoid signaling . Int. J. Mol. Med.29 ( 1 ), 18 – 24 ( 2012 ).
  • Lawless MW , O’byrneKJ , GraySG . Histone deacetylase inhibitors target diabetes via chromatin remodeling or as chemical chaperones?Curr. Diabetes Rev.5 ( 3 ), 201 – 209 ( 2009 ).
  • Liu C , LiJ , XiangXet al. PDGF receptor-alpha promotes TGF-beta signaling in hepatic stellate cells via transcriptional and posttranscriptional regulation of TGF-beta receptors . Am. J. Physiol. Gastrointest. Liver Physiol.307 ( 7 ), G749 – G759 ( 2014 ).
  • Borkham-Kamphorst E , MeurerSK , Van De LeurE , HaasU , TihaaL , WeiskirchenR . PDGF-D signaling in portal myofibroblasts and hepatic stellate cells proves identical to PDGF-B via both PDGF receptor type alpha and beta . Cell. Signal.27 ( 7 ), 1305 – 1314 ( 2015 ).
  • Niki T , RomboutsK , De BleserPet al. A histone deacetylase inhibitor, trichostatin A, suppresses myofibroblastic differentiation of rat hepatic stellate cells in primary culture . Hepatology29 ( 3 ), 858 – 867 ( 1999 ).
  • Quilichini E , HaumaitreC . Implication of epigenetics in pancreas development and disease . Best Pract. Res. Clin. Endocrinol. Metab.29 ( 6 ), 883 – 898 ( 2015 ).
  • Chang TK , AbbottFS . Oxidative stress as a mechanism of valproic acid-associated hepatotoxicity . Drug Metab. Rev.38 ( 4 ), 627 – 639 ( 2006 ).
  • Khan S , JenaG . Sodium butyrate, a HDAC inhibitor ameliorates eNOS, iNOS and TGF-beta1-induced fibrogenesis, apoptosis and DNA damage in the kidney of juvenile diabetic rats . Food Chem. Toxicol.73 , 127 – 139 ( 2014 ).
  • Kriz W , GretzN , LemleyKV . Progression of glomerular diseases: is the podocyte the culprit?Kidney Int.54 ( 3 ), 687 – 697 ( 1998 ).
  • Marumo T , HishikawaK , YoshikawaM , HirahashiJ , KawachiS , FujitaT . Histone deacetylase modulates the proinflammatory and -fibrotic changes in tubulointerstitial injury . Am. J. Physiol. Renal Physiol.298 ( 1 ), F133 – F141 ( 2010 ).
  • Van Beneden K , GeersC , PauwelsMet al. Valproic acid attenuates proteinuria and kidney injury . J. Am. Soc. Nephrol.22 ( 10 ), 1863 – 1875 ( 2011 ).
  • Pang M , MaL , LiuNet al. Histone deacetylase 1/2 mediates proliferation of renal interstitial fibroblasts and expression of cell cycle proteins . J. Cell. Biochem.112 ( 8 ), 2138 – 2148 ( 2011 ).
  • Villeneuve LM , NatarajanR . Epigenetics of diabetic complications . Expert Rev. Endocrinol. Metab.5 ( 1 ), 137 – 148 ( 2010 ).
  • Komorowsky C , OckerM , Goppelt-StruebeM . Differential regulation of connective tissue growth factor in renal cells by histone deacetylase inhibitors . J. Cell. Mol. Med.13 ( 8B ), 2353 – 2364 ( 2009 ).
  • Nakashima T , JinninM , YamaneKet al. Impaired IL-17 signaling pathway contributes to the increased collagen expression in scleroderma fibroblasts . J. Immunol.188 ( 8 ), 3573 – 3583 ( 2012 ).
  • Zhao W , O’MalleyY , RobbinsME . Irradiation of rat mesangial cells alters the expression of gene products associated with the development of renal fibrosis . Radiat. Res.152 ( 2 ), 160 – 169 ( 1999 ).
  • Zhan M , KanwarYS . Hierarchy of molecules in TGF-beta1 signaling relevant to myofibroblast activation and renal fibrosis . Am. J. Physiol. Renal Physiol.307 ( 4 ), F385 – F387 ( 2014 ).
  • Vesey DA , CheungCW , CuttleL , EndreZA , GobeG , JohnsonDW . Interleukin-1beta induces human proximal tubule cell injury, alpha-smooth muscle actin expression and fibronectin production . Kidney Int.62 ( 1 ), 31 – 40 ( 2002 ).
  • Morinaga J , KakizoeY , MiyoshiTet al. The antifibrotic effect of a serine protease inhibitor in the kidney . Am. J. Physiol. Renal Physiol.305 ( 2 ), F173 – F181 ( 2013 ).
  • Dai Q , LiuJ , DuYLet al. Histone deacetylase inhibitors attenuate P-aIgA1-induced cell proliferation and extracellular matrix synthesis in human renal mesangial cells in vitro . Acta Pharmacol. Sin.37 ( 2 ), 228 – 234 ( 2016 ).
  • Kume S , YamaharaK , YasudaM , MaegawaH , KoyaD . Autophagy: emerging therapeutic target for diabetic nephropathy . Semin. Nephrol.34 ( 1 ), 9 – 16 ( 2014 ).
  • Khan S , BhatZR , JenaG . Role of autophagy and histone deacetylases in diabetic nephropathy: Current status and future perspectives . Genes Dis. doi:10.1016/j.gendis.2016.04.003 ( 2016 ) ( Epub ahead of print ).
  • Kimura T , TakabatakeY , TakahashiAet al. Autophagy protects the proximal tubule from degeneration and acute ischemic injury . J. Am. Soc. Nephrol.22 ( 5 ), 902 – 913 ( 2011 ).
  • Wei Q , DongZ . HDAC4 blocks autophagy to trigger podocyte injury: non-epigenetic action in diabetic nephropathy . Kidney Int.86 ( 4 ), 666 – 668 ( 2014 ).
  • Ding Y , ChoiME . Regulation of autophagy by TGF-beta: emerging role in kidney fibrosis . Semin. Nephrol.34 ( 1 ), 62 – 71 ( 2014 ).
  • Wang X , LiuJ , ZhenJet al. Histone deacetylase 4 selectively contributes to podocyte injury in diabetic nephropathy . Kidney Int.86 ( 4 ), 712 – 725 ( 2014 ).
  • McKinsey TA . The biology and therapeutic implications of HDACs in the heart . Handb. Exp. Pharmacol.206 , 57 – 78 ( 2011 ).
  • Levick S , LochD , RolfeBet al. Antifibrotic activity of an inhibitor of group IIA secretory phospholipase A2 in young spontaneously hypertensive rats . J. Immunol.176 ( 11 ), 7000 – 7007 ( 2006 ).
  • Bugger H , AbelED . Molecular mechanisms of diabetic cardiomyopathy . Diabetologia57 ( 4 ), 660 – 671 ( 2014 ).
  • O’Reilly S , CiechomskaM , CantR , Van LaarJM . Interleukin-6 (IL-6) trans signaling drives a STAT3-dependent pathway that leads to hyperactive transforming growth factor-beta (TGF-beta) signaling promoting SMAD3 activation and fibrosis via Gremlin protein . J. Biol. Chem.289 ( 14 ), 9952 – 9960 ( 2014 ).
  • Backs J , OlsonEN . Control of cardiac growth by histone acetylation/deacetylation . Circ. Res.98 ( 1 ), 15 – 24 ( 2006 ).
  • Kee HJ , KookH . Roles and targets of class I and IIa histone deacetylases in cardiac hypertrophy . J. Biomed. Biotechnol.2011 , 928326 ( 2011 ).
  • Manabe I , ShindoT , NagaiR . Gene expression in fibroblasts and fibrosis: involvement in cardiac hypertrophy . Circ. Res.91 ( 12 ), 1103 – 1113 ( 2002 ).
  • Antos CL , McKinseyTA , DreitzMet al. Dose-dependent blockade to cardiomyocyte hypertrophy by histone deacetylase inhibitors . J. Biol. Chem.278 ( 31 ), 28930 – 28937 ( 2003 ).
  • Nural-Guvener HF , ZakharovaL , NimlosJ , PopovicS , MastroeniD , GaballaMA . HDAC class I inhibitor, Mocetinostat, reverses cardiac fibrosis in heart failure and diminishes CD90+ cardiac myofibroblast activation . Fibrogenesis Tissue Repair7 , 10 ( 2014 ).
  • Liu M , ChenJ , HuangYet al. Triptolide alleviates isoprenaline-induced cardiac remodeling in rats via TGF-beta1/Smad3 and p38 MAPK signaling pathway . Pharmazie70 ( 4 ), 244 – 250 ( 2015 ).
  • Matsumoto-Ida M , TakimotoY , AoyamaT , AkaoM , TakedaT , KitaT . Activation of TGF-beta1-TAK1-p38 MAPK pathway in spared cardiomyocytes is involved in left ventricular remodeling after myocardial infarction in rats . Am. J. Physiol. Heart Circ. Physiol.290 ( 2 ), H709 – H715 ( 2006 ).
  • Kee HJ , BaeEH , ParkSet al. HDAC inhibition suppresses cardiac hypertrophy and fibrosis in DOCA-salt hypertensive rats via regulation of HDAC6/HDAC8 enzyme activity . Kidney Blood Press. Res.37 ( 4–5 ), 229 – 239 ( 2013 ).
  • Bueno OF , De WindtLJ , TymitzKMet al. The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice . EMBO J.19 ( 23 ), 6341 – 6350 ( 2000 ).
  • Sanna B , BuenoOF , DaiYS , WilkinsBJ , MolkentinJD . Direct and indirect interactions between calcineurin-NFAT and MEK1-extracellular signal-regulated kinase 1/2 signaling pathways regulate cardiac gene expression and cellular growth . Mol. Cell. Biol.25 ( 3 ), 865 – 878 ( 2005 ).
  • Heineke J , MolkentinJD . Regulation of cardiac hypertrophy by intracellular signalling pathways . Nat. Rev. Mol. Cell Biol.7 ( 8 ), 589 – 600 ( 2006 ).
  • Kao YH , LiouJP , ChungCCet al. Histone deacetylase inhibition improved cardiac functions with direct antifibrotic activity in heart failure . Int. J. Cardiol.168 ( 4 ), 4178 – 4183 ( 2013 ).
  • Davis R , PetersDH , McTavishD . Valproic acid. A reappraisal of its pharmacological properties and clinical efficacy in epilepsy . Drugs47 ( 2 ), 332 – 372 ( 1994 ).
  • Cohen TS , PrinceA . Cystic fibrosis: a mucosal immunodeficiency syndrome . Nat. Med.18 ( 4 ), 509 – 519 ( 2012 ).
  • O’Sullivan BP , FreedmanSD . Cystic fibrosis . Lancet373 ( 9678 ), 1891 – 1904 ( 2009 ).
  • Dekkers JF , Van Der EntCK , KalkhovenE , BeekmanJM . PPARgamma as a therapeutic target in cystic fibrosis . Trends Mol. Med.18 ( 5 ), 283 – 291 ( 2012 ).
  • Bonfield TL , PanuskaJR , KonstanMWet al. Inflammatory cytokines in cystic fibrosis lungs . Am. J. Respir. Crit. Care Med.152 ( 6 Pt 1 ), 2111 – 2118 ( 1995 ).
  • Khan TZ , WagenerJS , BostT , MartinezJ , AccursoFJ , RichesDW . Early pulmonary inflammation in infants with cystic fibrosis . Am. J. Respir. Crit. Care Med.151 ( 4 ), 1075 – 1082 ( 1995 ).
  • Nagai Y , LimberisMP , ZhangH . Modulation of Treg function improves adenovirus vector-mediated gene expression in the airway . Gene Ther.21 ( 2 ), 219 – 224 ( 2014 ).
  • Paul T , LiS , KhuranaS , LeleikoNS , WalshMJ . The epigenetic signature of CFTR expression is co-ordinated via chromatin acetylation through a complex intronic element . Biochem. J.408 ( 3 ), 317 – 326 ( 2007 ).
  • Nissim-Rafinia M , AviramM , RandellSHet al. Restoration of the cystic fibrosis transmembrane conductance regulator function by splicing modulation . EMBO Rep.5 ( 11 ), 1071 – 1077 ( 2004 ).
  • Gonzalez-Cadavid NF . Mechanisms of penile fibrosis . J. Sex. Med.6 ( Suppl. 3 ), 353 – 362 ( 2009 ).
  • El-Sakka AI , YassinAA . Amelioration of penile fibrosis: myth or reality . J. Androl.31 ( 4 ), 324 – 335 ( 2010 ).
  • Ferrini MG , HlaingSM , ChanA , ArtazaJN . Treatment with a combination of ginger, L-citrulline, muira puama and Paullinia cupana can reverse the progression of corporal smooth muscle loss, fibrosis and veno-occlusive dysfunction in the aging rat . Andrology (Los Angel)4 ( 1 ), ( 2015 ).
  • Kutlu O , KaraguzelE , GurgenSGet al. Antifibrogenic role of valproic acid in streptozotocin induced diabetic rat penis . Andrologia4 ( 1 ), pii: 132 ( 2015 ).
  • Yerby MS , McCoyGB . Male infertility: possible association with valproate exposure . Epilepsia40 ( 4 ), 520 – 521 ( 1999 ).
  • Khan S , AhmadT , ParekhCV , TrivediPP , KushwahaS , JenaG . Investigation on sodium valproate induced germ cell damage, oxidative stress and genotoxicity in male Swiss mice . Reprod. Toxicol.32 ( 4 ), 385 – 394 ( 2011 ).
  • Luzina IG , AtamasSP . Fibrotic Skin Diseases . In : Clinical and Basic Immunodermatology . GaspariAA , TyringSK ( Eds ). Springer London , London , 721 – 737 ( 2008 ).
  • Shaw TJ , KishiK , MoriR . Wound-associated skin fibrosis: mechanisms and treatments based on modulating the inflammatory response . Endocr. Metab. Immune Disord. Drug Targets10 ( 4 ), 320 – 330 ( 2010 ).
  • Andrews JP , MarttalaJ , MacarakE , RosenbloomJ , UittoJ . Keloids: The paradigm of skin fibrosis – pathomechanisms and treatment . Matrix Biol.51 , 37 – 46 ( 2016 ).
  • Wells A , NuschkeA , YatesCC . Skin tissue repair: matrix microenvironmental influences . Matrix Biol.49 , 25 – 36 ( 2016 ).
  • Hemmatazad H , RodriguesHM , MaurerBet al. Histone deacetylase 7, a potential target for the antifibrotic treatment of systemic sclerosis . Arthritis. Rheum.60 ( 5 ), 1519 – 1529 ( 2009 ).
  • Russell SB , RussellJD , TrupinKMet al. Epigenetically altered wound healing in keloid fibroblasts . J. Invest. Dermatol.130 ( 10 ), 2489 – 2496 ( 2010 ).
  • Palumbo-Zerr K , ZerrP , DistlerAet al. Orphan nuclear receptor NR4A1 regulates transforming growth factor-beta signaling and fibrosis . Nat. Med.21 ( 2 ), 150 – 158 ( 2015 ).
  • Svegliati S , MarroneG , PezoneAet al. Oxidative DNA damage induces the ATM-mediated transcriptional suppression of the Wnt inhibitor WIF-1 in systemic sclerosis and fibrosis . Sci. Signal.7 ( 341 ), 84 ( 2014 ).
  • Lee SH , KimMY , KimHYet al. The dishevelled-binding protein CXXC5 negatively regulates cutaneous wound healing . J. Exp. Med.212 ( 7 ), 1061 – 1080 ( 2015 ).
  • Chung YL , WangAJ , YaoLF . Antitumor histone deacetylase inhibitors suppress cutaneous radiation syndrome: Implications for increasing therapeutic gain in cancer radiotherapy . Mol. Cancer Ther.3 ( 3 ), 317 – 325 ( 2004 ).
  • Fuller HR , ManNT , Lam LeT , ShamaninVA , AndrophyEJ , MorrisGE . Valproate and bone loss: iTRAQ proteomics show that valproate reduces collagens and osteonectin in SMA cells . J. Proteome Res.9 ( 8 ), 4228 – 4233 ( 2010 ).
  • Rosenbloom J , MendozaFA , JimenezSA . Strategies for anti-fibrotic therapies . Biochim. Biophys. Acta1832 ( 7 ), 1088 – 1103 ( 2013 ).
  • Bassett SA , BarnettMP . The role of dietary histone deacetylases (HDACs) inhibitors in health and disease . Nutrients6 ( 10 ), 4273 – 4301 ( 2014 ).
  • Zhang L , FangH , XuW . Strategies in developing promising histone deacetylase inhibitors . Med. Res. Rev.30 ( 4 ), 585 – 602 ( 2010 ).
  • Bisgin H , LiuZ , KellyR , FangH , XuX , TongW . Investigating drug repositioning opportunities in FDA drug labels through topic modeling . BMC Bioinformatics13 ( Suppl. 15 ), S6 ( 2012 ).

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