The significance of oxidative stress in the pathophysiology of Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Main Article Content
Abstract
Long COVID is now well accepted as an ongoing post-viral syndrome resulting from infection of a single virus, the pandemic SARS-CoV-2. It mirrors the post-viral fatigue syndrome, Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome, a global debilitating illness arising mainly from sporadic geographically-specific viral outbreaks, and from community endemic infections, but also from other stressors. Core symptoms of both syndromes are post-exertional malaise (a worsening of symptoms following mental or physical activity), pervasive fatigue, cognitive dysfunction (brain fog), and sleep disturbance. Long COVID patients frequently also suffer from shortness of breath, relating to the lung involvement of the SARS-CoV-2 virus. There is no universally accepted pathophysiology, or recognized biomarkers yet for Long COVID or indeed for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Clinical case definitions with very similar characteristics for each have been defined. Chronic inflammation, immune dysfunction, and disrupted energy production in the peripheral system has been confirmed in Long COVID and has been well documented in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Neuroinflammation occurs in the brain in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome as shown from a small number of positron emission tomography and magnetic resonance spectroscopy studies, and has now been demonstrated for Long COVID. Oxidative stress, an increase in reactive oxygen and reactive nitrogen species, and free radicals, has long been suggested as a potential cause for many of the symptoms seen in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, resulting from both activation of the brain’s immune system and dysregulation of mitochondrial function throughout the body. The brain as a high producer of energy may be particularly susceptible to oxidative stress. It has been shown in peripheral immune cells that the balanced production of proteins involved in regulation of the reactive oxygen species in mitochondria is disturbed in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Fluctuations in the chronic low level neuroinflammation during the ongoing course of Long COVID as well as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome have been proposed to cause the characteristic severe relapses in patients. This review explores oxidative stress as a likely significant contributor to the pathophysiology of Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, and the mechanisms by which oxidative stress could cause the symptoms seen in both syndromes. Treatments that could mitigate oxidative stress and thereby lessen the debilitating symptoms to improve the life of patients are discussed.
Article Details
How to Cite
WALKER, Max Oliver Mackay et al.
The significance of oxidative stress in the pathophysiology of Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).
Medical Research Archives, [S.l.], v. 10, n. 9, sep. 2022.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3050>. Date accessed: 27 july 2024.
doi: https://doi.org/10.18103/mra.v10i9.3050.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Choutka J, Jansari V, Hornig M, Iwasaki A. Unexplained post-acute infection syndromes. Nat Med. May 2022;28(5):911-923. doi:10.1038/s41591-022-01810-6
2. Davis HE, Assaf GS, McCorkell L, et al. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine. Aug 2021;38:101019. doi:10.1016/j.eclinm.2021.101019
3. WHO. A clinical case definition of post COVID-19 condition by a Delphi consensus. WHO https://www.who.int/publications/i/item/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1: WHO REFERENCE NUMBER: WHO/2019-nCoV/Post_COVID-19_condition/Clinical_case_definition/2021.1; 2021.
4. Tate W, Walker M, Sweetman E, et al. Molecular Mechanisms of Neuroinflammation in ME/CFS and Long COVID to Sustain Disease and Promote Relapses. Front Neurol. 2022;13:877772. doi:10.3389/fneur.2022.877772
5. Sweetman E, Noble A, Edgar C, et al. Current Research Provides Insight into the Biological Basis and Diagnostic Potential for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Diagnostics (Basel). Jul 10 2019;9(3)doi:10.3390/diagnostics9030073
6. Chan KS, Zheng JP, Mok YW, et al. SARS: prognosis, outcome and sequelae. Respirology. Nov 2003;8 Suppl(Suppl 1):S36-40. doi:10.1046/j.1440-1843.2003.00522.x
7. Moldofsky H, Patcai J. Chronic widespread musculoskeletal pain, fatigue, depression and disordered sleep in chronic post-SARS syndrome; a case-controlled study. BMC Neurol. Mar 24 2011;11:37. doi:10.1186/1471-2377-11-37
8. Institute of Medicine NAoS, USA. Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
The National Academies Collection: Reports funded by National Institutes of Health. 2015. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness.
9. Komaroff AL, Lipkin WI. Insights from myalgic encephalomyelitis/chronic fatigue syndrome may help unravel the pathogenesis of postacute COVID-19 syndrome. Trends in Molecular Medicine. 2021/09/01/ 2021;27(9):895-906. doi:https://doi.org/10.1016/j.molmed.2021.06.002
10. Carruthers BM, Jain AK, De Meirleir KL, et al. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Journal of Chronic Fatigue Syndrome. 2003/01/01 2003;11(1):7-115. doi:10.1300/J092v11n01_02
11. Carruthers BM, van de Sande MI, De Meirleir KL, et al. Myalgic encephalomyelitis: International Consensus Criteria. J Intern Med. 2011;270(4):327-338. doi:10.1111/j.1365-2796.2011.02428.x
12. Sukocheva OA, Maksoud R, Beeraka NM, et al. Analysis of post COVID-19 condition and its overlap with myalgic encephalomyelitis/chronic fatigue syndrome. Journal of Advanced Research. 2021/11/26/ 2021;doi:https://doi.org/10.1016/j.jare.2021.11.013
13. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. Dec 15 1994;121(12):953-9. doi:10.7326/0003-4819-121-12-199412150-00009
14. Aaron LA, Burke MM, Buchwald D. Overlapping conditions among patients with chronic fatigue syndrome, fibromyalgia, and temporomandibular disorder. Arch Intern Med. Jan 24 2000;160(2):221-7. doi:10.1001/archinte.160.2.221
15. Esfandyarpour R, Kashi A, Nemat-Gorgani M, Wilhelmy J, Davis RW. A nanoelectronics-blood-based diagnostic biomarker for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Proceedings of the National Academy of Sciences. 2019;116(21):10250-10257. doi:doi:10.1073/pnas.1901274116
16. Missailidis D, Annesley SJ, Allan CY, et al. An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients. Int J Mol Sci. Feb 6 2020;21(3)doi:10.3390/ijms21031074
17. Meeus M, Nijs J, McGregor N, et al. Unravelling intracellular immune dysfunctions in chronic fatigue syndrome: interactions between protein kinase R activity, RNase L cleavage and elastase activity, and their clinical relevance. In Vivo. Jan-Feb 2008;22(1):115-21.
18. Rossignol DA, Frye RE. Evidence linking oxidative stress, mitochondrial dysfunction, and inflammation in the brain of individuals with autism. Front Physiol. 2014;5:150. doi:10.3389/fphys.2014.00150
19. Felman A. Everything you need to know about inflammation. Medical News Today. Accessed 13 April 2020, https://www.medicalnewstoday.com/articles/248423
20. Harvard HP. Understanding acute and chronic inflammation 2020. https://www.health.harvard.edu/staying-healthy/understanding-acute-and-chronic-inflammation
21. Mohan C. Microglia in Acute and Chronic Inflammation. Science News. 2017(5).
22. Muzio L, Viotti A, Martino G. Microglia in Neuroinflammation and Neurodegeneration: From Understanding to Therapy. Front Neurosci. 2021;15:742065. doi:10.3389/fnins.2021.742065
23. Xu Y, Jin MZ, Yang ZY, Jin WL. Microglia in neurodegenerative diseases. Neural Regen Res. Feb 2021;16(2):270-280. doi:10.4103/1673-5374.290881
24. Hansen DV, Hanson JE, Sheng M. Microglia in Alzheimer's disease. J Cell Biol. Feb 5 2018;217(2):459-472. doi:10.1083/jcb.201709069
25. Ho MS. Microglia in Parkinson's Disease. Adv Exp Med Biol. 2019;1175:335-353. doi:10.1007/978-981-13-9913-8_13
26. Ma MW, Wang J, Zhang Q, et al. NADPH oxidase in brain injury and neurodegenerative disorders. Mol Neurodegener. Jan 17 2017;12(1):7. doi:10.1186/s13024-017-0150-7
27. Simpson DSA, Oliver PL. ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease. Antioxidants (Basel). Aug 13 2020;9(8)doi:10.3390/antiox9080743
28. Schilling T, Eder C. Amyloid-β-induced reactive oxygen species production and priming are differentially regulated by ion channels in microglia. J Cell Physiol. Dec 2011;226(12):3295-302. doi:10.1002/jcp.22675
29. Rogers J, Mastroeni D, Leonard B, Joyce J, Grover A. Neuroinflammation in Alzheimer's disease and Parkinson's disease: are microglia pathogenic in either disorder? Int Rev Neurobiol. 2007;82:235-46. doi:10.1016/s0074-7742(07)82012-5
30. Netea MG, Joosten LA, Latz E, et al. Trained immunity: A program of innate immune memory in health and disease. Science. Apr 22 2016;352(6284):aaf1098. doi:10.1126/science.aaf1098
31. Hornig M, Montoya JG, Klimas NG, et al. Distinct plasma immune signatures in ME/CFS are present early in the course of illness. Sci Adv. Feb 2015;1(1)doi:10.1126/sciadv.1400121
32. Ledderose C, Junger WG. Mitochondria Synergize With P2 Receptors to Regulate Human T Cell Function. Mini Review. Front Immunol. 2020-September-29 2020;11doi:10.3389/fimmu.2020.549889
33. Liu Y, Rao B, Li S, et al. Distinct Hypothalamic Paraventricular Nucleus Inputs to the Cingulate Cortex and Paraventricular Thalamic Nucleus Modulate Anxiety and Arousal. Front Pharmacol. 2022;13:814623-814623. doi:10.3389/fphar.2022.814623
34. Kempuraj D, Thangavel R, Selvakumar GP, et al. Brain and Peripheral Atypical Inflammatory Mediators Potentiate Neuroinflammation and Neurodegeneration. Review. Frontiers in Cellular Neuroscience. 2017-July-24 2017;11doi:10.3389/fncel.2017.00216
35. Montoya JG, Holmes TH, Anderson JN, et al. Cytokine signature associated with disease severity in chronic fatigue syndrome patients. Proc Natl Acad Sci U S A. Aug 22 2017;114(34):E7150-E7158. doi:10.1073/pnas.1710519114
10.1073/pnas.1710519114. Epub 2017 Jul 31.
36. Mandarano AH, Maya J, Giloteaux L, et al. Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations. J Clin Invest. Mar 2 2020;130(3):1491-1505. doi:10.1172/JCI132185
10.1172/JCI132185.
37. Sweetman E, Ryan M, Edgar C, MacKay A, Vallings R, Tate W. Changes in the transcriptome of circulating immune cells of a New Zealand cohort with myalgic encephalomyelitis/chronic fatigue syndrome. Int J Immunopathol Pharmacol. Jan-Dec 2019;33:2058738418820402. doi:10.1177/2058738418820402
38. Sweetman E, Kleffmann T, Edgar C, de Lange M, Vallings R, Tate W. A SWATH-MS analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction. J Transl Med. Sep 24 2020;18(1):365. doi:10.1186/s12967-020-02533-3
39. Lee JS, Kim HG, Lee DS, Son CG. Oxidative Stress is a Convincing Contributor to Idiopathic Chronic Fatigue. Sci Rep. Aug 27 2018;8(1):12890. doi:10.1038/s41598-018-31270-3
40. Wood E, Hall KH, Tate W. Role of mitochondria, oxidative stress and the response to antioxidants in myalgic encephalomyelitis/chronic fatigue syndrome: A possible approach to SARS-CoV-2 'long-haulers'? Chronic Dis Transl Med. Mar 2021;7(1):14-26. doi:10.1016/j.cdtm.2020.11.002
41. Fulle S, Pietrangelo T, Mancinelli R, Saggini R, Fanò G. Specific correlations between muscle oxidative stress and chronic fatigue syndrome: a working hypothesis. J Muscle Res Cell Motil. 2007;28(6):355-62. doi:10.1007/s10974-008-9128-y
42. Fulle S, Mecocci P, Fanó G, et al. Specific oxidative alterations in vastus lateralis muscle of patients with the diagnosis of chronic fatigue syndrome. Free Radic Biol Med. Dec 15 2000;29(12):1252-9. doi:10.1016/s0891-5849(00)00419-6
43. Pall ML. Elevated, sustained peroxynitrite levels as the cause of chronic fatigue syndrome. Med Hypotheses. Jan 2000;54(1):115-25. doi:10.1054/mehy.1998.0825
44. Brieger K, Schiavone S, Miller FJ, Jr., Krause KH. Reactive oxygen species: from health to disease. Swiss Med Wkly. 2012;142:w13659. doi:10.4414/smw.2012.13659
45. Alkadi H. A Review on Free Radicals and Antioxidants. Infect Disord Drug Targets. 2020;20(1):16-26. doi:10.2174/1871526518666180628124323
46. Wiseman H, Halliwell B. Damage to DNA by reactive oxygen and nitrogen species: role in inflammatory disease and progression to cancer. Biochem J. Jan 1 1996;313 ( Pt 1)(Pt 1):17-29. doi:10.1042/bj3130017
47. Ciencewicki J, Trivedi S, Kleeberger SR. Oxidants and the pathogenesis of lung diseases. J Allergy Clin Immunol. Sep 2008;122(3):456-68; quiz 469-70. doi:10.1016/j.jaci.2008.08.004
48. Mittal M, Siddiqui MR, Tran K, Reddy SP, Malik AB. Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal. Mar 1 2014;20(7):1126-67. doi:10.1089/ars.2012.5149
49. Paul BD, Lemle MD, Komaroff AL, Snyder SH. Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome. Proc Natl Acad Sci U S A. Aug 24 2021;118(34)doi:10.1073/pnas.2024358118
50. Morris G, Maes M. Oxidative and Nitrosative Stress and Immune-Inflammatory Pathways in Patients with Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS). Curr Neuropharmacol. Mar 2014;12(2):168-85. doi:10.2174/1570159x11666131120224653
51. Maes M, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E. Increased plasma peroxides as a marker of oxidative stress in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Med Sci Monit. Apr 2011;17(4):Sc11-5. doi:10.12659/msm.881699
52. Naviaux RK, Naviaux JC, Li K, et al. Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci U S A. Sep 13 2016;113(37):E5472-80. doi:10.1073/pnas.1607571113
53. Germain A, Ruppert D, Levine SM, Hanson MR. Metabolic profiling of a myalgic encephalomyelitis/chronic fatigue syndrome discovery cohort reveals disturbances in fatty acid and lipid metabolism. Mol Biosyst. Jan 31 2017;13(2):371-379. doi:10.1039/c6mb00600k
54. Germain A, Ruppert D, Levine SM, Hanson MR. Prospective Biomarkers from Plasma Metabolomics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Implicate Redox Imbalance in Disease Symptomatology. Metabolites. Dec 6 2018;8(4)doi:10.3390/metabo8040090
55. Booth NE, Myhill S, McLaren-Howard J. Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Int J Clin Exp Med. 2012;5(3):208-20.
56. Tomas C, Brown A, Strassheim V, Elson JL, Newton J, Manning P. Cellular bioenergetics is impaired in patients with chronic fatigue syndrome. PLoS One. 2017;12(10):e0186802. doi:10.1371/journal.pone.0186802
57. Myhill S, Booth NE, McLaren-Howard J. Chronic fatigue syndrome and mitochondrial dysfunction. Int J Clin Exp Med. 2009;2(1):1-16.
58. Missailidis D, Annesley SJ, Allan CY, et al. An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients. Int J Mol Sci. 2020;21(3):1074. doi:10.3390/ijms21031074
59. Behan WM, More IA, Behan PO. Mitochondrial abnormalities in the postviral fatigue syndrome. Acta Neuropathol. 1991;83(1):61-5. doi:10.1007/bf00294431
60. Lawson N, Hsieh CH, March D, Wang X. Elevated Energy Production in Chronic Fatigue Syndrome Patients. J Nat Sci. 2016;2(10)
61. Guo C, Sun L, Chen X, Zhang D. Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural Regen Res. Jul 25 2013;8(21):2003-14. doi:10.3969/j.issn.1673-5374.2013.21.009
62. Fukuda S, Nojima J, Motoki Y, et al. A potential biomarker for fatigue: Oxidative stress and anti-oxidative activity. Biol Psychol. Jul 2016;118:88-93. doi:10.1016/j.biopsycho.2016.05.005
63. Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E. Coenzyme Q10 deficiency in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is related to fatigue, autonomic and neurocognitive symptoms and is another risk factor explaining the early mortality in ME/CFS due to cardiovascular disorder. Neuro Endocrinol Lett. 2009;30(4):470-6.
64. Kennedy G, Spence VA, McLaren M, Hill A, Underwood C, Belch JJ. Oxidative stress levels are raised in chronic fatigue syndrome and are associated with clinical symptoms. Free Radic Biol Med. Sep 1 2005;39(5):584-9. doi:10.1016/j.freeradbiomed.2005.04.020
65. Robinson M, Gray SR, Watson MS, et al. Plasma IL-6, its soluble receptors and F2-isoprostanes at rest and during exercise in chronic fatigue syndrome. Scand J Med Sci Sports. Apr 2010;20(2):282-90. doi:10.1111/j.1600-0838.2009.00895.x
66. Godlewska BR, Williams S, Emir UE, et al. Neurochemical abnormalities in chronic fatigue syndrome: a pilot magnetic resonance spectroscopy study at 7 Tesla. Psychopharmacology (Berl). Jan 2022;239(1):163-171. doi:10.1007/s00213-021-05986-6
67. Mathew SJ, Mao X, Keegan KA, et al. Ventricular cerebrospinal fluid lactate is increased in chronic fatigue syndrome compared with generalized anxiety disorder: an in vivo 3.0 T (1)H MRS imaging study. NMR Biomed. Apr 2009;22(3):251-8. doi:10.1002/nbm.1315
68. Murrough JW, Mao X, Collins KA, et al. Increased ventricular lactate in chronic fatigue syndrome measured by 1H MRS imaging at 3.0 T. II: comparison with major depressive disorder. NMR Biomed. Jul 2010;23(6):643-50. doi:10.1002/nbm.1512
69. Shungu DC, Weiduschat N, Murrough JW, et al. Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology. NMR Biomed. Sep 2012;25(9):1073-87. doi:10.1002/nbm.2772
70. Paul BD, Snyder SH. Gasotransmitter hydrogen sulfide signaling in neuronal health and disease. Biochem Pharmacol. Mar 2018;149:101-109. doi:10.1016/j.bcp.2017.11.019
71. Vandiver MS, Paul BD, Xu R, et al. Sulfhydration mediates neuroprotective actions of parkin. Nat Commun. 2013;4:1626. doi:10.1038/ncomms2623
72. Lemle MD. Hypothesis: chronic fatigue syndrome is caused by dysregulation of hydrogen sulfide metabolism. Med Hypotheses. Jan 2009;72(1):108-9. doi:10.1016/j.mehy.2008.08.003
73. Cobley JN, Fiorello ML, Bailey DM. 13 reasons why the brain is susceptible to oxidative stress. Redox Biol. May 2018;15:490-503. doi:10.1016/j.redox.2018.01.008
74. Massaad CA, Klann E. Reactive oxygen species in the regulation of synaptic plasticity and memory. Antioxid Redox Signal. May 15 2011;14(10):2013-54. doi:10.1089/ars.2010.3208
75. Patel M. Targeting Oxidative Stress in Central Nervous System Disorders. Trends Pharmacol Sci. Sep 2016;37(9):768-778. doi:10.1016/j.tips.2016.06.007
76. Halliwell B. Oxidative stress and neurodegeneration: where are we now? J Neurochem. Jun 2006;97(6):1634-58. doi:10.1111/j.1471-4159.2006.03907.x
77. Ward RJ, Zucca FA, Duyn JH, Crichton RR, Zecca L. The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol. Oct 2014;13(10):1045-60. doi:10.1016/s1474-4422(14)70117-6
78. Scheiber IF, Mercer JF, Dringen R. Metabolism and functions of copper in brain. Prog Neurobiol. May 2014;116:33-57. doi:10.1016/j.pneurobio.2014.01.002
79. Sebio RM, Ferrarotti N, Lairion F, et al. Brain oxidative stress in rat with chronic iron or copper overload. J Inorg Biochem. Oct 2019;199:110799. doi:10.1016/j.jinorgbio.2019.110799
80. Shichiri M. The role of lipid peroxidation in neurological disorders. J Clin Biochem Nutr. May 2014;54(3):151-60. doi:10.3164/jcbn.14-10
81. Nakatomi Y, Mizuno K, Ishii A, et al. Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An (1)(1)C-(R)-PK11195 PET Study. J Nucl Med. Jun 2014;55(6):945-50. doi:10.2967/jnumed.113.131045
82. Visser D, Golla SSV, Verfaillie SCJ, et al. Long COVID is associated with extensive in-vivo neuroinflammation on [18F]DPA-714 PET. medRxiv. 2022:2022.06.02.22275916. doi:10.1101/2022.06.02.22275916
83. Matschke J, Lütgehetmann M, Hagel C, et al. Neuropathology of patients with COVID-19 in Germany: a post-mortem case series. Lancet Neurol. Nov 2020;19(11):919-929. doi:10.1016/s1474-4422(20)30308-2
84. de Boer E, Petrache I, Goldstein NM, et al. Decreased Fatty Acid Oxidation and Altered Lactate Production during Exercise in Patients with Post-acute COVID-19 Syndrome. Am J Respir Crit Care Med. Jan 1 2022;205(1):126-129. doi:10.1164/rccm.202108-1903LE
85. Nuhu F, Gordon A, Sturmey R, Seymour AM, Bhandari S. Measurement of Glutathione as a Tool for Oxidative Stress Studies by High Performance Liquid Chromatography. Molecules. Sep 13 2020;25(18)doi:10.3390/molecules25184196
86. Mandal PK, Saharan S, Tripathi M, Murari G. Brain glutathione levels--a novel biomarker for mild cognitive impairment and Alzheimer's disease. Biol Psychiatry. Nov 15 2015;78(10):702-10. doi:10.1016/j.biopsych.2015.04.005
87. Marrocco I, Altieri F, Peluso I. Measurement and Clinical Significance of Biomarkers of Oxidative Stress in Humans. Oxid Med Cell Longev. 2017;2017:6501046. doi:10.1155/2017/6501046
88. Sousa BC, Pitt AR, Spickett CM. Chemistry and analysis of HNE and other prominent carbonyl-containing lipid oxidation compounds. Free Radic Biol Med. Oct 2017;111:294-308. doi:10.1016/j.freeradbiomed.2017.02.003
89. Breitzig M, Bhimineni C, Lockey R, Kolliputi N. 4-Hydroxy-2-nonenal: a critical target in oxidative stress? Am J Physiol Cell Physiol. Oct 1 2016;311(4):C537-c543. doi:10.1152/ajpcell.00101.2016
90. Łuczaj W, Gindzienska-Sieskiewicz E, Jarocka-Karpowicz I, et al. The onset of lipid peroxidation in rheumatoid arthritis: consequences and monitoring. Free Radic Res. 2016;50(3):304-13. doi:10.3109/10715762.2015.1112901
91. Garcia YJ, Rodríguez-Malaver AJ, Peñaloza N. Lipid peroxidation measurement by thiobarbituric acid assay in rat cerebellar slices. J Neurosci Methods. May 15 2005;144(1):127-35. doi:10.1016/j.jneumeth.2004.10.018
92. Lagadu S, Lechevrel M, Sichel F, et al. 8-oxo-7,8-dihydro-2'-deoxyguanosine as a biomarker of oxidative damage in oesophageal cancer patients: lack of association with antioxidant vitamins and polymorphism of hOGG1 and GST. J Exp Clin Cancer Res. Dec 6 2010;29(1):157. doi:10.1186/1756-9966-29-157
93. Collins A. Comparison of different methods of measuring 8-oxoguanine as a marker of oxidative DNA damage. Free Radical Research. 2000/01/01 2000;32(4):333-341. doi:10.1080/10715760000300331
94. 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. Dec 1999;27(11-12):1151-63. doi:10.1016/s0891-5849(99)00206-3
95. Song YR, Kim JK, Lee HS, Kim SG, Choi EK. Serum levels of protein carbonyl, a marker of oxidative stress, are associated with overhydration, sarcopenia and mortality in hemodialysis patients. BMC Nephrol. Jul 16 2020;21(1):281. doi:10.1186/s12882-020-01937-z
96. Dalle-Donne I, Rossi R, Giustarini D, Milzani A, Colombo R. Protein carbonyl groups as biomarkers of oxidative stress. Clin Chim Acta. Mar 2003;329(1-2):23-38. doi:10.1016/s0009-8981(03)00003-2
97. Sidorova Y, Domanskyi A. Detecting Oxidative Stress Biomarkers in Neurodegenerative Disease Models and Patients. Methods Protoc. Sep 24 2020;3(4)doi:10.3390/mps3040066
98. Mackay A. A Paradigm for Post-Covid-19 Fatigue Syndrome Analogous to ME/CFS. Hypothesis and Theory. Frontiers in Neurology. 2021-August-02 2021;12doi:10.3389/fneur.2021.701419
99. Tomas C, Newton J, Watson S. A review of hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome. ISRN Neurosci. 2013;2013:784520. doi:10.1155/2013/784520
100. VanElzakker MB, Brumfield SA, Lara Mejia PS. Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods. Front Neurol. 2018;9:1033. doi:10.3389/fneur.2018.01033
101. Nelson T, Zhang LX, Guo H, Nacul L, Song X. Brainstem Abnormalities in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Scoping Review and Evaluation of Magnetic Resonance Imaging Findings. Front Neurol. 2021;12:769511. doi:10.3389/fneur.2021.769511
10.3389/fneur.2021.769511. eCollection 2021.
102. Barnden LR, Kwiatek R, Crouch B, Burnet R, Del Fante P. Autonomic correlations with MRI are abnormal in the brainstem vasomotor centre in Chronic Fatigue Syndrome. Neuroimage Clin. 2016;11:530-537. doi:10.1016/j.nicl.2016.03.017
10.1016/j.nicl.2016.03.017. eCollection 2016.
103. Yong SJ. Persistent Brainstem Dysfunction in Long-COVID: A Hypothesis. ACS Chem Neurosci. Feb 17 2021;12(4):573-580. doi:10.1021/acschemneuro.0c00793
10.1021/acschemneuro.0c00793. Epub 2021 Feb 4.
104. Mueller C, Lin JC, Sheriff S, Maudsley AA, Younger JW. Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy. Brain Imaging Behav. Apr 2020;14(2):562-572. doi:10.1007/s11682-018-0029-4
10.1007/s11682-018-0029-4.
105. Roerink ME, van der Schaaf ME, Dinarello CA, Knoop H, van der Meer JW. Interleukin-1 as a mediator of fatigue in disease: a narrative review. J Neuroinflammation. Jan 21 2017;14(1):16. doi:10.1186/s12974-017-0796-7
106. Hornig M. Can the light of immunometabolism cut through "brain fog"? J Clin Invest. Mar 2 2020;130(3):1102-1105. doi:10.1172/jci134985
107. Costantini D, Marasco V, Møller AP. A meta-analysis of glucocorticoids as modulators of oxidative stress in vertebrates. J Comp Physiol B. May 2011;181(4):447-56. doi:10.1007/s00360-011-0566-2
108. Spiers JG, Chen HJ, Sernia C, Lavidis NA. Activation of the hypothalamic-pituitary-adrenal stress axis induces cellular oxidative stress. Front Neurosci. 2014;8:456. doi:10.3389/fnins.2014.00456
109. Trifunovic S, Stevanovic I, Milosevic A, et al. The Function of the Hypothalamic-Pituitary-Adrenal Axis During Experimental Autoimmune Encephalomyelitis: Involvement of Oxidative Stress Mediators. Front Neurosci. 2021;15:649485. doi:10.3389/fnins.2021.649485
110. CDC. Long COVID or Post-COVID Conditions 2022 https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects/index.html
111. Castro-Marrero J, Cordero MD, Sáez-Francas N, et al. Could mitochondrial dysfunction be a differentiating marker between chronic fatigue syndrome and fibromyalgia? Antioxid Redox Signal. Nov 20 2013;19(15):1855-60. doi:10.1089/ars.2013.5346
112. Cordero MD, de Miguel M, Carmona-López I, Bonal P, Campa F, Moreno-Fernández AM. Oxidative stress and mitochondrial dysfunction in fibromyalgia. Neuro Endocrinol Lett. 2010;31(2):169-73.
113. Cordero MD, Díaz-Parrado E, Carrión AM, et al. Is inflammation a mitochondrial dysfunction-dependent event in fibromyalgia? Antioxid Redox Signal. Mar 1 2013;18(7):800-7. doi:10.1089/ars.2012.4892
114. Castro-Marrero J, Domingo JC, Cordobilla B, et al. Does Coenzyme Q10 Plus Selenium Supplementation Ameliorate Clinical Outcomes by Modulating Oxidative Stress and Inflammation in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome? Antioxid Redox Signal. Apr 2022;36(10-12):729-739. doi:10.1089/ars.2022.0018
115. Gueven N, Ravishankar P, Eri R, Rybalka E. Idebenone: When an antioxidant is not an antioxidant. Redox Biol. Jan 2021;38:101812. doi:10.1016/j.redox.2020.101812
116. Wishart DS, Feunang YD, Guo AC, et al. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. Jan 4 2018;46(D1):D1074-d1082. doi:10.1093/nar/gkx1037
117. Wishart DS. DrugBank 5.0. https://go.drugbank.com/drugs/DB09081
118. Lebedeva AV, Shchukin IA, Soldatov MA, et al. [Asthenia, emotional disorders and quality of life of patients with multiple sclerosis]. Zh Nevrol Psikhiatr Im S S Korsakova. 2014;114(10 Pt 2):99-104. Asteniia, émotsional'nye rasstroĭstva i kachestvo zhizni u patsientov s rasseiannym sklerozom.
119. Jordan AL, Yang J, Fisher CJ, Racke MK, Mao-Draayer Y. Progressive multifocal leukoencephalopathy in dimethyl fumarate-treated multiple sclerosis patients. Mult Scler. Jan 2022;28(1):7-15. doi:10.1177/1352458520949158
120. Ozel O, Vaughn CB, Eckert SP, Jakimovski D, Lizarraga AA, Weinstock-Guttman B. Dimethyl Fumarate in the Treatment of Relapsing-Remitting Multiple Sclerosis: Patient Reported Outcomes and Perspectives. Patient Relat Outcome Meas. 2019;10:373-384. doi:10.2147/prom.S168095
121. Johnson C. Did MitoQ mend us? A fibromyalgia and Chronic Fatigue syndrome (ME/CFS ) CoQ10 trial. https://www.healthrising.org/blog/2016/08/08/mendus-fibromyalgia-chronic-fatigue-syndrome-mitoq-coq10-trial/
122. Tereshin AE, Kiryanova VV, Reshetnik DA. [Correction of mitochondrial dysfunction in the complex rehabilitation of COVID-19]. Zh Nevrol Psikhiatr Im S S Korsakova. 2021;121(8):25-29. Korrektsiya mitokhondrial'noi disfunktsii v kompleksnoi reabilitatsii patsientov, perenesshikh COVID-19. doi:10.17116/jnevro202112108125
123. NZF. Dimethyl fumarate. https://nzf.org.nz/nzf_70465
124. Yoshino H. Edaravone for the treatment of amyotrophic lateral sclerosis. Expert Rev Neurother. Mar 2019;19(3):185-193. doi:10.1080/14737175.2019.1581610
125. Cruz MP. Edaravone (Radicava): A Novel Neuroprotective Agent for the Treatment of Amyotrophic Lateral Sclerosis. P t. Jan 2018;43(1):25-28.
126. Forman HJ, Zhang H. Targeting oxidative stress in disease: promise and limitations of antioxidant therapy. Nat Rev Drug Discov. Sep 2021;20(9):689-709. doi:10.1038/s41573-021-00233-1
127. Cassidy L, Fernandez F, Johnson JB, Naiker M, Owoola AG, Broszczak DA. Oxidative stress in alzheimer's disease: A review on emergent natural polyphenolic therapeutics. Complement Ther Med. Mar 2020;49:102294. doi:10.1016/j.ctim.2019.102294
128. Anderson MF, Nilsson M, Eriksson PS, Sims NR. Glutathione monoethyl ester provides neuroprotection in a rat model of stroke. Neurosci Lett. Jan 9 2004;354(2):163-5. doi:10.1016/j.neulet.2003.09.067
129. Xu R, Tao A, Bai Y, Deng Y, Chen G. Effectiveness of N-Acetylcysteine for the Prevention of Contrast-Induced Nephropathy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Am Heart Assoc. Sep 23 2016;5(9)doi:10.1161/jaha.116.003968
130. Conrad C, Lymp J, Thompson V, et al. Long-term treatment with oral N-acetylcysteine: affects lung function but not sputum inflammation in cystic fibrosis subjects. A phase II randomized placebo-controlled trial. J Cyst Fibros. Mar 2015;14(2):219-27. doi:10.1016/j.jcf.2014.08.008
131. Robledinos-Antón N, Fernández-Ginés R, Manda G, Cuadrado A. Activators and Inhibitors of NRF2: A Review of Their Potential for Clinical Development. Oxid Med Cell Longev. 2019;2019:9372182. doi:10.1155/2019/9372182
132. Yagishita Y, Fahey JW, Dinkova-Kostova AT, Kensler TW. Broccoli or Sulforaphane: Is It the Source or Dose That Matters? Molecules. Oct 6 2019;24(19)doi:10.3390/molecules24193593
133. Li J, Sapper TN, Mah E, et al. Green tea extract provides extensive Nrf2-independent protection against lipid accumulation and NFκB pro- inflammatory responses during nonalcoholic steatohepatitis in mice fed a high-fat diet. Mol Nutr Food Res. Apr 2016;60(4):858-70. doi:10.1002/mnfr.201500814
134. Frei B, England L, Ames BN. Ascorbate is an outstanding antioxidant in human blood plasma. Proc Natl Acad Sci U S A. Aug 1989;86(16):6377-81. doi:10.1073/pnas.86.16.6377
135. Bruno RS, Leonard SW, Atkinson J, et al. Faster plasma vitamin E disappearance in smokers is normalized by vitamin C supplementation. Free Radic Biol Med. Feb 15 2006;40(4):689-97. doi:10.1016/j.freeradbiomed.2005.10.051
136. Dysken MW, Sano M, Asthana S, et al. Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial. Jama. Jan 1 2014;311(1):33-44. doi:10.1001/jama.2013.282834
137. Sayin VI, Ibrahim MX, Larsson E, Nilsson JA, Lindahl P, Bergo MO. Antioxidants accelerate lung cancer progression in mice. Sci Transl Med. Jan 29 2014;6(221):221ra15. doi:10.1126/scitranslmed.3007653
138. Le Gal K, Ibrahim MX, Wiel C, et al. Antioxidants can increase melanoma metastasis in mice. Sci Transl Med. Oct 7 2015;7(308):308re8. doi:10.1126/scitranslmed.aad3740
139. Zou ZV, Le Gal K, El Zowalaty AE, et al. Antioxidants Promote Intestinal Tumor Progression in Mice. Antioxidants (Basel). Feb 4 2021;10(2)doi:10.3390/antiox10020241
2. Davis HE, Assaf GS, McCorkell L, et al. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine. Aug 2021;38:101019. doi:10.1016/j.eclinm.2021.101019
3. WHO. A clinical case definition of post COVID-19 condition by a Delphi consensus. WHO https://www.who.int/publications/i/item/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1: WHO REFERENCE NUMBER: WHO/2019-nCoV/Post_COVID-19_condition/Clinical_case_definition/2021.1; 2021.
4. Tate W, Walker M, Sweetman E, et al. Molecular Mechanisms of Neuroinflammation in ME/CFS and Long COVID to Sustain Disease and Promote Relapses. Front Neurol. 2022;13:877772. doi:10.3389/fneur.2022.877772
5. Sweetman E, Noble A, Edgar C, et al. Current Research Provides Insight into the Biological Basis and Diagnostic Potential for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Diagnostics (Basel). Jul 10 2019;9(3)doi:10.3390/diagnostics9030073
6. Chan KS, Zheng JP, Mok YW, et al. SARS: prognosis, outcome and sequelae. Respirology. Nov 2003;8 Suppl(Suppl 1):S36-40. doi:10.1046/j.1440-1843.2003.00522.x
7. Moldofsky H, Patcai J. Chronic widespread musculoskeletal pain, fatigue, depression and disordered sleep in chronic post-SARS syndrome; a case-controlled study. BMC Neurol. Mar 24 2011;11:37. doi:10.1186/1471-2377-11-37
8. Institute of Medicine NAoS, USA. Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
The National Academies Collection: Reports funded by National Institutes of Health. 2015. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness.
9. Komaroff AL, Lipkin WI. Insights from myalgic encephalomyelitis/chronic fatigue syndrome may help unravel the pathogenesis of postacute COVID-19 syndrome. Trends in Molecular Medicine. 2021/09/01/ 2021;27(9):895-906. doi:https://doi.org/10.1016/j.molmed.2021.06.002
10. Carruthers BM, Jain AK, De Meirleir KL, et al. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Journal of Chronic Fatigue Syndrome. 2003/01/01 2003;11(1):7-115. doi:10.1300/J092v11n01_02
11. Carruthers BM, van de Sande MI, De Meirleir KL, et al. Myalgic encephalomyelitis: International Consensus Criteria. J Intern Med. 2011;270(4):327-338. doi:10.1111/j.1365-2796.2011.02428.x
12. Sukocheva OA, Maksoud R, Beeraka NM, et al. Analysis of post COVID-19 condition and its overlap with myalgic encephalomyelitis/chronic fatigue syndrome. Journal of Advanced Research. 2021/11/26/ 2021;doi:https://doi.org/10.1016/j.jare.2021.11.013
13. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. Dec 15 1994;121(12):953-9. doi:10.7326/0003-4819-121-12-199412150-00009
14. Aaron LA, Burke MM, Buchwald D. Overlapping conditions among patients with chronic fatigue syndrome, fibromyalgia, and temporomandibular disorder. Arch Intern Med. Jan 24 2000;160(2):221-7. doi:10.1001/archinte.160.2.221
15. Esfandyarpour R, Kashi A, Nemat-Gorgani M, Wilhelmy J, Davis RW. A nanoelectronics-blood-based diagnostic biomarker for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Proceedings of the National Academy of Sciences. 2019;116(21):10250-10257. doi:doi:10.1073/pnas.1901274116
16. Missailidis D, Annesley SJ, Allan CY, et al. An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients. Int J Mol Sci. Feb 6 2020;21(3)doi:10.3390/ijms21031074
17. Meeus M, Nijs J, McGregor N, et al. Unravelling intracellular immune dysfunctions in chronic fatigue syndrome: interactions between protein kinase R activity, RNase L cleavage and elastase activity, and their clinical relevance. In Vivo. Jan-Feb 2008;22(1):115-21.
18. Rossignol DA, Frye RE. Evidence linking oxidative stress, mitochondrial dysfunction, and inflammation in the brain of individuals with autism. Front Physiol. 2014;5:150. doi:10.3389/fphys.2014.00150
19. Felman A. Everything you need to know about inflammation. Medical News Today. Accessed 13 April 2020, https://www.medicalnewstoday.com/articles/248423
20. Harvard HP. Understanding acute and chronic inflammation 2020. https://www.health.harvard.edu/staying-healthy/understanding-acute-and-chronic-inflammation
21. Mohan C. Microglia in Acute and Chronic Inflammation. Science News. 2017(5).
22. Muzio L, Viotti A, Martino G. Microglia in Neuroinflammation and Neurodegeneration: From Understanding to Therapy. Front Neurosci. 2021;15:742065. doi:10.3389/fnins.2021.742065
23. Xu Y, Jin MZ, Yang ZY, Jin WL. Microglia in neurodegenerative diseases. Neural Regen Res. Feb 2021;16(2):270-280. doi:10.4103/1673-5374.290881
24. Hansen DV, Hanson JE, Sheng M. Microglia in Alzheimer's disease. J Cell Biol. Feb 5 2018;217(2):459-472. doi:10.1083/jcb.201709069
25. Ho MS. Microglia in Parkinson's Disease. Adv Exp Med Biol. 2019;1175:335-353. doi:10.1007/978-981-13-9913-8_13
26. Ma MW, Wang J, Zhang Q, et al. NADPH oxidase in brain injury and neurodegenerative disorders. Mol Neurodegener. Jan 17 2017;12(1):7. doi:10.1186/s13024-017-0150-7
27. Simpson DSA, Oliver PL. ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease. Antioxidants (Basel). Aug 13 2020;9(8)doi:10.3390/antiox9080743
28. Schilling T, Eder C. Amyloid-β-induced reactive oxygen species production and priming are differentially regulated by ion channels in microglia. J Cell Physiol. Dec 2011;226(12):3295-302. doi:10.1002/jcp.22675
29. Rogers J, Mastroeni D, Leonard B, Joyce J, Grover A. Neuroinflammation in Alzheimer's disease and Parkinson's disease: are microglia pathogenic in either disorder? Int Rev Neurobiol. 2007;82:235-46. doi:10.1016/s0074-7742(07)82012-5
30. Netea MG, Joosten LA, Latz E, et al. Trained immunity: A program of innate immune memory in health and disease. Science. Apr 22 2016;352(6284):aaf1098. doi:10.1126/science.aaf1098
31. Hornig M, Montoya JG, Klimas NG, et al. Distinct plasma immune signatures in ME/CFS are present early in the course of illness. Sci Adv. Feb 2015;1(1)doi:10.1126/sciadv.1400121
32. Ledderose C, Junger WG. Mitochondria Synergize With P2 Receptors to Regulate Human T Cell Function. Mini Review. Front Immunol. 2020-September-29 2020;11doi:10.3389/fimmu.2020.549889
33. Liu Y, Rao B, Li S, et al. Distinct Hypothalamic Paraventricular Nucleus Inputs to the Cingulate Cortex and Paraventricular Thalamic Nucleus Modulate Anxiety and Arousal. Front Pharmacol. 2022;13:814623-814623. doi:10.3389/fphar.2022.814623
34. Kempuraj D, Thangavel R, Selvakumar GP, et al. Brain and Peripheral Atypical Inflammatory Mediators Potentiate Neuroinflammation and Neurodegeneration. Review. Frontiers in Cellular Neuroscience. 2017-July-24 2017;11doi:10.3389/fncel.2017.00216
35. Montoya JG, Holmes TH, Anderson JN, et al. Cytokine signature associated with disease severity in chronic fatigue syndrome patients. Proc Natl Acad Sci U S A. Aug 22 2017;114(34):E7150-E7158. doi:10.1073/pnas.1710519114
10.1073/pnas.1710519114. Epub 2017 Jul 31.
36. Mandarano AH, Maya J, Giloteaux L, et al. Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations. J Clin Invest. Mar 2 2020;130(3):1491-1505. doi:10.1172/JCI132185
10.1172/JCI132185.
37. Sweetman E, Ryan M, Edgar C, MacKay A, Vallings R, Tate W. Changes in the transcriptome of circulating immune cells of a New Zealand cohort with myalgic encephalomyelitis/chronic fatigue syndrome. Int J Immunopathol Pharmacol. Jan-Dec 2019;33:2058738418820402. doi:10.1177/2058738418820402
38. Sweetman E, Kleffmann T, Edgar C, de Lange M, Vallings R, Tate W. A SWATH-MS analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction. J Transl Med. Sep 24 2020;18(1):365. doi:10.1186/s12967-020-02533-3
39. Lee JS, Kim HG, Lee DS, Son CG. Oxidative Stress is a Convincing Contributor to Idiopathic Chronic Fatigue. Sci Rep. Aug 27 2018;8(1):12890. doi:10.1038/s41598-018-31270-3
40. Wood E, Hall KH, Tate W. Role of mitochondria, oxidative stress and the response to antioxidants in myalgic encephalomyelitis/chronic fatigue syndrome: A possible approach to SARS-CoV-2 'long-haulers'? Chronic Dis Transl Med. Mar 2021;7(1):14-26. doi:10.1016/j.cdtm.2020.11.002
41. Fulle S, Pietrangelo T, Mancinelli R, Saggini R, Fanò G. Specific correlations between muscle oxidative stress and chronic fatigue syndrome: a working hypothesis. J Muscle Res Cell Motil. 2007;28(6):355-62. doi:10.1007/s10974-008-9128-y
42. Fulle S, Mecocci P, Fanó G, et al. Specific oxidative alterations in vastus lateralis muscle of patients with the diagnosis of chronic fatigue syndrome. Free Radic Biol Med. Dec 15 2000;29(12):1252-9. doi:10.1016/s0891-5849(00)00419-6
43. Pall ML. Elevated, sustained peroxynitrite levels as the cause of chronic fatigue syndrome. Med Hypotheses. Jan 2000;54(1):115-25. doi:10.1054/mehy.1998.0825
44. Brieger K, Schiavone S, Miller FJ, Jr., Krause KH. Reactive oxygen species: from health to disease. Swiss Med Wkly. 2012;142:w13659. doi:10.4414/smw.2012.13659
45. Alkadi H. A Review on Free Radicals and Antioxidants. Infect Disord Drug Targets. 2020;20(1):16-26. doi:10.2174/1871526518666180628124323
46. Wiseman H, Halliwell B. Damage to DNA by reactive oxygen and nitrogen species: role in inflammatory disease and progression to cancer. Biochem J. Jan 1 1996;313 ( Pt 1)(Pt 1):17-29. doi:10.1042/bj3130017
47. Ciencewicki J, Trivedi S, Kleeberger SR. Oxidants and the pathogenesis of lung diseases. J Allergy Clin Immunol. Sep 2008;122(3):456-68; quiz 469-70. doi:10.1016/j.jaci.2008.08.004
48. Mittal M, Siddiqui MR, Tran K, Reddy SP, Malik AB. Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal. Mar 1 2014;20(7):1126-67. doi:10.1089/ars.2012.5149
49. Paul BD, Lemle MD, Komaroff AL, Snyder SH. Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome. Proc Natl Acad Sci U S A. Aug 24 2021;118(34)doi:10.1073/pnas.2024358118
50. Morris G, Maes M. Oxidative and Nitrosative Stress and Immune-Inflammatory Pathways in Patients with Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS). Curr Neuropharmacol. Mar 2014;12(2):168-85. doi:10.2174/1570159x11666131120224653
51. Maes M, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E. Increased plasma peroxides as a marker of oxidative stress in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Med Sci Monit. Apr 2011;17(4):Sc11-5. doi:10.12659/msm.881699
52. Naviaux RK, Naviaux JC, Li K, et al. Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci U S A. Sep 13 2016;113(37):E5472-80. doi:10.1073/pnas.1607571113
53. Germain A, Ruppert D, Levine SM, Hanson MR. Metabolic profiling of a myalgic encephalomyelitis/chronic fatigue syndrome discovery cohort reveals disturbances in fatty acid and lipid metabolism. Mol Biosyst. Jan 31 2017;13(2):371-379. doi:10.1039/c6mb00600k
54. Germain A, Ruppert D, Levine SM, Hanson MR. Prospective Biomarkers from Plasma Metabolomics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Implicate Redox Imbalance in Disease Symptomatology. Metabolites. Dec 6 2018;8(4)doi:10.3390/metabo8040090
55. Booth NE, Myhill S, McLaren-Howard J. Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Int J Clin Exp Med. 2012;5(3):208-20.
56. Tomas C, Brown A, Strassheim V, Elson JL, Newton J, Manning P. Cellular bioenergetics is impaired in patients with chronic fatigue syndrome. PLoS One. 2017;12(10):e0186802. doi:10.1371/journal.pone.0186802
57. Myhill S, Booth NE, McLaren-Howard J. Chronic fatigue syndrome and mitochondrial dysfunction. Int J Clin Exp Med. 2009;2(1):1-16.
58. Missailidis D, Annesley SJ, Allan CY, et al. An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients. Int J Mol Sci. 2020;21(3):1074. doi:10.3390/ijms21031074
59. Behan WM, More IA, Behan PO. Mitochondrial abnormalities in the postviral fatigue syndrome. Acta Neuropathol. 1991;83(1):61-5. doi:10.1007/bf00294431
60. Lawson N, Hsieh CH, March D, Wang X. Elevated Energy Production in Chronic Fatigue Syndrome Patients. J Nat Sci. 2016;2(10)
61. Guo C, Sun L, Chen X, Zhang D. Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural Regen Res. Jul 25 2013;8(21):2003-14. doi:10.3969/j.issn.1673-5374.2013.21.009
62. Fukuda S, Nojima J, Motoki Y, et al. A potential biomarker for fatigue: Oxidative stress and anti-oxidative activity. Biol Psychol. Jul 2016;118:88-93. doi:10.1016/j.biopsycho.2016.05.005
63. Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E. Coenzyme Q10 deficiency in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is related to fatigue, autonomic and neurocognitive symptoms and is another risk factor explaining the early mortality in ME/CFS due to cardiovascular disorder. Neuro Endocrinol Lett. 2009;30(4):470-6.
64. Kennedy G, Spence VA, McLaren M, Hill A, Underwood C, Belch JJ. Oxidative stress levels are raised in chronic fatigue syndrome and are associated with clinical symptoms. Free Radic Biol Med. Sep 1 2005;39(5):584-9. doi:10.1016/j.freeradbiomed.2005.04.020
65. Robinson M, Gray SR, Watson MS, et al. Plasma IL-6, its soluble receptors and F2-isoprostanes at rest and during exercise in chronic fatigue syndrome. Scand J Med Sci Sports. Apr 2010;20(2):282-90. doi:10.1111/j.1600-0838.2009.00895.x
66. Godlewska BR, Williams S, Emir UE, et al. Neurochemical abnormalities in chronic fatigue syndrome: a pilot magnetic resonance spectroscopy study at 7 Tesla. Psychopharmacology (Berl). Jan 2022;239(1):163-171. doi:10.1007/s00213-021-05986-6
67. Mathew SJ, Mao X, Keegan KA, et al. Ventricular cerebrospinal fluid lactate is increased in chronic fatigue syndrome compared with generalized anxiety disorder: an in vivo 3.0 T (1)H MRS imaging study. NMR Biomed. Apr 2009;22(3):251-8. doi:10.1002/nbm.1315
68. Murrough JW, Mao X, Collins KA, et al. Increased ventricular lactate in chronic fatigue syndrome measured by 1H MRS imaging at 3.0 T. II: comparison with major depressive disorder. NMR Biomed. Jul 2010;23(6):643-50. doi:10.1002/nbm.1512
69. Shungu DC, Weiduschat N, Murrough JW, et al. Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology. NMR Biomed. Sep 2012;25(9):1073-87. doi:10.1002/nbm.2772
70. Paul BD, Snyder SH. Gasotransmitter hydrogen sulfide signaling in neuronal health and disease. Biochem Pharmacol. Mar 2018;149:101-109. doi:10.1016/j.bcp.2017.11.019
71. Vandiver MS, Paul BD, Xu R, et al. Sulfhydration mediates neuroprotective actions of parkin. Nat Commun. 2013;4:1626. doi:10.1038/ncomms2623
72. Lemle MD. Hypothesis: chronic fatigue syndrome is caused by dysregulation of hydrogen sulfide metabolism. Med Hypotheses. Jan 2009;72(1):108-9. doi:10.1016/j.mehy.2008.08.003
73. Cobley JN, Fiorello ML, Bailey DM. 13 reasons why the brain is susceptible to oxidative stress. Redox Biol. May 2018;15:490-503. doi:10.1016/j.redox.2018.01.008
74. Massaad CA, Klann E. Reactive oxygen species in the regulation of synaptic plasticity and memory. Antioxid Redox Signal. May 15 2011;14(10):2013-54. doi:10.1089/ars.2010.3208
75. Patel M. Targeting Oxidative Stress in Central Nervous System Disorders. Trends Pharmacol Sci. Sep 2016;37(9):768-778. doi:10.1016/j.tips.2016.06.007
76. Halliwell B. Oxidative stress and neurodegeneration: where are we now? J Neurochem. Jun 2006;97(6):1634-58. doi:10.1111/j.1471-4159.2006.03907.x
77. Ward RJ, Zucca FA, Duyn JH, Crichton RR, Zecca L. The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol. Oct 2014;13(10):1045-60. doi:10.1016/s1474-4422(14)70117-6
78. Scheiber IF, Mercer JF, Dringen R. Metabolism and functions of copper in brain. Prog Neurobiol. May 2014;116:33-57. doi:10.1016/j.pneurobio.2014.01.002
79. Sebio RM, Ferrarotti N, Lairion F, et al. Brain oxidative stress in rat with chronic iron or copper overload. J Inorg Biochem. Oct 2019;199:110799. doi:10.1016/j.jinorgbio.2019.110799
80. Shichiri M. The role of lipid peroxidation in neurological disorders. J Clin Biochem Nutr. May 2014;54(3):151-60. doi:10.3164/jcbn.14-10
81. Nakatomi Y, Mizuno K, Ishii A, et al. Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An (1)(1)C-(R)-PK11195 PET Study. J Nucl Med. Jun 2014;55(6):945-50. doi:10.2967/jnumed.113.131045
82. Visser D, Golla SSV, Verfaillie SCJ, et al. Long COVID is associated with extensive in-vivo neuroinflammation on [18F]DPA-714 PET. medRxiv. 2022:2022.06.02.22275916. doi:10.1101/2022.06.02.22275916
83. Matschke J, Lütgehetmann M, Hagel C, et al. Neuropathology of patients with COVID-19 in Germany: a post-mortem case series. Lancet Neurol. Nov 2020;19(11):919-929. doi:10.1016/s1474-4422(20)30308-2
84. de Boer E, Petrache I, Goldstein NM, et al. Decreased Fatty Acid Oxidation and Altered Lactate Production during Exercise in Patients with Post-acute COVID-19 Syndrome. Am J Respir Crit Care Med. Jan 1 2022;205(1):126-129. doi:10.1164/rccm.202108-1903LE
85. Nuhu F, Gordon A, Sturmey R, Seymour AM, Bhandari S. Measurement of Glutathione as a Tool for Oxidative Stress Studies by High Performance Liquid Chromatography. Molecules. Sep 13 2020;25(18)doi:10.3390/molecules25184196
86. Mandal PK, Saharan S, Tripathi M, Murari G. Brain glutathione levels--a novel biomarker for mild cognitive impairment and Alzheimer's disease. Biol Psychiatry. Nov 15 2015;78(10):702-10. doi:10.1016/j.biopsych.2015.04.005
87. Marrocco I, Altieri F, Peluso I. Measurement and Clinical Significance of Biomarkers of Oxidative Stress in Humans. Oxid Med Cell Longev. 2017;2017:6501046. doi:10.1155/2017/6501046
88. Sousa BC, Pitt AR, Spickett CM. Chemistry and analysis of HNE and other prominent carbonyl-containing lipid oxidation compounds. Free Radic Biol Med. Oct 2017;111:294-308. doi:10.1016/j.freeradbiomed.2017.02.003
89. Breitzig M, Bhimineni C, Lockey R, Kolliputi N. 4-Hydroxy-2-nonenal: a critical target in oxidative stress? Am J Physiol Cell Physiol. Oct 1 2016;311(4):C537-c543. doi:10.1152/ajpcell.00101.2016
90. Łuczaj W, Gindzienska-Sieskiewicz E, Jarocka-Karpowicz I, et al. The onset of lipid peroxidation in rheumatoid arthritis: consequences and monitoring. Free Radic Res. 2016;50(3):304-13. doi:10.3109/10715762.2015.1112901
91. Garcia YJ, Rodríguez-Malaver AJ, Peñaloza N. Lipid peroxidation measurement by thiobarbituric acid assay in rat cerebellar slices. J Neurosci Methods. May 15 2005;144(1):127-35. doi:10.1016/j.jneumeth.2004.10.018
92. Lagadu S, Lechevrel M, Sichel F, et al. 8-oxo-7,8-dihydro-2'-deoxyguanosine as a biomarker of oxidative damage in oesophageal cancer patients: lack of association with antioxidant vitamins and polymorphism of hOGG1 and GST. J Exp Clin Cancer Res. Dec 6 2010;29(1):157. doi:10.1186/1756-9966-29-157
93. Collins A. Comparison of different methods of measuring 8-oxoguanine as a marker of oxidative DNA damage. Free Radical Research. 2000/01/01 2000;32(4):333-341. doi:10.1080/10715760000300331
94. 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. Dec 1999;27(11-12):1151-63. doi:10.1016/s0891-5849(99)00206-3
95. Song YR, Kim JK, Lee HS, Kim SG, Choi EK. Serum levels of protein carbonyl, a marker of oxidative stress, are associated with overhydration, sarcopenia and mortality in hemodialysis patients. BMC Nephrol. Jul 16 2020;21(1):281. doi:10.1186/s12882-020-01937-z
96. Dalle-Donne I, Rossi R, Giustarini D, Milzani A, Colombo R. Protein carbonyl groups as biomarkers of oxidative stress. Clin Chim Acta. Mar 2003;329(1-2):23-38. doi:10.1016/s0009-8981(03)00003-2
97. Sidorova Y, Domanskyi A. Detecting Oxidative Stress Biomarkers in Neurodegenerative Disease Models and Patients. Methods Protoc. Sep 24 2020;3(4)doi:10.3390/mps3040066
98. Mackay A. A Paradigm for Post-Covid-19 Fatigue Syndrome Analogous to ME/CFS. Hypothesis and Theory. Frontiers in Neurology. 2021-August-02 2021;12doi:10.3389/fneur.2021.701419
99. Tomas C, Newton J, Watson S. A review of hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome. ISRN Neurosci. 2013;2013:784520. doi:10.1155/2013/784520
100. VanElzakker MB, Brumfield SA, Lara Mejia PS. Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods. Front Neurol. 2018;9:1033. doi:10.3389/fneur.2018.01033
101. Nelson T, Zhang LX, Guo H, Nacul L, Song X. Brainstem Abnormalities in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Scoping Review and Evaluation of Magnetic Resonance Imaging Findings. Front Neurol. 2021;12:769511. doi:10.3389/fneur.2021.769511
10.3389/fneur.2021.769511. eCollection 2021.
102. Barnden LR, Kwiatek R, Crouch B, Burnet R, Del Fante P. Autonomic correlations with MRI are abnormal in the brainstem vasomotor centre in Chronic Fatigue Syndrome. Neuroimage Clin. 2016;11:530-537. doi:10.1016/j.nicl.2016.03.017
10.1016/j.nicl.2016.03.017. eCollection 2016.
103. Yong SJ. Persistent Brainstem Dysfunction in Long-COVID: A Hypothesis. ACS Chem Neurosci. Feb 17 2021;12(4):573-580. doi:10.1021/acschemneuro.0c00793
10.1021/acschemneuro.0c00793. Epub 2021 Feb 4.
104. Mueller C, Lin JC, Sheriff S, Maudsley AA, Younger JW. Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy. Brain Imaging Behav. Apr 2020;14(2):562-572. doi:10.1007/s11682-018-0029-4
10.1007/s11682-018-0029-4.
105. Roerink ME, van der Schaaf ME, Dinarello CA, Knoop H, van der Meer JW. Interleukin-1 as a mediator of fatigue in disease: a narrative review. J Neuroinflammation. Jan 21 2017;14(1):16. doi:10.1186/s12974-017-0796-7
106. Hornig M. Can the light of immunometabolism cut through "brain fog"? J Clin Invest. Mar 2 2020;130(3):1102-1105. doi:10.1172/jci134985
107. Costantini D, Marasco V, Møller AP. A meta-analysis of glucocorticoids as modulators of oxidative stress in vertebrates. J Comp Physiol B. May 2011;181(4):447-56. doi:10.1007/s00360-011-0566-2
108. Spiers JG, Chen HJ, Sernia C, Lavidis NA. Activation of the hypothalamic-pituitary-adrenal stress axis induces cellular oxidative stress. Front Neurosci. 2014;8:456. doi:10.3389/fnins.2014.00456
109. Trifunovic S, Stevanovic I, Milosevic A, et al. The Function of the Hypothalamic-Pituitary-Adrenal Axis During Experimental Autoimmune Encephalomyelitis: Involvement of Oxidative Stress Mediators. Front Neurosci. 2021;15:649485. doi:10.3389/fnins.2021.649485
110. CDC. Long COVID or Post-COVID Conditions 2022 https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects/index.html
111. Castro-Marrero J, Cordero MD, Sáez-Francas N, et al. Could mitochondrial dysfunction be a differentiating marker between chronic fatigue syndrome and fibromyalgia? Antioxid Redox Signal. Nov 20 2013;19(15):1855-60. doi:10.1089/ars.2013.5346
112. Cordero MD, de Miguel M, Carmona-López I, Bonal P, Campa F, Moreno-Fernández AM. Oxidative stress and mitochondrial dysfunction in fibromyalgia. Neuro Endocrinol Lett. 2010;31(2):169-73.
113. Cordero MD, Díaz-Parrado E, Carrión AM, et al. Is inflammation a mitochondrial dysfunction-dependent event in fibromyalgia? Antioxid Redox Signal. Mar 1 2013;18(7):800-7. doi:10.1089/ars.2012.4892
114. Castro-Marrero J, Domingo JC, Cordobilla B, et al. Does Coenzyme Q10 Plus Selenium Supplementation Ameliorate Clinical Outcomes by Modulating Oxidative Stress and Inflammation in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome? Antioxid Redox Signal. Apr 2022;36(10-12):729-739. doi:10.1089/ars.2022.0018
115. Gueven N, Ravishankar P, Eri R, Rybalka E. Idebenone: When an antioxidant is not an antioxidant. Redox Biol. Jan 2021;38:101812. doi:10.1016/j.redox.2020.101812
116. Wishart DS, Feunang YD, Guo AC, et al. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. Jan 4 2018;46(D1):D1074-d1082. doi:10.1093/nar/gkx1037
117. Wishart DS. DrugBank 5.0. https://go.drugbank.com/drugs/DB09081
118. Lebedeva AV, Shchukin IA, Soldatov MA, et al. [Asthenia, emotional disorders and quality of life of patients with multiple sclerosis]. Zh Nevrol Psikhiatr Im S S Korsakova. 2014;114(10 Pt 2):99-104. Asteniia, émotsional'nye rasstroĭstva i kachestvo zhizni u patsientov s rasseiannym sklerozom.
119. Jordan AL, Yang J, Fisher CJ, Racke MK, Mao-Draayer Y. Progressive multifocal leukoencephalopathy in dimethyl fumarate-treated multiple sclerosis patients. Mult Scler. Jan 2022;28(1):7-15. doi:10.1177/1352458520949158
120. Ozel O, Vaughn CB, Eckert SP, Jakimovski D, Lizarraga AA, Weinstock-Guttman B. Dimethyl Fumarate in the Treatment of Relapsing-Remitting Multiple Sclerosis: Patient Reported Outcomes and Perspectives. Patient Relat Outcome Meas. 2019;10:373-384. doi:10.2147/prom.S168095
121. Johnson C. Did MitoQ mend us? A fibromyalgia and Chronic Fatigue syndrome (ME/CFS ) CoQ10 trial. https://www.healthrising.org/blog/2016/08/08/mendus-fibromyalgia-chronic-fatigue-syndrome-mitoq-coq10-trial/
122. Tereshin AE, Kiryanova VV, Reshetnik DA. [Correction of mitochondrial dysfunction in the complex rehabilitation of COVID-19]. Zh Nevrol Psikhiatr Im S S Korsakova. 2021;121(8):25-29. Korrektsiya mitokhondrial'noi disfunktsii v kompleksnoi reabilitatsii patsientov, perenesshikh COVID-19. doi:10.17116/jnevro202112108125
123. NZF. Dimethyl fumarate. https://nzf.org.nz/nzf_70465
124. Yoshino H. Edaravone for the treatment of amyotrophic lateral sclerosis. Expert Rev Neurother. Mar 2019;19(3):185-193. doi:10.1080/14737175.2019.1581610
125. Cruz MP. Edaravone (Radicava): A Novel Neuroprotective Agent for the Treatment of Amyotrophic Lateral Sclerosis. P t. Jan 2018;43(1):25-28.
126. Forman HJ, Zhang H. Targeting oxidative stress in disease: promise and limitations of antioxidant therapy. Nat Rev Drug Discov. Sep 2021;20(9):689-709. doi:10.1038/s41573-021-00233-1
127. Cassidy L, Fernandez F, Johnson JB, Naiker M, Owoola AG, Broszczak DA. Oxidative stress in alzheimer's disease: A review on emergent natural polyphenolic therapeutics. Complement Ther Med. Mar 2020;49:102294. doi:10.1016/j.ctim.2019.102294
128. Anderson MF, Nilsson M, Eriksson PS, Sims NR. Glutathione monoethyl ester provides neuroprotection in a rat model of stroke. Neurosci Lett. Jan 9 2004;354(2):163-5. doi:10.1016/j.neulet.2003.09.067
129. Xu R, Tao A, Bai Y, Deng Y, Chen G. Effectiveness of N-Acetylcysteine for the Prevention of Contrast-Induced Nephropathy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Am Heart Assoc. Sep 23 2016;5(9)doi:10.1161/jaha.116.003968
130. Conrad C, Lymp J, Thompson V, et al. Long-term treatment with oral N-acetylcysteine: affects lung function but not sputum inflammation in cystic fibrosis subjects. A phase II randomized placebo-controlled trial. J Cyst Fibros. Mar 2015;14(2):219-27. doi:10.1016/j.jcf.2014.08.008
131. Robledinos-Antón N, Fernández-Ginés R, Manda G, Cuadrado A. Activators and Inhibitors of NRF2: A Review of Their Potential for Clinical Development. Oxid Med Cell Longev. 2019;2019:9372182. doi:10.1155/2019/9372182
132. Yagishita Y, Fahey JW, Dinkova-Kostova AT, Kensler TW. Broccoli or Sulforaphane: Is It the Source or Dose That Matters? Molecules. Oct 6 2019;24(19)doi:10.3390/molecules24193593
133. Li J, Sapper TN, Mah E, et al. Green tea extract provides extensive Nrf2-independent protection against lipid accumulation and NFκB pro- inflammatory responses during nonalcoholic steatohepatitis in mice fed a high-fat diet. Mol Nutr Food Res. Apr 2016;60(4):858-70. doi:10.1002/mnfr.201500814
134. Frei B, England L, Ames BN. Ascorbate is an outstanding antioxidant in human blood plasma. Proc Natl Acad Sci U S A. Aug 1989;86(16):6377-81. doi:10.1073/pnas.86.16.6377
135. Bruno RS, Leonard SW, Atkinson J, et al. Faster plasma vitamin E disappearance in smokers is normalized by vitamin C supplementation. Free Radic Biol Med. Feb 15 2006;40(4):689-97. doi:10.1016/j.freeradbiomed.2005.10.051
136. Dysken MW, Sano M, Asthana S, et al. Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial. Jama. Jan 1 2014;311(1):33-44. doi:10.1001/jama.2013.282834
137. Sayin VI, Ibrahim MX, Larsson E, Nilsson JA, Lindahl P, Bergo MO. Antioxidants accelerate lung cancer progression in mice. Sci Transl Med. Jan 29 2014;6(221):221ra15. doi:10.1126/scitranslmed.3007653
138. Le Gal K, Ibrahim MX, Wiel C, et al. Antioxidants can increase melanoma metastasis in mice. Sci Transl Med. Oct 7 2015;7(308):308re8. doi:10.1126/scitranslmed.aad3740
139. Zou ZV, Le Gal K, El Zowalaty AE, et al. Antioxidants Promote Intestinal Tumor Progression in Mice. Antioxidants (Basel). Feb 4 2021;10(2)doi:10.3390/antiox10020241