Tag: oxidative stress

The Pall Protocol for Treating CFS/ME

Dr. Martin Pall’s NO/ONOO– (“No! Oh, no!”) hypothesis is probably the most comprehensive explanation of cellular dysregulation in CFS and other oxidative stress illnesses. His model proposes that the chronic stage of CFS is driven by a vicious cycle of oxidative stress, in which the basic mechanisms that are meant to control pathogens don’t turn off. The result is oxidants run amok, creating havoc in the cell’s energy cycles, and increasing inflammation.

The protocol described here was originally put together by Dr. Pall and by Dr. Grace Ziem. It is based on antioxidant treatments which break the vicious cycle of oxidative stress as well as other agents that act to lower other parts of the cycle, such as lowering inflammatory responses, improving mitochondrial function and lowering excessive NMDA activity. However, taking large quantities of single antioxidants can actually increase oxidative stress. Once antioxidants such as tocopherols (vitamin E), vitamin C, and flavonoids react with free radicals, these antioxidants are themselves converted into free radicals. Other antioxidants are then needed to neutralize those newly formed free radicals. Therefore, a wide variety of antioxidants is optimal.

PLEASE NOTE: Dr. Pall emphasizes that he is a Ph.D., not an M.D., and none of these therapies should be viewed as medical advice.

Below is a list of Dr. Pall’s therapies. More detailed information follows.

  1. Nebulized reduced glutathione
  2. Nebulized inhaled hydroxocobalamin
  3. Mixed natural tocopherols
  4. Buffered C
  5. Magnesium, as malate
  6. Four flavonoids: gingko, cranberry extract, silymarin and bilberry
  7. Selenium, as selenium-grown yeast
  8. CoQ10
  9. Folic acid
  10. Carotenoids including lycopene, lutein and B carotene
  11. Alpha lipoic acid
  12. Zinc (modest dose), manganese (low dose), copper (low dose)
  13. Vitamin B6, as pyridoxal phosphate
  14. Riboflavin 5′-phosphate
  15. Betaine (trimethylglycine)
  16. Acetyl-carnitine
  17. Taurine

Detailed antioxidant protocol:

Vitamin C. Pall suggests doses on the order of 500 to 1000 mg/day, taken several times per day. Vitamin C can act to regenerate tetrahydrobiopterin (BH4) and, therefore, may act to lower nitric oxide synthase (NOS) uncoupling, and high doses of vitamin C can be useful in scavenging peroxynitrite (ONOO–), the most central element in his NO/ONOO– cycle hypothesis.

CoQ10. CoQ10 has been used in a number of diseases to improve mitochondrial function. It scavenges free radicals, protects against loss of mitochondrial respiratory function, increases energy metabolism, and down regulates NMDA activity. Take early in the day.

Magnesium. This mineral lowers NMDA activity, reducing excitotoxicity. Dr. Pall believes that “magnesium is one of the most promising agents for treatment of multisystem diseases, but, like other such agents, it produces modest responses and may best be used in a complex, combination therapy.”

Selenium. Selenium is considered an antioxidant because certain proteins that contain selenium have antioxidant properties. Selenium occurs in glutathione peroxidases, enzymes that eliminate peroxide in cells. Selenium is also essential in making T3, the most active form of thyroid hormone. The best form of selenium is selenomethionine, which is a selenium-grown yeast. (For those who are yeast-sensitive, there are non-yeast forms.)

Carotenoids. These are plant pigments which are quite active in scavenging free radicals. Lycopene is more active than beta-carotene as a peroxynitrite scavenger. Lutein and zeaxanthin, two carotenoids, may also have special roles as antioxidants because of the way they insert into biological membranes.

Flavonoids. Anthocyanidins, which are found in purple plants, lower inflammatory activity, act as potent chain-breaking antioxidants, and regenerate other chain-breaking antioxidants after they have been converted to free radicals. Flavonoids also act as chelators for free iron, protecting cells from oxidative damage. Many flavonoids are soluble in both water and lipids. Flavonoids from green tea, citrus, grape seed extract, gingko, soy, olive, hawthorn, blueberry, and purple rice are effective antioxidants. Silymarin scavenges peroxynitrite, and increases the synthesis of SOD (superoxide dismutase), which makes it especially important. Flavonoids are rapidly absorbed in foods, and are quickly excreted through the kidneys, so they need to be eaten (or taken) throughout the day.

Acetyl-L-carnitine. Carnitine transports fatty acids into mitochondria, and is therefore essential for providing cellular energy. Acetyl-L-carnitine is more effective than L-carnitine because most oral L-carnitine ends up being excreted by the kidneys before it can be transported through the blood-brain barrier. Acetyl-L-carnitine is transported more efficiently. Recently, it has been shown that acetyl-L-carnitine lowers excessive NMDA activity and this may well be more important than the effects on mitochondrial function for lowering the NO/ONOO– cycle.

Reductive Stress Agents. Reductive stress causes oxidative stress. Methyl groups – SAMe, betaine, and carnitine – act as protective agents. Dr. Pall’s preference for a methylated compound is betaine (TMG.) It is cheaper and more stable than SAMe.

Hydroxocobalamin form of B12. B12 is a potent nitric oxide scavenger, but it is difficult to absorb. Oral absorption of B12 is limited by intrinsic factor. [Independent of intrinsic factor, the absorption rate of B12 is less than 1% of the total amount ingested.] Hydroxocobalamin taken as a nasal spray or injection is more effective.

Folate (folic acid). Reduced folate decreases uncoupling of NOS activity. Reduced folate in the form of 5-methyltetrahydrofolate (5-MTHF) is a potent scavenger of peroxynitrite and may well turn out to be among the most useful agents for lowering the NO/ONOO– cycle. Optimal dosage may well vary among different individuals but, in general, it should be taken along with quite a bit of vitamin C (at least 500 mg and preferably perhaps twice this amount). The reaction between peroxynitrite and 5-MTHF is important not only because it can be used to lower peroxynitrite levels. It is also important because in NO/ONOO– diseases, elevated peroxynitrite will act to lower the levels of 5-MTHF, lowering methylation cycle activity, and will also act to lower all reduced folates in the body. In this way, lowered methylation activity may be caused by the NO/ONOO– cycle.

B6, as P5P. B6 minimizes neurotoxicity. The best form is pyridoxine phosphate (P5P).

Riboflavin. Riboflavin is important for the production of reduced glutathione. It is also useful in the treatment of migraine.

Alpha Lipoic Acid (ALA) scavenges free radicals. As an added benefit, it can regenerate other antioxidants by reducing oxidized and free radical forms of glutathione, tocopherols, vitamin C and flavonoids. It can maintain glutathione pools by turning oxidized glutathione into its active form, reduced glutathione. ALA can cross the blood-brain barrier, making it an effective tool for reducing damage due to oxidative stress in the brain.

Zinc, Manganese and Copper. These minerals are components of superoxide dismutases (SOD), the enzymes that convert the oxidant superoxide into hydrogen peroxide and oxygen. Zinc, copper and manganese deficiencies can produce oxidative stress, part of which may be due to the lowered ability to produce SODs. Doses of these metals can be tricky. Excessive levels of copper and manganese can themselves produce oxidative stress. Excessive zinc lowers copper levels. Dr. Pall suggests “modest levels.”

Taurine is an unusual amino acid, because it is an antioxidant as well as a neurotransmitter. Taurine acts to stimulate the synthesis of GABA, and is transported easily across the blood-brain barrier, allowing it to work in the brain. Taurine stimulates several inhibitory receptors, leading to lowered NMDA activity. It also acts to lower intracellular calcium levels, thus lowering NO synthesis.

Long-chain omega-3 fatty acids. Polyunsaturated fatty acids (PUFAs) are more susceptible to lipid peroxidation than are other fatty acids, and consequently they tend to be depleted whenever there is oxidative stress. Fish oil, borage oil and flaxseed oil are sources of long-chain omega-3 fatty acids.

Curcumin, honokiol (from magnolia), cat’s claw, vinpocetine and feverfew all reduce inflammation by lowering NF-kappaB activity, as do a number of conventional pharmaceuticals.

Vitamin E should not be taken as synthetic alpha-tocopherol, which is the most commonly taken form, Pall argues. Rather, it should be taken as relatively high doses of gamma-tocopherol and tocotrienols with modest amounts of natural alpha-tocopherol. These other forms of vitamin E have important functions, such as lowering inflammation, scavenging an important breakdown product of peroxynitrite, lowering excessive NMDA activity and improving mitochondrial function, all important for lowering NO/ONOO– cycle diseases.

Algal supplements. Both chlorella and blue-green algae are rich in antioxidants. Blue-green algae contain phycocyanin, which is a potent free radical scavenger.

FURTHER READING:

Pall, Martin. Explaining “Unexplained Illnesses”: Disease Paradigm for Chronic Fatigue Syndrome, Multiple Chemical Sensitivity, Fibromyalgia, Post-Traumatic Stress Disorder, Gulf War Syndrome and Others. New York: Harrington Park Press, trade division of Haworth Press, Inc. 2007.

This book is technical, but well worth reading. Dr. Pall has made a remarkable contribution to the study of “unexplained illnesses.”

“How Can We Cure NO/ONOO– Cycle Diseases: Approaches to Curing Chronic Fatigue Syndrome/Myalgic Encephalomyelitis, Fibromyalgia, Multiple Chemical Sensitivity, Gulf War Syndrome and Possibly Many Others.” Martin Pall. Townsend Letter. Feb/March 2010.

Excellent paper by Martin Pall on agents that lower parts of the NO/ONOO? cycle. Contains detailed information on protocols and potential therapeutic agents. 

Martin Pall – MEPedia’s comprehensive page on Dr. Pall includes publications, talks, interviews, papers, and more.

Antioxidant Suggestions from Dr. Martin Pall, Ph.D.  Tables of supplements recommended by Dr. Pall, along with mechanisms and comments.

Significant aggravation of pre-existing myalgic encephalomyelitis/chronic fatigue syndrome following proton beam therapy for sphenoid wing meningioma: case report

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem disorder characterized by profound fatigue, post-exertional malaise (PEM), immune dysregulation, and mitochondrial dysfunction. While radiation exposure has been linked to fatigue syndromes with overlapping pathophysiology, no previous reports have described the effects of therapeutic radiation, including proton beam radiotherapy (PBRT), in patients with ME/CFS.

Case presentation: We report the case of a 46-year-old woman with a pre-existing, clinically confirmed diagnosis of ME/CFS (Bell score 60, ECOG 1), who underwent postoperative PBRT (50.4 Gy in 28 fractions) for a recurrent left sphenoid wing meningioma (CNS WHO grade 1). The tumor had been surgically resected but showed residual disease with early postoperative progression and close proximity to the left optic nerve, prompting the indication for adjuvant radiotherapy. The patient initially tolerated treatment well, with only mild acute worsening of pre-existing fatigue and transient corticosteroid-responsive symptoms. However, within weeks of completing radiotherapy, she developed progressive and severe worsening of fatigue, myalgia, vertigo, and hypersensitivity to sensory stimuli as well as cognitive decline. Over several months, she became completely bedridden (Bell score 0, ECOG 4) with persistent ME/CFS aggravation unresponsive to supportive measures persisting until the last known contact 20 months after radiation. Follow-up imaging showed stable postoperative findings without tumor progression or new structural brain lesions.

Discussion: This case illustrates a profound and irreversible deterioration of ME/CFS following PBRT, suggesting that radiation-induced mitochondrial dysfunction, oxidative stress, and chronic inflammatory activation may critically worsen pre-existing metabolic fragility. Despite the theoretical advantages of proton radiotherapy in reducing normal tissue exposure, its protective effects may be insufficient in patients with baseline mitochondrial malfunction.

Conclusion: This is, to our knowledge, the first reported case of severe and sustained ME/CFS exacerbation after radiotherapy. The case emphasizes the urgent need for risk stratification, tailored consent processes, and research in the field of radiotherapy tolerance in ME/CFS patients, as conventional expectations regarding side effects may not predict outcomes in this vulnerable population.

Source: Fischer C, Seidlitz A, Krause M. Significant aggravation of pre-existing myalgic encephalomyelitis/chronic fatigue syndrome following proton beam therapy for sphenoid wing meningioma: case report. Strahlenther Onkol. 2026 Jun 11. doi: 10.1007/s00066-026-02553-w. Epub ahead of print. PMID: 42277311. https://link.springer.com/article/10.1007/s00066-026-02553-w (Full text)

Multi-omics analysis of long COVID (post-COVID-19 condition) reveals persistent mitochondrial dysfunction, suppressed oxidative phosphorylation, and immune dysregulation

Abstract:

Introduction: Post-COVID Syndrome (PCS), or long-COVID, is a major public health burden, but its underlying mechanisms remain poorly understood. Because acute SARS-CoV-2 infection induces marked suppression of mitochondrial oxidative phosphorylation (OXPHOS), we investigated whether persistent immunometabolic remodeling is a recurring transcriptional, metabolic, and proteomic feature of PCS.

Methods: We performed an integrated multi-omics analysis of transcriptomic, proteomic, and metabolomic datasets across multiple tissues from Syrian hamster models and human cohorts spanning acute infection through post-acute and PCS stages extending up to 12 months post-infection.

Results: Across species and tissues, we observed overlapping signatures of mitochondrial dysfunction, including sustained suppression of OXPHOS, activation of mitochondrial stress responses, and enrichment of inflammatory pathways. Skeletal muscle exhibited the most pronounced and persistent mitochondrial repression in both hamsters and PCS patient biopsies, consistent with fatigue-associated phenotypes. Hamster heart and kidney tissues also showed persistent OXPHOS suppression, while lung tissue demonstrated prolonged inflammatory signaling despite partial metabolic recovery. In the nervous system, transcriptional profiles revealed region-specific patterns, including persistent cortical mitochondrial repression and partial recovery in sensory-associated regions. Peripheral blood mononuclear cells (PBMCs) transcriptomics and serum metabolic datasets suggested prolonged downregulation of OXPHOS-associated programs up to 12 months post-infection, potentially contributing to persistent immune dysregulation in susceptible individuals with underlying conditions. Longitudinal serum proteomics in PCS patients revealed sustained mitochondrial stress responses, increased oxidative stress signatures, and persistent immune activation at 1 and 6 months post-infection compared to recovered controls.

Discussion: Together, these multi-omics results identify persistent mitochondrial repression and immune dysregulation as recurring features across PCS-associated datasets, providing a framework linking bioenergetic dysfunction with chronic immune activation and supporting future mechanistic and therapeutic investigation.

Source: Tasoula A, Arif S, Waisberg E, Bauer L, Aslinger E, Guarnieri JW. Multi-omics analysis of long COVID (post-COVID-19 condition) reveals persistent mitochondrial dysfunction, suppressed oxidative phosphorylation, and immune dysregulation. Front Immunol. 2026 May 21;17:1776555. doi: 10.3389/fimmu.2026.1776555. PMID: 42253978; PMCID: PMC13234542. https://pmc.ncbi.nlm.nih.gov/articles/PMC13234542/ (Full text)

Pathophysiological, Translational, and Diagnostic Aspects of ME/CFS: A Focus on Skeletal Muscle Involvement

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic, multisystemic disorder characterized by severe, persistent fatigue not alleviated by rest and worsened by minimal exertion, often accompanied by post-exertional malaise (PEM), unrefreshing sleep, cognitive dysfunction, and autonomic disturbances. Despite decades of research, its pathophysiology remains incompletely understood, and skeletal muscle involvement has only recently gained attention.

This review aims to provide a historical and pathophysiological synthesis of ME/CFS, emphasizing the pivotal role of skeletal muscle in the onset and persistence of symptoms, and to integrate molecular, cellular, and pathophysiological evidence into a coherent explanatory framework.

This is a narrative review of published literature (1990-2025) with critical integration of clinical, biochemical, and experimental data on oxidative stress, mitochondrial dysfunction, Excitation-Contraction (E-C coupling) dysregulation, and muscle secretome alterations in ME/CFS also in relation to post-viral syndromes (e.g., Long COVID).

Evidence consistently points to mitochondrial oxidative stress, redox imbalance, impaired Ca2+ handling, and altered signaling pathways in skeletal muscle of patients with ME/CFS. Historical milestones show an evolution from psychogenic interpretations toward recognition of ME/CFS as a biological disorder with neuromuscular and metabolic underpinnings.

ME/CFS can be interpreted as a skeletal muscle-metabolic disorder characterized by oxidative distress, mitochondrial dysfunction, and impaired energy regulation, leading to the clinical picture of exercise intolerance and post-exertional malaise. Integrating basic and clinical research through a translational approach provides the foundation for new diagnostic tools, targeted therapies, and biomarkers.

Source: Fanò-Illic G, Coscia F, Gigliotti PV, Checcaglini F, Carraro U, Fulle S, Mancinelli R. Pathophysiological, Translational, and Diagnostic Aspects of ME/CFS: A Focus on Skeletal Muscle Involvement. Diagnostics (Basel). 2026 Mar 28;16(7):1019. doi: 10.3390/diagnostics16071019. PMID: 41975732. https://www.mdpi.com/2075-4418/16/7/1019 (Full text)

Insights into the Complex Biological Network Underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem disorder characterized by immune dysregulation, metabolic impairments, neuroendocrine disturbances, endothelial dysfunction, and gastrointestinal abnormalities.

Immune alterations include reduced natural killer cell cytotoxicity, T-cell exhaustion, abnormal B-cell subsets, and the presence of diverse autoantibodies, suggesting an autoimmune component.

Gut dysbiosis and increased intestinal permeability may promote systemic inflammation and contribute to neurocognitive symptoms via the gut-brain axis. Neuroendocrine findings such as hypothalamic-pituitary-adrenal (HPA) axis hypofunction and altered thyroid hormone metabolism further compound metabolic and immune abnormalities.

Metabolomic and mitochondrial studies identify impaired ATP generation, redox imbalance, and compensatory shifts toward alternative energy pathways underlying hallmark symptoms like post-exertional malaise.

Endothelial dysfunction driven by oxidative and nitrosative stress, along with autoantibody-mediated receptor interference, may explain orthostatic intolerance and impaired perfusion. Collectively, ME/CFS appears to arise from a self-sustaining cycle of chronic inflammation, metabolic insufficiency, and neuroimmune imbalance.

Source: Dudova D, Bozhkova M, Petrov S, Nikolova R, Kalfova T, Ivanovska M, Vaseva K, Nikolova M, Ivanov IN. Insights into the Complex Biological Network Underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Int J Mol Sci. 2025 Dec 26;27(1):268. doi: 10.3390/ijms27010268. PMID: 41516145; PMCID: PMC12785471. https://pmc.ncbi.nlm.nih.gov/articles/PMC12785471/ (Full text)

The Role of Nuclear and Mitochondrial DNA in Myalgic Encephalomyelitis: Molecular Insights into Susceptibility and Dysfunction

Abstract:

Myalgic Encephalomyelitis (ME), also known as chronic fatigue syndrome (CFS), is a debilitating and heterogeneous disorder marked by persistent fatigue, post-exertional malaise, cognitive impairment, and multisystem dysfunction. Despite its prevalence and impact, the molecular mechanisms underlying ME remain poorly understood.
This review synthesizes current evidence on the role of DNA, both nuclear and mitochondrial, in the susceptibility and pathophysiology of ME. We examined genetic predispositions, including familial clustering and candidate gene associations, and highlighted emerging insights from genome-wide and multi-omics studies.
Mitochondrial DNA variants and oxidative stress-related damage are discussed in relation to impaired bioenergetics and symptom severity. Epigenetic modifications, particularly DNA methylation dynamics and transposable element activation, are explored as mediators of gene–environment interactions and immune dysregulation.
Finally, we explored the translational potential of DNA-based biomarkers and therapeutic targets, emphasizing the need for integrative molecular approaches to advance diagnosis and treatment. Understanding the DNA-associated mechanisms in ME offers a promising path toward precision medicine in post-viral chronic diseases.
Source: Elremaly W, Elbakry M, Vahdani Y, Franco A, Moreau A. The Role of Nuclear and Mitochondrial DNA in Myalgic Encephalomyelitis: Molecular Insights into Susceptibility and Dysfunction. DNA. 2025; 5(4):53. https://doi.org/10.3390/dna5040053 https://www.mdpi.com/2673-8856/5/4/53 (Full text)

Metabolic neuroimaging of myalgic encephalomyelitis/chronic fatigue syndrome and Long-COVID

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long-COVID are complex, disabling conditions that have emerged as significant public health challenges, affecting millions worldwide. Despite their growing prevalence, effective diagnostics and treatments remain limited, largely due to an incomplete understanding of their underlying pathophysiology. Both conditions share hallmark symptoms of chronic fatigue, cognitive dysfunction, and postexertional malaise, but their biological underpinnings remain to be elucidated. Neuroimaging offers a promising, noninvasive window into the brain’s metabolic landscape and has the potential to uncover objective biomarkers for these conditions.

In this mini review, we highlight recent advancements in metabolic neuroimaging, particularly positron emission tomography and magnetic resonance imaging/magnetic resonance spectroscopy, that reveal alterations in glucose and oxygen metabolism, neurotransmitter balance, and oxidative stress. These insights point toward shared disruptions in brain energy metabolism and neuroinflammatory processes, which may underlie the persistent symptoms in both ME/CFS and Long-COVID.

Importantly, while some findings overlap, inconsistencies in metabolite profiles between ME/CFS and Long-COVID underscore the need for further stratification and longitudinal research. Standardizing definitions, such as identifying Long-COVID patients who meet ME/CFS diagnostic criteria, could help improve study comparability.

By summarizing current imaging evidence, this review underscores the potential of neuroimaging to identify imaging biomarkers to advance the clinical diagnosis of Long-COVID and identify therapeutic targets for treatment development. As we continue to face the growing burden of Long-COVID and ME/CFS, metabolic imaging may serve as a powerful tool to bridge gaps in knowledge and accelerate progress toward effective care.

Source: Zhu Y, Quan P, Yamazaki T, Norweg A, Natelson B, Xu X. Metabolic neuroimaging of myalgic encephalomyelitis/chronic fatigue syndrome and Long-COVID. Immunometabolism (Cobham). 2025 Sep 12;7(4):e00068. doi: 10.1097/IN9.0000000000000068. PMID: 40958852; PMCID: PMC12435251. https://pmc.ncbi.nlm.nih.gov/articles/PMC12435251/ (Full text)

Haptoglobin phenotypes and structural variants associate with post-exertional malaise and cognitive dysfunction in myalgic encephalomyelitis

Abstract:

Background: Myalgic encephalomyelitis (ME) is a chronic, multisystem illness characterized by post-exertional malaise (PEM) and cognitive dysfunction, yet the molecular mechanisms driving these hallmark symptoms remain unclear. This study investigated haptoglobin (Hp) as a potential biomarker of PEM severity and cognitive impairment in ME, with a focus on Hp phenotypes and structural proteoforms.

Methods: A longitudinal case-control study was conducted in 140 ME patients and 44 matched sedentary healthy controls. In the discovery phase, global plasma proteomic profiling was performed in 61 ME patients and 20 controls before and after a standardized, non-invasive stress protocol in order to induce PEM. Associations between Hp levels, phenotype, and cognitive performance were assessed. In the validation phase, plasma Hp concentrations and proteoform composition were analyzed in an independent cohort of 89 ME patients and 24 controls using high-performance liquid chromatography (HPLC).

Results: ME patients demonstrated a significant reduction in Hp levels following post-exertional stress. Lower baseline Hp concentrations were associated with impaired cognitive performance. Hp phenotypes were differentially associated with symptom burden, with the Hp2-1 phenotype enriched in ME and linked to greater PEM severity and cognitive deficits compared to Hp1-1 and Hp2-2. HPLC analysis revealed altered Hp proteoform profiles in the Hp2-1 subgroup, including increased high-mass tetrameric and pentameric forms and shorter retention times indicative of structural changes. In contrast, the Hp1-1 phenotype was associated with milder symptoms and greater cognitive resilience.

Conclusions: These findings suggest that Hp phenotype and proteoform structure modulate the physiological response to post-exertion in ME, offering insight into the molecular basis of PEM and its clinical heterogeneity. Hp may serve as a translational biomarker for patient stratification and a potential therapeutic target to mitigate oxidative stress and cognitive dysfunction in ME.

Source: Moezzi A, Ushenkina A, Widgren A, Bergquist J, Li P, Xiao W, Rostami-Afshari B, Leveau C, Elremaly W, Caraus I, Franco A, Godbout C, Nepotchatykh O, Moreau A. Haptoglobin phenotypes and structural variants associate with post-exertional malaise and cognitive dysfunction in myalgic encephalomyelitis. J Transl Med. 2025 Aug 28;23(1):970. doi: 10.1186/s12967-025-07006-z. PMID: 40877900. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-025-07006-z (Full text)

How pandemics reshape our brain: Common links and targets between long-haul COVID-19, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), oxidative stress, and neurodegeneration

Highlights:

  • Fatiguing syndromes affect millions of patients in the United States and globally, but are grossly underserved in the clinic and in the contemplative design of basic research.
  • Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multisystem metabolic-immune-inflammatory disorder. Although research on this condition is in its infancy, it appears to involve the immune system and central nervous system malfunction, with cellular oxidative stress as a predominant feature.
  • Approximately half of the cases of long-haul coronavirus disease 2019 meet the diagnostic criteria for ME/CFS, burgeoning the number of affected individuals.
  • Recent strides in neurobiology have yet to transfer the understanding of the neurodegenerative aspects, and potential for neuroprotection, of ME/CFS.
  • ME/CFS may represent a useful paradigm and research model for the study of the impact of sustained oxidative stress on the central nervous system and the body at large.

Archeological findings from the bubonic plague era onward have demonstrated how pandemics can exert selective pressures, as will be highlighted. In particular, the short-term survival advantage during pandemics of individuals with greater immune “plasticity” comes at the cost of increased susceptibility to autoimmunity. Certain viral infections appear to trigger persistent immune system dysregulation, leading to broad autoimmunity and a sequelae of multisystem pathophysiologies with diverse symptoms long after the virus is cleared.

Human coronavirus 2019 (HCoV-19) is the most recent virus that appears to have elevated the incidence of autoimmune diseases in infected individuals. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an autoimmune, multisystem fatiguing syndrome affecting approximately 20 million people globally, representing 1.3% of adults in the United States.1, 2 It involves metabolic, immune, and inflammatory processes, with central nervous system (CNS) dysfunction and cellular oxidative stress being prominent features. Notably, about half of long-haul coronavirus disease 2019 (COVID-19) cases meet the diagnostic criteria for ME/CFS, potentially doubling or tripling its prevalence.

This article highlights ME/CFS, a nascent research area, as a model for neurological pathophysiological outcomes resulting from persistently high oxidative stress levels. Patients with ME/CFS, many who have had this condition for decades, form an underutilized patient population for this study.

A second objective of this Research Highlight is to correct recent reports that have attempted to “retrofit” principles and outcomes from other neurologic diseases to ME/CFS. This has led some neuroscientists to extrapolate erroneously that ME/CFS is not a neurodegenerative disorder. However, substantial evidence indicates that autoimmune ME/CFS is a neurodegenerative disease.

Source: Herman ME. How pandemics reshape our brain: common links and targets between long-haul COVID-19, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), oxidative stress, and neurodegeneration. Neuroprotection. 2025; 1–8. doi:10.1002/nep3.70007 https://onlinelibrary.wiley.com/doi/10.1002/nep3.70007 (Full text)

 

Measuring Biomarkers of Oxidative Stress in ME/CFS Patients

Abstract:

Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have a deficiency in energy production as a result of dysfunctions in their mitochondrial metabolism, defects in the complexes of the electron transport chain, and in the regulation of reactive oxygen species (ROS). This can lead to an imbalance and excess of these species with subsequent modifications of proteins, lipids, and DNA.

Oxidative stress is defined as an accumulation of ROS due to a loss of regulation and the subsequent inability to detoxify them. The modifications to the cellular macromolecules by ROS can be used as biomarkers of oxidative stress and so have the potential to monitor the disease course of a condition like ME/CFS.

Proteins are especially vulnerable to oxidative stress as amino acid residues are naturally modified as part of cell signaling so, in an imbalance between ROS and antioxidants, proteins become modified at multiple sites potentially altering structure and function. Protein carbonyl modifications are stable and can be measured using 2,4-dinitrophenylhydrazine using a commercial ELISA assay. This has been applied here to immune cell proteins and plasma from ME/CFS patients who had moderate functional activity before and during an exercise protocol, and was shown to have potential as a marker of oxidative stress in these patients. The methods used to measure the DNA modification, 8-hydroxy-2′-deoxyguanosine (8-OHdG) are known to give varied results depending on the technology used.

Here, a commercial ELISA assay did not have the sensitivity to detect the modifications in the DNA before and during the exercise protocol of these ME/CFS patients.

Source: Walker M. Measuring Biomarkers of Oxidative Stress in ME/CFS Patients. Methods Mol Biol. 2025;2920:225-244. doi: 10.1007/978-1-0716-4498-0_13. PMID: 40372686. https://link.springer.com/protocol/10.1007/978-1-0716-4498-0_13