ME and CFS Medical Abnormalities – Oxidative Stress and Inflammation

 

Following is a list of articles about abnormalities in oxidative stress and inflammation in ME and CFS.

Links to the more than 1,000 peer-reviewed journal articles are listed on the ME and CFS Medical Abnormalities page of this website.

 

Lechner J, Huesker K, Von Baehr V. Impact of Rantes from jawbone on Chronic Fatigue Syndrome. J Biol Regul Homeost Agents. 2017 Apr-Jun;31(2):321-327. PMID: 28685531

This study elucidates the question of whether chronic inflammation in the jawbone contributes to the development of Chronic Fatigue Syndrome (CFS). Fatty degenerative osteonecrosis in jawbone (FDOJ) may contribute to CFS by induction of inflammatory mediators. We examined seven cytokines by multiplex analysis in jawbone samples from two groups of patients. The researchers concluded that constituting a hidden source of silent inflammation, FDOJ may represent a hitherto unknown cause for the development of CFS.

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Morris G, Anderson G, Maes M. Hypothalamic-Pituitary-Adrenal Hypofunction in Myalgic Encephalomyelitis(ME)/Chronic Fatigue Syndrome (CFS) as a Consequence of Activated Immune-Inflammatory and Oxidative and Nitrosative Pathways. Mol Neurobiol. 2017 Nov;54(9):6806-6819. PMID: 27766535

There is evidence that immune-inflammatory and oxidative and nitrosative stress (O&NS) pathways play a role in the pathophysiology of myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS). There is also evidence that these neuroimmune diseases are accompanied by hypothalamic-pituitary-adrenal (HPA) axis hypoactivity as indicated by lowered baseline glucocorticoid levels. This paper reviews the bidirectional communications between immune-inflammatory and O&NS pathways and HPA axis hypoactivity in ME/CFS.

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Morris G, Berk M, Klein H, Walder K, Galecki P, Maes M. Nitrosative Stress, Hypernitrosylation, and Autoimmune Responses to Nitrosylated Proteins: New Pathways in Neuroprogressive Disorders Including Depression and Chronic Fatigue Syndrome. Mol Neurobiol. 2017 Aug;54(6):4271-4291. PMID: 27339878

Nitric oxide plays an indispensable role in modulating cellular signaling and redox pathways. Hypernitrosylation, as a consequence of chronically elevated O&NS and activated immune-inflammatory pathways, can explain many characteristic abnormalities observed in neuroprogressive disease including major depression and chronic fatigue syndrome/myalgic encephalomyelitis. In those disorders, increased bacterial translocation may drive hypernitrosylation and autoimmune responses against nitrosylated proteins.

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Fukuda S, Nojima J, Motoki Y, Yamaguti K, Nakatomi Y, Okawa N, Fujiwara K, Watanabe Y, Kuratsune H. A potential biomarker for fatigue: Oxidative stress and anti-oxidative activity. Biol Psychol. 2016 Jul;118:88-93. PMID: 27224647

The authors sought to determine whether oxidative stress and anti-oxidative activity could act as biomarkers that discriminate patients with chronic fatigue syndrome (CFS) from healthy volunteers at acute and sub-acute fatigue and resting conditions. We calculated the oxidative stress index (OSI) from reactive oxygen metabolites-derived compounds (d-ROMs) and the biological antioxidant potential (BAP). Resting condition yielded higher d-ROMs, higher OSI, and lower BAP in patients with CFS than in healthy volunteers, but lower d-ROMs and OSI when compared with sub-acute controls.

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Maes M, Leunis JC. Attenuation of autoimmune responses to oxidative specific epitopes, but not nitroso-adducts, is associated with a better clinical outcome in Myalgic Encephalomyelitis/chronic fatigue syndrome. Neuro Endocrinol Lett. 2014;35(7):577-85. PMID: 25617880

Autoimmune responses to oxidative specific epitopes are involved in the pathophysiology of ME/CFS.

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Morris G1, 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 Apr 22. PMID: 24752591

Glutathione depletion and concomitant increase in oxidative and nitrosative stress pathways as well as mitochondrial dysfunctions play a role in the pathophysiology of diverse neuroimmune disorders, including depression, myalgic encephalomyelitis/chronic fatigue syndrome and Parkinson’s disease, suggesting that depleted GSH is an integral part of these diseases.

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Morris G, Maes M. Oxidative and Nitrosative Stress and Immune-Inflammatory Pathways in Patients with Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS). Curr Neuropharmacol. 2014 Mar;12(2):168-85. PMID: 24669210

Sources of continuous activation of O&NS and immune-inflammatory pathways in ME/CFS are chronic, intermittent and opportunistic infections, bacterial translocation, autoimmune responses, mitochondrial dysfunctions, activation of the Toll-Like Receptor Radical Cycle, and decreased antioxidant levels. Consequences of chronically activated O&NS and immune-inflammatory pathways in ME/CFS are brain disorders, including neuroinflammation and brain hypometabolism / hypoperfusion, toxic effects of nitric oxide and peroxynitrite, lipid peroxidation and oxidative damage to DNA, secondary autoimmune responses directed against disrupted lipid membrane components and proteins, mitochondrial dysfunctions with a disruption of energy metabolism (e.g. compromised ATP production) and dysfunctional intracellular signaling pathways.

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Morris G, Berk M, Galecki P, Maes M. The Emerging Role of Autoimmunity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Mol Neurobiol. 2013 Sep 26. PMID: 24068616

Abnormalities in ME/CFS include elevated oxidative and nitrosative stress (O&NS), activation of immuno-inflammatory pathways, and mitochondrial dysfunctions with depleted levels of adenosine triphosphate (ATP) synthesis. There is also evidence that many patients with ME/CFS (up to around 60%) may suffer from autoimmune responses. This paper reviews the potential sources of the autoimmunity.

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Castro-Marrero J, Cordero MD, Saez-Francas N, Jimenez-Gutiérrez C, Aguilar-Montilla FJ, Aliste L, Alegre-Martin J. Could mitochondrial dysfunction be a differentiating marker between Chronic Fatigue Syndrome and Fibromyalgia? Antioxid Redox Signal. 2013 Apr 22. PMID: 23600892

Peripheral blood mononuclear cells (PBMC) showed decreased levels of CoQ10 and ATP from CFS and FM subjects compared to controls. CFS/FM patients had significantly increased levels of lipid peroxidation, indicative of oxidative stress-induced damage. Mitochondrial citrate synthase activity, mitochondrial DNA content (mtDNA/gDNA ratio) and expression levels of PGC-1α and TFAM were significantly lower in FM patients than in controls.

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Broderick G, Katz BZ, Fernandes H, Fletcher MA, Klimas N, Smith FA, O’Gorman MR, Vernon SD, Taylor R. Cytokine expression profiles of immune imbalance in post-mononucleosis chronic fatigue. J Transl Med. 2012 Sep 13;10:191. PMID: 22973830

Researchers measured the concentrations of IL-1a, 1b, 2, 4, 5, 6, 8, 10, 12 (p70), 13, 15, 17 and 23, IFN-γ, TNF-α and TNF-β in CFS patients vs. controls. Study results suggest that co-expression patterns in as few as 5 cytokines associated with Th17 function may hold promise as a tool for the diagnosis of post-infectious CFS.

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Zhang HY, Liu ZD, Hu CJ, Wang DX, Zhang YB, Li YZ. Up-regulation of TGF-β1 mRNA expression in peripheral blood mononuclear cells of patients with chronic fatigue syndrome. J Formos Med Assoc. 2011 Nov;110(11):701-4. PMID: 22118314

The expression of TGF-β1 in PBMCs is significantly elevated in patients with CFS.

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Maes M, Twisk FN, Kubera M, Ringel K. Evidence for inflammation and activation of cell-mediated immunity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Increased interleukin-1, tumor necrosis factor-α, PMN-elastase, lysozyme and neopterin. J Affect Disord. 2011 Oct 3. PMID: 21975140

The findings show that ME/CFS is characterized by low-grade inflammation and activation of cell-mediated immunity and suggest that inflammatory mediators such as IL-1 and TNFα are factors in the disease.

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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. 2011 Apr;17(4):SC11-5. PMID: 21455120

Plasma peroxide concentrations were significantly higher in patients with ME/CFS than in normal controls. There was a trend towards significantly higher serum oxLDL antibodies in ME/CFS than in controls. Both biomarkers contributed significantly in discriminating between patients with ME/CFS and normal controls. Plasma peroxide and serum oxLDL antibody levels were both significantly related to one of the FF symptoms. The results show that ME/CFS is characterized by increased oxidative stress.

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Brkic S, Tomic S, Maric D, Novakov Mikic A, Turkulov V. Lipid peroxidation is elevated in female patients with chronic fatigue syndrome. Med Sci Monit. 2010 Nov 30;16(12):CR628-32. PMID: 21119582

CFS is associated with lipid peroxidation and oxidative stress.  High levels of malondialdehyde, positively correlated with total cholesterol and lower HDL cholesterol levels, might be indicative of proatherogenic events in female CFS patients.

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Kennedy G, Khan F, Hill A, Underwood C, Belch JJ. Biochemical and vascular aspects of pediatric chronic fatigue syndrome. Arch Pediatr Adolesc Med. 2010 Sep;164(9):817-23. PMID: 20819963

Biomedical anomalies seen in adults with CFS/ME-increased oxidative stress and increased white blood cell apoptosis-can also be observed in children with clinically diagnosed CFS/ME compared with matched controls.

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Miwa K, Fujita M. Fluctuation of serum vitamin E (alpha-tocopherol) concentrations during exacerbation and remission phases in patients with chronic fatigue syndrome. Heart Vessels. 2010 Jul;25(4):319-23. PMID: 20676841

CFS patients have lower levels of Vitamin E (and therefore possible greater oxidative stress) during times of exacerbation than during times of remission.

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Jason LA, Porter N, Herrington J, Sorenson M, Kubow S. Kindling and Oxidative Stress as Contributors to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. J Behav Neurosci Res. 2009 Jan 1;7(2):1-17. PMID: 21253446

CFS can affect the immune, neuroendocrine, autonomic, and neurologic systems. Abnormal biological findings among some patients have included aberrant ion transport and ion channel activity, cortisol deficiency, sympathetic nervous system hyperactivity, EEG spike waves, left ventricular dysfunction in the heart, low natural killer cell cytotoxicity, and a shift from Th1 to Th2 cytokines. We propose that the kindling and oxidative stress theories provide a heuristic template for better understanding of this illness.

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Maes M, Twisk FN. Why myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may kill you: disorders in the inflammatory and oxidative and nitrosative stress (IO&NS) pathways may explain cardiovascular disorders in ME/CFS. Neuro Endocrinol Lett. 2009;30(6):677-93. PMID: 20038921

Previous reports suggest that CFS patients dying of heart failure do so at a significantly lower age than non-patients (59 years vs. 83 years). A number of abnormalities in CFS may be responsible for this, including: a) chronic low grade inflammation with extended production of nuclear factor kappa B and COX-2 and increased levels of tumour necrosis factor alpha; b) increased O&NS with increased peroxide levels, and phospholipid oxidation including oxidative damage to phosphatidylinositol; c) decreased levels of specific antioxidants, i.e. coenzyme Q10, zinc and dehydroepiandrosterone-sulphate; d) bacterial translocation as a result of leaky gut; e) decreased omega-3 polyunsatutared fatty acids (PUFAs), and increased omega-6 PUFA and saturated fatty acid levels; and f) the presence of viral and bacterial infections and psychological stressors.

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Miwa K, Fujita M. Increased oxidative stress suggested by low serum vitamin E concentrations in patients with chronic fatigue syndrome. Int J Cardiol. 2009 Aug 14;136(2):238-9. PMID: 18684522

Patients with CFS have lower serum alpha-tocopherol concentrations, suggesting the presence of oxidative stress in the illness.

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Raison CL, Lin JM, Reeves WC. Association of peripheral inflammatory markers with chronic fatigue in a population-based sample. Brain Behav Immun. 2009 Mar;23(3):327-37. PMID: 19111923

CFS patients as well as patients with general fatigue had abnormally elevated levels of plasma concentrations of high-sensitivity c-reactive protein (hs-CRP).

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Spence VA, Kennedy G, Belch JJ, Hill A, Khan F. Low-grade inflammation and arterial wave reflection in patients with chronic fatigue syndrome. Clin Sci (Lond). 2008 Apr;114(8):561-6. PMID: 18031285

Measures related to oxidative stress were studied in CFS patients.

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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. PMID: 18274865

The role of oxidative stress in CFS is an emerging focus of research due to evidence of its association with some pathological features of this syndrome. New data collectively support the presence of specific critical points in the muscle that are affected by free radicals.

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Pall ML, Bedient SA. The NO/ONOO- cycle as the etiological mechanism of tinnitus. Int Tinnitus J. 2007;13(2):99-104. PMID: 18229788

Tinnitis may be related to abnormal levels of such cycle elements as N-methyl-D-aspartate activity; oxidative stress; nitric oxide; peroxynitrite; vanilloid activity; NF-kappaB activity; and intracellular calcium levels.

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Richards RS, Wang L, Jelinek H. Erythrocyte oxidative damage in chronic fatigue syndrome. Arch Med Res. 2007 Jan;38(1):94-8. PMID: 17174731

CFS patients showed oxidative stress evidence in terms of misshapen red blood cells and levels of malondialdehyde (MDA), methemoglobin (metHb) and 2,3-diphosphoglyceric acid (2,3-DPG).

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Maes M, Mihaylova I, Leunis JC. Chronic fatigue syndrome is accompanied by an IgM-related immune response directed against neopitopes formed by oxidative or nitrosative damage to lipids and proteins. Neuro Endocrinol Lett. 2006 Oct;27(5):615-21. PMID: 17159817

CFS is characterized by an IgM-related immune response directed against disrupted lipid membrane components, by-products of lipid peroxidation, S-farnesyl-L-cysteine, and NO-modified amino-acids, which are normally not detected by the immune system but due to oxidative and nitrosative damage have become immunogenic.

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Maes M, Mihaylova I, De Ruyter M. Lower serum zinc in Chronic Fatigue Syndrome (CFS): relationships to immune dysfunctions and relevance for the oxidative stress status in CFS. J Affect Disord. 2006 Feb;90(2-3):141-7. PMID: 16338007

CFS is accompanied by a low serum zinc status and that the latter is related to signs of inflammation and defects in early T cell activation pathways. Since zinc is a strong anti-oxidant, the present results further support the findings that CFS is accompanied by increased oxidative stress.

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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. 2005 Sep 1;39(5):584-9. PMID: 16085177

CFS patients showed elevations in a variety of measures, including isoprostanes, of oxidative stress.

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Pall ML. Nitric oxide and the etiology of chronic fatigue syndrome: giving credit where credit is due. Med Hypotheses. 2005;65(3):631-3.

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Nijs J, Van de Velde B, De Meirleir K. Pain in patients with chronic fatigue syndrome: does nitric oxide trigger central sensitisation? Med Hypotheses. 2005;64(3):558-62. PMID: 15617866

It is hypothesised that a nitric oxide (NO)-dependent reduction in inhibitory activity of the central nervous system and consequent central sensitisation accounts for chronic widespread pain in CFS patients.

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Chaudhuri A, Behan PO. In vivo magnetic resonance spectroscopy in chronic fatigue syndrome. Prostaglandins Leukot Essent Fatty Acids. 2004 Sep;71(3):181-3. PMID: 15253888

Cell membrane oxidative stress may offer a common explanation for the observed MRS changes in the muscles and brain of CFS patients and this may have important therapeutic implications.

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Smirnova IV, Pall ML. Elevated levels of protein carbonyls in sera of chronic fatigue syndrome patients. Mol Cell Biochem. 2003 Jun;248(1-2):93-5. PMID: 12870659

Elevated protein carbonyl levels confirm earlier reports suggesting that oxidative stress is associated with CFS and are consistent with a prediction of the elevated nitric oxide/peroxynitrite theory of chronic fatigue syndrome and related conditions.

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Vecchiet J, Cipollone F, Falasca K, Mezzetti A, Pizzigallo E, Bucciarelli T, De Laurentis S, Affaitati G, De Cesare D, Giamberardino MA. Relationship between musculoskeletal symptoms and blood markers of oxidative stress in patients with chronic fatigue syndrome. Neurosci Lett. 2003 Jan 2;335(3):151-4. PMID: 12531455

Increased oxidative stress and decreased antioxidant defenses are related to the extent of symptomatology in CFS.

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Manuel y Keenoy B, Moorkens G, Vertommen J, De Leeuw I. Antioxidant status and lipoprotein peroxidation in chronic fatigue syndrome.Life Sci. 2001 Mar 16;68(17):2037-49. PMID: 11388705

Patients with CFS have increased susceptibility of LDL and VLDL to copper-induced peroxidation, and this is related both to their lower levels of serum transferrin and to other unidentified pro-oxidising effects of CFS.

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Pall ML. Common etiology of posttraumatic stress disorder, fibromyalgia, chronic fatigue syndrome and multiple chemical sensitivity via elevated nitric oxide/peroxynitrite. Med Hypotheses. 2001 Aug;57(2):139-45. PMID: 11461161

Evidence supporting the role of elevated nitric oxide/peroxynitrite in CFS and other disease states is summarized

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Richards RS, Roberts TK, Dunstan RH, McGregor NR, Butt HL. Free radicals in chronic fatigue syndrome: cause or effect? Redox Rep. 2000;5(2-3):146-7. PMID: 10939298

Free radicals may be a problem in CFS.

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Fulle S, Mecocci P, Fanó G, Vecchiet I, Vecchini A, Racciotti D, Cherubini A, Pizzigallo E, Vecchiet L, Senin U, Beal MF. Specific oxidative alterations in vastus lateralis muscle of patients with the diagnosis of chronic fatigue syndrome. Free Rad Biciol Med. 2000 Dec 15;29(12):1252-9. PMID: 11118815

The authors detected oxidative damage to DNA and lipids in muscle specimens of CFS patients as compared to age-matched controls, as well as increased activity of the antioxidant enzymes catalase, glutathione peroxidase, and transferase, and increases in total glutathione plasma levels.

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Richards RS, Roberts TK, McGregor NR, Dunstan RH, Butt HL. Blood parameters indicative of oxidative stress are associated with symptom expression in chronic fatigue syndrome. Redox Rep. 2000;5(1):35-41. PMID: 10905542

CFS patients had increases in malondialdehyde, methaemoglobin, mean erythrocyte volume and 2,3-diphosphoglycerate compared with controls. Methaemoglobin was found to be the major component associated with variation in symptom expression, including fatigue, musculoskeletal symptoms, pain and sleep disturbance. Variation in levels of malondialdehyde and 2,3-diphosphoglycerate were associated with variations in cognitive symptoms and sleep disturbance. These data suggest that oxidative stress due to excess free radical formation is a contributor to the pathology of CFS and was associated with symptom presentation.

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Pall ML. Elevated, sustained peroxynitrite levels as the cause of chronic fatigue syndrome. Med Hypotheses. 2000 Jan;54(1):115-25. PMID: 10790736

The author proposes a hypothesis of CFS in which either viral or bacterial infection induces one or more cytokines, IL-1beta IL-6, TNF-alpha and IFN-gamma. These induce nitric oxide synthase (iNOS), leading to increased nitric oxide levels. Nitric oxide, in turn, reacts with superoxide radical to generate the potent oxidant peroxynitrite. Multiple amplification and positive feedback mechanisms are proposed by which once peroxynitrite levels are elevated, they tend to be sustained at a high level.

 

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