Oxidative Stress Reduction (Prong-3)

  • Nicholas L. DePace
  • Joseph Colombo


Stress reduction is a major theme of the recommendations in this book. Oxidative stress is “stress” at the cellular level. Arguably, the most critical damage caused by oxidative stress is to mitochondria function. There is a direct causal relationship between oxidative stress, mitochondrial dysfunction, and many clinical syndromes, especially those that may be relieved but are difficult to cure, including parasympathetic and sympathetic dysfunctions. Reducing mitochondrial dysfunction is the beginning to the cure of many of these syndromes and a critical step on the path to wellness. A little oxidative stress is healthy. Too much oxidative stress accelerates diseases and ultimately the aging process, destroying mitochondria, and thereby cells, and thereby membranes, and thereby tissues, and ultimately organs and organ systems. While mitochondria, when they themselves are dysfunctional, contribute to oxidative stress, the reactive species they produce normally are helpful to the body, including the immune system, contributing to the passive defense, literally “burning out” foreign agents. Reducing oxidative stress also helps to maintain proper nitric oxide function which feeds back and helps to further reduce stress, preventing the dark side of nitric oxide. The main object of this chapter is to demonstrate means of reducing oxidative stress and how reducing oxidative stress helps to relieve diseases and establish and maintain wellness.

A proper antioxidant reservoir and maintaining a proper antioxidant-oxidant balance are the keys to minimizing oxidative stress effects. A proper reservoir is built on supplements including alpha-lipoic acid and CoQ10; B vitamins, including folic acid (vitamin B9); tryptophan; and nitric oxide.


Aging Aldehydes Alpha-lipoic acid Autonomic neuropathy Bipolar disease B vitamins Cardiovascular disease Diabetes Fatty liver disease Folic acid Homocysteine Mast cells Mitochondrial dysfunction Nitric oxide Obesity Oxidative stress Parasympathetic and sympathetic Pollution Reactive oxygen species Smoking Tryptophan 


  1. 1.
    Hensley K, Floyd RA, editors. Methods in biological oxidative stress. Methods in pharmacology and toxicology. Totowa: Humana Press; 2010.Google Scholar
  2. 2.
    Rahal A, Kumar A, Singh V, Yadev B, Tiwari R, Chakraborty S, Dhama K. Oxidative stress, Prooxidants, and antioxidants: The interplay. Biomed Res Int. 2014, Article ID 761264, 19 pages.Google Scholar
  3. 3.
    Nicolson G. Mitochondrial dysfunction and chronic disease: treatment with natural supplements. Altern Ther Health Med. 2014;20(Suppl 1):18–25.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Kroemer G, Galluzzi L, Brenner C. Mitochondrial membrane permeabilization in cell death. Physiol Rev. 2007;87(1):99–163. Review. Scholar
  5. 5.
    Parikh S, Goldstein A, Karaa A, Koenig MK, Anselm I, Brunel-Guitton C, Christodoulou J, Cohen BH, Dimmock D, Enns GM, Falk MJ, Feigenbaum A, Frye RE, Ganesh J, Griesemer D, Haas R, Horvath R, Korson M, Kruer MC, Mancuso M, McCormack S, Raboisson MJ, Reimschisel T, Salvarinova R, Saneto RP, Scaglia F, Shoffner J, Stacpoole PW, Sue CM, Tarnopolsky M, Van Karnebeek C, Wolfe LA, Cunningham ZZ, Rahman S, Chinnery PF. Patient care standards for primary mitochondrial disease: a consensus statement from the mitochondrial medicine society. Genet Med. 2017. [Epub ahead of print] Review.Google Scholar
  6. 6.
    Mammucari C, Gherardi G, Rizzuto R. Structure, activity regulation, and role of the mitochondrial calcium uniporter in health and disease. Front Oncol. 2017;7:139. eCollection 2017. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Picca A, Lezza AMS, Leeuwenburgh C, Pesce V, Calvani R, Landi F, Bernabei R, Marzetti E. Fueling inflamm-aging through mitochondrial dysfunction: mechanisms and molecular targets. Int J Mol Sci. 2017;18(5). pii: E933. Review.PubMedCentralCrossRefGoogle Scholar
  8. 8.
    Li R, Jia Z, Trush MA. Defining ROS in biology and medicine. Reactive oxygen species (Apex, NC). 2016;1(1):9–21.
  9. 9.
    Dizaj SM, Lotfipour F, Barzegar-Jalali M, Zarrintan MH, Adibkia K. Antimicrobial activity of the metals and metal oxide nanoparticles. Mater Sci Eng C Mater Biol Appl. 2014;44:278–84. Epub 2014 Aug 16. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Vatansever F, de Melo WC, Avci P, Vecchio D, Sadasivam M, Gupta A, Chandran R, Karimi M, Parizotto NA, Yin R, Tegos GP, Hamblin MR. Antimicrobial strategies centered around reactive oxygen species – bactericidal antibiotics, photodynamic therapy, and beyond. FEMS Microbiol Rev. 2013;37(6):955–89. Epub 2013 Jul 25. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Brynildsen MP, Winkler JA, Spina CS, MacDonald IC, Collins JJ. Potentiating antibacterial activity by predictably enhancing endogenous microbial ROS production. Nat Biotechnol. 2013;31(2):160–5. Epub 2013 Jan 6.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Dan Dunn J, Alvarez LA, Zhang X, Soldati T. Reactive oxygen species and mitochondria: a nexus of cellular homeostasis. Redox Biol. 2015;6:472–85. Epub 2015 Sept 10. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    D’Autréaux B, Toledano MB. ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis. Nat Rev Mol Cell Biol. 2007;8(10):813–24. Review.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Liou GY, Storz P. Reactive oxygen species in cancer. Free Radic Res. 2010;44(5):479–96. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Hafstad AD, Nabeebaccus AA, Shah AM. Novel aspects of ROS signalling in heart failure. Basic Res Cardiol. 2013;108(4):359. Epub 2013 Jun 6. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Zhang M, Shah AM. ROS signalling between endothelial cells and cardiac cells. Cardiovasc Res. 2014;102(2):249–57. Epub 2014 Mar 3. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Yuste JE, Tarragon E, Campuzano CM, Ros-Bernal F. Implications of glial nitric oxide in neurodegenerative diseases. Front Cell Neurosci. 2015;9:322. eCollection 2015. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Frye RE, Rossignol DA. Mitochondrial dysfunction can connect the diverse medical symptoms associated with autism spectrum disorders. Pediatr Res. 2011;69(5 Pt 2):41R–7R. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Meeus M, Nijs J, Hermans L, Goubert D, Calders P. The role of mitochondrial dysfunctions due to oxidative and nitrosative stress in the chronic pain or chronic fatigue syndromes and fibromyalgia patients: peripheral and central mechanisms as therapeutic targets? Expert Opin Ther Targets. 2013;17(9):1081–9. Epub 2013 Jul 9. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Tanaka M, Tajima S, Mizuno K, Ishii A, Konishi Y, Miike T, Watanabe Y. Frontier studies on fatigue, autonomic nerve dysfunction, and sleep-rhythm disorder. J Physiol Sci. 2015;65(6):483–98. Epub 2015 Sept 29. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Van Cauwenbergh D, Nijs J, Kos D, Van Weijnen L, Struyf F, Meeus M. Malfunctioning of the autonomic nervous system in patients with chronic fatigue syndrome: a systematic literature review. Eur J Clin Investig. 2014;44(5):516–26. Review.CrossRefGoogle Scholar
  22. 22.
    El-Hattab AW, Scaglia F. Mitochondrial cardiomyopathies. Front Cardiovasc Med. 2016;3:25. eCollection 2016. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Cardinali DP. Autonomic nervous system: basic and clinical aspects. Cham: Springer International Publishing AG; 2018.CrossRefGoogle Scholar
  24. 24.
    Sharafati-Chaleshtori R, Shirzad H, Rafieian-Kopaei M, Soltani A. Melatonin and human mitochondrial diseases. J Res Med Sci. 2017;22:2. eCollection 2017. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Li S, Tan HY, Wang N, Zhang ZJ, Lao L, Wong CW, Feng Y. The role of oxidative stress and antioxidants in liver diseases. Int J Mol Sci. 2015;16(11):26087–124. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Martínez-Martínez LA, Mora T, Vargas A, Fuentes-Iniestra M, Martínez-Lavín M. Sympathetic nervous system dysfunction in fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and interstitial cystitis: a review of case-control studies. J Clin Rheumatol. 2014;20(3):146–50. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Zsurka G, Kunz WS. Mitochondrial dysfunction and seizures: the neuronal energy crisis. Lancet Neurol. 2015;14(9):956–66. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Murphy MP. Understanding and preventing mitochondrial oxidative damage. Biochem Soc Trans. 2016;44(5):1219–26. Review.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Li AN, Li S, Zhang YJ, Xu XR, Chen YM, Li HB. Resources and biological activities of natural polyphenols. Nutrients. 2014;6:6020–47.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Feng Y, Wang N, Ye X, Li H, Feng Y, Cheung F, Nagamatsu T. Hepatoprotective effect and its possible mechanism of Coptidis rhizoma aqueous extract on carbon tetrachloride-induced chronic liver hepatotoxicity in rats. J Ethnopharmacol. 2011;138:683–90.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Singal AK, Jampana SC, Weinman SA. Antioxidants as therapeutic agents for liver disease. Liver Int. 2011;31:1432–48.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Medina J, Moreno-Otero R. Pathophysiological basis for antioxidant therapy in chronic liver disease. Drugs. 2005;65:2445–61.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Kelly FJ. Oxidative stress: its role in air pollution and adverse health effects. Occup Environ Med. 2003;60:612–6. Scholar
  34. 34.
    Al-Dalaen SM, Al-Qtaitat AI. Review article: oxidative stress versus antioxidants. Am J Biosci Bioeng. 2014;2(5):60–71.Google Scholar
  35. 35.
    Sindhi V, Gupta V, Sharma K, Bhatnagar S, Kumari R, Dhaka N. Potential applications of antioxidants – a review. J Pharm Res. 2013;7(9):828–835. ISSN 0974-6943. Scholar
  36. 36.
    Villamena FA. Molecular basis of oxidative stress: chemistry, mechanisms, and disease pathogenesis. Hoboken: John Wiley & Sons, Inc.; 2013.CrossRefGoogle Scholar
  37. 37.
    Carr AC, McCall MR, Frei B. Oxidation of LDL by myeloperoxidase and reactive nitrogen species: reaction pathways and antioxidant protection. Arterioscler Thromb Vasc Biol. 2000;20:1716–23.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Daugherty A, Dunn JL, Rateri DL, Heinecke JW. Myeloperoxidase, a catalyst for lipoprotein oxidation, is expressed in human atherosclerotic lesions. J Clin Invest. 1994;94:437–44.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Adly AAM. Oxidative stress and disease: an updated review. Res J Immunol. 2010;3:129–45.CrossRefGoogle Scholar
  40. 40.
    Ho E, Karimi Galougahi K, Liu CC, Bhindi R, Figtree GA. Biological markers of oxidative stress: applications to cardiovascular research and practice. Redox Biol. 2013;1:483–91. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Kirkman HN, Gaetani GF. Mammalian catalase: a venerable enzyme with new mysteries. Trends Biochem Sci. 2007;32(1):44–50. Epub 2006 Dec 8. Review.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Garrido N, Meseguer M, Simon C, Pellicer A, Remohi J. Pro-oxidative and anti-oxidative imbalance in human semen and its relation with male fertility. Asian J Androl. 2004;6(1):59–65.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Sonoda J, Pei L, Evans RM. Nuclear receptors: decoding metabolic disease. FEBS Lett. 2008;582(1):2–9.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Cai D. NFkappaB-mediated metabolic inflammation in peripheral tissues versus central nervous system. Cell Cycle. 2009;8:2542–8.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Lumeng CN, Saltiel AR. Inflammatory links between obesity and metabolic disease. J Clin Invest. 2011;121(6):2111–7.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Muriach M, Flores-Bellver M, Romero FJ, Barcia JM. Diabetes and the brain: oxidative stress, inflammation, and autophagy. Oxidative Med Cell Longev. 2014;2014:102158. Epub 2014 Aug 24. Review.CrossRefGoogle Scholar
  47. 47.
    Cai D, Liu T. Inflammatory cause of metabolic syndrome via brain stress and NF-𝜅B. Aging. 2012;4(2):98–115.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Zhang X, Zhang G, Zhang H, Karin M, Bai H, Cai D. Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell. 2008;135:61–73.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    DeSouza CT, Araujo EP, Bordin S, et al. Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology. 2005;146(10):4192–9.CrossRefGoogle Scholar
  50. 50.
    Belgardt BF, Mauer J, Wunderlich FT, et al. Hypothalamic and pituitary c-Jun N-terminal kinase 1 signaling coordinately regulates glucose metabolism. Proc Natl Acad Sci U S A. 2010;107(13):6028–33.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Ozcan U, Yilmaz E, Ozcan L, et al. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science. 2006;313(5790):1137–40.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature. 2006;443(7113):787–95.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Brown MK, Naidoo N. The endoplasmic reticulum stress response in aging and age-related diseases. Front Physiol. 2012;3:263.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Cadenas E, Davies KJA. Mitochondrial free radical generation, oxidative stress, and aging. Free Radic Biol Med. 2000;29(3–4):222–30.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Hotamisligil GS. Endoplasmic reticulum stress and the inflammatory bas is of metabolic disease. Cell. 2010;140(6):900–17.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Tabas I, Ron D. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol. 2011;13(3):184–90.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Meng Y, Yong Y, Yang G, et al. Autophagy alleviates neurodegeneration caused by mild impairment of oxidative metabolism. J Neurochem. 2013;126(6):805–18.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Rao RV, Ellerby HM, Bredesen DE. Coupling endoplasmic reticulum stress to the cell death program. Cell Death Differ. 2004;11(4):372–80.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Purkayastha S, Zhang G, Cai D. Uncoupling the mechanisms of obesity and hypertension by targeting hypothalamic IKK-beta and NF-kappaB. Nat Med. 2011;17:883–7.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Cullinan SB, Diehl JA. Coordination of ER and oxidative stress signaling: the PERK/Nrf2 signaling pathway. Int J Biochem Cell Biol. 2006;38(3):317–32.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Kar SK, Choudhury I. An empirical review on oxidative stress markers and their relevance in obsessive-compulsive disorder. Int J Nutr Pharmacol Neurol Dis. 2016;6:139–45.CrossRefGoogle Scholar
  62. 62.
    Nisar A, Mamat AS, Hatim MI, Aslam MS, Muhammad MS. Identification of flavonoids (quercetin, gallic acid and rutin) from catharanthus roseus plant parts using deep eutectic solvent. Recent Adv Biol Med. 2017;3:1–6. Scholar
  63. 63.
    Halliwell B, Gutteridge J. Free radicals in biology and medicine. Oxford: Oxford University Press; 2007.Google Scholar
  64. 64.
    Powers SK, Jackson MJ. Exercise-induced oxidative stress: cellular mechanisms and impact on muscle force production. Physiol Rev. 2008;88(4):1243–76. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Alam MN, Bristi NJ, Rafiquzzaman M. Review on in vivo and in vitro methods evaluation of antioxidant activity. Saudi Pharm J. 2013;21(2):143–52. Epub 2012 Jun 15.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Davies MJ, Fu S, Wang H, Dean RT. Stable markers of oxidant damage to proteins and their application in the study of human disease. Free Radic Biol Med. 1999;27:1151–63.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Diplock AT. Introduction: markers of oxidative damage and antioxidant modulation. Free Radic Res. 2000;33(Suppl):S21–6.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Han D, Loukianoff S, McLaughlin L. Oxidative stress indices: analytical aspects and significance. In: Sen CK, Packer L, Hanninen O, editors. Handbook of oxidants and antioxidants in exercise. Amsterdam: Elsevier; 2000. p. 433–83.CrossRefGoogle Scholar
  69. 69.
    Hwang ES, Kim GH. Biomarkers for oxidative stress status of DNA, lipids, proteins in vitro and in vivo cancer research. Toxicology. 2007;229:1–10.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Jones DP. Redefining oxidative stress. Antioxid Redox Signal. 2006;8:1865–79.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Lawson JA, Rokach J, FitzGerald GA. Isoprostanes: formation, analysis and use as indices of lipid peroxidation in vivo. J Biol Chem. 1999;274:24441–4.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Roberts LJ, Morrow JD. Measurement of F(2)-isoprostanes as an index of oxidative stress in vivo. Free Radic Biol Med. 2000;28:505–13.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Sachdev S, Davies KJ. Production, detection, adaptive responses to free radicals in exercise. Free Radic Biol Med. 2008;44:215–23.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Kasai H. Analysis of a form of oxidative DNA damage, 8-hydroxy-2′-deoxyguanosine, as a marker of cellular oxidative stress during carcinogenesis. Mutat Res. 1997;387:147–63.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Pillon NJ, Soulage CO. Chapter 19: lipid peroxidation by-products and the metabolic syndrome. In: Catala A, editor. Lipid peroxidation; 2012. Google Scholar
  76. 76.
    Cheng J, Wang F, Yu DF, Wu PF, Chen JG. The cytotoxic mechanism of malondialdehyde and protective effect of carnosine via protein crosslinking/mitochondrial dysfunction/reactive oxygen species/AMPK pathway in neurons. Eur J Pharmacol. 2011;650:184–94.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Long EK, Murphy TC, Leiphon LJ, Watt J, Morrow JD, Milne GL, Howard JRH, Picklo MJ. Trans-4-hydroxy-2-hexenal is a neurotoxic product of docosahexaenoic (22:6; n-3) acid oxidation. J Neurochem. 2008;105:714–24.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Bae EH, Cho S, Joo SY, Ma SK, Kim SH, Lee J, Kim SW. 4-Hydroxy-2-hexenalinduced apoptosis in human renal proximal tubular epithelial cells. Nephrol Dial Transplant. 2011;26:3866–73.PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Uchida K, Shiraishi M, Naito Y, Torii Y, Nakamura Y, Osawa T. Activation of stress signaling pathways by the end product of lipid peroxidation. 4-hydroxy-2-nonenal is a potential inducer of intracellular peroxide production. J Biol Chem. 1999;274:2234–42.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Lee JY, Jung GY, Heo HJ, Yun MR, Park JY, Bae SS, Hong KW, Lee WS, Kim CD. 4-Hydroxynonenal induces vascular smooth muscle cell apoptosis through mitochondrial generation of reactive oxygen species. Toxicol Lett. 2006;166:212–21.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Pillon NJ, Croze ML, Vella RE, Soulère L, Lagarde M, Soulage CO. The lipid peroxidation by-product 4-hydroxy-2-nonenal (4-HNE) induces insulin resistance in skeletal muscle through both carbonyl and oxidative stress. Endocrinology. 2012;153:2099–111.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Luo J, Robinson JP, Shi R. Acrolein-induced cell death in PC12 cells: role of mitochondria-mediated oxidative stress. Neurochem Int. 2005;47:449–57.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Kostyuk V, Potapovich A, Cesareo E, Brescia S, Guerra L, Valacchi G, Pecorelli A, Raskovic D, De Luca C, Pastore S, Korkina L. Dysfunction of glutathione S-transferase leads to excess 4-hydroxy-2-nonenal and H2O2 and impaired cytokine pattern in cultured keratinocytes and blood of vitiligo patients. Antioxid Redox Signal. 2010. Scholar
  84. 84.
    Curtis JM, Grimsrud PA, Wright WS, Xu X, Foncea RE, Graham DW, Brestoff JR, Wiczer BM, Ilkayeva O, Cianflone K, Muoio DE, Arriaga EA, Bernlohr DA. Downregulation of adipose glutathione S-transferase A4 leads to increased protein carbonylation, oxidative stress, and mitochondrial dysfunction. Diabetes. 2010;59:1132–42.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M, Shimomura I. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest. 2004;114:1752–61.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Wellen KE, Hotamisligil GS. Obesity-induced inflammatory changes in adipose tissue. J Clin Invest. 2003;112:1785–8.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Soares AF, Guichardant M, Cozzone D, Bernoud-Hubac N, Bouzaidi-Tiali N, Lagarde M, Geloen A. Effects of oxidative stress on adiponectin secretion and lactate production in 3T3-L1 adipocytes. Free Radic Biol Med. 2005;38:882–9.PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Wang Z, Dou X, Gu D, Shen C, Yao T, Nguyen V, Braunschweig C, Song Z. 4-Hydroxynonenal differentially regulates adiponectin gene expression and secretion via activating PPARγ and accelerating ubiquitin-proteasome degradation. Mol Cell Endocrinol. 2012;349:222–31.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Trevisan M, Browne R, Ram M, Muti P, Freudenheim J, Carosella AM, Armstrong D. Correlates of markers of oxidative status in the general population. Am J Epidemiol. 2001;154:348–56.PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Menon V, Ram M, Dorn J, Armstrong D, Muti P, Freudenheim JL, Browne R, Schunemann H, Trevisan M. Oxidative stress and glucose levels in a population-based sample. Diabet Med. 2004;21:1346–52.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Maxwell SR, Thomason H, Sandler D, Leguen C, Baxter MA, Thorpe GH, Jones AF, Barnett AH. Antioxidant status in patients with uncomplicated insulin-dependent and non-insulin-dependent diabetes mellitus. Eur J Clin Investig. 1997;27:484–90.CrossRefGoogle Scholar
  92. 92.
    Dierckx N, Horvath G, van Gils C, Vertommen J, van de Vliet J, De Leeuw I, Manuel-y-Keenoy B. Oxidative stress status in patients with diabetes mellitus: relationship to diet. Eur J Clin Nutr. 2003;57:999–1008.PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Kamenova P. Improvement of insulin sensitivity in patients with type 2 diabetes mellitus after oral administration of alpha-lipoic acid. Hormones (Athens). 2006;5:251–8.CrossRefGoogle Scholar
  94. 94.
    Vincent HK, Bourguignon CM, Weltman AL, Vincent KR, Barrett E, Innes KE, Taylor AG. Effects of antioxidant supplementation on insulin sensitivity, endothelial adhesion molecules, and oxidative stress in normal-weight and overweight young adults. Metab Clin Exp. 2009;58:254–62.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Bashan N, Kovsan J, Kachko I, Ovadia H, Rudich A. Positive and negative regulation of insulin signaling by reactive oxygen and nitrogen species. Physiol Rev. 2009;89:27–71.PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Adabag AS, Luepker RV, Roger VL, Gersh BJ. Sudden cardiac death: epidemiology and risk factors. Nat Rev Cardiol. 2010;7(4):216–25. Scholar
  97. 97.
    Zimniak P. 4-Hydroxynonenal and fat storage: a paradoxical pro-obesity mechanism? Cell Cycle. 2010;9:3393–4.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Jacob S, Streeper RS, Fogt DL, Hokama JY, Tritschler HJ, Dietze GJ, Henriksen EJ. The antioxidant alpha-lipoic acid enhances insulin-stimulated glucose metabolism in insulin-resistant rat skeletal muscle. Diabetes. 1996;45:1024–9.PubMedCrossRefPubMedCentralGoogle Scholar
  99. 99.
    Ziegler D, Gries F. Alpha-lipoic acid and the treatment of diabetic peripheral autonomic cardiac neuropathy. Diabetes. 1997;46(Suppl 2):S62–6.PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Prendergast JJ. Diabetic autonomic neuropathy: part 1. Early detection. Pract Diabetol. 2001;20(1):7–14.Google Scholar
  101. 101.
    Prendergast JJ. Diabetic autonomic neuropathy: part 2. Treatment. Pract Diabetol. 2001:30–6.Google Scholar
  102. 102.
    Ziegler D, Ametov A, Barinov A, Dyck PJ, Gurieva I, Low PA, Munzel U, Yakhno N, Raz I, Novosadova M, Maus J, Samigullin R. Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: The SYDNEY 2 trial. Diabetes Care. 2006;29(11):2365–70.PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Ametov AS, Barinov A, Dyck PJ, Hermann R, Kozlova N, Litchy WJ, Low PA, Nehrdich D, Novosadova M, O’Brien PC, Reljanovic M, Samigullin R, Schuette K, Strokov I, Tritschler HJ, Wessel K, Yakhno N, Ziegler D, SYDNEY Trial Study Group. The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid. The SYDNEY trial. Diabetes Care. 2003;26(3):770–6.PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Ziegler D, Low PA, Litchy WJ, Boulton AJM, Vinik AI, Freeman R, The NATHAN 1 Trial Group. Efficacy and safety of antioxidant treatment with α-lipoic acid over 4 years in diabetic polyneuropathy. Diabetes Care. 2011;34:2054–60.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Manning PJ, Sutherland WHF, Walker RJ, Williams SM, De Jong SA, Ryalls AR, Berry EA. Effect of high-dose vitamin E on insulin resistance and associated parameters in overweight subjects. Diabetes Care. 2004;27:2166–71.PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Rudich A, Tirosh A, Potashnik R, Khamaisi M, Bashan N. Lipoic acid protects against oxidative stress induced impairment in insulin stimulation of protein kinase B and glucose transport in 3T3-L1 adipocytes. Diabetologia. 1999;42:949–57.PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Maddux BA, See W, Lawrence JC Jr, Goldfine AL, Goldfine ID, Evans JL. Protection against oxidative stress-induced insulin resistance in rat L6 muscle cells by micromolar concentrations of alpha-lipoic acid. Diabetes. 2001;50:404–10.PubMedCrossRefPubMedCentralGoogle Scholar
  108. 108.
    Jungas T, Motta I, Duffieux F, Fanen P, Stoven V, Ojcius DM. Glutathione levels and BAX activation during apoptosis due to oxidative stress in cells expressing wild-type and mutant cystic fibrosis transmembrane conductance regulator. J Biol Chem. 2002;277:27912–8.PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Dominy JE, Hwang J, Stipanuk MH. Overexpression of cysteine dioxygenase reduces intracellular cysteine and glutathione pools in HepG2/C3A cells. Am J Physiol Endocrinol Metab. 2007;293:E62–9.PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Miyata T, Izuhara Y, Sakai H, Kurokawa K. Carbonyl stress: increased carbonyl modification of tissue and cellular proteins in uremia. Perit Dial Int. 1999;19(Suppl 2):S58–61.PubMedPubMedCentralGoogle Scholar
  111. 111.
    Kirkham PA, Barnes PJ. Oxidative stress in COPD. Chest. 2013;144(1):266–73. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Ziegler D, Gries F. Alpha-lipoic acid and the treatment of diabetic peripheral autonomic cardiac neuropathy. Diabetes. 1997;46(Suppl 2):S62–6.PubMedCrossRefPubMedCentralGoogle Scholar
  113. 113.
    Ziegler D, Ametov A, Barinov A, Dyck PJ, Gurieva I, Low PA, Munzel U, Yakhno N, Raz I, Novosadova M, Maus J, Samigullin R. Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care. 2006;29(11):2365–70.PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Ametov AS, Barinov A, Dyck PJ, Hermann R, Kozlova N, Litchy WJ, Low PA, Nehrdich D, Novosadova M, O’Brien PC, Reljanovic M, Samigullin R, Schuette K, Strokov I, Tritschler HJ, Wessel K, Yakhno N, Ziegler D, SYDNEY Trial Study Group. The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid. The SYDNEY trial. Diabetes Care. 2003;26(3):770–6.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Ziegler D, Low PA, Litchy WJ, Boulton AJM, Vinik AI, Freeman R, The NATHAN 1 Trial Group. Efficacy and safety of antioxidant treatment with α-lipoic acid over 4 years in diabetic polyneuropathy. Diabetes Care. 2011;34:2054–60.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Colombo J, Arora RR, DePace NL, Vinik AI. Clinical autonomic dysfunction: measurement, indications, therapies, and outcomes. New York: Springer Science + Business Media; 2014.Google Scholar
  117. 117.
    Vinik A, Ziegler D. Diabetic cardiovascular autonomic neuropathy. Circulation. 2007;115:387–97.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Vinik AI, Maser RE, Nakave AA. Diabetic cardiovascular autonomic nerve dysfunction. US Endocr Dis. 2007;2:2–9.Google Scholar
  119. 119.
    Ali AM, Awad TG, Al-Adl NM. Efficacy of combined topiramate/thioctic acid therapy in migraine prophylaxis. Saudi Pharm J. 2010;18(4):239–43. Epub 2010 Jul 30.CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Mahboob A, Farhat SM, Iqbal G, Babar MM, Zaidi NU, Nabavi SM, Ahmed T. Alpha-lipoic acid-mediated activation of muscarinic receptors improves hippocampus- and amygdala-dependent memory. Brain Res Bull. 2016;122:19–28. Epub 2016 Feb 18.CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Logan AC, Wong C. Chronic fatigue syndrome: oxidative stress and dietary modifications. Altern Med Rev. 2001;6(5):450–9. Review.PubMedPubMedCentralGoogle Scholar
  122. 122.
    Hiller S, DeKroon R, Hamlett ED, Xu L, Osorio C, Robinette J, Winnik W, Simington S, Maeda N, Alzate O, Yi X. Alpha-lipoic acid supplementation protects enzymes from damage by nitrosative and oxidative stress. Biochim Biophys Acta. 2016;1860(1 Pt A):36–45. Epub 2015 Sept 4.CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Wollen KA. Alzheimer’s disease: the pros and cons of pharmaceutical, nutritional, botanical, and stimulatory therapies, with a discussion of treatment strategies from the perspective of patients and practitioners. Altern Med Rev. 2010;15(3):223–44. Review.PubMedPubMedCentralGoogle Scholar
  124. 124.
    Ajith TA, Padmajanair G. Mitochondrial pharmaceutics: a new therapeutic strategy to ameliorate oxidative stress in Alzheimer’s disease. Curr Aging Sci. 2015;8(3):235–40. Review.PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Li YH, He Q, Yu JZ, Liu CY, Feng L, Chai Z, Wang Q, Zhang HZ, Zhang GX, Xiao BG, Ma CG. Lipoic acid protects dopaminergic neurons in LPS-induced Parkinson’s disease model. Metab Brain Dis. 2015;30(5):1217–26. Epub 2015 Jun 19.CrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    Zhao H, Zhao X, Liu L, Zhang H, Xuan M, Guo Z, Wang H, Liu C. Neurochemical effects of the R form of α-lipoic acid and its neuroprotective mechanism in cellular models of Parkinson’s disease. Int J Biochem Cell Biol. 2017;87:86–94. Epub 2017 Apr 6.CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Zhao H, Zhao X, Liu L, Zhang H, Xuan M, Guo Z, Wang H, Liu C. Neurochemical effects of the R form of α-lipoic acid and its neuroprotective mechanism in cellular models of Parkinson's disease. Int J Biochem Cell Biol. 2017;87:86–94. Epub 2017 Apr 6.CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Namazi N, Larijani B, Azadbakht L. Alpha-lipoic acid supplement in obesity treatment: a systematic review and meta-analysis of clinical trials. Clin Nutr. 2017. pii: S0261-5614(17)30212-1. [Epub ahead of print] Review.PubMedCrossRefPubMedCentralGoogle Scholar
  129. 129.
    DePace NL, Mears JP, Yayac M, Colombo J. Cardiac autonomic testing and diagnosing heart disease. “A clinical perspective.”. Heart Int. 2014;9(2):37–44.; published online 12/5/2014 12:29:58 PM.CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    DePace NL, Mears JP, Yayac M, Colombo J. Cardiac autonomic testing and treating heart disease. “A clinical perspective.”. Heart Int. 2014;9(2):45–52.; published online 11/19/2014 1:16:08 PM.CrossRefPubMedPubMedCentralGoogle Scholar
  131. 131.
    Sorescu D, Weiss D, Lassegue B, Clempus RE, Szocs K, Sorescu GP, Valppu L, Quinn MT, Lambeth JD, Vega JD, Taylor WR, Griendling KK. Superoxide production and expression of Nox family proteins in human atherosclerosis. Circulation. 2002;105:1429–35.PubMedCrossRefGoogle Scholar
  132. 132.
    Ashar FN, Zhang Y, Longchamps RJ, Lane J, Moes A, Grove ML, Mychaleckyj JC, Taylor KD, Coresh J, Rotter JI, Boerwinkle E, Pankratz N, Guallar E, Arking DE. Association of mitochondrial DNA copy number with cardiovascular disease. JAMA Cardiol. 2017. [Epub ahead of print].PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Förstermann U, Münzel T. Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation. 2006;113:1708–14.PubMedCrossRefPubMedCentralGoogle Scholar
  134. 134.
    Li H, Wallerath T, Münzel T, Förstermann U. Regulation of endothelial-type NO synthase expression in pathophysiology and in response to drugs. Nitric Oxide Biol Chem. 2002;7:149–64.CrossRefGoogle Scholar
  135. 135.
    Drummond GR, Cai H, Davis ME, Ramasamy S, Harrison DG. Transcriptional and posttranscriptional regulation of endothelial nitric oxide synthase expression by hydrogen peroxide. Circ Res. 2000;86:347–54.PubMedCrossRefPubMedCentralGoogle Scholar
  136. 136.
    Riha RL, Diefenbach K, Jennum P, et al. Genetic aspects of hypertension and metabolic disease in the obstructive sleep apnoea-hypopnoea syndrome. Sleep Med Rev. 2008;12:49–63.PubMedCrossRefPubMedCentralGoogle Scholar
  137. 137.
    Goldbart AD, Row BW, Kheirandish-Gozal L, et al. High fat/refined carbohydrate diet enhances the susceptibility to spatial learning deficits in rats exposed to intermittent hypoxia. Brain Res. 2006;1090:190–6.PubMedCrossRefPubMedCentralGoogle Scholar
  138. 138.
    Somers VK, Mark AL, Abboud FM. Sympathetic activation by hypoxia and hypercapnia – implications for sleep apnea. Clin Exp Hypertens A. 1988;10(Suppl. 1):413–22.PubMedPubMedCentralGoogle Scholar
  139. 139.
    Hedner J, Darpo B, Ejnell H, et al. Reduction in sympathetic activity after long-term CPAP treatment in sleep apnoea: cardiovascular implications. Eur Respir J. 1995;8:222–9.PubMedCrossRefGoogle Scholar
  140. 140.
    Carlson JT, Hedner J, Elam M, et al. Augmented resting sympathetic activity in awake patients with obstructive sleep apnea. Chest. 1993;103:1763–8.PubMedCrossRefPubMedCentralGoogle Scholar
  141. 141.
    Narkiewicz K, Somers VK. Obstructive sleep apnea as a cause of neurogenic hypertension. Curr Hypertens Rep. 1999;1:268–73.PubMedCrossRefPubMedCentralGoogle Scholar
  142. 142.
    Lavie L, Lavie P. Molecular mechanisms of cardiovascular disease in OSAHS: the oxidative stress link. Eur Respir J. 2009;33:1467–84.PubMedCrossRefGoogle Scholar
  143. 143.
    Tsuji H, Venditti FJ Jr, Manders ES, Evans JC, Larson MG, Feldman CL, Levy D. Reduced heart rate variability and mortality risk in an elderly cohort. The Framingham Heart Study. Circulation. 1994;90(2):878–83.PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic neuropathy. Diabetes Care. 2003;26(5):1553–79.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Maser R, Mitchell B, Vinik AI, Freeman R. The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes, a meta-analysis. Diabetes Care. 2003;26(6):1895–901.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    DePace NL, Mears JP, Yayac M, Colombo J. Cardiac autonomic testing and diagnosing heart disease. “A clinical perspective”. Heart Int. 2014;9(2):37–44.; published online 12/5/2014 12:29:58 PM.CrossRefPubMedPubMedCentralGoogle Scholar
  147. 147.
    DePace NL, Mears JP, Yayac M, Colombo J. Cardiac autonomic testing and treating heart disease. “A clinical perspective”. Heart Int. 2014;9(2):45–52.; published online 11/19/2014 1:16:08 PM.CrossRefPubMedPubMedCentralGoogle Scholar
  148. 148.
    Bullinga JR, Alharethi R, Schram MS, Bristow MR, Gilbert EM. Changes in heart rate variability are correlated to hemodynamic improvement with chronic CARVEDILOL therapy in heart failure. J Card Fail. 2005;11(9):693–9.PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Fatoni C, Raffa S, Regoli F, Giraldi F, La Rovere MT, Prentice J, Pastori F, Fratini S, Salerno-Uriarte JA, Klein HU, Auricchio A. Cardiac resynchronization therapy improves heart rate profile and heart rate variability of patients with moderate to severe heart failure. J Am Coll Cardiol. 2005;46(10):1875–82.CrossRefGoogle Scholar
  150. 150.
    Fathizadeh P, Shoemaker WC, Woo CCJ, Colombo J. Autonomic activity in trauma patients based on variability of heart rate and respiratory rate. Crit Care Med. 2004;32(5):1300–5.PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Chen JY, Fung JW, Yu CM. The mechanisms of atrial fibrillation. J Cardiovasc Electrophysiol. 2006;17(Suppl 3):S2–7.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Copie X, Lamaison D, Salvador M, Sadoul N, DaCosta A, Faucher L, Legal F, Le Heuzey JY, VALID Investigators. Heart rate variability before ventricular arrhythmias in patients with coronary artery disease and an implantable cardioverter defibrillator. Ann Noninvasive Electrocardiol. 2003;8(3):179–84.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Alter P, Grimm W, Vollrath A, Czerny F, Maisch B. Heart rate variability in patients with cardiac hypertrophy – relation to left ventricular mass and etiology. Am Heart J. 2006;151(4):829–36.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Debono M, Cachia E. The impact of cardiovascular autonomic neuropathy in diabetes: is it associated with left ventricular dysfunction? Auton Neurosci. 2007;132(1–2):1–7.PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Just H. Peripheral adaptations in congestive heart failure: a review. Am J Med. 1991;90:23S–6S.PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Nakamura K, Matsumura K, Kobayashi S, Kaneko T. Sympathetic premotor neurons mediating thermoregulatory functions. Neurosci Res. 2005;51(1):1–8.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Manfrini O, Morgagni G, Pizzi C, Fontana F, Bugiardini R. Changes in autonomic nervous system activity: spontaneous versus balloon-induced myocardial ischemia. Eur Heart J. 2004;25(17):1502–8.PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Clarke B, Ewing D, Campbell I. Diabetic autonomic neuropathy. Diabetologia. 1979;17:195–212.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Arora R. Recent insights into the role of the autonomic nervous system in the creation of substrate for atrial fibrillation. Implications for therapies targeting the atrial autonomic nervous system. Circ Arrhythm Electrophysiol. 2012;5:850–9.PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Ng J, Villuendas R, Cokic I, Schliamser JE, Gordon D, Koduri H, Benefield B, Simon J, Murthy SN, Lomasney JW, Wasserstrom JA, Goldberger JJ, Aistrup GL, Arora R. Autonomic remodeling in the left atrium and pulmonary veins in heart failure: creation of a dynamic substrate for atrial fibrillation. Circ Arrhythm Electrophysiol. 2011;4:388–96.PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Kishi T, Hirooks Y. Oxidative stress in the brain causes hypertension via sympathoexcitation. Front Physiol. 2012;17:335. eCollection 2012.CrossRefGoogle Scholar
  162. 162.
    Kishi T, Hirooka Y, Sakai K, Shigematsu H, Shimokawa H, Takeshita A. Overexpression of eNOS in the RVLM causes hypotension and bradycardia via GABA release. Hypertension. 2001;38:896–901.PubMedCrossRefGoogle Scholar
  163. 163.
    Patel K, Li YF, Hirooka Y. Role of nitric oxide in central sympathetic outflow. Exp Biol Med. 2001;226:814–24.CrossRefGoogle Scholar
  164. 164.
    Noble A, Johnson R, Thomas A, Bass P. Arterial blood pressure. In: The cardiovascular system, systems of the body series. 2nd ed. Edinburgh: Elsevier; 2010.Google Scholar
  165. 165.
    Li DP, Chen SR, Pan HL. Nitric oxide inhibits spinally projecting paraventricular neurons through potentiation of presynaptic GABA release. J Neurophysiol. 2002;88:2664–74.PubMedCrossRefPubMedCentralGoogle Scholar
  166. 166.
    Garthwaite J. Concepts of neural nitric oxide-mediated transmission. Eur J Neurosci. 2008;27:2783–802.PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Kimura Y, Hirooka Y, Sagara Y, Ito K, Kishi T, Shimokawa H, Takeshita A, Sunagawa K. Overexpression of inducible nitric oxide synthase in rostral ventrolateral medulla causes hypertension and sympathoexcitation via an increase in oxidative stress. Circ Res. 2005;96:252–60.PubMedCrossRefPubMedCentralGoogle Scholar
  168. 168.
    Oliveira-Sales EB, Colombari DSA, Davisson RL, Kasparov S, Hirata AE, Campos RR, Paton JFR. Kidney-induced hypertension depends on superoxide signaling in the rostral ventrolateral medulla. Hypertension. 2010;56:290–6.PubMedCrossRefPubMedCentralGoogle Scholar
  169. 169.
    Golbidi S, Frisbee JC, Laher XI. Chronic stress impacts the cardiovascular system: animal models and clinical outcomes. Review. Am J Physiol Heart Circ Physiol. 2015;308:H1476–98.PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Gao L, Mao Q, Cao J, Wang Y, Zhou X, Fan L. Effects of coenzyme Q10 on vascular endothelial function in humans: a meta-analysis of randomized controlled trials. Atherosclerosis. 2012;221(2):311–6. Scholar
  171. 171.
    Zhou M, Zhi Q, Tang Y, Yu D, Han J. Effects of coenzyme Q10 on myocardial protection during cardiac valve replacement and scavenging free radical activity in vitro. J Cardiovasc Surg. 1999;40(3):355–61.Google Scholar
  172. 172.
    Rosenfeldt F, Marasco S, Lyon W, Wowk M, Sheeran F, Bailey M, Esmore D, Davis B, Pick A, Rabinov M, Smith J, Nagley P, Pepe S. Coenzyme Q10 therapy before cardiac surgery improves mitochondrial function and in vitro contractility of myocardial tissue. J Thorac Cardiovasc Surg. 2005;129(1):25–32.PubMedCrossRefPubMedCentralGoogle Scholar
  173. 173.
    Mordente A, Martorana GE, Santini SA, Miggiano GA, Petitti T, Giardina B, Battino M, Littarru GP. Antioxidant effect of coenzyme Q on hydrogen peroxide-activated myoglobin. Clin Investig. 1993;71(8 Suppl):S92–6.PubMedPubMedCentralGoogle Scholar
  174. 174.
    Folkers K, Littarru GP, Ho L, Runge TM, Havanonda S, Cooley D. Evidence for a deficiency of coenzyme Q10 in human heart disease. Int Z Vitaminforsch. 1970;40(3):380–90.PubMedPubMedCentralGoogle Scholar
  175. 175.
    Folkers K, Vadhanavikit S, Mortensen SA. Biochemical rationale and myocardial tissue data on the effective therapy of cardiomyopathy with coenzyme Q10. Proc Natl Acad Sci U S A. 1985;82(3):901–4.PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Mortensen SA. Overview on coenzyme Q10 as adjunctive therapy in chronic heart failure. Rationale, design and end-points of “Q-symbio” – a multinational trial. Biofactors. 2003;18(1–4):79–89.PubMedCrossRefPubMedCentralGoogle Scholar
  177. 177.
    Rosenfeldt F, Hilton D, Pepe S, Krum H. Systematic review of effect of coenzyme Q10 in physical exercise, hypertension and heart failure. Biofactors. 2003;18(1–4):91–100.PubMedCrossRefPubMedCentralGoogle Scholar
  178. 178.
    Sander S, Coleman CI, Patel AA, Kluger J, White CM. The impact of coenzyme Q10 on systolic function in patients with chronic heart failure. J Card Fail. 2006;12(6):464–72.PubMedCrossRefPubMedCentralGoogle Scholar
  179. 179.
    Kumar A, Singh RB, Saxena M, Niaz MA, Josh SR, Chattopadhyay P, Mechirova V, Pella D, Fedacko J. Effect of carni Q-gel (ubiquinol and carnitine) on cytokines in patients with heart failure in the Tishcon study. Acta Cardiol. 2007;62(4):349–54.PubMedCrossRefPubMedCentralGoogle Scholar
  180. 180.
    Hargreaves IP, Hargreaves AK. Coenzyme Q10 from fact to fiction. New York: Nova Science Publishers Inc; 2015. p. 67.Google Scholar
  181. 181.
    Morisco C, Trimarco B, Condorelli M. Effect of coenzyme Q10 therapy in patients with congestive heart failure: a long-term multicenter randomized study. Clin Investig. 1993;71(8 Suppl):S134–6.PubMedPubMedCentralGoogle Scholar
  182. 182.
    Tarnopolsky MA, Beal MF. Potential for creatine and other therapies targeting cellular energy dysfunction in neurological disorders. Ann Neurol. 2001;49(5):561–74.PubMedCrossRefPubMedCentralGoogle Scholar
  183. 183.
    Matthews RT, Yang L, Browne S, Baik M, Beal MF. Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects. Proc Natl Acad Sci U S A. 1998;95(15):8892–7.PubMedPubMedCentralCrossRefGoogle Scholar
  184. 184.
    Rustin P, von Kleist-Retzow JC, Chantrel-Groussard K, Sidi D, Munnich A, Rötig A. Effect of idebenone on cardiomyopathy in Friedreich’s ataxia: a preliminary study. Lancet. 1999;354(9177):477–9.PubMedCrossRefPubMedCentralGoogle Scholar
  185. 185.
    Lodi R, Schapira AH, Manners D, Styles P, Wood NW, Taylor DJ, Warner TT. Abnormal in vivo skeletal muscle energy metabolism in Huntington’s disease and dentatorubropallidoluysian atrophy. Ann Neurol. 2000;48(1):72–6.PubMedCrossRefPubMedCentralGoogle Scholar
  186. 186.
    Huntington Study Group. A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington’s disease. Neurology. 2001;57(3):397–404.Google Scholar
  187. 187.
    Sack MN, Fyhrquist FY, Saijonmaa OJ, Fuster V, Kovacic JC. Basic biology of oxidative stress and the cardiovascular system: part 1 of a 3-part series. J Am Coll Cardiol. 2017;70(2):196–211. Scholar
  188. 188.
    Schaper J, Meiser E, Stämmler G. Ultrastructural morphometric analysis of myocardium from dogs, rats, hamsters, mice, and from human hearts. Circ Res. 1985;56(3):377–91.PubMedCrossRefPubMedCentralGoogle Scholar
  189. 189.
    Sack MN. Type 2 diabetes mitochondrial biology in the heart. J Mol Cell Cardiol. 2009;46:842–9.PubMedPubMedCentralCrossRefGoogle Scholar
  190. 190.
    Munzel T, Gori T, Keaney JF Jr, Macck C, Daiver A. Pathophysiologic role of oxidative stress in systolic and diastolic heart failure and the therapeutic implications. Eur Heart J. 2015;36:2555–64.PubMedCrossRefPubMedCentralGoogle Scholar
  191. 191.
    Sack MN. Mitochondrial depolarization in the role of uncoupling proteins and ischemia tolerance. Cardiovasc Res. 2006;72:210–9.PubMedCrossRefPubMedCentralGoogle Scholar
  192. 192.
    Oka T, Hikoso S, Yamaguchi G, et al. Mitochondrial DNA that escapes from autophagy cause inflammation and heart failure. Nature. 2012;485:251–5.PubMedPubMedCentralCrossRefGoogle Scholar
  193. 193.
    Blikseen M, Maierlo H, Omh IK, et al. Pre-circulating mitochondrial DNA after myocardial infarction. Int J Cardiol. 2012;158:132–4.CrossRefGoogle Scholar
  194. 194.
    Okonko DO, Shah AM. Heart failure: mitochondrial dysfunction and oxidative stress in CHF. Nat Rev Cardiol. 2015;12(1):6–8. Epub 2014 Nov 25.CrossRefPubMedPubMedCentralGoogle Scholar
  195. 195.
    Smith RA, Murphy MP. Animal and human studies with the mitochondria-targeted antioxidant MitoQ. Ann N Y Acad Sci. 2010;1201:96–103. Scholar
  196. 196.
    von Zglinicki T. Oxidative stress shortens telomeres. Trends Biochem Sci. 2002;27(7):339–44. PMID: 12114022.CrossRefGoogle Scholar
  197. 197.
    Song Z, von Figura G, Liu Y, Kraus JM, Torrice C, Dillon P, Rudolph-Watabe M, Ju Z, Kestler HA, Sanoff H, Lenhard Rudolph K. Lifestyle impacts on the aging-associated expression of biomarkers of DNA damage and telomere dysfunction in human blood. Aging Cell. 2010;9(4):607–15. Epub 2010 Jun 17.CrossRefPubMedPubMedCentralGoogle Scholar
  198. 198.
    Njajou OT, Hsueh WC, Blackburn EH, Newman AB, Wu SH, Li R, Simonsick EM, Harris TM, Cummings SR, Cawthon RM, Health ABC study. Association between telomere length, specific causes of death, and years of healthy life in health, aging, and body composition, a population-based cohort study. J Gerontol A Biol Sci Med Sci. 2009;64(8):860–4. Epub 2009 May 12.CrossRefPubMedPubMedCentralGoogle Scholar
  199. 199.
    Ornish D, Lin J, Chan JM, Epel E, Kemp C, Weidner G, Marlin R, Frenda SJ, Magbanua MJ, Daubenmier J, Estay I, Hills NK, Chainani-Wu N, Carroll PR, Blackburn EH. Effect of comprehensive lifestyle changes on telomerase activity and telomere length in men with biopsy-proven low-risk prostate cancer: 5-year follow-up of a descriptive pilot study. Lancet Oncol. 2013;14(11):1112–20. Epub 2013 Sept 17.CrossRefPubMedPubMedCentralGoogle Scholar
  200. 200.
    Farzaneh-Far R, Lin J, Epel ES, Harris WS, Blackburn EH, Whooley MA. Association of marine omega-3 fatty acid levels with telomeric aging in patients with coronary heart disease. JAMA. 2010;303(3):250–7. Scholar
  201. 201.
    Saliques S, Teyssier JR, Vergely C, Lorgis L, Lorin J, Farnier M, Donzel A, Sicard P, Berchoud J, Lagrost AC, Touzery C, Ragot S, Cottin Y, Rochette L, Zeller M. Circulating leukocyte telomere length and oxidative stress: a new target for statin therapy. Atherosclerosis. 2011;219(2):753–60. Epub 2011 Sept 16.CrossRefPubMedPubMedCentralGoogle Scholar
  202. 202.
    de Kreutzenberg SV, Ceolotto G, Cattelan A, Pagnin E, Mazzucato M, Garagnani P, Borelli V, Bacalini MG, Franceschi C, Fadini GP, Avogaro A. Metformin improves putative longevity effectors in peripheral mononuclear cells from subjects with prediabetes. A randomized controlled trial. Nutr Metab Cardiovasc Dis. 2015;25(7):686–93. Epub 2015 Mar 24.CrossRefPubMedPubMedCentralGoogle Scholar
  203. 203.
    Cherkas LF, Hunkin JL, Kato BS, Richards JB, Gardner JP, Surdulescu GL, Kimura M, Lu X, Spector TD, Aviv A. The association between physical activity in leisure time and leukocyte telomere length. Arch Intern Med. 2008;168(2):154–8. Scholar
  204. 204.
    Laimer M, Melmer A, Lamina C, Raschenberger J, Adamovski P, Engl J, Ress C, Tschoner A, Gelsinger C, Mair L, Kiechl S, Willeit J, Willeit P, Stettler C, Tilg H, Kronenberg F, Ebenbichler C. Telomere length increase after weight loss induced by bariatric surgery: results from a 10 year prospective study. Int J Obes. 2016;40(5):773–8. Epub 2015 Nov 26.CrossRefGoogle Scholar
  205. 205.
    Correia-Melo C, Hewitt G, Passos JF. Telomeres, oxidative stress and inflammatory factors: partners in cellular senescence? Longev Healthspan. 2014;3(1):1. Scholar
  206. 206.
    Bayne S, Liu JP. Hormones and growth factors regulate telomerase activity in ageing and cancer. Mol Cell Endocrinol. 2005;240(1–2):11–22.PubMedCrossRefPubMedCentralGoogle Scholar
  207. 207.
    Münzel T, Camici GG, Maack C, Bonetti NR, Fuster V, Kovacic JC. Impact of oxidative stress on the heart and vasculature: part 2 of a 3-part series. J Am Coll Cardiol. 2017;70(2):212–29. Scholar
  208. 208.
    Maack C, Kartes T, Kilter H, et al. Oxygen free radical release in human failing myocardium is associated with increased activity of rac1-GTPase and represents a target for statin treatment. Circulation. 2003;108:1567–74.PubMedCrossRefPubMedCentralGoogle Scholar
  209. 209.
    Mollnau H, Oelze M, August M, et al. Mechanisms of increased vascular superoxide production in an experimental model of idiopathic dilated cardiomyopathy. Arterioscler Thromb Vasc Biol. 2005;25:2554–9.PubMedCrossRefPubMedCentralGoogle Scholar
  210. 210.
    Belch JJ, Bridges AB, Scott N, Chopra M. Oxygen free radicals and congestive heart failure. Br Heart J. 1991;65:245–8.PubMedPubMedCentralCrossRefGoogle Scholar
  211. 211.
    Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145–53.CrossRefGoogle Scholar
  212. 212.
    Lonn E, Bosch J, Yusuf S, et al., HOPE and HOPE-TOO Trial Investigators. Effects of longterm vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA. 2005;293:1338–47.Google Scholar
  213. 213.
    Förstermann U. Nitric oxide and oxidative stress in vascular disease. Pflugers Arch. 2010;459:923–39.PubMedCrossRefPubMedCentralGoogle Scholar
  214. 214.
    Förstermann U, Münzel T. Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation. 2006;113:1708–14.PubMedCrossRefPubMedCentralGoogle Scholar
  215. 215.
    Gryglewski RJ, Palmer RM, Moncada S. Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor. Nature. 1986;320:454–6.PubMedCrossRefPubMedCentralGoogle Scholar
  216. 216.
    Li H, Horke S, Förstermann U. Vascular oxidative stress, nitric oxide and atherosclerosis. Atherosclerosis. 2014;237:208–19.PubMedCrossRefPubMedCentralGoogle Scholar
  217. 217.
    Libby P. Interleukin-1 Beta as a target for atherosclerosis therapy: biological basis of CANTOS and beyond. J Am Coll Cardiol. 2017;70(18):2278–89. Scholar
  218. 218.
    Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova R, Lorenzatti A, Forster T, Kobalava Z, Vida-Simiti L, Flather M, Shimokawa H, Ogawa H, Dellborg M, Rossi PRF, Troquay RPT, Libby P, Glynn RJ, CANTOS Trial Group. Anti-inflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12):1119–31. Epub 2017 Aug 27.CrossRefGoogle Scholar
  219. 219.
    Libby P. Inflammatory and immune mechanisms in atherogenesis. In: Leaf A, Weber P, editors. Atheroclerosis reviews. New York: Raven Press; 1990. p. 79–89.Google Scholar
  220. 220.
    Libby P, Ridker PM, Hansson GK. Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol. 2009;54:2129–38.PubMedPubMedCentralCrossRefGoogle Scholar
  221. 221.
    Lichtman AH, Binder CJ, Tsimikas S, Witztum JL. Adaptive immunity in atherogenesis: new insights and therapeutic approaches. J Clin Invest. 2013;123:27–36.PubMedPubMedCentralCrossRefGoogle Scholar
  222. 222.
    Hansson GK, Libby P, Tabas I. Inflammation and plaque vulnerability. J Intern Med. 2015;278:483–93.PubMedPubMedCentralCrossRefGoogle Scholar
  223. 223.
    Libby P, Hansson GK. Inflammation and immunity in diseases of the arterial tree: players and layers. Circ Res. 2015;116:307–11.PubMedPubMedCentralCrossRefGoogle Scholar
  224. 224.
    Nus M, Mallat Z. Immune-mediated mechanisms of atherosclerosis and implications for the clinic. Expert Rev Clin Immunol. 2016;12:1217–37.PubMedCrossRefPubMedCentralGoogle Scholar
  225. 225.
    Weber C, Shantsila E, Hristov M, et al. Role and analysis of monocyte subsets in cardiovascular disease. Joint consensus document of the European Society of Cardiology (ESC) Working Groups “Atherosclerosis and Vascular Biology” and “Thrombosis.”. Thromb Haemost. 2016;116:626–37.PubMedCrossRefPubMedCentralGoogle Scholar
  226. 226.
    Libby P. History of discovery: inflammation in atherosclerosis. Arterioscler Thromb. 2012;32:2045–51.CrossRefGoogle Scholar
  227. 227.
    Cook NR, Paynter NP, Eaton CB, et al. Comparison of the Framingham and Reynolds Risk scores for global cardiovascular risk prediction in the multiethnic Women’s Health Initiative. Circulation. 2012;125:1748–56, S1741–11.PubMedPubMedCentralCrossRefGoogle Scholar
  228. 228.
    Ridker PM. A test in context: high-sensitivity c-reactive protein. J Am Coll Cardiol. 2016;67:712–23.PubMedCrossRefPubMedCentralGoogle Scholar
  229. 229.
    Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195–207.PubMedPubMedCentralCrossRefGoogle Scholar
  230. 230.
    Schonbeck U, Libby P. Inflammation, immunity, and HMG-CoA reductase inhibitors: statins as antiinflammatory agents? Circulation. 2004;109:II18–26.PubMedCrossRefPubMedCentralGoogle Scholar
  231. 231.
    Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352:20–8.PubMedPubMedCentralCrossRefGoogle Scholar
  232. 232.
    Jain MK, Sangwung P, Hamik A. Regulation of an inflammatory disease: Kruppel-like factors and atherosclerosis. Arterioscler Thromb. 2014;34:499–508.CrossRefGoogle Scholar
  233. 233.
    Libby P. The forgotten majority: unfinished business in cardiovascular risk reduction. J Am Coll Cardiol. 2005;46:1225–8.PubMedPubMedCentralCrossRefGoogle Scholar
  234. 234.
    Jernberg T, Asvold P, Henriksson M, Hjelm H, Thuresson M, Janzon M. Cardiovascular risk in post-myocardial infarction patients: nationwide real world data demonstrate the importance of a long-term perspective. Eur Heart J. 2015;36:1163–70.PubMedCrossRefPubMedCentralGoogle Scholar
  235. 235.
    Masoudi FA, Ponirakis A, de Lemos JA, et al. Trends in U.S. cardiovascular care: 2016 report from 4 ACC national cardiovascular data registries. J Am Coll Cardiol. 2017;69:1427–50.PubMedCrossRefGoogle Scholar
  236. 236.
    Evrard SM, Lecce L, Michelis KC, Nomura-Kitabayashi A, Pandey G, Purushothaman KR, d’Escamard V, Li JR, Hadri L, Fujitani K, Moreno PR, Benard L, Rimmele P, Cohain A, Mecham B, Randolph GJ, Nabel EG, Hajjar R, Fuster V, Boehm M, Kovacic JC. Endothelial to mesenchymal transition is common in atherosclerotic lesions and is associated with plaque instability. Nat Commun. 2016;7:11853. Scholar
  237. 237.
    Camici GG, Savarese G, Akhmedov A, Lüscher TF. Molecular mechanism of endothelial and vascular aging: implications for cardiovascular disease. Eur Heart J. 2015;36(48):3392–403. Epub 2015 Nov 4. PMID: 26543043.CrossRefPubMedPubMedCentralGoogle Scholar
  238. 238.
    Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley WC. Myocardial fatty acid metabolism in health and disease. Physiol Rev. 2010;90:207–58.PubMedCrossRefPubMedCentralGoogle Scholar
  239. 239.
    Niemann B, Rohrbach S, Miller MR, Newby DE, Fuster V, Kovacic JC. Oxidative stress and cardiovascular risk: obesity, diabetes, smoking, and pollution: part 3 of a 3-part series. J Am Coll Cardiol. 2017;70(2):230–51. Scholar
  240. 240.
    Anderson EJ, Kypson AP, Rodriguez E, Anderson CA, Lehr EJ, Neufer PD. Substrate specific derangements in mitochondrial metabolism and redox balance in the atrium of the type 2 diabetic human heart. J Am Coll Cardiol. 2009;54:1891–8.PubMedPubMedCentralCrossRefGoogle Scholar
  241. 241.
    Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414:813–20.PubMedPubMedCentralCrossRefGoogle Scholar
  242. 242.
    Salonen JT, Nyyssönen K, Tuomainen TP, et al. Increased risk of non-insulin dependent diabetes mellitus at low plasma vitamin E concentrations: a four year follow up study in men. BMJ. 1995;311:1124–7.PubMedPubMedCentralCrossRefGoogle Scholar
  243. 243.
    Itoh K, Mimura J, Yamamoto M. Discovery of the negative regulator of Nrf2, Keap1: a historical overview. Antioxid Redox Signal. 2010;13:1665–78.PubMedCrossRefPubMedCentralGoogle Scholar
  244. 244.
    Wegner M, Neddermann D, Piorunska-Stolzmann M, Jagodzinski PP. Role of epigenetic mechanisms in the development of chronic complications of diabetes. Diabetes Res Clin Pract. 2014;105:164–75.PubMedCrossRefPubMedCentralGoogle Scholar
  245. 245.
    Kayama Y, Raaz U, Jagger A, et al. Diabetic cardiovascular disease induced by oxidative stress. Int J Mol Sci. 2015;16:25234–63.PubMedPubMedCentralCrossRefGoogle Scholar
  246. 246.
    Aurich AC, Niemann B, Pan R, et al. Age dependent effects of high fat-diet on murine left ventricles: role of palmitate. Basic Res Cardiol. 2013;108:369.PubMedCrossRefPubMedCentralGoogle Scholar
  247. 247.
    Ghosh S, Rodrigues B. Cardiac cell death in early diabetes and its modulation by dietary fatty acids. Biochim Biophys Acta. 1761;2006:1148–62.Google Scholar
  248. 248.
    van de Weijer T, Schrauwen-Hinderling VB, Schrauwen P. Lipotoxicity in type 2 diabetic cardiomyopathy. Cardiovasc Res. 2011;92:10–8.PubMedCrossRefPubMedCentralGoogle Scholar
  249. 249.
    Niemann B, Chen Y, Teschner M, Li L, Silber RE, Rohrbach S. Obesity induces signs of premature cardiac aging in younger patients: the role of mitochondria. J Am Coll Cardiol. 2011;57:577–85.PubMedCrossRefPubMedCentralGoogle Scholar
  250. 250.
    The Heart Outcomes Prevention Evaluation Study Investigators. Vitamin E supplementation and cardiovascular events in high-risk patients. N Engl J Med. 2000;342:154–60.CrossRefGoogle Scholar
  251. 251.
    Centers for Disease Control and Prevention (US), National Center for Chronic Disease Prevention and Health Promotion (US), Office on Smoking and Health (US). How tobacco smoke causes disease: the biology and behavioral basis for smoking- attributable disease: a report of the Surgeon General. Atlanta: Centers for Disease Control and Prevention; 2010. Available at: Accessed 15 May 2017.
  252. 252.
    Cesaroni G, Forastiere F, Stafoggia M, et al. Long term exposure to ambient air pollution and incidence of acute coronary events: prospective cohort study and meta-analysis in 11 European cohorts from the ESCAPE project. BMJ. 2014;348:f7412.PubMedPubMedCentralCrossRefGoogle Scholar
  253. 253.
    Chen H, Goldberg MS, Burnett RT, Jerrett M, Wheeler AJ, Villeneuve PJ. Long-term exposure to traffic-related air pollution and cardiovascular mortality. Epidemiology. 2013;24:35–43.PubMedCrossRefGoogle Scholar
  254. 254.
    Miller KA, Siscovick DS, Sheppard L, et al. Long-term exposure to air pollution and incidence of cardiovascular events in women. N Engl J Med. 2007;356:447–58.PubMedCrossRefPubMedCentralGoogle Scholar
  255. 255.
    Pope CA III, Verrier RL, Lovett EG, et al. Heart rate variability associated with particulate air pollution. Am Heart J. 1999;138:890–9.PubMedCrossRefGoogle Scholar
  256. 256.
    Hoffmann B, Moebus S, Kröger K, et al. Residential exposure to urban air pollution, ankle brachial index, and peripheral arterial disease. Epidemiology. 2009;20:280–8.PubMedCrossRefPubMedCentralGoogle Scholar
  257. 257.
    Fowkes FG, Aboyans V, Fowkes FJ, McDermott MM, Sampson UK, Criqui MH. Peripheral artery disease: epidemiology and global perspectives. Nat Rev Cardiol. 2017;14:156–70.PubMedCrossRefPubMedCentralGoogle Scholar
  258. 258.
    Atkinson RW, Carey IM, Kent AJ, van Staa TP, Anderson HR, Cook DG. Long-term exposure to outdoor air pollution and incidence of cardiovascular diseases. Epidemiology. 2013;24:44–53.PubMedCrossRefPubMedCentralGoogle Scholar
  259. 259.
    Shah AS, Langrish JP, Nair H, et al. Global association of air pollution and heart failure: a systematic review and meta-analysis. Lancet. 2013;382:1039–48.PubMedPubMedCentralCrossRefGoogle Scholar
  260. 260.
    Shah AS, Lee KK, McAllister DA, et al. Short term exposure to air pollution and stroke: systematic review and meta-analysis. BMJ. 2015;350:h1295.PubMedPubMedCentralCrossRefGoogle Scholar
  261. 261.
    Stafoggia M, Cesaroni G, Peters A, et al. Long-term exposure to ambient air pollution and incidence of cerebrovascular events: results from 11 European cohorts within the ESCAPE project. Environ Health Perspect. 2014;122:919–25.PubMedPubMedCentralCrossRefGoogle Scholar
  262. 262.
    Low RB, Bielory L, Qureshi AI, Dunn V, Stuhlmiller DF, Dickey DA. The relation of stroke admissions to recent weather, airborne allergens, air pollution, seasons, upper respiratory infections, and asthma incidence, September 11, 2001, and day of the week. Stroke. 2006;37:951–7.PubMedCrossRefPubMedCentralGoogle Scholar
  263. 263.
    Raza A, Bellander T, Bero-Bedada G, et al. Short-term effects of air pollution on out-of hospital cardiac arrest in Stockholm. Eur Heart J. 2014;35:861–8.PubMedCrossRefGoogle Scholar
  264. 264.
    D’Alessandro A, Boeckelmann I, Hammwhösner M, Goette A. Nicotine, cigarette smoking and cardiac arrhythmia: an overview. Eur J Prev Cardiol. 2012;19:297–305.PubMedCrossRefPubMedCentralGoogle Scholar
  265. 265.
    Baccarelli A, Martinelli I, Pegoraro V, et al. Living near major traffic roads and risk of deep vein thrombosis. Circulation. 2009;119:3118–24.PubMedPubMedCentralCrossRefGoogle Scholar
  266. 266.
    Messner B, Bernhard D. Smoking and cardiovascular disease: mechanisms of endothelial dysfunction and early atherogenesis. Arterioscler Thromb Vasc Biol. 2014;34:509–15.PubMedCrossRefGoogle Scholar
  267. 267.
    Mills NL, Donaldson K, Hadoke PW, et al. Adverse cardiovascular effects of air pollution. Nat Clin Pract Cardiovasc Med. 2009;6:36–44.PubMedCrossRefGoogle Scholar
  268. 268.
    Brook RD, Rajagopalan S. Particulate matter, air pollution, and blood pressure. J Am Soc Hypertens. 2009;3:332–50.PubMedCrossRefGoogle Scholar
  269. 269.
    Liang R, Zhang B, Zhao X, Ruan Y, Lian H, Fan Z. Effect of exposure to PM2.5 on blood pressure: a systematic review and meta-analysis. J Hypertens. 2014;32:2130–40, discussion 2141.PubMedCrossRefPubMedCentralGoogle Scholar
  270. 270.
    Wauters A, Dreyfuss C, Pochet S, et al. Acute exposure to diesel exhaust impairs nitric oxide mediated endothelial vasomotor function by increasing endothelial oxidative stress. Hypertension. 2013;62:352–8.PubMedCrossRefGoogle Scholar
  271. 271.
    Brook RD, Rajagopalan S, Pope CA III, et al. Particulate matter air pollution and cardiovascular disease: an update to the scientific statement from the American Heart Association. Circulation. 2010;121:2331–78.PubMedCrossRefGoogle Scholar
  272. 272.
    Forbes LJ, Patel MD, Rudnicka AR, et al. Chronic exposure to outdoor air pollution and markers of systemic inflammation. Epidemiology. 2009;20:245–53.PubMedCrossRefGoogle Scholar
  273. 273.
    Goodman JE, Prueitt RL, Sax SN, et al. Ozone exposure and systemic biomarkers: evaluation of evidence for adverse cardiovascular health impacts. Crit Rev Toxicol. 2015;45:412–52.PubMedCrossRefGoogle Scholar
  274. 274.
    Yatera K, Hsieh J, Hogg JC, et al. Particulate matter air pollution exposure promotes recruitment of monocytes into atherosclerotic plaques. Am J Physiol Heart Circ Physiol. 2008;294:H944–53.PubMedCrossRefPubMedCentralGoogle Scholar
  275. 275.
    Bartoli CR, Wellenius GA, Coull BA, et al. Concentrated ambient particles alter myocardial blood flow during acute ischemia in conscious canines. Environ Health Perspect. 2009;117:333–7.PubMedCrossRefPubMedCentralGoogle Scholar
  276. 276.
    Campen MJ, Babu NS, Helms GA, et al. Nonparticulate components of diesel exhaust promote constriction in coronary arteries from ApoE_/_ mice. Toxicol Sci. 2005;88:95–102.PubMedCrossRefGoogle Scholar
  277. 277.
    Cherng TW, Campen MJ, Knuckles TL, Gonzalez Bosc L, Kanagy NL. Impairment of coronary endothelial cell ETB receptor function after short-term inhalation exposure to whole diesel emissions. Am J Physiol Regul Integr Comp Physiol. 2009;297:R640–7.PubMedPubMedCentralCrossRefGoogle Scholar
  278. 278.
    Lemos M, Mohallen SV, Macchione M, et al. Chronic exposure to urban air pollution induces structural alterations in murine pulmonary and coronary arteries. Inhal Toxicol. 2006;18:247–53.PubMedCrossRefGoogle Scholar
  279. 279.
    Brucker N, Moro AM, Charão MF, et al. Biomarkers of occupational exposure to air pollution, inflammation and oxidative damage in taxi drivers. Sci Total Environ. 2013;463–464:884–93.PubMedCrossRefGoogle Scholar
  280. 280.
    Sørensen M, Daneshvar B, Hansen M, et al. Personal PM2.5 exposure and markers of oxidative stress in blood. Environ Health Perspect. 2003;111:161–6.PubMedPubMedCentralCrossRefGoogle Scholar
  281. 281.
    Li W, Wilker EH, Dorans KS, et al. Short-term exposure to air pollution and biomarkers of oxidative stress: the Framingham Heart Study. J Am Heart Assoc. 2016;5:e002742.PubMedPubMedCentralGoogle Scholar
  282. 282.
    Bagryantseva Y, Novotna B, Rossner P Jr, et al. Oxidative damage to biological macromolecules in Prague bus drivers and garagemen: impact of air pollution and genetic polymorphisms. Toxicol Lett. 2010;199:60–8.PubMedCrossRefPubMedCentralGoogle Scholar
  283. 283.
    Ren C, Fang S, Wright RO, Suh H, Schwartz J. Urinary 8-hydroxy-20-deoxyguanosine as a biomarker of oxidative DNA damage induced by ambient pollution in the Normative Aging Study. Occup Environ Med. 2011;68:562–9.PubMedCrossRefGoogle Scholar
  284. 284.
    Rossner P Jr, Rossnerova A, Sram RJ. Oxidative stress and chromosomal aberrations in an environmentally exposed population. Mutat Res. 2011;707:34–41.PubMedCrossRefGoogle Scholar
  285. 285.
    Huang W, Wang G, Lu SE, et al. Inflammatory and oxidative stress responses of healthy young adults to changes in air quality during the Beijing Olympics. Am J Respir Crit Care Med. 2012;186:1150–9.PubMedPubMedCentralCrossRefGoogle Scholar
  286. 286.
    Pell JP, Haw S, Cobbe S, et al. Smoke-free legislation and hospitalizations for acute coronary syndrome. N Engl J Med. 2008;359:482–91.PubMedCrossRefPubMedCentralGoogle Scholar
  287. 287.
    Bondy SC, Campbell A, editors. Inflammation, aging, and oxidative stress. Oxidative stress in applied basic research and clinical practice. Cham: Springer International Publishing; 2016.Google Scholar
  288. 288.
    Vinik AI, Arora RR, Colombo J. Age matched attenuation of both autonomic branches in chronic disease: II. Diabetes mellitus. Cleveland Clinic Heart-Brain Summit, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, 23–24 Sept 2010.Google Scholar
  289. 289.
    American Diabetes Association. Standards of medical care in diabetes – 2008. Diabetes Care. 2008;31(Suppl 1):S12–54.CrossRefGoogle Scholar
  290. 290.
    American Diabetes Association. Standards of medical care in diabetes – 2013. Diabetes Care. 2013;36(Suppl 1):S11–66.CrossRefGoogle Scholar
  291. 291.
    Umetani K, Singer DH, McCraty R, Atkinson M. Twenty-four hour time domain heart rate variability and heart rate: relations to age and gender over nine decades. J Am Coll Cardiol. 1998;31(3):593–601.CrossRefGoogle Scholar
  292. 292.
    Maser R, Mitchell B, Vinik AI, Freeman R. The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes, a meta-analysis. Diabetes Care. 2003;26(6):1895–901.PubMedPubMedCentralCrossRefGoogle Scholar
  293. 293.
    Cheyuo C, Jacob A, Wu R, Zhou M, Coppa GF, Wang P. The parasympathetic nervous system in the quest for stroke therapeutics. J Cereb Blood Flow Metab. 2011;31(5):1187–95. Epub 2011 Mar 2. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  294. 294.
    Hayflick L. Biological aging is no longer an unsolved problem. Ann N Y Acad Sci. 2007;1100:1–13.PubMedCrossRefPubMedCentralGoogle Scholar
  295. 295.
    Kirkwood TB. Understanding the odd science of aging. Cell. 2005;120:437–47.PubMedCrossRefPubMedCentralGoogle Scholar
  296. 296.
    Beckman KB, Ames BN. The free radical theory of aging matures. Physiol Rev. 1998;78:547–81.PubMedCrossRefPubMedCentralGoogle Scholar
  297. 297.
    Lee CK, Klopp RG, Weindruch R, Prolla TA. Gene expression profile of aging and its retardation by caloric restriction. Science. 1999;285:1390–3.PubMedCrossRefPubMedCentralGoogle Scholar
  298. 298.
    Stadtman ER. Protein oxidation and aging. Science. 1992;257:1220–4.PubMedCrossRefPubMedCentralGoogle Scholar
  299. 299.
    Balaban RS, Nemoto S, Finkel T. Mitochondria, oxidants, and aging. Cell. 2005;120:483–95.PubMedCrossRefPubMedCentralGoogle Scholar
  300. 300.
    Olshansky B, Sabbah HH, Hauptman PJ, Colucci WS. Parasympathetic nervous system and heart failure. Circulation. 2008;118:863–871, originally published August 18, 2008. Scholar
  301. 301.
    Cencioni C, Spallotta F, Martelli F, Valente S, Mai A, Zeiher AM, Gaetano C. Oxidative stress and epigenetic regulation in aging and age-related diseases. Int J Mol Sci. 2013;14(9):17643–63. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  302. 302.
    Haigis MC, Yankner BA. The aging stress response. Mol Cell. 2010;40:333–44.PubMedPubMedCentralCrossRefGoogle Scholar
  303. 303.
    Sohal RS, Weindruch R. Oxidative stress, caloric restriction, and aging. Science. 1996;273:59–63.PubMedPubMedCentralCrossRefGoogle Scholar
  304. 304.
    Davies KJ. Oxidative stress, antioxidant defenses, and damage removal, repair, and replacement systems. IUBMB Life. 2000;50:279–89.PubMedCrossRefPubMedCentralGoogle Scholar
  305. 305.
    Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of aging. Nature. 2000;408:239–47.PubMedPubMedCentralCrossRefGoogle Scholar
  306. 306.
    Stadtman ER. Protein oxidation in aging and age-related diseases. Ann N Y Acad Sci. 2001;928:22–38.PubMedCrossRefPubMedCentralGoogle Scholar
  307. 307.
    Ben-Avraham D, Muzumdar RH, Atzmon G. Epigenetic genome-wide association methylation in aging and longevity. Epigenomics. 2012;4:503–9.PubMedPubMedCentralCrossRefGoogle Scholar
  308. 308.
    Boon RA, Iekushi K, Lechner S, Seeger T, Fischer A, Heydt S, Kaluza D, Treguer K, Carmona G, Bonauer A, et al. MicroRNA-34a regulates cardiac aging and function. Nature. 2013;495:107–10.PubMedCrossRefPubMedCentralGoogle Scholar
  309. 309.
    North BJ, Sinclair DA. The intersection between aging and cardiovascular disease. Circ Res. 2012;110:1097–108.PubMedPubMedCentralCrossRefGoogle Scholar
  310. 310.
    Oxenham H, Sharpe N. Cardiovascular aging and heart failure. Eur J Heart Fail. 2003;5:427–34.PubMedCrossRefPubMedCentralGoogle Scholar
  311. 311.
    Versari D, Daghini E, Virdis A, Ghiadoni L, Taddei S. The aging endothelium, cardiovascular risk and disease in man. Exp Physiol. 2009;94:317–21.PubMedCrossRefPubMedCentralGoogle Scholar
  312. 312.
    Strait JB, Lakatta EG. Aging-associated cardiovascular changes and their relationship to heart failure. Heart Fail Clin. 2012;8:143–64.PubMedPubMedCentralCrossRefGoogle Scholar
  313. 313.
    Ota H, Tokunaga E, Chang K, Hikasa M, Iijima K, Eto M, Kozaki K, Akishita M, Ouchi Y, Kaneki M. SIRT1 inhibitor, Sirtinol, induces senescence-like growth arrest with attenuated Ras-MAPK signaling in human cancer cells. Oncogene. 2006;25:176–85.PubMedCrossRefPubMedCentralGoogle Scholar
  314. 314.
    Ota H, Eto M, Kano MR, Kahyo T, Setou M, Ogawa S, Iijima K, Akishita M, Ouchi Y. Induction of endothelial nitric oxide synthase, SIRT1, and catalase by statins inhibits endothelial senescence through the Akt pathway. Arterioscler Thromb Vasc Biol. 2010;30:2205–11.PubMedCrossRefPubMedCentralGoogle Scholar
  315. 315.
    Rahman I, Marwick J, Kirkham P. Redox modulation of chromatin remodeling: impact on histone acetylation and deacetylation, NF-kappaB and pro-inflammatory gene expression. Biochem Pharmacol. 2004;68:1255–67.PubMedCrossRefPubMedCentralGoogle Scholar
  316. 316.
    Repine JE, Bast A, Lankhorst I. The oxidative stress study group. Oxidative stress in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1997;156:341–57.PubMedCrossRefPubMedCentralGoogle Scholar
  317. 317.
    Tuder RM, Kern JA, Miller YE. Senescence in chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2012;9:62–3.PubMedPubMedCentralCrossRefGoogle Scholar
  318. 318.
    Yao H, Rahman I. Role of histone deacetylase 2 in epigenetics and cellular senescence: implications in lung inflammaging and COPD. Am J Physiol Lung Cell Mol Physiol. 2012;303:L557–66.PubMedPubMedCentralCrossRefGoogle Scholar
  319. 319.
    Sundar IK, Yao H, Rahman I. Oxidative stress and chromatin remodeling in chronic obstructive pulmonary disease and smoking-related diseases. Antioxid Redox Signal. 2012;18:1956–71.PubMedCrossRefPubMedCentralGoogle Scholar
  320. 320.
    Adenuga D, Yao H, March TH, Seagrave J, Rahman I. Histone deacetylase 2 is phosphorylated, ubiquitinated, and degraded by cigarette smoke. Am J Respir Cell Mol Biol. 2009;40:464–73.PubMedCrossRefPubMedCentralGoogle Scholar
  321. 321.
    Marwick JA, Kirkham PA, Stevenson CS, Danahay H, Giddings J, Butler K, Donaldson K, Macnee W, Rahman I. Cigarette smoke alters chromatin remodeling and induces proinflammatory genes in rat lungs. Am J Respir Cell Mol Biol. 2004;31:633–42.PubMedCrossRefPubMedCentralGoogle Scholar
  322. 322.
    Moodie FM, Marwick JA, Anderson CS, Szulakowski P, Biswas SK, Bauter MR, Kilty I, Rahman I. Oxidative stress and cigarette smoke alter chromatin remodeling but differentially regulate NF-κB activation and proinflammatory cytokine release in alveolar epithelial cells. FASEB J. 2004;18:1897–9.PubMedCrossRefPubMedCentralGoogle Scholar
  323. 323.
    Rajendrasozhan S, Yang SR, Kinnula VL, Rahman I. SIRT1, an antiinflammatory and antiaging protein, is decreased in lungs of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2008;177:861–70.PubMedPubMedCentralCrossRefGoogle Scholar
  324. 324.
    Yang SR, Chida AS, Bauter MR, Shafiq N, Seweryniak K, Maggirwar SB, Kilty I, Rahman I. Cigarette smoke induces proinflammatory cytokine release by activation of NF-κB and posttranslational modifications of histone deacetylase in macrophages. Am J Physiol Lung Cell Mol Physiol. 2006;291:L46–57.PubMedCrossRefPubMedCentralGoogle Scholar
  325. 325.
    Kedar NP. Can we prevent Parkinson’s and Alzheimer’s disease? J Postgrad Med. 2003;49:236–45.PubMedPubMedCentralGoogle Scholar
  326. 326.
    Coppede F, Migliore L. Evidence linking genetics, environment, and epigenetics to impaired DNA repair in Alzheimer’s disease. J Alzheimers Dis. 2010;20:953–66.PubMedCrossRefPubMedCentralGoogle Scholar
  327. 327.
    Myung NH, Zhu X, Kruman II, Castellani RJ, Petersen RB, Siedlak SL, Perry G, Smith MA, Lee HG. Evidence of DNA damage in Alzheimer disease: phosphorylation of histone H2AX in astrocytes. Age. 2008;30:209–15.PubMedPubMedCentralCrossRefGoogle Scholar
  328. 328.
    Zawia NH, Lahiri DK, Cardozo-Pelaez F. Epigenetics, oxidative stress, and Alzheimer disease. Free Radic Biol Med. 2009;46:1241–9.PubMedPubMedCentralCrossRefGoogle Scholar
  329. 329.
    Rimm EB. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. Bibl Nutr Dieta. 2001;55:42–5. Review.Google Scholar
  330. 330.
    Gupta A, Moustapha A, Jacobsen DW, Goormastic M, Tuzcu EM, Hobbs R, Young J, James K, McCarthy P, van Lente F, Green R, Robinson K. High homocysteine, low folate, and low vitamin B6 concentrations: prevalent risk factors for vascular disease in heart transplant recipients. Transplantation. 1998;65(4):544–50.PubMedCrossRefPubMedCentralGoogle Scholar
  331. 331.
    Rimm EB, Willett WC, Hu FB, Sampson L, Colditz GA, Manson JE, Hennekens C, Stampfer MJ. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA. 1998;279(5):359–64.PubMedCrossRefPubMedCentralGoogle Scholar
  332. 332.
    Saito A, Kaseda R, Hosojima M, Sato H. Proximal tubule cell hypothesis for cardiorenal syndrome in diabetes. Int J Nephrol. 2010;2011:957164. Scholar
  333. 333.
    Alkaitis MS, Crabtree MJ. Recoupling the cardiac nitric oxide synthases: tetrahydrobiopterin synthesis and recycling. Curr Heart Fail Rep. 2012;9(3):200–10. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  334. 334.
    Clarke R, Bennett DA, Parish S, Verhoef P, Dötsch-Klerk M, Lathrop M, Xu P, Nordestgaard BG, Holm H, Hopewell JC, Saleheen D, Tanaka T, Anand SS, Chambers JC, Kleber ME, Ouwehand WH, Yamada Y, Elbers C, Peters B, Stewart AF, Reilly MM, Thorand B, Yusuf S, Engert JC, Assimes TL, Kooner J, Danesh J, Watkins H, Samani NJ, Collins R, Peto R, MTHFR Studies Collaborative Group. Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias. PLoS Med. 2012;9(2):e1001177. Epub 2012 Feb 21.CrossRefPubMedPubMedCentralGoogle Scholar
  335. 335.
    Soinio M, Marniemi J, Laakso M, Lehto S, Rönnemaa T. Elevated plasma homocysteine level is an independent predictor of coronary heart disease events in patients with type 2 diabetes mellitus. Ann Intern Med. 2004;140:94–100.PubMedCrossRefPubMedCentralGoogle Scholar
  336. 336.
    Moustafa AA, Hewedi DH, Eissa AM, Frydecka D, Błażej M. Homocysteine levels in schizophrenia and affective disorders – focus on cognition. Front Behav Neurosci. 2014;8:343–55.PubMedPubMedCentralCrossRefGoogle Scholar
  337. 337.
    Majewski M, Kozlowska A, Thoene M, Lepiarczyk E, Grzegorzewski WJ. Overview of the role of vitamins and minerals on the kynurenine pathway in health and disease. J Physiol Pharmacol. 2016;67(1):3–19. Review.PubMedPubMedCentralGoogle Scholar
  338. 338.
    Uribarri J, Tuttle KR. Advanced glycation end products and nephrotoxicity of high-protein diets. Clin J Am Soc Nephrol. 2006;1(6):1293–9. Epub 2006 Sept 27.PubMedCrossRefPubMedCentralGoogle Scholar
  339. 339.
    Ferrier DP. Biochemistry. 6th ed. Philadelphia: Lippincott, Williams & Williams, a Wolters Kluwer Business; 2014.Google Scholar
  340. 340.
    Vinik AI, Casellini C, Nakave A, Patel C. Diabetic neuropathies.; Last edited by Rushakoff R. 2009.
  341. 341.
    DePace NL, Dowinsky SK, Sherman M. The heart repair manual. New York: WW Norton and Co; 1993.Google Scholar
  342. 342.
    Dimitropoulos G, Tahrani AA, Stevens MJ. Cardiac autonomic neuropathy in patients with diabetes mellitus. World J Diabetes. 2014;5(1):17–39. Published online Feb 15, 2014. Scholar
  343. 343.
    Yarandi S, Srinivasan S. Diabetic gastrointestinal motility disorders and the role of enteric nervous system: current status and future directions. Neurogastroenterol Motil. 2014;26(5):611–24. Published online 2014 Mar 24. Scholar
  344. 344.
    Konturek SJ, Konturek PC, Brzozowski T, Bubenik GA. Role of melatonin in upper gastrointestinal tract. J Physiol Pharmacol. 2007;58(Suppl 6):23–52. Review.PubMedPubMedCentralGoogle Scholar
  345. 345.
    Czesnikiewicz-Guzik M, Konturek SJ, Loster B, Wisniewska G, Majewski S. Melatonin and its role in oxidative stress related diseases of oral cavity. J Physiol Pharmacol. 2007;58(Suppl 3):5–19. Review.PubMedPubMedCentralGoogle Scholar
  346. 346.
    Newsholme P, Cruzat VF, Keane KN, Carlessi R, de Bittencourt PIH. Molecular mechanisms of ROS production and oxidative stress in diabetes. Biochem J. 2016;473(24):4527–50.PubMedCrossRefPubMedCentralGoogle Scholar
  347. 347.
    Ilie M, Margină D. Trends in the evaluation of lipid peroxidation processes. In: Catala A, editor. Lipid peroxidation, Ch 5; 2012. p. 111–30. Google Scholar
  348. 348.
    Granata S, Dalla Gassa A, Tomei P, Lupo A, Zaza G. Mitochondria: a new therapeutic target in chronic kidney disease. Nutr Metab (Lond). 2015;12:49. eCollection 2015. Review.CrossRefGoogle Scholar
  349. 349.
    Esteban Zubero E, García-Gil FA, López-Pingarrón L, Alatorre-Jiménez MA, Ramirez JM, Tan DX, García JJ, Reiter RJ. Melatonin role preventing steatohepatitis and improving liver transplantation results. Cell Mol Life Sci. 2016;73(15):2911–27. Scholar
  350. 350.
    Bavarsad Shahripour R, Harrigan MR, Alexandrov AV. N-acetylcysteine (NAC) in neurological disorders: mechanisms of action and therapeutic opportunities. Brain Behav. 2014;4(2):108–22. Epub 2014 Jan 13. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  351. 351.
    Berk M, Malhi GS, Gray LJ, Dean OM. The promise of N-acetylcysteine in neuropsychiatry. Trends Pharmacol Sci. 2013;34(3):167–77. Epub 2013 Jan 29. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  352. 352.
    Dean O, Giorlando F, Berk M. N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action. J Psychiatry Neurosci. 2011;36(2):78–86. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  353. 353.
    Smaga I, Pomierny B, Krzyżanowska W, Pomierny-Chamioło L, Miszkiel J, Niedzielska E, Ogórka A, Filip M. N-acetylcysteine possesses antidepressant-like activity through reduction of oxidative stress: behavioral and biochemical analyses in rats. Prog Neuro-Psychopharmacol Biol Psychiatry. 2012;39(2):280–7. Epub 2012 Jul 20.CrossRefGoogle Scholar
  354. 354.
    Berk M, Kapczinski F, Andreazza AC, Deana OM, Giorlando F, Maes M, Yücelb M, Gama CS, Dodd S, Dean B, Magalhãesa PVS, Amminger P, McGorry P, Malhi GS. Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors. Neurosci Biobehav Rev. 2011;35:804–17.PubMedCrossRefPubMedCentralGoogle Scholar
  355. 355.
    Lott J. The mother of all antioxidants: how health gurus are misleading you and what you should know about glutathione. Archangel Ink; 2014.Google Scholar
  356. 356.
    Varga ZV, Giricz Z, Liaudet L, Haskó G, Ferdinandy P, Pacher P. Interplay of oxidative, nitrosative/nitrative stress, inflammation, cell death and autophagy in diabetic cardiomyopathy. Biochim Biophys Acta Mol basis Dis. 2015;1852(2):232–42. Scholar
  357. 357.
    Berk M, Bodemer W, van Oudenhove T, Butkow N. Dopamine increases platelet intracellular calcium in bipolar affective disorder and controls. Int Clin Psychopharmacol. 1994;9(4):291–3.PubMedCrossRefPubMedCentralGoogle Scholar
  358. 358.
    Christy AL, Brown MA. The multitasking mast cell: positive and negative roles in the progression of autoimmunity. J Immunol. 2007;179(5):2673–9.PubMedCrossRefGoogle Scholar
  359. 359.
    Gramlich T, Kleiner DE, McCullough AJ, Matteoni CA, Boparai N, Younossi ZM. Pathologic features associated with fibrosis in nonalcoholic fatty liver disease. Hum Pathol. 2004;35(2):196–9.PubMedCrossRefPubMedCentralGoogle Scholar
  360. 360.
    Forester BP, Harper DG, Georgakas J, Ravichandran C, Madurai N, Cohen BM. Antidepressant effects of open label treatment with coenzyme Q10 in geriatric bipolar depression. J Clin Psychopharmacol. 2015;35(3):338–40. Scholar
  361. 361.
    Wald DS, Wald NJ, Morris JK, Law M. Folic acid, homocysteine, and cardiovascular disease: judging causality in the face of inconclusive trial evidence. BMJ. 2006;333(7578):1114–7. Review.PubMedPubMedCentralCrossRefGoogle Scholar
  362. 362.
    Jenkins DJA, Spence JD, Giovannucci EL, Kim YI, Josse R, Vieth R, Blanco Mejia S, Viguiliouk E, Nishi S, Sahye-Pudaruth S, Paquette M, Patel D, Mitchell S, Kavanagh M, Tsirakis T, Bachiri L, Maran A, Umatheva N, McKay T, Trinidad G, Bernstein D, Chowdhury A, Correa-Betanzo J, Del Principe G, Hajizadeh A, Jayaraman R, Jenkins A, Jenkins W, Kalaichandran R, Kirupaharan G, Manisekaran P, Qutta T, Shahid R, Silver A, Villegas C, White J, Kendall CWC, Pichika SC, Sievenpiper JL. Supplemental vitamins and minerals for CVD prevention and treatment. J Am Coll Cardiol. 2018;71(22):2570–84. Scholar
  363. 363.
    Abrahaham JM, et al. The homocysteine hypothesis: still relevant to the prevention and treatment of cardiovascular disease? Cleve Clin J Med. 2010;77(12):911–8.CrossRefGoogle Scholar
  364. 364.
    Kong X, Huang X, Zhao M, Xu B, Xu R, Song Y, Yu Y, Yang W, Zhang J, Liu L, Zhang Y, Tang G, Wang B, Hou FF, Li P, Cheng X, Zhao S, Wang X, Qin X, Li J, Huo Y. Platelet count affects efficacy of folic acid in preventing first stroke. J Am Coll Cardiol. 2018;71(19):2136–46. Scholar
  365. 365.
    Glynn SA, Albanes D. Folate and cancer: a review of the literature. Nutr Cancer. 1994;22(2):101–19. Review.PubMedCrossRefPubMedCentralGoogle Scholar
  366. 366.
    Common questions about diet and cancer: folate and folic acid. American Cancer Society. 2017.
  367. 367.
    Wien TN, Pike E, Wisløff T, Staff A, Smeland S, Klemp M. Cancer risk with folic acid supplements: a systematic review and meta-analysis. BMJ Open. 2012;2(1):e000653. Print 2012.CrossRefPubMedPubMedCentralGoogle Scholar
  368. 368.
    Wang R, Zheng Y, Huang JY, Zhang AQ, Zhou YH, Wang JN. Folate intake, serum folate levels, and prostate cancer risk: a meta-analysis of prospective studies. BMC Public Health. 2014;14:1326. Scholar
  369. 369.
    Stott DJ, MacIntosh G, Lowe GD, Rumley A, McMahon AD, Langhorne P, Tait RC, O’Reilly DS, Spilg EG, MacDonald JB, MacFarlane PW, Westendorp RG. Randomized controlled trial of homocysteine-lowering vitamin treatment in elderly patients with vascular disease. Am J Clin Nutr. 2005;82(6):1320–6.PubMedCrossRefPubMedCentralGoogle Scholar
  370. 370.
    Clarke R. Lowering blood homocysteine with folic acid-based supplements: meta-analysis of randomised trials. Indian Heart J. 2000;52(7 Suppl):S59–64.PubMedPubMedCentralGoogle Scholar
  371. 371.
    Huo Y, Li J, Qin X, Huang Y, Wang X, Gottesman RF, Tang G, Wang B, Chen D, He M, Fu J, Cai Y, Shi X, Zhang Y, Cui Y, Sun N, Li X, Cheng X, Wang J, Yang X, Yang T, Xiao C, Zhao G, Dong Q, Zhu D, Wang X, Ge J, Zhao L, Hu D, Liu L, Hou FF, CSPPT Investigators. Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial. JAMA. 2015;313(13):1325–35. Scholar
  372. 372.
    Xu X, Qin X, Li Y, Sun D, Wang J, Liang M, Wang B, Huo Y, Hou FF, Investigators of the Renal Substudy of the China Stroke Primary Prevention Trial (CSPPT). Efficacy of folic acid therapy on the progression of chronic kidney disease: the renal substudy of the China stroke primary prevention trial. JAMA Intern Med. 2016;176(10):1443–50. Scholar
  373. 373.
    Mandaviya PR, Stolk L, Heil SG. Homocysteine and DNA methylation: a review of animal and human literature. Mol Genet Metab. 2014;113(4):243–52. Epub 2014 Oct 14. Review.CrossRefPubMedGoogle Scholar
  374. 374.
    Joshi R, Adhikari S, Patro BS, Chattopadhyay S, Mukherjee T. Free radical scavenging behavior of folic acid: evidence for possible antioxidant activity. Free Radic Biol Med. 2001;30(12):1390–9.PubMedCrossRefGoogle Scholar
  375. 375.
    Zhao M, Chen YH, Dong XT, Zhou J, Chen X, Wang H, Wu SX, Xia MZ, Zhang C, Xu DX. Folic acid protects against lipopolysaccharide-induced preterm delivery and intrauterine growth restriction through its anti-inflammatory effect in mice. PLoS One. 2013;8(12):e82713. eCollection 2013.CrossRefPubMedPubMedCentralGoogle Scholar
  376. 376.
    Cantó C, Menzies KJ, Auwerx J. NAD(+) metabolism and the control of energy homeostasis: a balancing act between mitochondria and the nucleus. Cell Metab. 2015;22:31–53.PubMedPubMedCentralCrossRefGoogle Scholar
  377. 377.
    Huang J-Y, Hirschey MD, Shimazu T, Ho L, Verdin E. Mitochondrial sirtuins. Biochim Biophys Acta. 2010;1804:1645–51.PubMedCrossRefGoogle Scholar
  378. 378.
    Correia M, Perestrelo T, Rodrigues AS, et al. Sirtuins in metabolism, stemness and differentiation. Biochim Biophys Acta. 2017;1861(1 Pt A):3444–55.CrossRefGoogle Scholar
  379. 379.
    Cheng H-L, Mostoslavsky R, Saito S, et al. Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Proc Natl Acad Sci U S A. 2003;100:10794–9.PubMedPubMedCentralCrossRefGoogle Scholar
  380. 380.
    Kirkland JB. Niacin requirements for genomic stability. Mutat Res. 2012;733:14–20.PubMedCrossRefPubMedCentralGoogle Scholar
  381. 381.
    Shi H, Enriquez A, Rapadas M, Martin EMMA, Wang R, Moreau J, Lim CK, Szot JO, Ip E, Hughes JN, Sugimoto K, Humphreys DT, McInerney-Leo AM, Leo PJ, Maghzal GJ, Halliday J, Smith J, Colley A, Mark PR, Collins F, Sillence DO, Winlaw DS, Ho JWK, Guillemin GJ, Brown MA, Kikuchi K, Thomas PQ, Stocker R, Giannoulatou E, Chapman G, Duncan EL, Sparrow DB, Dunwoodie SL. NAD deficiency, congenital malformations, and niacin supplementation. N Engl J Med. 2017;377(6):544–52. Scholar
  382. 382.
    Celinski K, Konturek PC, Slomka M, Cichoz-Lach H, Brzozowski T, Konturek SJ, Korolczuk A. Effects of treatment with melatonin and tryptophan on liver enzymes, parameters of fat metabolism and plasma levels of cytokines in patients with non-alcoholic fatty liver disease – 14 months follow up. J Physiol Pharmacol. 2014;65(1):75–82.PubMedPubMedCentralGoogle Scholar
  383. 383.
    Vinik AI, Maser RE, Nakave AA. Diabetic cardiovascular autonomic nerve dysfunction. US Endocr Dis. 2007;2:2–9.Google Scholar
  384. 384.
    Vinik A, Ziegler D. Diabetic cardiovascular autonomic neuropathy. Circulation. 2007;115:387–97.PubMedPubMedCentralCrossRefGoogle Scholar
  385. 385.
    Vinik AI, Freeman R, Erbas T. Diabetic autonomic neuropathy. Semin Neurol. 2003;23:365–72.PubMedCrossRefPubMedCentralGoogle Scholar
  386. 386.
    Vinik A, Erbas T, Pfeifer M, Feldman E, Stevens M, Russell J. Diabetic autonomic neuropathy. In: Zucchi SE, editor. The diabetes mellitus manual: a primary care companion to Ellenberg and Rifkin’s. 6th ed. New York: McGraw Hill; 2004. p. 351.Google Scholar
  387. 387.
    Ziegler D, Low PA, Litchy WJ, Boulton AJM, Vinik AI, Freeman R, The NATHAN 1 Trial Group. Efficacy and safety of antioxidant treatment with α-lipoic acid over 4 years in diabetic polyneuropathy. Diabetes Care. 2011;34:2054–60.PubMedPubMedCentralCrossRefGoogle Scholar
  388. 388.
    Vinik AI, Maser RE, Ziegler D. Neuropathy. The crystal ball for cardiovascular disease. Diabetes Care. 2010;33(7):1688–90.PubMedPubMedCentralCrossRefGoogle Scholar
  389. 389.
    Vinik AI, Maser RE, Ziegler D. Autonomic imbalance: prophet of doom or scope for hope? Diabet Med. 2011;28:643–51.PubMedPubMedCentralCrossRefGoogle Scholar
  390. 390.
    Vinik AI. The conductor of the autonomic orchestra. Front Endocrinol. 2012;3(71):1–13.Google Scholar
  391. 391.
    Vinik AI, Nevoret ML, Casellini CM, Parson H. Diabetic neuropathy. Endocrinol Metab Clin N Am. 2013;42(4):747–87. Review.CrossRefGoogle Scholar
  392. 392.
    Maser RE, Mitchell BD, Vinik AI, et al. The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes: A meta-analysis. Diabetes Care. 2003;26:1895–901.PubMedPubMedCentralCrossRefGoogle Scholar
  393. 393.
    Vinik AI, Erbas T, Casellini CM. Diabetic cardiac autonomic neuropathy, inflammation and cardiovascular disease. J Diab Invest. 2013;4(1):4–18.CrossRefGoogle Scholar
  394. 394.
    Vinik AI, Mehrabyan A. Diabetic neuropathies. Med Clin N Am. 2004;88:947–99.PubMedCrossRefGoogle Scholar
  395. 395.
    Vinik AI, Strotmeyer ES, Nakave AA, Patel CV. Diabetic neuropathy in older adults. Clin Geriatr Med. 2008;24:407–35.PubMedPubMedCentralCrossRefGoogle Scholar
  396. 396.
    Vinik AI, Erbas T. Cardiovascular autonomic neuropathy: diagnosis and management. Curr Diab Rep. 2006;6:424–30.PubMedCrossRefPubMedCentralGoogle Scholar
  397. 397.
    Feldman EL. Oxidative stress and diabetic neuropathy: a new understanding of an old problem. J Clin Invest. 2003;111(4):431–3.PubMedPubMedCentralCrossRefGoogle Scholar
  398. 398.
    Tsuji H, Venditti FJ Jr, Manders ES, Evans JC, Larson MG, Feldman CL, Levy D. Reduced heart rate variability and mortality risk in an elderly cohort. The Framingham Heart Study. Circulation. 1994;90(2):878–83.PubMedPubMedCentralCrossRefGoogle Scholar
  399. 399.
    Vallianou N, Evangelopoulos A, Koutalas P. Alpha-lipoic acid and diabetic neuropathy. Rev Diabet Stud. 2009;6(4):230–6. Epub 2009 Dec 30.CrossRefPubMedGoogle Scholar
  400. 400.
    Ziegler D, Sohr CG, Nourooz-Zadeh J. Oxidative stress and antioxidant defense in relation to the severity of diabetic polyneuropathy and cardiovascular autonomic neuropathy. Diabetes Care. 2004;27:2178–83.PubMedCrossRefPubMedCentralGoogle Scholar
  401. 401.
    Ziegler D, Gries F. Alpha-lipoic acid and the treatment of diabetic peripheral autonomic cardiac neuropathy. Diabetes. 1997;46(Suppl 2):S62–6.PubMedCrossRefPubMedCentralGoogle Scholar
  402. 402.
    Prendergast JJ. Diabetic autonomic neuropathy: part 2. Treatment. Pract Diabetol. 2001:30–6.Google Scholar
  403. 403.
    Ziegler D, Ametov A, Barinov A, Dyck PJ, Gurieva I, Low PA, Munzel U, Yakhno N, Raz I, Novosadova M, Maus J, Samigullin R. Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: The SYDNEY 2 trial. Diabetes Care. 2006;29(11):2365–70.PubMedCrossRefPubMedCentralGoogle Scholar
  404. 404.
    Ametov AS, Barinov A, Dyck PJ, Hermann R, Kozlova N, Litchy WJ, Low PA, Nehrdich D, Novosadova M, O’Brien PC, Reljanovic M, Samigullin R, Schuette K, Strokov I, Tritschler HJ, Wessel K, Yakhno N, Ziegler D, SYDNEY Trial Study Group. The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid. The SYDNEY trial. Diabetes Care. 2003;26(3):770–6.PubMedCrossRefPubMedCentralGoogle Scholar
  405. 405.
    Ziegler D, Low PA, Litchy WJ, Boulton AJM, Vinik AI, Freeman R, The NATHAN 1 Trial Group. Efficacy and safety of antioxidant treatment with α-lipoic acid over 4 years in diabetic polyneuropathy. Diabetes Care. 2011;34:2054–60.PubMedPubMedCentralCrossRefGoogle Scholar
  406. 406.
    Serhiyenko VA, Serhiyenko AA. Diabetic cardiac autonomic neuropathy: do we have any treatment perspectives? World J Diabetes. 2015;6(2):245–58. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  407. 407.
    Keen H, Payan J, Allawi J, Walker J, Jamal GA, Weir AI, Henderson LM, Bissessar EA, Watkins PJ, Sampson M, Gale EA, Scarpello J, Boddie HG, Hardy KJ, Thomas PK, Misra P, Halonen JP. Treatment of diabetic neuropathy with gamma-linolenic acid. Diabetes Care. 1993;16:8–15.PubMedCrossRefPubMedCentralGoogle Scholar
  408. 408.
    De Marchi E, Baldassari F, Bononi A, Wieckowski MR, Pinton P. Oxidative stress in cardiovascular diseases and obesity: role of p66Shc and protein kinase C. Oxidative Med Cell Longev. 2013;2013:564961. Epub 2013 Mar 27. Review.CrossRefGoogle Scholar
  409. 409.
    Pittenger G, Vinik A. Nerve growth factor and diabetic neuropathy. Exp Diabesity Res. 2003;4:271–85.PubMedPubMedCentralCrossRefGoogle Scholar
  410. 410.
    Rivard A, Silver M, Chen D, Kearney M, Magner M, Annex B, Peters K, Isner JM. Rescue of diabetes-related impairment of angiogenesis by intramuscular gene therapy with adeno-VEGF. Am J Pathol. 1999;154:355–63.PubMedPubMedCentralCrossRefGoogle Scholar
  411. 411.
    Tam J, Rosenberg L, Maysinger D. INGAP peptide improves nerve function and enhances regeneration in streptozotocin-induced diabetic C57BL/6 mice. FASEB J. 2004;18:1767–9.PubMedCrossRefPubMedCentralGoogle Scholar
  412. 412.
    Milicevic Z, Newlon PG, Pittenger GL, Stansberry KB, Vinik AI. Anti-ganglioside GM1 antibody and distal symmetric “diabetic polyneuropathy” with dominant motor features. Diabetologia. 1997;40:1364–5.PubMedCrossRefPubMedCentralGoogle Scholar
  413. 413.
    Sharma K, Cross J, Farronay O, Ayyar D, Sheber R, Bradley W. Demyelinating neuropathy in diabetes mellitus. Arch Neurol. 2002;59:758–65.PubMedCrossRefPubMedCentralGoogle Scholar
  414. 414.
    Krendel DA, Costigan DA, Hopkins LC. Successful treatment of neuropathies in patients with diabetes mellitus. Arch Neurol. 1995;52:1053–61.PubMedCrossRefPubMedCentralGoogle Scholar
  415. 415.
    Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic neuropathy. Diabetes Care. 2003;26(5):1553–79.PubMedPubMedCentralCrossRefGoogle Scholar
  416. 416.
    Pfeifer MA, Weinberg CR, Cook DL, Reenan A, Halter JB, Ensinck JW. Autonomic neural dysfunction in recently diagnosed diabetic subjects. Diabetes Care. 1984;7:447–53.PubMedCrossRefPubMedCentralGoogle Scholar
  417. 417.
    Stansberry KB, Hill MA, Shapiro SA, McNitt PM, Bhatt BA, Vinik AI. Impairment of peripheral blood flow responses in diabetes resembles an enhanced aging effect. Diabetes Care. 1997;20:1711–6.PubMedCrossRefPubMedCentralGoogle Scholar
  418. 418.
    Stansberry KB, Shapiro SA, Hill MA, McNitt PM, Meyer MD, Vinik AI. Impaired peripheral vasomotion in diabetes. Diabetes Care. 1996;19:715–21.PubMedCrossRefPubMedCentralGoogle Scholar
  419. 419.
    Stansberry KB, Hill MA, Shapiro SA, McNitt PM, Bhatt BA, Vinik AI. Impairment of peripheral blood flow responses in diabetes resembles an enhanced aging effect. Diabetes Care. 1997;20:1711–6.PubMedCrossRefPubMedCentralGoogle Scholar
  420. 420.
    Stansberry KB. Primary nociceptive afferents mediate the blood flow dysfunction in non-glabrous (hairy) skin of type 2 diabetes. Diabetes Care. 1999;22:1549–54.PubMedCrossRefPubMedCentralGoogle Scholar
  421. 421.
    Haak ES, Usadel KH, Kohleisen M, Yilmaz A, Kusterer K, Haak T. The effect of alpha-lipoic on the neurovascular reflex arc in patients with diabetic neuropathy assessed by capillary microscopy. Microvasc Res. 1999;58:28–34.PubMedCrossRefPubMedCentralGoogle Scholar
  422. 422.
    Ziegler D. Diabetic cardiovascular autonomic neuropathy: prognosis, diagnosis and treatment. Diabetes Metab Rev. 1994;10:339–83.PubMedCrossRefPubMedCentralGoogle Scholar
  423. 423.
    Valensi P. Diabetic autonomic neuropathy: what are the risks? Diabetes Metab. 1998;24:66–72.PubMedPubMedCentralGoogle Scholar
  424. 424.
    Levitt NS, Stansberry KB, Wychanck S, Vinik AI. Natural progression of autonomic neuropathy and autonomic function tests in a cohort of IDDM. Diabetes Care. 1996;19:751–4.PubMedCrossRefPubMedCentralGoogle Scholar
  425. 425.
    Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348:383–93.PubMedCrossRefPubMedCentralGoogle Scholar
  426. 426.
    Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358:580–91.PubMedCrossRefPubMedCentralGoogle Scholar
  427. 427.
    Edwards JL, Vincent AM, Cheng HT, Feldman EL. Diabetic neuropathy: mechanisms to management. Pharmacol Ther. 2008;120:1–34.PubMedPubMedCentralCrossRefGoogle Scholar
  428. 428.
    Vinik AI, Freeman R, Erbas T. Diabetic autonomic neuropathy. Semin Neurol. 2003;23:365–72.PubMedCrossRefPubMedCentralGoogle Scholar
  429. 429.
    Leinninger GM, Edwards JL, Lipshaw MJ, Feldman EL. Mechanisms of disease: mitochondria as new therapeutic targets in diabetic neuropathy. Nat Clin Pract Neurol. 2006;2:620–8.PubMedCrossRefPubMedCentralGoogle Scholar
  430. 430.
    Soriano FG, Virág L, Szabó C. Diabetic endothelial dysfunction: role of reactive oxygen and nitrogen species production and poly(ADP-ribose) polymerase activation. J Mol Med (Berl). 2001;79:437–48.CrossRefGoogle Scholar
  431. 431.
    Obrosova IG, Julius UA. Role for poly(ADP-ribose) polymerase activation in diabetic nephropathy, neuropathy and retinopathy. Curr Vasc Pharmacol. 2005;3:267–83.PubMedCrossRefPubMedCentralGoogle Scholar
  432. 432.
    Yamagishi S, Uehara K, Otsuki S, Yagihashi S. Differential influence of increased polyol pathway on protein kinase C expressions between endoneurial and epineurial tissues in diabetic mice. J Neurochem. 2003;87:497–507.PubMedCrossRefPubMedCentralGoogle Scholar
  433. 433.
    Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res. 2010;107:1058–70.PubMedPubMedCentralCrossRefGoogle Scholar
  434. 434.
    Williams B, Gallacher B, Patel H, Orme C. Glucose-induced protein kinase C activation regulates vascular permeability factor mRNA expression and peptide production by human vascular smooth muscle cells in vitro. Diabetes. 1997;46:1497–503.PubMedCrossRefPubMedCentralGoogle Scholar
  435. 435.
    Russell JW, Sullivan KA, Windebank AJ, Herrmann DN, Feldman EL. Neurons undergo apoptosis in animal and cell culture models of diabetes. Neurobiol Dis. 1999;6:347–63.PubMedCrossRefPubMedCentralGoogle Scholar
  436. 436.
    Ramasamy R, Vannucci SJ, Yan SS, Herold K, Yan SF, Schmidt AM. Advanced glycation end products and RAGE: a common thread in aging, diabetes, neurodegeneration, and inflammation. Glycobiology. 2005;15:16R–28R.PubMedCrossRefPubMedCentralGoogle Scholar
  437. 437.
    Kolm-Litty V, Sauer U, Nerlich A, Lehmann R, Schleicher ED. High glucose-induced transforming growth factor beta1 production is mediated by the hexosamine pathway in porcine glomerular mesangial cells. J Clin Invest. 1998;101:160–9.PubMedPubMedCentralCrossRefGoogle Scholar
  438. 438.
    Wada R, Yagihashi S. Role of advanced glycation end products and their receptors in development of diabetic neuropathy. Ann N Y Acad Sci. 2005;1043:598–604.PubMedCrossRefPubMedCentralGoogle Scholar
  439. 439.
    Sayeski PP, Kudlow JE. Glucose metabolism to glucosamine is necessary for glucose stimulation of transforming growth factor-alpha gene transcription. J Biol Chem. 1996;271:15237–43.PubMedCrossRefPubMedCentralGoogle Scholar
  440. 440.
    Narkiewicz K, Somers VK. Sympathetic nerve activity in obstructive sleep apnoea. Acta Physiol Scand. 2003;177:385–90.PubMedCrossRefPubMedCentralGoogle Scholar
  441. 441.
    Bradley TD, Floras JS. Obstructive sleep apnoea and its cardiovascular consequences. Lancet. 2009;373:82–93.PubMedCrossRefPubMedCentralGoogle Scholar
  442. 442.
    Tahrani AA, Ali A, Raymond NT, Begum S, Dubb K, Mughal S, Jose B, Piya MK, Barnett AH, Stevens MJ. Obstructive sleep apnea and diabetic neuropathy: a novel association in patients with type 2 diabetes. Am J Respir Crit Care Med. 2012;186:434–41.PubMedPubMedCentralCrossRefGoogle Scholar
  443. 443.
    Ficker JH, Dertinger SH, Siegfried W, König HJ, Pentz M, Sailer D, Katalinic A, Hahn EG. Obstructive sleep apnoea and diabetes mellitus: the role of cardiovascular autonomic neuropathy. Eur Respir J. 1998;11(1):14–9.PubMedCrossRefPubMedCentralGoogle Scholar
  444. 444.
    Janovsky CC, Rolim LC, de Sá JR, Poyares D, Tufik S, Silva AB, Dib SA. Cardiovascular autonomic neuropathy contributes to sleep apnea in young and lean type 1 diabetes mellitus patients. Front Endocrinol (Lausanne). 2014;5:119. eCollection 2014.CrossRefGoogle Scholar
  445. 445.
    Axelrod S, Lishner M, Oz O, Bernheim J, Ravid M. Spectral analysis of fluctuations in heart rate: an objective evaluation of autonomic nervous control in chronic renal failure. Nephron. 1987;45:202–6.PubMedCrossRefPubMedCentralGoogle Scholar
  446. 446.
    Felten SY, Peterson RG, Shea PA, Besch HR, Felten DL. Effects of streptozotocin diabetes on the noradrenergic innervation of the rat heart: a longitudinal histofluorescence and neurochemical study. Brain Res Bull. 1982;8:593–607.PubMedCrossRefPubMedCentralGoogle Scholar
  447. 447.
    Poulsen PL, Hansen KW, Mogensen CE. Increase in nocturnal blood pressure and progression to microalbuminuria in diabetes. N Engl J Med. 2003;348:260–24; author reply 260–24.PubMedCrossRefPubMedCentralGoogle Scholar
  448. 448.
    Hirabara SM, Silveira LR, Alberici LC, Leandro CV, Lambertucci RH, Polimeno GC, Cury Boaventura MF, Procopio J, Vercesi AE, Curi R. Acute effect of fatty acids on metabolism and mitochondrial coupling in skeletal muscle. Biochim Biophys Acta. 2006;1757:57–66.PubMedCrossRefPubMedCentralGoogle Scholar
  449. 449.
    Schrauwen P, Hoeks J, Hesselink MK. Putative function and physiological relevance of the mitochondrial uncoupling protein-3: involvement in fatty acid metabolism. Prog Lipid Res. 2006;45:17–41.PubMedCrossRefPubMedCentralGoogle Scholar
  450. 450.
    Collins-Nakai RL, Noseworthy D, Lopaschuk GD. Epinephrine increases ATP production in hearts by preferentially increasing glucose metabolism. Am J Phys. 1994;267:H1862–71.Google Scholar
  451. 451.
    Francis GS. Diabetic cardiomyopathy: fact or fiction. Heart. 2001;85:247–8.PubMedPubMedCentralCrossRefGoogle Scholar
  452. 452.
    Frustaci A, Kajstura J, Chimenti C, Jakoniuk I, Leri A, Maseri A, Nadal-Ginard B, Anversa P. Myocardial cell death in human diabetes. Circ Res. 2000;87:1123–32.PubMedCrossRefPubMedCentralGoogle Scholar
  453. 453.
    Katz AM. Potential deleterious effects of inotropic agents in the therapy of chronic heart failure. Circulation. 1986;73:III184–90.PubMedPubMedCentralGoogle Scholar
  454. 454.
    Eichhorn EJ, Bristow MR. Medical therapy can improve the biological properties of the chronically failing heart. A new era in the treatment of heart failure. Circulation. 1996;94:2285–96.PubMedCrossRefPubMedCentralGoogle Scholar
  455. 455.
    Yaplito-Lee J, Weintraub R, Jamsen K, Chow CW, Thorburn DR, Boneh A. Cardiac manifestations in oxidative phosphorylation disorders of childhood. J Pediatr. 2007;150:407–11.PubMedCrossRefPubMedCentralGoogle Scholar
  456. 456.
    Givertz MM, Sawyer DB, Colucci WS. Antioxidants and myocardial contractility: illuminating the “dark side” of beta-adrenergic receptor activation. Circulation. 2001;103:782–3.PubMedCrossRefPubMedCentralGoogle Scholar
  457. 457.
    Scacco S, Vergari R, Scarpulla RC, Technikova-Dobrova Z, Sardanelli A, Lambo R, Lorusso V, Papa S. cAMP-dependent phosphorylation of the nuclear encoded 18-kDa (IP) subunit of respiratory complex I and activation of the complex in serum-starved mouse fibroblast cultures. J Biol Chem. 2000;275:17578–82.PubMedCrossRefPubMedCentralGoogle Scholar
  458. 458.
    An D, Rodrigues B. Role of changes in cardiac metabolism in development of diabetic cardiomyopathy. Am J Physiol Heart Circ Physiol. 2006;291:H1489–506.PubMedCrossRefPubMedCentralGoogle Scholar
  459. 459.
    Iwai-Kanai E, Hasegawa K, Araki M, Kakita T, Morimoto T, Sasayama S. Alpha- and beta-adrenergic pathways differentially regulate cell type-specific apoptosis in rat cardiac myocytes. Circulation. 1999;100:305–11. Communal C, Singh K, Pimentel DR, Colucci WS. Norepinephrine stimulates apoptosis in adult rat ventricular myocytes by activation of the beta-adrenergic pathway. Circulation. 1998;98:1329–1334.PubMedCrossRefPubMedCentralGoogle Scholar
  460. 460.
    Communal C, Singh K, Pimentel DR, Colucci WS. Norepinephrine stimulates apoptosis in adult rat ventricular myocytes by activation of the beta-adrenergic pathway. Circulation. 1998;98:1329–34.PubMedCrossRefPubMedCentralGoogle Scholar
  461. 461.
    Carnethon MR, Prineas RJ, Temprosa M, Zhang ZM, Uwaifo G, Molitch ME. The association among autonomic nervous system function, incident diabetes, and intervention arm in the Diabetes Prevention Program. Diabetes Care. 2006;29:914–9.PubMedPubMedCentralCrossRefGoogle Scholar
  462. 462.
    Maser RE, Lenhard MJ. An overview of the effect of weight loss on cardiovascular autonomic function. Curr Diabetes Rev. 2007;3:204–11.PubMedPubMedCentralCrossRefGoogle Scholar
  463. 463.
    Voulgari C, Pagoni S, Vinik A, Poirier P. Exercise improves cardiac autonomic function in obesity and diabetes. Metabolism. 2013;62:609–21.CrossRefGoogle Scholar
  464. 464.
    Golbidi S, Ebadi SA, Laher I. Antioxidants in the treatment of diabetes. Curr Diabetes Rev. 2011;7:106–25.PubMedCrossRefPubMedCentralGoogle Scholar
  465. 465.
    Rhee SH, Pothoulakis C, Mayer EA. Principles and clinical implications of the brain-gut-enteric microbiota axis. Nat Rev Gastroenterol Hepatol. 2009;6:306–14.PubMedCrossRefPubMedCentralGoogle Scholar
  466. 466.
    Finaud J, Lac G, Filaire E. Oxidative stress. Sports Med. 2006;36:327–58.PubMedCrossRefPubMedCentralGoogle Scholar
  467. 467.
    Powers SK, Talbert EE, Adhihetty PJ. Reactive oxygen and nitrogen species as intracellular signals in skeletal muscle. J Physiol. 2011;589:2129–38.PubMedPubMedCentralCrossRefGoogle Scholar
  468. 468.
    Silvestri S, Orlando P, Armeni T, Padella L, Brugè F, Seddaiu G, Littarru GP, Tiano L. Coenzyme Q10 and α-lipoic acid: antioxidant and pro-oxidant effects in plasma and peripheral blood lymphocytes of supplemented subjects. J Clin Biochem Nutr. 2015;57(1):21–6. Published online 2015 Apr 16.
  469. 469.
    Dröge W. Free radicals in the physiological control of cell function. Physiol Rev. 2002;82:47–95.PubMedPubMedCentralCrossRefGoogle Scholar
  470. 470.
    Niess AM. Generation and disposal of reactive oxygen and nitrogen species. In: Mooren FC, Volker K, editors. Molecular and cellular exercise physiology. Champaign: Human Kinetics; 2005. p. 179–97.Google Scholar
  471. 471.
    Powers SK, Deruisseau KC, Quindry J, Hamilton KL. Dietary antioxidants and exercise. J Sports Sci. 2004;22:81–94.PubMedCrossRefPubMedCentralGoogle Scholar
  472. 472.
    Christofidou-Solomidou M, Muzykantov VR. Antioxidant strategies in respiratory medicine. Treat Respir Med. 2006;5(1):47–78. Review.PubMedCrossRefPubMedCentralGoogle Scholar
  473. 473.
    Halliwell B. Oxidative stress and neurodegeneration: where are we now? J Neurochem. 2006;97(6):1634–58. Review.PubMedCrossRefPubMedCentralGoogle Scholar
  474. 474.
    Sies H. Oxidative stress: oxidants and antioxidants. Exp Physiol. 1997;82(2):291–5. Review.PubMedCrossRefPubMedCentralGoogle Scholar
  475. 475.
    Aruoma OI, Halliwell B, Laughton MJ, Quinlan GJ, Gutteridge JM. The mechanism of initiation of lipid peroxidation. Evidence against a requirement for an iron(II)-iron(III) complex. Biochem J. 1989;258(2):617–20.PubMedPubMedCentralCrossRefGoogle Scholar
  476. 476.
    Elroy-Stein O, Bernstein Y, Groner Y. Overproduction of human Cu/Zn-superoxide dismutase in transfected cells: extenuation of paraquat-mediated cytotoxicity and enhancement of lipid peroxidation. EMBO J. 1986;5(3):615–22.PubMedPubMedCentralCrossRefGoogle Scholar
  477. 477.
    Freinbichler W, Colivicchi MA, Stefanini C, Bianchi L, Ballini C, Misini B, Weinberger P, Linert W, Varešlija D, Tipton KF, Della CL. Highly reactive oxygen species: detection, formation, and possible functions. Cell Mol Life Sci. 2011;68(12):2067–79. Epub 2011 May 2. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  478. 478.
    Halliwell B, Gutteridge JM. Role of iron in oxygen radical reactions. Methods Enzymol. 1984;105:47–56.PubMedCrossRefGoogle Scholar
  479. 479.
    Velayutham M, Hemann C, Zweier JL. Removal of H2O2 and generation of superoxide radical: role of cytochrome c and NADH. Free Radic Biol Med. 2011;51(1):160–70. Epub 2011 Apr 13.CrossRefPubMedPubMedCentralGoogle Scholar
  480. 480.
    Gordon MH. Significance of dietary antioxidants for health. Int J Mol Sci. 2012;13(1):173–9. Epub 2011 Dec 23. Review.CrossRefPubMedGoogle Scholar
  481. 481.
    Halliwell B. Reactive species and antioxidants. Redox biology is a fundamental theme of aerobic life. Plant Physiol. 2006;141(2):312–22.PubMedPubMedCentralCrossRefGoogle Scholar
  482. 482.
    Halliwell B. Phagocyte-derived reactive species: salvation or suicide? Trends Biochem Sci. 2006;31(9):509–15. Epub 2006 Aug 4. Review.PubMedCrossRefPubMedCentralGoogle Scholar
  483. 483.
    Powers SK, Lennon SL. Analysis of cellular responses to free radicals: focus on exercise and skeletal muscle. Proc Nutr Soc London. 1999;58:1025–33.CrossRefGoogle Scholar
  484. 484.
    Seifried HE, Anderson DE, Fisher EI, Milner JA. A review of the interaction among dietary antioxidants and reactive oxygen species. J Nutr Biochem. 2007;18:567–79.PubMedCrossRefPubMedCentralGoogle Scholar
  485. 485.
    MacRae HS, Mefferd KM. Dietary antioxidant supplementation combined with quercetin improves cycling time trial performance. Int J Sport Nutr Exerc Metab. 2006;16:405–19.PubMedCrossRefPubMedCentralGoogle Scholar
  486. 486.
    Oh J, Shin Y, Yoon J, et al. Effect of supplementation with Ecklonia cava polyphenol on endurance performance of college students. Int J Sport Nutr Exerc Metab. 2010;20:72–9.PubMedCrossRefPubMedCentralGoogle Scholar
  487. 487.
    Villegas L, Stidham T, Nozik-Grayck E. Oxidative stress and therapeutic development in lung diseases. J Pulm Respir Med. 2014;4(4). pii: 194. Epub 2014 Jul 15.Google Scholar
  488. 488.
    Chapple SJ, Cheng X, Mann GE. Effects of 4-hydroxynonenal on vascular endothelial and smooth muscle cell redox signaling and function in health and disease. Redox Biol. 2013;1:319–31.PubMedPubMedCentralCrossRefGoogle Scholar
  489. 489.
    Ushio-Fukai M. VEGF signaling through NADPH oxidase-derived ROS. Antioxid Redox Signal. 2007;9:731–9.PubMedCrossRefPubMedCentralGoogle Scholar
  490. 490.
    Urao N, Ushio-Fukai M. Redox regulation of stem/progenitor cells and bone marrow niche. Free Radic Biol Med. 2013;54:26–39.PubMedCrossRefPubMedCentralGoogle Scholar
  491. 491.
    Baran CP, Zeigler MM, Tridandapani S, Marsh CB. The role of ROS and RNS in regulating life and death of blood monocytes. Curr Pharm Des. 2004;10:855–66.PubMedCrossRefPubMedCentralGoogle Scholar
  492. 492.
    Fialkow L, Wang Y, Downey GP. Reactive oxygen and nitrogen species as signaling molecules regulating neutrophil function. Free Radic Biol Med. 2007;42:153–64.PubMedCrossRefPubMedCentralGoogle Scholar
  493. 493.
    Birukov KG. Cyclic stretch, reactive oxygen species, and vascular remodeling. Antioxid Redox Signal. 2009;11:1651–67.PubMedPubMedCentralCrossRefGoogle Scholar
  494. 494.
    Frazziano G, Champion HC, Pagano PJ. NADPH oxidase-derived ROS and the regulation of pulmonary vessel tone. Am J Physiol Heart Circ Physiol. 2012;302:H2166–77.PubMedPubMedCentralCrossRefGoogle Scholar
  495. 495.
    Knock GA, Ward JP. Redox regulation of protein kinases as a modulator of vascular function. Antioxid Redox Signal. 2011;15:1531–47.PubMedCrossRefGoogle Scholar
  496. 496.
    Janssen LJ. Isoprostanes and lung vascular pathology. Am J Respir Cell Mol Biol. 2008;39:383–9.PubMedCrossRefPubMedCentralGoogle Scholar
  497. 497.
    Janssen LJ, Catalli A, Helli P. The pulmonary biology of isoprostanes. Antioxid Redox Signal. 2005;7:244–55.PubMedCrossRefGoogle Scholar
  498. 498.
    Ckless K. Redox proteomics: from bench to bedside. Adv Exp Med Biol. 2014;806:301–17.PubMedCrossRefPubMedCentralGoogle Scholar
  499. 499.
    Matsuo M, Kaneko T. The chemistry of reactive oxygen species and related free radicals. In: Radak Z, editor. Free radicals in exercise and aging. Leeds: Human Kinetics; 2000. p. 1–34.Google Scholar
  500. 500.
    Sawka MN, Burke LM, Eichner ER, Maughan RJ, Montain SJ, et al. American College of Sports Medicine position stand. Exercise and fluid replacement. Med Sci Sports Exerc. 2007;39(2):377–90. PMID: 17277604.PubMedPubMedCentralCrossRefGoogle Scholar
  501. 501.
    Paik IY, Jeong MH, Jin HE, Kim YI, Suh AR, et al. Fluid replacement following dehydration reduces oxidative stress during recovery. Biochem Biophys Res Commun. 2009;383(1):103–7. Scholar
  502. 502.
    Ziegler D, Schatz H, Conrad F, Gries FA, Ulrich H, Reichel G. Effects of treatment with the antioxidant alpha-lipoic acid on cardiac autonomic neuropathy in NIDDM patients. A 4-month randomized controlled multicenter trial (DEKAN Study). Deutsche Kardiale Autonome Neuropathy. Diabetes Care. 1997;20:369–73.PubMedCrossRefPubMedCentralGoogle Scholar
  503. 503.
    Spallone V, Ziegler D, Freeman R, Bernardi L, Frontoni S, Pop-Busui R, Stevens M, Kempler P, Hilsted J, Tesfaye S, Low P, Valensi P; On Behalf of the Toronto Consensus Panel on Diabetic Neuropathy∗. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev. 2011;27(7):639–53; Epub ahead of print.PubMedCrossRefPubMedCentralGoogle Scholar
  504. 504.
    Manzella D, Barbieri M, Ragno E, Paolisso G. Chronic administration of pharmacologic doses of vitamin E improves the cardiac autonomic nervous system in patients with type 2 diabetes. Am J Clin Nutr. 2001;73:1052–7.PubMedCrossRefPubMedCentralGoogle Scholar
  505. 505.
    Ametov AS, Barinov A, Dyck PJ, Hermann R, Kozlova N, Litchy WJ, Low PA, Nehrdich D, Novosadova M, O’Brien PC, Reljanovic M, Samigullin R, Schuette K, Strokov I, Tritschler HJ, Wessel K, Yakhno N, Ziegler D. The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial. Diabetes Care. 2003;26:770–6.PubMedCrossRefPubMedCentralGoogle Scholar
  506. 506.
    Ruhnau KJ, Meissner HP, Finn R, Reljanovic M, Lobisch M, Schutte K, Nehrdich D, Tritschler H, Mehnert H, Ziegler D. Effects of 3-week oral treatment with the antioxidant thioctic acid (alpha-lipoic acid) in symptomatic diabetic polyneuropathy. Diabet Med. 1999;16(12):1040–3.PubMedCrossRefPubMedCentralGoogle Scholar
  507. 507.
    Ziegler D, Hanefeld M, Ruhnau KJ, Meissner HP, Lobisch M, Schutte K, Gries FA. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study). Diabetologia. 1995;38:1425–33.PubMedCrossRefPubMedCentralGoogle Scholar
  508. 508.
    Reljanovic M, Reichel G, Rett K, Lobisch M, Schuette K, Moller W, Tritschler HJ, Mehnert H. Treatment of diabetic polyneuropathy with the antioxidant thioctic acid (alpha-lipoic acid): a two year multicenter randomized double-blind placebo-controlled trial (ALADIN II). Alpha Lipoic Acid in Diabetic Neuropathy. Free Radic Res. 1999;31(3):171–9.PubMedCrossRefPubMedCentralGoogle Scholar
  509. 509.
    Ziegler D, Nowak H, Kempler P, Vargha P, Low PA. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a meta-analysis. Diabet Med. 2004;21:114–21.PubMedCrossRefPubMedCentralGoogle Scholar
  510. 510.
    Mortensen SA, Rosenfeldt F, Kumar A, Dolliner P, Filipiak KJ, Pella D, Alehagen U, Steurer G, Littarru GP, Q-SYMBIO Study Investigators. The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: results from Q-SYMBIO: a randomized double-blind trial. JACC Heart Fail. 2014;2(6):641–9. Epub 2014 Oct 1.CrossRefPubMedPubMedCentralGoogle Scholar
  511. 511.
    Rosenfeldt FL, Haas SJ, Krum H, Hadj A, Ng K, Leong JY, Watts GF. Coenzyme Q10 in the treatment of hypertension: a meta-analysis of the clinical trials. J Hum Hypertens. 2007;21(4):297–306. Epub 2007 Feb 8.PubMedCrossRefPubMedCentralGoogle Scholar
  512. 512.
    Rosenfeldt F, Hilton D, Pepe S, Krum H. Systematic review of effect of coenzyme Q10 in physical exercise, hypertension and heart failure. Biofactors. 2003;18(1–4):91–100. Review.PubMedCrossRefPubMedCentralGoogle Scholar
  513. 513.
    Deichmann R, Lavie C, Andrews S. Coenzyme q10 and statin-induced mitochondrial dysfunction. Ochsner J. 2010;10(1):16–21.PubMedPubMedCentralGoogle Scholar
  514. 514.
    Greene DA, Arezzo JC, Brown MB. Effect of aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathy. Zenarestat Study Group. Neurology. 1999;53:580–91.PubMedCrossRefPubMedCentralGoogle Scholar
  515. 515.
    Hotta N, Toyota T, Matsuoka K, Shigeta Y, Kikkawa R, Kaneko T, Takahashi A, Sugimura K, Koike Y, Ishii J, Sakamoto N, The SNK-860 Diabetic Neuropathy Study Group. Clinical efficacy of fidarestat, a novel aldose reductase inhibitor, for diabetic peripheral neuropathy. Diabetes Care. 2001;24:1776–82.PubMedCrossRefPubMedCentralGoogle Scholar
  516. 516.
    Hotta N, Shigeta Y, Sakamoto N. Long-term effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy: A 3-y multicenter comparative study, ARI-diabetes complications trial (ADCT) (abstract). Diabetes. 2005;54:A213.Google Scholar
  517. 517.
    Vinik AI, Mehrabyan A. Diabetic neuropathies. Med Clin North Am. 2004;88:947–99, xi.PubMedCrossRefPubMedCentralGoogle Scholar
  518. 518.
    Vinik AI, Bril V, Litchy WJ, Price KL, Bastyr EJ III. Sural sensory action potential identifies diabetic peripheral neuropathy responders to therapy. Muscle Nerve. 2005;32(5):619–25.PubMedCrossRefPubMedCentralGoogle Scholar
  519. 519.
    Casellini CM, Barlow PM, Rice AL, Casey M, Simmons K, Pittenger G, Bastyr EJ III, Wolka AM, Vinik AI. A 6-month, randomized, double-masked, placebo-controlled study evaluating the effects of the protein kinase C-{beta} inhibitor ruboxistaurin on skin microvascular blood flow and other measures of diabetic peripheral neuropathy. Diabetes Care. 2007;30:896–902.PubMedCrossRefPubMedCentralGoogle Scholar
  520. 520.
    Myung SK, Ju W, Cho B, Oh SW, Park SM, Koo BK, Park BJ. Efficacy of vitamin and antioxidant supplements in prevention of cardiovascular disease: systematic review and meta-analysis of randomised controlled trials. BMJ. 2013;346:f10. Published online 2013 Jan 18. PubMedPubMedCentralCrossRefGoogle Scholar
  521. 521.
    Abilés J, de la Cruz AP, Castaño J, Rodríguez-Elvira M, Aguayo E, Moreno-Torres R, Llopis J, Aranda P, Argüelles S, Ayala A, de la Quintana AM, Planells EM. Oxidative stress is increased in critically ill patients according to antioxidant vitamins intake, independent of severity: a cohort study. Crit Care. 2006;10(5):R146.PubMedPubMedCentralCrossRefGoogle Scholar
  522. 522.
    Therond P, Bonnefont-Rousselout D, Davit-Sparaul A, Conti M, Legrand A. Biomarkers of oxidative stress: an analytical approach. Curr Opin Clin Nutr Metab Care. 2000;3:373–84. Scholar
  523. 523.
    Alonso de la Vega JM, Díaz J, Serrano E, Carbonell LF. Plasma redox status relates to severity in critically ill patients. Crit Care Med. 2000;28:1812–4. Scholar
  524. 524.
    Motoyama T, Okamoto K, Kukita I, Hamaguchi M, Kinoshita Y, Ogawa H. Possible role of increase oxidant stress in multiple organ failure after systemic inflammatory response syndrome. Crit Care Med. 2003;31:1048–52. Scholar
  525. 525.
    Goode HF, Cowley HC, Walker BE, Howdle PD, Webster NR. Decreased antioxidant status and increased lipid peroxidation in patients with septic shock and secondary organ dysfunction. Crit Care Med. 1995;23:646–51. Scholar
  526. 526.
    Grimble RF. Nutrition antioxidants and the modulation of inflammation theory and practice. New Horiz. 1994;2:175–85.PubMedPubMedCentralGoogle Scholar
  527. 527.
    Hammerman C, Kaplan M. Ischemia and reperfusion injury. Clin Perinatol. 1998;25:757–77.PubMedCrossRefPubMedCentralGoogle Scholar
  528. 528.
    Yu BP. Cellular defenses against damage from reactive species. Physiol Rev. 1994;74:139–62.PubMedCrossRefPubMedCentralGoogle Scholar
  529. 529.
    Jeevanandam M, Begay CK, Shahbazian LM, Scott R, Petersen MD. Altered plasma cytokines and total glutathione levels in parenterally fed critically ill trauma patients with adjuvant recombinant human growth hormone therapy. Crit Care Med. 2000;28:324–9. Scholar
  530. 530.
    Nathens AB, Neff MJ, Jurkavich GJ. Randomized, prospective trial of antioxidant supplementation in critically ill surgical patients. Ann Surg. 2002;236:814–22. Scholar
  531. 531.
    Preiser JC, Gossum AV, Berré J, Vincent JL, Carpentier Y. Enteral feeding with a solution enriched with antioxidant vitamins A, C and E enhances the resistance to oxidative stress. Crit Care Med. 2000;28:3828–32. Scholar
  532. 532.
    Crimi E, Liguori A, Condorelli M, Cioffi M, Astuto M, Bontempo P, Pignalosa O, Viteri MT, Molinari AM, Sica V, et al. The beneficial effects of antioxidant supplementation in enteral feeding in critically ill patients: a prospective, randomized, double-blind, placebo-controlled trial. Anesth Analg. 2004;99:857–63. Scholar
  533. 533.
    Rahman I, Biswas SK, Kode A. Oxidant and antioxidant balance in the airways and airway diseases. Eur J Pharmacol. 2006;533(1–3):222–39. Epub 2006 Feb 28. Review.PubMedCrossRefPubMedCentralGoogle Scholar
  534. 534.
    Spickett CM, Forman HJ, editors. Lipid oxidation in health and disease. Oxidative stress and disease. Boca Raton: CRC Press; 2015.Google Scholar
  535. 535.
    Freeman R, Abuzinadah A, Gibbons C, Jones P, Miglis M, Sinn,D. Orthostatic hypotension. J Am Coll Cardiol State Art Rev 2018; 22(7); 1294–1309.PubMedCrossRefPubMedCentralGoogle Scholar
  536. 536.
    Liu G, Zhang C, Yin J, Li X, Cheng F, Li Y, Yang H, Uéda K, Chan P, Yu S. Alpha-synuclein is differentially expressed in mitochondria from different rat brain regions and dose-dependently down-regulates complex I activity. Neurosci Lett. 2009;454(3):187–92. Scholar
  537. 537.
    Murray GL, Colombo J. (R)alpha lipoic acid is a safe, effective pharmacologic therapy of chronic orthostatic hypotension associated with low sympathetic tone. Int J Angiol. 2019 (eFirst); 1.
  538. 538.
    Zhang H, Jia H, Liu J, Ao N, Yan B, Shen W, Wang X, et al. Combined R-alpha-lipoic acid and acetyl-L-carnitine exerts efficient preventative effects in a cellular model of Parkinson’s disease. J Cell Mol Med. 2010;14(1–2):215–25.PubMedCrossRefPubMedCentralGoogle Scholar
  539. 539.
    Biosa A, Outiero T, Bubacco L, Bisaglia M. Diabetes mellitus as a risk factor for Parkinson’s disease: a molecular point of view. Mol Neurobiol. 2018;28:1025–9. Scholar
  540. 540.
    Lee W, Kim S, Kim G, Han S, Won J, Jung C, et al. Alpha-lipoic acid activates dimethylaminohydrolase in cultured endothelial cells. Biochem Biophys Res Commun. 2010;398(4):653–8.PubMedCrossRefPubMedCentralGoogle Scholar
  541. 541.
    Goudy S, Regalia J, Cai F, Helke C. Alpha-lipoic acid treatment prevents the diabetes-induced attenuation of the afferent limb of the baroreceptor reflex in rats. Auton Neurosci. 2003;108(1–2):32–44.CrossRefGoogle Scholar
  542. 542.
    Queiroz TM, Guimarães DD, Mendes-Junior LG, Braga VA. α-lipoic acid reduces hypertension and increases baroreflex sensitivity in renovascular hypertensive rats. Molecules. 2012;17(11):13357–67.PubMedPubMedCentralCrossRefGoogle Scholar
  543. 543.
    Mohammadi V, Khorvash F, Feizi A, Askari G. Does alpha-lipoic acid supplementation modulate cardiovascular risk factors in patients with stroke? A randomized, double-blind clinical trial. Int J Prev Med. 2018;9:34.PubMedPubMedCentralCrossRefGoogle Scholar
  544. 544.
    Tardif J, Rheaume E. Lipoic acid supplementation and endothelial function. Br J Pharmacol. 2008;153(8):1587–8.PubMedPubMedCentralCrossRefGoogle Scholar
  545. 545.
    Circu ML, Aw TY. Glutathione and apoptosis. Free Radic Res. 2008;42(8):689–706. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  546. 546.
    Franco R, Cidlowski JA. Apoptosis and glutathione: beyond an antioxidant. Cell Death Differ. 2009;16(10):1303–14. Epub 2009 Aug 7. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  547. 547.
    Circu ML, Aw TY. Glutathione and modulation of cell apoptosis. Biochim Biophys Acta. 2012;1823(10):1767–77. Epub 2012 Jun 23. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  548. 548.
    Franco R, Cidlowski JA. Glutathione efflux and cell death. Antioxid Redox Signal. 2012;17(12):1694–713. Epub 2012 Jul 16. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  549. 549.
    Konradi C, Eaton M, MacDonald ML, Walsh J, Benes FM, Heckers S. Molecular evidence for mitochondrial dysfunction in bipolar disorder. Arch Gen Psychiatry. 2004;61(3):300–8. Erratum in: Arch Gen Psychiatry. 2004 Jun;61(6):538.PubMedCrossRefPubMedCentralGoogle Scholar
  550. 550.
    Chen AT, Chibnall JT, Nasrallah HA. Placebo-controlled augmentation trials of the antioxidant NAC in schizophrenia: a review. Ann Clin Psychiatry. 2016;28(3):190–6.PubMedPubMedCentralGoogle Scholar
  551. 551.
    Vavilin VA, Safronova OG, Manankin NA, Kaznacheeva LF, Lyakhovich VV. Glutathione-S-transferase polymorphism and clinical features of acute drug poisoning in children. Bull Exp Biol Med. 2005;139(4):431–3.PubMedCrossRefPubMedCentralGoogle Scholar
  552. 552.
    Morris G, Anderson G, Dean O, Berk M, Galecki P, Martin-Subero M, Maes M. The glutathione system: a new drug target in neuroimmune disorders. Mol Neurobiol. 2014;50(3):1059–84. Epub 2014 Apr 22. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  553. 553.
    Yeligar SM, Harris FL, Hart CM, Brown LA. Glutathione attenuates ethanol-induced alveolar macrophage oxidative stress and dysfunction by downregulating NADPH oxidases. Am J Physiol Lung Cell Mol Physiol. 2014;306(5):L429–41. Epub 2014 Jan 17.CrossRefPubMedPubMedCentralGoogle Scholar
  554. 554.
    Kodama Y, Kishimoto Y, Muramatsu Y, Tatebe J, Yamamoto Y, Hirota N, Itoigawa Y, Atsuta R, Koike K, Sato T, Aizawa K, Takahashi K, Morita T, Homma S, Seyama K, Ishigami A. Antioxidant nutrients in plasma of Japanese patients with chronic obstructive pulmonary disease (COPD), asthma-COPD overlap syndrome, and bronchial asthma. Clin Respir J. 2015. [Epub ahead of print].PubMedCrossRefPubMedCentralGoogle Scholar
  555. 555.
    Vicentini GE, Fracaro L, de Souza SR, Martins HA, Guarnier FA, Zanoni JN. Experimental cancer cachexia changes neuron numbers and peptide levels in the intestine: partial protective effects after dietary supplementation with L-glutamine. PLoS One. 2016;11(9):e0162998. eCollection 2016.CrossRefPubMedPubMedCentralGoogle Scholar
  556. 556.
    Jason LA, Boulton A, Porter NS, Jessen T, Njoku MG, Friedberg F. Classification of myalgic encephalomyelitis/chronic fatigue syndrome by types of fatigue. Behav Med. 2010;36(1):24–31. Scholar
  557. 557.
    Mathew SJ. Treatment-resistant depression: recent developments and future directions. Depress Anxiety. 2008;25(12):989–92. Scholar
  558. 558.
    Kato T, Kubota M, Kasahara T. Animal models of bipolar disorder. Neurosci Biobehav Rev. 2007;31(6):832–42. Epub 2007 Mar 27. Review.PubMedCrossRefPubMedCentralGoogle Scholar
  559. 559.
    Baxter LR Jr, Phelps ME, Mazziotta JC, Schwartz JM, Gerner RH, Selin CE, Sumida RM. Cerebral metabolic rates for glucose in mood disorders. Studies with positron emission tomography and fluorodeoxyglucose F 18. Arch Gen Psychiatry. 1985;42(5):441–7.PubMedCrossRefPubMedCentralGoogle Scholar
  560. 560.
    Caliyurt O, Altiay G. Resting energy expenditure in manic episode. Bipolar Disord. 2009;11(1):102–6. Scholar
  561. 561.
    Shao L, Martin MV, Watson SJ, Schatzberg A, Akil H, Myers RM, Jones EG, Bunney WE, Vawter MP. Mitochondrial involvement in psychiatric disorders. Ann Med. 2008;40(4):281–95. Review. Erratum in: Ann Med. 2011 Jun;43(4):329.CrossRefPubMedPubMedCentralGoogle Scholar
  562. 562.
    Konradi C, Eaton M, MacDonald ML, Walsh J, Benes FM, Heckers S. Molecular evidence for mitochondrial dysfunction in bipolar disorder. Arch Gen Psychiatry. 2004;61(3):300–8. Erratum in: Arch Gen Psychiatry. 2004 Jun;61(6):538.PubMedCrossRefPubMedCentralGoogle Scholar
  563. 563.
    Andreazza AC, Kapczinski F, Kauer-Sant’Anna M, Walz JC, Bond DJ, Gonçalves CA, Young LT, Yatham LN. 3-Nitrotyrosine and glutathione antioxidant system in patients in the early and late stages of bipolar disorder. J Psychiatry Neurosci. 2009;34(4):263–71.PubMedPubMedCentralGoogle Scholar
  564. 564.
    Maurer IC, Schippel P, Volz HP. Lithium-induced enhancement of mitochondrial oxidative phosphorylation in human brain tissue. Bipolar Disord. 2009;11(5):515–22. Scholar
  565. 565.
    Machado-Vieira R, Andreazza AC, Viale CI, Zanatto V, Cereser V Jr, da Silva Vargas R, Kapczinski F, Portela LV, Souza DO, Salvador M, Gentil V. Oxidative stress parameters in unmedicated and treated bipolar subjects during initial manic episode: a possible role for lithium antioxidant effects. Neurosci Lett. 2007;421(1):33–6. Epub 2007 May 22.PubMedCrossRefPubMedCentralGoogle Scholar
  566. 566.
    Rosa AR, Frey BN, Andreazza AC, Ceresér KM, Cunha AB, Quevedo J, Santin A, Gottfried C, Gonçalves CA, Vieta E, Kapczinski F. Increased serum glial cell line-derived neurotrophic factor immunocontent during manic and depressive episodes in individuals with bipolar disorder. Neurosci Lett. 2006;407(2):146–50. Epub 2006 Sept 7.PubMedCrossRefPubMedCentralGoogle Scholar
  567. 567.
    Cui J, Shao L, Young LT, Wang JF. Role of glutathione in neuroprotective effects of mood stabilizing drugs lithium and valproate. Neuroscience. 2007;144(4):1447–53. Epub 2006 Dec 19.PubMedCrossRefPubMedCentralGoogle Scholar
  568. 568.
    Dodd S, Dean O, Copolov DL, Malhi GS, Berk M. N-acetylcysteine for antioxidant therapy: pharmacology and clinical utility. Expert Opin Biol Ther. 2008;8(12):1955–62. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  569. 569.
    Laux I, Nel A. Evidence that oxidative stress-induced apoptosis by menadione involves Fas-dependent and Fas-independent pathways. Clin Immunol. 2001;101(3):335–44.PubMedCrossRefPubMedCentralGoogle Scholar
  570. 570.
    Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 2007;87(1):315–424. Review.PubMedPubMedCentralCrossRefGoogle Scholar
  571. 571.
    Triposkiadis F, Karayannis G, Giamouzis G, Skoularigis J, Louridas G, Butler J. The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications. J Am Coll Cardiol. 2009;54(19):1747–62. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  572. 572.
    Olshansky B, Sabbah HN, Hauptman PJ, Colucci WS. Parasympathetic nervous system and heart failure: pathophysiology and potential implications for therapy. Circulation. 2008;118(8):863–71. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  573. 573.
    Kinugawa T, Dibner-Dunlap ME. Altered vagal and sympathetic control of heart rate in left ventricular dysfunction and heart failure. Am J Phys. 1995;268:R317–23.CrossRefGoogle Scholar
  574. 574.
    Newton GE, Parker AB, Landzberg JS, Colucci WS, Parker JD. Muscarinic receptor modulation of basal and beta-adrenergic stimulated function of the failing human left ventricle. J Clin Invest. 1996;98:2756–63.PubMedPubMedCentralCrossRefGoogle Scholar
  575. 575.
    Zhao G, Shen W, Xu X, Ochoa M, Bernstein R, Hintze TH. Selective impairment of vagally mediated, nitric oxide-dependent coronary vasodilation in conscious dogs after pacing-induced heart failure. Circulation. 1995;91:2655–63.PubMedCrossRefPubMedCentralGoogle Scholar
  576. 576.
    Dibner-Dunlap ME, Thames MD. Control of sympathetic nerve activity by vagal mechanoreflexes is blunted in heart failure. Circulation. 1992;86:1929–34.PubMedCrossRefPubMedCentralGoogle Scholar
  577. 577.
    Eschenhagen T, Mende U, Nose M, Schmitz W, Scholz H, Schulte am Esch J, Sempell R, Warnholtz A, Wustel JM. Regulation and possible functional implications of G-protein mRNA expression in nonfailing and failing ventricular myocardium. Basic Res Cardiol. 1992;87:51–64.PubMedPubMedCentralGoogle Scholar
  578. 578.
    Ferramosca A, Di Giacomo M, Zara V. Antioxidant dietary approach in treatment of fatty liver: new insights and updates. World J Gastroenterol. 2017;23(23):4146–57. Scholar
  579. 579.
    Bhatia LS, Curzen NP. Non-alcoholic fatty liver disease: a new and important cardiovascular risk factor? Eur Heart J. 2012;33(10):1190–200. Epub 2012 Mar 8.CrossRefPubMedPubMedCentralGoogle Scholar
  580. 580.
    Reddy JK, Rao MS. Lipid metabolism and liver inflammation. II. Fatty liver disease and fatty acid oxidation. Am J Physiol Gastrointest Liver Physiol. 2006;290(5):G852–8.PubMedCrossRefPubMedCentralGoogle Scholar
  581. 581.
    Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002;346(16):1221–31.PubMedCrossRefPubMedCentralGoogle Scholar
  582. 582.
    Bayard M, Holt J, Boroughs E. Nonalcoholic fatty liver disease. Am Fam Physician. 2006;73(11):1961–8.PubMedPubMedCentralGoogle Scholar
  583. 583.
    Medina J, Fernández-Salazar LI, García-Buey L, Moreno-Otero R. Approach to the pathogenesis and treatment of non-alcoholic steatohepatitis. Diabetes Care. 2004;27(8):2057–66.PubMedCrossRefPubMedCentralGoogle Scholar
  584. 584.
    Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology. 1998;114(4):842–5.PubMedCrossRefPubMedCentralGoogle Scholar
  585. 585.
    Zafrani ES. Non-alcoholic fatty liver disease: an emerging pathological spectrum. Virchows Arch. 2004;444(1):3–12.PubMedCrossRefPubMedCentralGoogle Scholar
  586. 586.
    Ma J, Hennein R, Liu C, Long MT, Hoffmann U, Jacques PF, Lichtenstein AH, Hu FB, Levy D. Improved diet quality associates with reduction in liver fat, particularly in individuals with high genetic risk scores for nonalcoholic fatty liver disease. Gastroenterology. 2018. pii: S0016–5085(18)30345–7. [Epub ahead of print].PubMedPubMedCentralCrossRefGoogle Scholar
  587. 587.
    Valent P. Mast cell activation syndromes: definition and classification. Allergy. 2013;68(4):417–24.PubMedCrossRefPubMedCentralGoogle Scholar
  588. 588.
    Akin C, Valent P, Metcalfe DD. Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol. 2010;126:1099–104.PubMedPubMedCentralCrossRefGoogle Scholar
  589. 589.
    Akin C. Mast cell activation syndromes presenting as anaphylaxis. Immunol Allergy Clin N Am. 2015;35(2):277–85.CrossRefGoogle Scholar
  590. 590.
    Milner J. Research update: POTS, EDS, MCAS Genetics. Dysautonomia International Conference & CME. Washington, DC. Dysautonomia International Research Update: POTS, EDS, MCAS Genetics. Web; 2015.Google Scholar
  591. 591.
    Szczawinska-Poplonyk A. An overlapping syndrome of allergy and immune deficiency in children. J Allergy. 2012;2012:1–9.Google Scholar
  592. 592.
    Talkington J, Nickell SP. Borrelia burgdorferi spirochetes induce mast cell activation and cytokine release. Infect Immun. 1999;67(3):1107–15.PubMedPubMedCentralGoogle Scholar
  593. 593.
    Gao L, Mao Q, Cao J, Wang Y, Zhou X, Fan L. Effects of coenzyme Q10 on vascular endothelial function in humans: a meta-analysis of randomized controlled trials. Atherosclerosis. 2012;221(2):311–6. Epub 2011 Oct 25. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  594. 594.
    Yoritaka A, Kawajiri S, Yamamoto Y, Nakahara T, Ando M, Hashimoto K, Nagase M, Saito Y, Hattori N. Randomized, double-blind, placebo-controlled pilot trial of reduced coenzyme Q10 for Parkinson’s disease. Parkinsonism Relat Disord. 2015;21(8):911–6. Epub 2015 May 29.CrossRefPubMedPubMedCentralGoogle Scholar
  595. 595.
    Butt JH, Franzmann U, Kruuse C. Endothelial function in migraine with aura – a systematic review. Headache. 2015;55(1):35–54. Epub 2014 Dec 24. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  596. 596.
    Dalla Volta G, Carli D, Zavarise P, Ngonga G, Vollaro S. P026. Pilot study on the use of coenzyme Q10 in a group of patients with episodic migraine without aura. J Headache Pain. 2015;16(Suppl 1):A186. Scholar
  597. 597.
    Shoeibi A, Olfati N, Soltani Sabi M, Salehi M, Mali S, Akbari Oryani M. Effectiveness of coenzyme Q10 in prophylactic treatment of migraine headache: an open-label, add-on, controlled trial. Acta Neurol Belg. 2017;117(1):103–9. Epub 2016 Sept 26.CrossRefPubMedGoogle Scholar
  598. 598.
    Scapagnini G, Davinelli S, Drago F, De Lorenzo A, Oriani G. Antioxidants as antidepressants: fact or fiction? CNS Drugs. 2012;26(6):477–90. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  599. 599.
    Morris G, Anderson G, Berk M, Maes M. Coenzyme Q10 depletion in medical and neuropsychiatric disorders: potential repercussions and therapeutic implications. Mol Neurobiol. 2013;48(3):883–903. Epub 2013 Jun 13. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  600. 600.
    Maurya PK, Noto C, Rizzo LB, Rios AC, Nunes SO, Barbosa DS, Sethi S, Zeni M, Mansur RB, Maes M, Brietzke E. The role of oxidative and nitrosative stress in accelerated aging and major depressive disorder. Prog Neuro-Psychopharmacol Biol Psychiatry. 2016;65:134–44. Epub 2015 Sept 6. Review.CrossRefGoogle Scholar
  601. 601.
    Sanoobar M, Dehghan P, Khalili M, Azimi A, Seifar F. Coenzyme Q10 as a treatment for fatigue and depression in multiple sclerosis patients: a double blind randomized clinical trial. Nutr Neurosci. 2016;19(3):138–43. Epub 2015 Jan 20.CrossRefPubMedPubMedCentralGoogle Scholar
  602. 602.
    Salviati L, Trevisson E, Doimo M, Navas P. Primary coenzyme Q10 deficiency. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle: University of Washington; 2017. p. 1993–2017.Google Scholar
  603. 603.
    Mitsui J, Matsukawa T, Yasuda T, Ishiura H, Tsuji S. Plasma coenzyme Q10 levels in patients with multiple system atrophy. JAMA Neurol. 2016;73(8):977–80. Scholar
  604. 604.
    Singh RB, Kartik C, Otsuka K, Pella D, Pella J. Brain-heart connection and the risk of heart attack. Biomed Pharmacother. 2002;56(Suppl 2):257s–65s.PubMedCrossRefPubMedCentralGoogle Scholar
  605. 605.
    Li Z, Wang P, Yu Z, Cong Y, Sun H, Zhang J, Zhang J, Sun C, Zhang Y, Ju X. The effect of creatine and coenzyme q10 combination therapy on mild cognitive impairment in Parkinson’s disease. Eur Neurol. 2015;73(3–4):205–11. Epub 2015 Mar 10.CrossRefPubMedPubMedCentralGoogle Scholar
  606. 606.
    Atalay Guzel N, Erikoglu Orer G, Sezen Bircan F, Coskun Cevher S. Effects of acute L-carnitine supplementation on nitric oxide production and oxidative stress after exhaustive exercise in young soccer players. J Sports Med Phys Fitness. 2015;55(1–2):9–15. Epub 2014 Oct 7.PubMedPubMedCentralGoogle Scholar
  607. 607.
    Lim HB, Smith M. Systemic complications after head injury: a clinical review. Anaesthesia. 2007;62(5):474–82. Review.PubMedCrossRefPubMedCentralGoogle Scholar
  608. 608.
    Tobias H, Vinitsky A, Bulgarelli RJ, Ghosh-Dastidar S, Colombo J. Autonomic nervous system monitoring of patients with excess parasympathetic responses to sympathetic challenges – clinical observations. US Neurology. 2010;5(2):62–6.CrossRefGoogle Scholar
  609. 609.
    Procaccini C, Pucino V, De Rosa V, Marone G, Matarese G. Neuro-endocrine networks controlling immune system in health and disease. Front Immunol. 2014;5:143. eCollection 2014. Review.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Nicholas L. DePace
    • 1
  • Joseph Colombo
    • 2
  1. 1.Franklin Cardiovascular Associates, PA and Autonomic Dysfunction and POTS CenterSewellUSA
  2. 2.TMCAMS, Inc.Franklin Cardiovascular Associates, PA and Autonomic Dysfunction and POTS CenterRichboroUSA

Personalised recommendations