Oxidative/nitrative stress in the pathogenesis of systemic sclerosis: are antioxidants beneficial?

References

• Pattanaik D, Brown M, Postlethwaite AE. Vascular involvement in systemic sclerosis (scleroderma). J Inflamm Res. 2011;4:105–125.
   PubMedGoogle Scholar
• Bhattacharyya S, Wei J, Varga J. Understanding fibrosis in systemic sclerosis: shifting paradigms, emerging opportunities. Nat Rev Rheumatol. 2012;8:42–54.
   Web of Science ®Google Scholar
• Nourooz-Zadeh J. Key issues in F2-isoprostane analysis. Biochm Soc Trans. 2008;36:1060–1065.
   PubMed Web of Science ®Google Scholar
• Panieri E, Santoro MM. ROS signaling and redox biology in endothelial cells. Cell Mol Life Sci. 2015;72:3281–3303.
   PubMed Web of Science ®Google Scholar
• Abello N, Kerstjens HAM, Postma DS, et al. Protein tyrosine nitration: selectivity, physicochemical and biological consequences, denitration, and proteomics methods for the identification of tyrosine-nitrated proteins. J Proteome Res. 2009;8:3222–3238.
   PubMed Web of Science ®Google Scholar
• Villacorta L, Gao Z, Schopfer FJ. Nitro-fatty acids in cardiovascular regulation and diseases: characteristics and molecular mechanisms. Front Biosci. 2016;21:873–889.
   Web of Science ®Google Scholar
• Wang W, Li C, Yang T. Protection of nitro-fatty acid against kidney diseases. Am J Physiol Renal Physiol. 2016;310:F697–F704.
   PubMed Web of Science ®Google Scholar
• Dadoniene J, Cypiene A, Ryliskyte L, et al. Skin autofluorescence in systemic sclerosis is related to the disease and vascular damage: a cross-sectional analytic study of comparative groups. Dis Markers. 2015;2015:837470.
   PubMedGoogle Scholar
• Brown DI, Griendling KK. Nox proteins in signal transduction. Free Radic Biol Med. 2009;47:1239–1253.
   PubMed Web of Science ®Google Scholar
• van Bon L, Cossu M, Loof A. Proteomic analysis of plasma identifies the Toll-like receptor agonists S100A8/A9 as a novel possible marker for systemic sclerosis phenotype. Ann Rheum Dis. 2014;73:1585–1589.
   PubMed Web of Science ®Google Scholar
• Piera-Velazquez S, Jimenez SA. Role of cellular senescence and NOX4-mediated oxidative stress in systemic sclerosis pathogenesis. Curr Rheumatol Rep. 2015;17:473.
   PubMed Web of Science ®Google Scholar
• Sambo P, Baroni SS, Luchetti M, et al. Oxidative stress in scleroderma: maintenance of scleroderma fibroblast phenotype by the constitutive up-regulation of reactive oxygen species generation through the NADPH oxidase complex pathway. Arthritis Rheum. 2001;44:2653–2664.
   PubMed Web of Science ®Google Scholar
• Ellmark SH, Dusting GJ, Fui MN, et al. The contribution of Nox4 to NADPH oxidase activity in mouse vascular smooth muscle. Cardiovasc Res. 2005;65:495–504.
   PubMed Web of Science ®Google Scholar
• Bretón-Romero R, Lamas S. Hydrogen peroxide signaling in vascular endothelial cells. Redox Biol. 2014;2:529–534.
   PubMed Web of Science ®Google Scholar
• Sambo P, Jannino L, Candela M, et al. Monocytes of patients with systemic sclerosis (scleroderma spontaneously release in vitro increased amounts of superoxide anion. J Invest Dermatol. 1999;112:78–84.
   PubMed Web of Science ®Google Scholar
• Amico D, Spadoni T, Rovinelli M, et al. Intracellular free radical production by peripheral blood T lymphocytes from patients with systemic sclerosis: role of NADPH oxidase and ERK1/2. Arthritis Res Ther. 2015;17:68.
   PubMed Web of Science ®Google Scholar
• Gill R, Tsung A, Billiar T. Linking oxidative stress to inflammation: toll-like receptors. Free Radic Biol Med. 2010;48:1121–1132.
   PubMed Web of Science ®Google Scholar
• Bhattacharyya S, Kelley K, Melichian DS, et al. Toll-like receptor 4 signaling augments transforming growth factor-beta responses: a novel mechanism for maintaining and amplifying fibrosis in scleroderma. Am J Pathol. 2013;182:192–205.
   PubMed Web of Science ®Google Scholar
• Karki R, Igwe OJ. Toll-like receptor 4-mediated nuclear factor kappa B activation is essential for sensing exogenous oxidants to propagate and maintain oxidative/nitrosative cellular stress. PLoS One. 2013;8:e73840.
   PubMed Web of Science ®Google Scholar
• Manček-Keber M, Frank-Bertoncelj M, Hafner-Bratkovič I, et al. Toll-like receptor 4 senses oxidative stress mediated by the oxidation of phospholipids in extracellular vesicles. Sci Signal. 2015;8:ra60.
   PubMed Web of Science ®Google Scholar
• Stifano G, Affandi AJ, Mathes AL, et al. Chronic Toll-like receptor 4 stimulation in skin induces inflammation, macrophage activation, transforming growth factor beta signature gene expression, and fibrosis. Arthritis Res Ther. 2014;16:R136.
   PubMed Web of Science ®Google Scholar
• Fang F, Marangoni RG, Zhou X, et al. Toll-like receptor 9 signaling is augmented in systemic sclerosis and elicits transforming growth factor beta-dependent fibroblast activation. Arthritis Rheumatol. 2016;68:1989–2002.
   PubMed Web of Science ®Google Scholar
• Piera-Velazquez S, Makul A, Jiménez SA. Increased expression of NAPDH oxidase 4 in systemic sclerosis dermal fibroblasts: regulation by transforming growth factor β. Arthritis Rheumatol. 2015;67:2749–2758.
   PubMed Web of Science ®Google Scholar
• Guo W, Saito S, Sanchez CG, et al. TGF-beta1 stimulates HDAC4 nucleus-to-cytoplasm translocation and NADPH oxidase 4-derived reactive oxygen species in normal human lung fibroblasts. Am J Physiol Lung Cell Mol Physiol. 2017;312:L936–LL944.
   PubMed Web of Science ®Google Scholar
• Bauernfeind FG, Horvath G, Stutz A, et al. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol. 2009;183:787–791.
   PubMed Web of Science ®Google Scholar
• Bauernfeind F, Bartok E, Rieger A, et al. Cutting edge: reactive oxygen species inhibitors block priming, but not activation, of the NLRP3 inflammasome. J Immunol. 2011;187:613–617.
   PubMed Web of Science ®Google Scholar
• Abais JM, Xia M, Zhang Y, et al. Redox regulation of NLRP3 inflammasomes: ROS as trigger or effector? Antioxid Redox Signal. 2015;22:1111–1129.
   PubMed Web of Science ®Google Scholar
• Martínez-Godínez MA, Cruz-Domínguez MP, Jara LJ. Expression of NLRP3 inflammasome, cytokines and vascular mediators in the skin of systemic sclerosis patients. Isr Med Assoc J. 2015;17:5–10.
   PubMed Web of Science ®Google Scholar
• Artlett CM, Sassi-Gaha S, Rieger JL, et al. The inflammasome activating caspase 1 mediates fibrosis and myofibroblast differentiation in systemic sclerosis. Arthritis Rheum. 2011;63:3563–3574.
   PubMedGoogle Scholar
• Artlett CM, Sassi-Gaha S, Hope JL, et al. Mir-155 is overexpressed in systemic sclerosis fibroblasts and is required for NLRP3 inflammasome-mediated collagen synthesis during fibrosis. Arthritis Res Ther. 2017;19:144.
   PubMed Web of Science ®Google Scholar
• Leinonen HM, Kansanen E, Pölönen P, et al. Role of the Keap1-Nrf2 pathway in cancer. Adv Cancer Res. 2014;122:281–320.
   PubMed Web of Science ®Google Scholar
• Hennig P, Garstkiewicz M, Grossi S, et al. The crosstalk between Nrf2 and Inflammasomes. IJMS. 2018;19:562.
   Google Scholar
• Brewer AC, Murray TVA, Arno M, et al. Nox4 regulates Nrf2 and glutathione redox in cardiomyocytes in vivo. Free Radic Biol Med. 2011;51:205–215.
   PubMed Web of Science ®Google Scholar
• Schroder K, Zhang M, Benkhoff S, et al. Nox4 is a protective reactive oxygen species generating vascular NADPH oxidase. Circ Res. 2012;110:1217–1225.
   PubMed Web of Science ®Google Scholar
• Bretón-Romero R, González de Orduña C, Romero N, et al. Critical role of hydrogen peroxide signaling in the sequential activation of p38 MAPK and eNOS in laminar shear stress. Free Radic Biol Med. 2012;52:1093–1100.
   PubMed Web of Science ®Google Scholar
• Jiang F, Liu G-S, Dusting GJ, et al. NADPH oxidase-dependent redox signaling in TGF-beta-mediated fibrotic responses. Redox Biol. 2014;2:267–272.
   PubMed Web of Science ®Google Scholar
• Lyle AN, Deshpande NN, Taniyama Y, et al. Poldip2, a novel regulator of Nox4 and cytoskeletal integrity in vascular smooth muscle cells. Circ Res. 2009;105:249–259.
   PubMed Web of Science ®Google Scholar
• Mittal M, Roth M, Konig P, et al. Hypoxia-dependent regulation of nonphagocytic NADPH oxidase subunit NOX4 in the pulmonary vasculature. Circ Res. 2007;101:258–267.
   PubMed Web of Science ®Google Scholar
• Pierce GF, Mustoe TA, Altrock BW, et al. Role of platelet-derived growth factor in wound healing. J Cell Biochem. 1991;45:319–326.
   PubMed Web of Science ®Google Scholar
• Trojanowska M. Role of PDGF in fibrotic diseases and systemic sclerosis. Rheumatology. 2008;47:v2–v4.
   PubMed Web of Science ®Google Scholar
• Gay S, Jones RE, Huang G-q, et al. Immunohistologic demonstration of platelet-derived growth factor (PDGF) and sis-oncogene expression in scleroderma. J Invest Dermatol. 1989;92:301–303.
   PubMed Web of Science ®Google Scholar
• Svegliati Baroni S, Santillo M, Bevilacqua F, et al. Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N Engl J Med. 2006;354:2667–2676.
   PubMed Web of Science ®Google Scholar
• Bae YS, Sung J-Y, Kim O-S, et al. Platelet-derived growth factor-induced H(2)O(2) production requires the activation of phosphatidylinositol 3-kinase. J Biol Chem. 2000;275:10527–10531.
   PubMed Web of Science ®Google Scholar
• Kawaguchi Y, Takagi K, Hara M, et al. Angiotensin II in the lesional skin of systemic sclerosis patients contributes to tissue fibrosis via angiotensin II type 1 receptors. Arthritis Rheum. 2004;50:216–226.
   PubMed Web of Science ®Google Scholar
• Lee D-Y, Wauquier F, Eid AA, et al. Nox4 NADPH oxidase mediates peroxynitrite-dependent uncoupling of endothelial nitric-oxide synthase and fibronectin expression in response to angiotensin II: role of mitochondrial reactive oxygen species. J Biol Chem. 2013;288:28668–28686.
   PubMed Web of Science ®Google Scholar
• Luo J-Y, Liu X, Jiang M, et al. Oxidative stress markers in blood in systemic sclerosis: a meta-analysis. Mod Rheumatol. 2017;27:306–314.
   PubMed Web of Science ®Google Scholar
• Ames PRJ, Merashli M, Bucci T, et al. Isoprostane in systemic sclerosis: a systematic review and meta-analysis. Mod Rheumatol. 2018;1-6. doi:10.1080/14397595.2018.1469458.
   PubMed Web of Science ®Google Scholar
• Rommelaere S, Millet V, Gensollen T, et al. PPARalpha regulates the production of serum Vanin-1 by liver. FEBS Lett. 2013;587:3742–3748.
   PubMed Web of Science ®Google Scholar
• Lebo RV, Kredich NM. Inactivation of human gamma-glutamylcysteine synthetase by cystamine. Demonstration and quantification of enzyme-ligand complexes. J Biol Chem. 1978;253:2615–2623.
   PubMed Web of Science ®Google Scholar
• Calkins MJ, Townsend JA, Johnson DA, et al. Cystamine protects from 3-nitropropionic acid lesioning via induction of nf-e2 related factor 2 mediated transcription. Exp Neurol. 2010;224:307–317.
   PubMed Web of Science ®Google Scholar
• Kavian N, Mehlal S, Marut W, et al. Imbalance of the Vanin-1 pathway in systemic sclerosis. J Immunol. 2016;197:3326–3335.
   PubMed Web of Science ®Google Scholar
• Cutolo M, Sulli A, Smith V. Assessing microvascular changes in systemic sclerosis diagnosis and management. Nat Rev Rheumatol. 2010;6:578–587.
   PubMed Web of Science ®Google Scholar
• Altorok N, Wang Y, Kahaleh B. Endothelial dysfunction in systemic sclerosis. Curr Opin Rheumatol. 2014;26:615–620.
   PubMed Web of Science ®Google Scholar
• Au K, Singh MK, Bodukam V, et al. Atherosclerosis in systemic sclerosis: a systematic review and meta-analysis. Arthritis Rheum. 2011;63:2078–2090.
   PubMedGoogle Scholar
• Meiszterics Z, Tímár O, Gaszner B, et al. Early morphologic and functional changes of atherosclerosis in systemic sclerosis-a systematic review and meta-analysis. Rheumatology. 2016;55:2119–2130.
   PubMed Web of Science ®Google Scholar
• Faccini A, Agricola E, Oppizzi M, et al. Coronary microvascular dysfunction in asymptomatic patients affected by systemic sclerosis – limited vs. diffuse form. Circ J. 2015;79:825–829.
   PubMed Web of Science ®Google Scholar
• Rollando D, Bezante GP, Sulli A. Brachial artery endothelial-dependent flow-mediated dilation identifies early-stage endothelial dysfunction in systemic sclerosis and correlates with nailfold microvascular impairment. J Rheumatol. 2010;37:1168–1173.
   PubMed Web of Science ®Google Scholar
• Hettema ME, Bootsma H, Kallenberg CG. Macrovascular disease and atherosclerosis in SSc. Rheumatology. 2008;47:578–583.
   PubMed Web of Science ®Google Scholar
• Merkel PA, Herlyn K, Martin RW, et al. Measuring disease activity and functional status in patients with scleroderma and Raynaud’s phenomenon. Arthritis Rheum. 2002;46:2410–2420.
   PubMed Web of Science ®Google Scholar
• Chung L, Fiorentino D. Digital ulcers in patients with systemic sclerosis. Autoimmun Rev. 2006;5:125–128.
   PubMed Web of Science ®Google Scholar
• Nihtyanova SI, Brough GM, Black CM, et al. Clinical burden of digital vasculopathy in limited and diffuse cutaneous systemic sclerosis. Ann Rheum Dis. 2008;67:120–123.
   PubMed Web of Science ®Google Scholar
• Aviña-Zubieta JA, Man A, Yurkovich M, et al. Early cardiovascular disease after the diagnosis of systemic sclerosis. Am J Med. 2016;129:324–331.
   PubMed Web of Science ®Google Scholar
• Chu S-Y, Chen Y-J, Liu C-J, et al. Increased risk of acute myocardial infarction in systemic sclerosis: a nationwide population-based study. Am J Med. 2013;126:982–988.
   PubMed Web of Science ®Google Scholar
• D'Angelo WA, Fries JF, Masi AT, et al. Pathologic observations in systemic sclerosis (scleroderma). A study of fifty-eight autopsy cases and fifty-eight matched controls. Am J Med. 1969;46:428–440.
   PubMed Web of Science ®Google Scholar
• Gyllenhammar T, Kanski M, Engblom H, et al. Decreased global myocardial perfusion at adenosine stress as a potential new biomarker for microvascular disease in systemic sclerosis: a magnetic resonance study. BMC Cardiovasc Disord. 2018;18:16.
   PubMed Web of Science ®Google Scholar
• Stein CM, Tanner SB, Awad JA, et al. Evidence of free radical-mediated injury (isoprostane overproduction) in scleroderma. Arthritis Rheum. 1996;39:1146–1150.
   PubMed Web of Science ®Google Scholar
• Cracowski J-L, Kom GD, Salvat-Melis M, et al. Postocclusive reactive hyperemia inversely correlates with urinary 15-F2t-isoprostane levels in systemic sclerosis. Free Radic Biol Med. 2006;40:1732–1737.
   PubMed Web of Science ®Google Scholar
• Volpe A, Biasi D, Caramaschi P, et al. Levels of F2-isoprostanes in systemic sclerosis: correlation with clinical features. Rheumatology.2006;45:314–320.
   PubMed Web of Science ®Google Scholar
• Ogawa F, Shimizu K, Muroi E, et al. Serum levels of 8-isoprostane, a marker of oxidative stress, are elevated in patients with systemic sclerosis. Rheumatology. 2006;45:815–818.
   PubMed Web of Science ®Google Scholar
• Riccieri V, Spadaro A, Fuksa L, et al. Specific oxidative stress parameters differently correlate with nailfold capillaroscopy changes and organ involvement in systemic sclerosis. Clin Rheumatol. 2008;27:225–230.
   PubMed Web of Science ®Google Scholar
• Kahaleh BM, Pan-Sheng F, Cerinic MM, et al. Study of endothelial dependent relaxation in scleroderma. Arthritis Rheum. 1993;36(Suppl):B233.
   Google Scholar
• Yamamoto T, Katayama I, Nishioka K. Nitric oxide production and inducible nitric oxide synthase expression in systemic sclerosis. J Rheumatol. 1998;25:314–317.
   PubMed Web of Science ®Google Scholar
• Dooley A, Gao B, Bradley N, et al. Abnormal nitric oxide metabolism in systemic sclerosis: increased levels of nitrated proteins and asymmetric dimethylarginine. Rheumatology. 2006;45:676–684.
   PubMed Web of Science ®Google Scholar
• Shimizu K, Ogawa F, Muroi E, et al. Increased serum levels of nitrotyrosine, a marker for peroxynitrite production, in systemic sclerosis. Clin Exp Rheumatol. 2007;25:281–286.
   PubMed Web of Science ®Google Scholar
• Cotton SA, Herrick AL, Jayson MIV, et al. Endothelial expression of nitric oxide synthases and nitrotyrosine in systemic sclerosis skin. J Pathol. 1999;189:273–278.
   PubMed Web of Science ®Google Scholar
• Dreger H, Ludwig A, Weller A, et al. Epigenetic suppression of iNOS expression in human endothelial cells: a potential role of Ezh2-mediated H3K27me3. Genomics. 2016;107:145–149.
   PubMed Web of Science ®Google Scholar
• Balligand JL, Ungureanu-Longrois D, Simmons WW, et al. Induction of NO synthase in rat cardiac microvascular endothelial cells by IL-1 beta and IFN-gamma. Am J Physiol. 1995;268:H1293–H1303.
   PubMedGoogle Scholar
• Lass A, Sohal RS. Effect of coenzyme Q(10) and alpha-tocopherol content of mitochondria on the production of superoxide anion radicals. FASEB J. 2000;14:87–94.
   PubMed Web of Science ®Google Scholar
• Nakamura YK, Omaye ST. Lipophilic compound-mediated gene expression and implication for intervention in reactive oxygen species (ROS)-related diseases: mini-review. Nutrients. 2010;2:725–736.
   PubMed Web of Science ®Google Scholar
• Ohta A, Uitto J. Procollagen gene expression by scleroderma fibroblasts in culture. Inhibition of collagen production and reduction of pro alpha 1(I) and pro alpha 1(III) collagen messenger RNA steady-state levels by retinoids. Arthritis Rheum. 1987;30:404–411.
   PubMed Web of Science ®Google Scholar
• Cracowski J-L, Girolet S, Imbert B, et al. Effects of short-term treatment with vitamin E in systemic sclerosis: a double blind, randomized, controlled clinical trial of efficacy based on urinary isoprostane measurement. Free Radic Biol Med. 2005;38:98–103.
   PubMed Web of Science ®Google Scholar
• Herrick AL, Hollis S, Schofield D, et al. A double-blind placebo-controlled trial of antioxidant therapy in limited cutaneous systemic sclerosis. Clin Exp Rheumatol. 2000;18:349–356.
   PubMed Web of Science ®Google Scholar
• de Souza RBC, Macedo AR, Kuruma KA, et al. Pentoxyphylline in association with vitamin E reduces cutaneous fibrosis in systemic sclerosis. Clin Rheumatol. 2009;28:1207–1212.
   PubMed Web of Science ®Google Scholar
• Ostojic P, Damjanov N. Effects of micronutrient antioxidants (alpha-tocopherol and ascorbic acid) on skin thickening and lung function in patients with early diffuse systemic sclerosis. Rheumatol Int. 2011;31:1051–1054.
   PubMed Web of Science ®Google Scholar
• Fiori G, Galluccio F, Braschi F, et al. Vitamin E gel reduces time of healing of digital ulcers in systemic sclerosis. Clin Exp Rheumatol. 2009;27:(Suppl 54):51–54.
   PubMedGoogle Scholar
• Kremer JM. Treatment of systemic sclerosis with topical tretinoin: report of two cases. Arthritis Rheum. 1996;39:1070.
   PubMedGoogle Scholar
• Ikeda T, Uede K, Hashizume H, et al. The vitamin A derivative etretinate improves skin sclerosis in patients with systemic sclerosis. J Dermatol Sci. 2004;34:62–66.
   PubMed Web of Science ®Google Scholar
• Samuni Y, Goldstein S, Dean OM, et al. The chemistry and biological activities of N-acetylcysteine. Biochim Biophys Acta. 2013;1830:4117–4129.
   PubMed Web of Science ®Google Scholar
• Meister A, Anderson ME. Glutathione. Annu Rev Biochem. 1983;52:711–760.
   PubMed Web of Science ®Google Scholar
• Rushworth GF, Megson IL. Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits. Pharmacol Ther. 2014;141:150–159.
   PubMed Web of Science ®Google Scholar
• Deponte M. Glutathione catalysis and the reaction mechanisms of glutathione-dependent enzymes. Biochim Biophys Acta. 2013;1830:3217–3266.
   PubMed Web of Science ®Google Scholar
• Aldini G, Altomare A, Baron G, et al. N-acetylcysteine as an antioxidant and disulphide breaking agent: the reasons why. Free Radic Res. 2018;52:751–762.
   PubMed Web of Science ®Google Scholar
• Furst DE, Clements PJ, Harris R, et al. Measurement of clinical change in progressive systemic sclerosis: a 1 year double-blind placebo-controlled trial of N-acetylcysteine. Ann Rheum Dis. 1979;38:356–361.
   PubMed Web of Science ®Google Scholar
• Correa MJ, Mariz HA, Andrade LE, et al. Oral N-acetylcysteine in the treatment of Raynaud’s phenomenon secondary to systemic sclerosis: a randomized, double-blind, placebo-controlled clinical trial. Rev Bras Reumatol. 2014;54:452–458.
   PubMed Web of Science ®Google Scholar
• Rosato E, Borghese F, Pisarri S, et al. The treatment with N-acetylcysteine of Raynaud’s phenomenon and ischemic ulcers therapy in sclerodermic patients: a prospective observational study of 50 patients. Clin Rheumatol. 2009;28:1379–1384.
   PubMed Web of Science ®Google Scholar
• Rosato E, Rossi C, Molinaro I, et al. Long-term N-acetylcysteine therapy in systemic sclerosis interstitial lung disease: a retrospective study. Int J Immunopathol Pharmacol. 2011;24:727–733.
   PubMed Web of Science ®Google Scholar
• Rosato E, Cianci R, Barbano B, et al. N-acetylcysteine infusion reduces the resistance index of renal artery in the early stage of systemic sclerosis. Acta Pharmacol Sin. 2009;30:1283–1288.
   PubMed Web of Science ®Google Scholar
• Herbert CM, Jayson MIV, Lindberg KA, et al. Biosynthesis and maturation of skin collagen in scleroderma, and effect of d-penicillamine. Lancet. 1974;303:1187–192.
   Google Scholar
• Nimni ME. A defect in the intramolecular and intermolecular cross-linking of collagen caused by penicillamine. I. Metabolic and functional abnormalities in soft tissues. J Biol Chem. 1968;243:1457–1466.
   PubMed Web of Science ®Google Scholar
• Nimni ME. Penicillamine and collagen metabolism. Scand J Rheumatol. 1979;8:71–78.
   PubMedGoogle Scholar
• Uitto J, Helin P, Rasmussen O, et al. Skin collagen in patients with scleroderma: biosynthesis and maturation in vitro, and the effect of d-penicillamine. Ann Clin Res. 1970;2:228–234.
   PubMedGoogle Scholar
• Trachootham D, Lu W, Ogasawara MA, et al. Redox regulation of cell survival. Antioxid Redox Signal. 2008;10:1343–1374.
   PubMed Web of Science ®Google Scholar
• Wadhwa S, Mumper RJ. D-penicillamine and other low molecular weight thiols: review of anticancer effects and related mechanisms. Cancer Lett. 2013;337:8–21.
   PubMed Web of Science ®Google Scholar
• Harris ED, Jr, Sjoerdsma A. Effect of penicillamine on human collagen and its possible application to treatment of scleroderma. Lancet. 1966;288:996–999.
   Google Scholar
• Fulghum DD, Katz R. Penicillamine for scleroderma. Arch Dermatol. 1968;98:51–52.
   PubMedGoogle Scholar
• Bluestone R, Grahame R, Holloway V, et al. Treatment of systemic sclerosis with d-penicillamine. A new method of observing the effects of treatment. Ann Rheum Dis. 1970;29:153–158.
   PubMed Web of Science ®Google Scholar
• Jayson MI, Lovell C, Black CM, et al. Penicillamine therapy in systemic sclerosis. Proc R Soc Med. 1977;70:82–88.
   PubMedGoogle Scholar
• Furst DE, Clements PJ. D-penicillamine is not an effective treatment in systemic sclerosis. Scand J Rheumatol. 2001;30:189–191.
   PubMed Web of Science ®Google Scholar
• Medsger TA, Jr., Lucas M, Wildy KS, et al. D-penicillamine in systemic sclerosis? Yes! Scand J Rheumatol. 2001;30:192–194.
   PubMed Web of Science ®Google Scholar
• Clements PJ, Seibold JR, Furst DE, et al. High-dose versus low-dose d-penicillamine in early diffuse systemic sclerosis trial: lessons learned. Semin Arthritis Rheum. 2004;33:249–263.
   PubMed Web of Science ®Google Scholar
• Derk CT, Huaman G, Jimenez SA. A retrospective randomly selected cohort study of d-penicillamine treatment in rapidly progressive diffuse cutaneous systemic sclerosis of recent onset. Br J Dermatol. 2008;158:1063–1068.
   PubMed Web of Science ®Google Scholar
• Steen VD, Medsger TA. Jr. Improvement in skin thickening in systemic sclerosis associated with improved survival. Arthritis Rheum. 2001;44:2828–2835.
   PubMed Web of Science ®Google Scholar
• Jimenez SA, Sigal SH. A 15-year prospective study of treatment of rapidly progressive systemic sclerosis with d-penicillamine [see comment]. J Rheumatol. 1991;18:1496–1503.
   PubMed Web of Science ®Google Scholar
• Derk CT, Jimenez SA. Goodpasture-like syndrome induced by d-penicillamine in a patient with systemic sclerosis: report and review of the literature. J Rheumatol. 2003;30:1616–1620.
   PubMed Web of Science ®Google Scholar
• Dawkins RL, Zilko PJ, Carrano J, et al. Immunobiology of d-penicillamine. J Rheumatol Suppl. 1981;7:56–61.
   PubMedGoogle Scholar
• Stocker R. Molecular mechanisms underlying the antiatherosclerotic and antidiabetic effects of Probucol, succinobucol, and other Probucol analogues. Curr Opin Lipidol. 2009;20:227–235.
   PubMed Web of Science ®Google Scholar
• Witting PK, Wu BJ, Raftery M, et al. Probucol protects against hypochlorite-induced endothelial dysfunction: identification of a novel pathway of Probucol oxidation to a biologically active intermediate. J Biol Chem. 2005;280:15612–15618.
   PubMed Web of Science ®Google Scholar
• Deng YM, Wu BJ, Witting PK, et al. Probucol protects against smooth muscle cell proliferation by upregulating heme oxygenase-1. Circulation. 2004;110:1855–1860.
   PubMed Web of Science ®Google Scholar
• Alam J, Stewart D, Touchard C, et al. Nrf2, a Cap’n’Collar transcription factor, regulates induction of the heme oxygenase-1 gene. J Biol Chem. 1999;274:26071–26078.
   PubMed Web of Science ®Google Scholar
• Takabe W, Matsukawa N, Kodama T, et al. Chemical structure-dependent gene expression of proteasome subunits via regulation of the antioxidant response element. Free Radic Res. 2006;40:21–30.
   PubMed Web of Science ®Google Scholar
• Zucoloto AZ, Manchope MF, Staurengo-Ferrari L, et al. Probucol attenuates lipopolysaccharide-induced leukocyte recruitment and inflammatory hyperalgesia: effect on NF-κB activation and cytokine production. Eur J Pharmacol. 2017;809:52–63.
   PubMed Web of Science ®Google Scholar
• Jiang JL, Zhang XH, Li NS, et al. Probucol decreases asymmetrical dimethylarginine level by alternation of protein arginine methyltransferase I and dimethylarginine dimethylaminohydrolase activity. Cardiovasc Drugs Ther. 2006;20:281–294.
   PubMed Web of Science ®Google Scholar
• Singla DK, Kaur K, Sharma AK, et al. Probucol promotes endogenous antioxidant reserve and confers protection against reperfusion injury. Can J Physiol Pharmacol. 2007;85:439–443.
   PubMed Web of Science ®Google Scholar
• Denton CP, Bunce TD, Dorado MB, et al. Probucol improves symptoms and reduces lipoprotein oxidation susceptibility in patients with Raynaud’s phenomenon. Rheumatology.1999;38:309–315.
   PubMed Web of Science ®Google Scholar
• Wassmann S, Laufs U, Müller K, et al. Cellular antioxidant effects of atorvastatin in vitro and in vivo. Arterioscler Thromb Vasc Biol. 2002;22:300–305.
   PubMed Web of Science ®Google Scholar
• Laufs U, Liao JK. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem. 1998;273:24266–24271.
   PubMed Web of Science ®Google Scholar
• Ming X-F, Viswambharan H, Barandier C, et al. Rho GTPase/Rho kinase negatively regulates endothelial nitric oxide synthase phosphorylation through the inhibition of protein kinase B/Akt in human endothelial cells. Mol Cell Biol. 2002;22:8467–8477.
   PubMed Web of Science ®Google Scholar
• Feron O, Dessy C, Desager J-P, et al. Hydroxy-methylglutaryl-coenzyme A reductase inhibition promotes endothelial nitric oxide synthase activation through a decrease in caveolin abundance. Circulation. 2001;103:113–118.
   PubMed Web of Science ®Google Scholar
• Kleikers PWM, Wingler K, Hermans JJR, et al. NADPH oxidases as a source of oxidative stress and molecular target in ischemia/reperfusion injury. J Mol Med. 2012;90:1391–1406.
   PubMed Web of Science ®Google Scholar
• Brandes RP, Beer S, Ha T, et al. Withdrawal of cerivastatin induces monocyte chemoattractant protein 1 and tissue factor expression in cultured vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2003;23:1794–1800.
   PubMed Web of Science ®Google Scholar
• Christ M, Bauersachs J, Liebetrau C, et al. Glucose increases endothelial-dependent superoxide formation in coronary arteries by NAD(P)H oxidase activation: attenuation by the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin. Diabetes. 2002;51:2648–2652.
   PubMed Web of Science ®Google Scholar
• Wei Y-M, Li X, Xiong J, et al. Attenuation by statins of membrane raft-redox signaling in coronary arterial endothelium. J Pharmacol Exp Ther. 2013;345:170–179.
   PubMed Web of Science ®Google Scholar
• Wagner AH, Ko¨hler T, Ru¨ckschloss U, et al. Improvement of nitric oxide-dependent vasodilatation by HMG-CoA Reductase Inhibitors through attenuation of endothelial superoxide anion formation. Arterioscler Thromb Vasc Biol. 2000;20:61–69.
   PubMed Web of Science ®Google Scholar
• Antoniades C, Bakogiannis C, Tousoulis D, et al. Preoperative atorvastatin treatment in CABG patients rapidly improves vein graft redox state by inhibition of Rac1 and NADPH-oxidase activity. Circulation. 2010;122:S66–S73.
   PubMed Web of Science ®Google Scholar
• Kurusu A, Shou I, Nakamura S, et al. Effects of the new hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin on anti-oxidant enzyme activities and renal function in streptozotocin-induced diabetic rats. Clin Exp Pharmacol Physiol. 2000;27:767–770.
   PubMed Web of Science ®Google Scholar
• Zhu B, Shen H, Zhou J, et al. Effects of simvastatin on oxidative stress in streptozotocin-induced diabetic rats: a role for glomeruli protection. Nephron Exp Nephrol. 2005;101:e1–e8.
   PubMedGoogle Scholar
• Pérez-Guerrero C, de Sotomayor MA, Jimenez L, et al. Effects of simvastatin on endothelial function after chronic inhibition of nitric oxide synthase by L-NAME. J Cardiovasc Pharmacol. 2003;42:204–210.
   PubMed Web of Science ®Google Scholar
• Colucci R, Fornai M, Duranti E, et al. Rosuvastatin prevents angiotensin II-induced vascular changes by inhibition of NAD(P)H oxidase and COX-1. Br J Pharmacol. 2013;169:554–566.
   PubMed Web of Science ®Google Scholar
• Dichtl W, Dulak J, Frick M, et al. HMG-CoA reductase inhibitors regulate inflammatory transcription factors in human endothelial and vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2003;23:58–63.
   PubMed Web of Science ®Google Scholar
• Ladak K, Pope JE. A review of the effects of statins in systemic sclerosis. Semin Arthritis Rheum. 2016;45:698–705.
   PubMed Web of Science ®Google Scholar
• Del Papa N, Cortiana M, Vitali C, et al. Simvastatin reduces endothelial activation and damage but is partially ineffective in inducing endothelial repair in systemic sclerosis. J Rheumatol. 2008;35:1323–1328.
   PubMed Web of Science ®Google Scholar
• Abou-Raya A, Abou-Raya S, Helmii M. Statins: potentially useful in therapy of systemic sclerosis-related Raynaud’s phenomenon and digital ulcers. J Rheumatol. 2008;35:1801–1808.
   PubMed Web of Science ®Google Scholar
• Timár O, Szekanecz Z, Kerekes G, et al. Rosuvastatin improves impaired endothelial function, lowers high sensitivity CRP, complement and immuncomplex production in patients with systemic sclerosis – a prospective case-series study. Arthritis Res Ther. 2013;15:R105.
   PubMed Web of Science ®Google Scholar
• Kuwana M, Okazaki Y, Kaburaki J. Long-term beneficial effects of statins on vascular manifestations in patients with systemic sclerosis. Mod Rheumatol. 2009;19:530–535.
   PubMed Web of Science ®Google Scholar
• Rossi M, Bazzichi L, Ghiadoni L, et al. Increased finger skin vasoreactivity and stimulated vasomotion associated with simvastatin therapy in systemic sclerosis hypercholesterolemic patients. Rheumatol Int. 2012;32:3715–3721.
   PubMed Web of Science ®Google Scholar
• Furukawa S, Yasuda S, Amengual O, et al. Protective effect of pravastatin on vascular endothelium in patients with systemic sclerosis: a pilot study. Ann Rheum Dis. 2006;65:1118–1120.
   PubMed Web of Science ®Google Scholar
• Sadik HY, Moore TL, Vail A, et al. Lack of effect of 8 weeks atorvastatin on microvascular endothelial function in patients with systemic sclerosis. Rheumatology. 2010;49:990–996.
   PubMed Web of Science ®Google Scholar
• Tsou P-S, Talia NN, Pinney AJ, et al. Effect of oxidative stress on protein tyrosine phosphatase 1B in scleroderma dermal fibroblasts. Arthritis Rheum. 2012;64:1978–1989.
   PubMedGoogle Scholar
• Rothstein JD. Edaravone: a new drug approved for ALS. Cell. 2017;171:725.
   PubMed Web of Science ®Google Scholar
• Wang H-M, Zhang T, Huang J-K, et al. Edaravone attenuates the proinflammatory response in amyloid-beta-treated microglia by inhibiting NLRP3 inflammasome-mediated IL-1beta secretion. Cell Physiol Biochem. 2017;43:1113–1125.
   PubMed Web of Science ®Google Scholar
• Mikawa K, Akamatsu H, Nishina K, et al. Effects of edaravone on human neutrophil function. Acta Anaesthesiol Scand. 2005;49:385–389.
   PubMed Web of Science ®Google Scholar
• Watanabe T, Tahara M, Todo S. The novel antioxidant edaravone: from bench to bedside. Cardiovasc Therap. 2008;26:101–114.
   PubMed Web of Science ®Google Scholar
• Yoshizaki A, Yanaba K, Ogawa A, et al. The specific free radical scavenger edaravone suppresses fibrosis in the bleomycin-induced and tight skin mouse models of systemic sclerosis. Arthritis Rheum. 2011;63:3086–3097.
   PubMed Web of Science ®Google Scholar
• Park S, Karunakaran U, Jeoung N, et al. Physiological effect and therapeutic application of alpha lipoic acid. Curr Med Chem. 2014;21:3636–3645.
   PubMed Web of Science ®Google Scholar
• Jones W, Li X, Qu Z-c, et al. Uptake, recycling, and antioxidant actions of alpha-lipoic acid in endothelial cells. Free Radic Biol Med. 2002;33:83–93.
   PubMed Web of Science ®Google Scholar
• Wada H, Shintani D, Ohlrogge J. Why do mitochondria synthesize fatty acids? Evidence for involvement in lipoic acid production. Proc Natl Acad Sci USA. 1997;94:1591–1596.
   PubMed Web of Science ®Google Scholar
• Biewenga GP, Haenen GR, Bast A. The pharmacology of the antioxidant lipoic acid. Gen Pharmacol. 1997;29:315–331.
   PubMedGoogle Scholar
• Bast A, Haenen GR. Lipoic acid: a multifunctional antioxidant. Biofactors. 2003;17:207–213.
   PubMed Web of Science ®Google Scholar
• Petersen Shay K, Moreau RF, Smith EJ, et al. Is alpha-lipoic acid a scavenger of reactive oxygen species in vivo? Evidence for its initiation of stress signaling pathways that promote endogenous antioxidant capacity. IUBMB Life. 2008;60:362–367.
   PubMed Web of Science ®Google Scholar
• Busse E, Zimmer G, Schopohl B, et al. Influence of alpha-lipoic acid on intracellular glutathione in vitro and in vivo. Arzneimittelforschung. 1992;42:829–831.
   PubMed Web of Science ®Google Scholar
• Han D, Handelman G, Marcocci L, et al. Lipoic acid increases de novo synthesis of cellular glutathione by improving cystine utilization. Biofactors. 1997;6:321–338.
   PubMed Web of Science ®Google Scholar
• Mary J, Vougier S, Picot CR, et al. Enzymatic reactions involved in the repair of oxidized proteins. Exp Gerontol. 2004;39:1117–1123.
   PubMed Web of Science ®Google Scholar
• Ying Z, Kampfrath T, Sun Q, et al. Evidence that α-lipoic acid inhibits NF-κB activation independent of its antioxidant function. Inflamm Res. 2011;60:219–225.
   PubMed Web of Science ®Google Scholar
• Ou P, Tritschler HJ, Wolff SP. Thioctic (lipoic) acid: a therapeutic metal-chelating antioxidant? Biochem Pharmacol. 1995;50:123–126.
   PubMed Web of Science ®Google Scholar
• Goralska M, Dackor R, Holley B, et al. Alpha lipoic acid changes iron uptake and storage in lens epithelial cells. Exp Eye Res. 2003;76:241–248.
   PubMed Web of Science ®Google Scholar
• Tsou PS, Balogh B, Pinney AJ, et al. Lipoic acid plays a role in scleroderma: insights obtained from scleroderma dermal fibroblasts. Arthritis Res Ther. 2014;16:411.
   PubMedGoogle Scholar
• Kavian N, Marut W, Servettaz A, et al. Pantethine prevents murine systemic sclerosis through the inhibition of microparticle shedding. Arthritis Rheumatol. 2015;67:1881–1890.
   PubMed Web of Science ®Google Scholar
• Bian D, Zhang J, Wu X, et al. Asiatic acid isolated from Centella asiatica inhibits TGF-beta1-induced collagen expression in human keloid fibroblasts via PPAR-gamma activation. Int J Biol Sci. 2013;9:1032–1042.
   PubMed Web of Science ®Google Scholar
• Xia X, Dai C, Yu H, et al. Asiatic acid prevents the development of interstitial lung disease in a hypochlorous acid-induced mouse model of scleroderma. Oncol Lett. 2018;15:8711–8716.
   PubMed Web of Science ®Google Scholar
• Liu M, Yang J, Li M. Tanshinone IIA attenuates interleukin-17A-induced systemic sclerosis patient-derived dermal vascular smooth muscle cell activation via inhibition of the extracellular signal-regulated kinase signaling pathway. Clinics. 2015;70:250–256.
   PubMed Web of Science ®Google Scholar
• Song Y, Zhu L, Li M. Antifibrotic effects of crocetin in scleroderma fibroblasts and in bleomycin-induced sclerotic mice. Clinics. 2013;68:1350–1357.
   PubMed Web of Science ®Google Scholar
• Dooley A, Shi-Wen X, Aden N, et al. Modulation of collagen type I, fibronectin and dermal fibroblast function and activity, in systemic sclerosis by the antioxidant epigallocatechin-3-gallate. Rheumatology. 2010;49:2024–2036.
   PubMed Web of Science ®Google Scholar
• Dooley A, Bruckdorfer KR, Abraham DJ. Modulation of fibrosis in systemic sclerosis by nitric oxide and antioxidants. Cardiol Res Pract. 2012; 2012:521958.
   PubMedGoogle Scholar
• Venkatesan N, Punithavathi V, Chandrakasan G. Curcumin protects bleomycin-induced lung injury in rats. Life Sci. 1997;61:PL51–PL58.
   PubMed Web of Science ®Google Scholar
• Tourkina E, Gooz P, Oates JC, et al. Curcumin-induced apoptosis in scleroderma lung fibroblasts: role of protein kinase cepsilon. Am J Respir Cell Mol Biol. 2004;31:28–35.
   PubMed Web of Science ®Google Scholar
• Rushworth SA, Ogborne RM, Charalambos CA, et al. Role of protein kinase C delta in curcumin-induced antioxidant response element-mediated gene expression in human monocytes. Biochem Biophys Res Commun. 2006;341:1007–1016.
   PubMed Web of Science ®Google Scholar
• Song K, Peng S, Sun Z, et al. Curcumin suppresses TGF-beta signaling by inhibition of TGIF degradation in scleroderma fibroblasts. Biochem Biophys Res Commun. 2011;411:821–825.
   PubMed Web of Science ®Google Scholar
• Aggarwal BB, Sundaram C, Malani N, et al. Curcumin: the Indian solid gold. Adv Exp Med Biol. 2007;595:1–75.
   PubMed Web of Science ®Google Scholar
• Sharma RA, Steward WP, Gescher AJ. Pharmacokinetics and pharmacodynamics of curcumin. Adv Exp Med Biol. 2007;595:453–470.
   PubMed Web of Science ®Google Scholar
• Smulik R, Dębski D, Zielonka J, et al. Nitroxyl (HNO) reacts with molecular oxygen and forms peroxynitrite at physiological pH. J Biol Chem. 2014;289:35570–35581.
   PubMed Web of Science ®Google Scholar
• Samarakoon R, Overstreet JM, Higgins PJ. TGF-beta signaling in tissue fibrosis: redox controls, target genes and therapeutic opportunities. Cell Signal. 2013;25:264–268.
   PubMed Web of Science ®Google Scholar
• Cucoranu I, Clempus R, Dikalova A, et al. NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. Circ Res. 2005;97:900–907.
   PubMed Web of Science ®Google Scholar
• Sturrock A, Cahill B, Norman K, et al. Transforming growth factor-beta1 induces Nox4 NAD(P)H oxidase and reactive oxygen species-dependent proliferation in human pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2006;290:L661–LL673.
   PubMed Web of Science ®Google Scholar
• Jiang F, Zhang Y, Dusting GJ. NADPH oxidase-mediated redox signaling: roles in cellular stress response, stress tolerance, and tissue repair. Pharmacol Rev. 2011;63:218–242.
   PubMed Web of Science ®Google Scholar
• Barcellos-Hoff MH, Dix TA. Redox-mediated activation of latent transforming growth factor-beta 1. Mol Endocrinol. 1996;10:1077–1083.
   PubMed Web of Science ®Google Scholar
• Leonarduzzi G, Scavazza A, Biasi F, et al. The lipid peroxidation end product 4-hydroxy-2,3-nonenal up-regulates transforming growth factor beta1 expression in the macrophage lineage: a link between oxidative injury and fibrosclerosis. FASEB J. 1997;11:851–857.
   PubMed Web of Science ®Google Scholar
• Hecker L, Vittal R, Jones T, et al. NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury. Nat Med. 2009;15:1077–1081.
   PubMed Web of Science ®Google Scholar
• Teixeira G, Szyndralewiez C, Molango S, et al. Therapeutic potential of NADPH oxidase 1/4 inhibitors. Br J Pharmacol. 2017;174:1647–1669.
   PubMed Web of Science ®Google Scholar
• Murphy-Marshman H, Quensel K, Shi-wen X et al. Antioxidants and NOX1/NOX4 inhibition blocks TGFbeta1-induced CCN2 and alpha-SMA expression in dermal and gingival fibroblasts. PLoS One. 2017;12:e0186740.
   PubMed Web of Science ®Google Scholar
• Parnham MJ, Haber VE, Giamarellos-Bourboulis EJ, et al. Azithromycin: mechanisms of action and their relevance for clinical applications. Pharmacol Ther. 2014;143:225–245.
   PubMed Web of Science ®Google Scholar
• Tsubouchi K, Araya J, Minagawa S, et al. Azithromycin attenuates myofibroblast differentiation and lung fibrosis development through proteasomal degradation of NOX4. Autophagy. 2017;13:1420–1434.
   PubMed Web of Science ®Google Scholar
• Dosoki H, Stegemann A, Taha M, et al. Targeting of NADPH oxidase in vitro and in vivo suppresses fibroblast activation and experimental skin fibrosis. Exp Dermatol. 2017;26:73–81.
   PubMed Web of Science ®Google Scholar
• Pignatelli P, Carnevale R, Pastori D, et al. Immediate antioxidant and antiplatelet effect of atorvastatin via inhibition of Nox2. Circulation. 2012;126:92–103.
   PubMed Web of Science ®Google Scholar
• Pignatelli P, Carnevale R, Di Santo S, et al. Rosuvastatin reduces platelet recruitment by inhibiting NADPH oxidase activation. Biochem Pharmacol. 2012;84:1635–1642.
   PubMed Web of Science ®Google Scholar
• Zhou G, Wang Y, He P, et al. Probucol inhibited Nox2 expression and attenuated podocyte injury in type 2 diabetic nephropathy of db/db mice. Biol Pharm Bull. 2013;36:1883–1890.
   PubMed Web of Science ®Google Scholar
• Zhu BB, Wang H, Chi YF, et al. Protective effects of probucol on Ox-LDL-induced epithelial-mesenchymal transition in human renal proximal tubular epithelial cells via LOX-1/ROS/MAPK signaling. Mol Med Rep. 2018;17:1289–1296.
   PubMed Web of Science ®Google Scholar
• Cruz-Solbes AS, Youker K. Epithelial to mesenchymal transition (EMT) and endothelial to mesenchymal transition (EndMT): role and implications in kidney fibrosis. Results Probl Cell Differ. 2017;60:345–372.
   PubMedGoogle Scholar
• O'Neill HC, Rancourt RC, White CW. Lipoic acid suppression of neutrophil respiratory burst: effect of NADPH. Antioxid Redox Signal. 2008;10:277–285.
   PubMed Web of Science ®Google Scholar
• Dong Y, Wang H, Chen Z. Alpha-lipoic acid attenuates cerebral ischemia and reperfusion injury via insulin receptor and PI3K/Akt-Dependent inhibition of NADPH oxidase. Int J Endocrinol. 2015;2015:1.
   Web of Science ®Google Scholar