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Malaisamy AK, Vaidyanathan R, Kumar A, Choudhary N, Priyadarshini P, Bagaria DK, Subramanian A, Soni KD, Kumar A, Bhavesh NS. A pilot study on hemodynamically stable isolated chest trauma patients reveals dysregulation of oxidative metabolism. Metabolomics 2025; 21:49. [PMID: 40167841 DOI: 10.1007/s11306-025-02241-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 02/19/2025] [Indexed: 04/02/2025]
Abstract
BACKGROUND Metabolomic dysregulation precedes clinical deterioration following injury. However, despite receiving comparable treatment, patients with similar injury severity often follow different clinical trajectories and outcomes. METHODS This prospective cohort study at a level 1 trauma centre screened 4541 acutely injured patients with chest trauma between September 2019 and February 2023. Fifty hemodynamically stable patients with isolated chest trauma were recruited for the final analysis. Urine samples were collected on the injury days 1, 3, and 7. For healthy subjects, the urine sample was collected once. NMR-based metabolomics was performed. RESULTS The study found that the majority of injured patients were young (median age of 40 years), with road traffic injuries being the most common. The median time to presentation of the patient to the ED was 3.08 h, and 92% of patients had multiple rib fractures, pulmonary contusion (60%), and pleural involvement (88%). No patient died. The study found that twenty metabolites were dysregulated (p-value < 0.001). Twelve metabolites were upregulated, while the other eight showed downregulation. However, only five metabolites showed temporal association. 4-HPA, phenylalanine, aconitate, and carnitine represent a high potential for use as a biomarker in patients with isolated blunt trauma chest patients who remain hemodynamically stable. These differentially regulated metabolites were involved in Glyoxylate and dicarboxylate metabolism pathways, glycine, serine, and threonine metabolism, and the Citrate cycle (TCA cycle). CONCLUSIONS AND RELEVANCE Metabolomics can accurately characterize metabolism in isolated blunt chest trauma patients, revealing perturbed pathways of traits such as oxidative stress and amino acid metabolisms. These metabolites could serve as biomarkers to detect systemic changes following chest injuries early. Metabolic profiling following an injury can aid in detecting systemic changes early and identifying novel biomarkers, enabling targeted interventions to improve patient outcomes.
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Affiliation(s)
- Arun Kumar Malaisamy
- Transcription Regulation Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, 110067, India
| | - Ramesh Vaidyanathan
- Division of Trauma Surgery and Critical Care, Jai Prakash Narayan Apex Trauma Center (JPNATC), All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, India
| | - Anand Kumar
- Department of Laboratory Medicine, Jai Prakash Narayan Apex Trauma Center (JPNATC), All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, India
| | - Narendra Choudhary
- Division of Trauma Surgery and Critical Care, Jai Prakash Narayan Apex Trauma Center (JPNATC), All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, India
| | - Pratyusha Priyadarshini
- Division of Trauma Surgery and Critical Care, Jai Prakash Narayan Apex Trauma Center (JPNATC), All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, India
| | - Dinesh Kumar Bagaria
- Division of Trauma Surgery and Critical Care, Jai Prakash Narayan Apex Trauma Center (JPNATC), All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, India
| | - Arulselvi Subramanian
- Department of Laboratory Medicine, Jai Prakash Narayan Apex Trauma Center (JPNATC), All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, India
| | - Kapil Dev Soni
- Critical & Intensive Care, Jai Prakash Narayan Apex Trauma Center (JPNATC), All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, India
| | - Abhinav Kumar
- Division of Trauma Surgery and Critical Care, Jai Prakash Narayan Apex Trauma Center (JPNATC), All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, India.
| | - Neel Sarovar Bhavesh
- Transcription Regulation Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, 110067, India.
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Davis L, Higgs M, Snaith A, Lodge TA, Strong J, Espejo-Oltra JA, Kujawski S, Zalewski P, Pretorius E, Hoerger M, Morten KJ. Dysregulation of lipid metabolism, energy production, and oxidative stress in myalgic encephalomyelitis/chronic fatigue syndrome, Gulf War Syndrome and fibromyalgia. Front Neurosci 2025; 19:1498981. [PMID: 40129725 PMCID: PMC11931034 DOI: 10.3389/fnins.2025.1498981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 02/17/2025] [Indexed: 03/26/2025] Open
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Gulf War Syndrome (GWS), and Fibromyalgia (FM) are complex, chronic illnesses with overlapping clinical features. Symptoms that are reported across these conditions include post-exertional malaise (PEM), fatigue, and pain, yet the etiology of these illnesses remains largely unknown. Diagnosis is challenging in patients with these conditions as definitive biomarkers are lacking; patients are required to meet clinical criteria and often undergo lengthy testing to exclude other conditions, a process that is often prolonged, costly, and burdensome for patients. The identification of reliable validated biomarkers could facilitate earlier and more accurate diagnosis and drive the development of targeted pharmacological therapies that might address the underlying pathophysiology of these diseases. Major driving forces for biomarker identification are the advancing fields of metabolomics and proteomics that allow for comprehensive characterization of metabolites and proteins in biological specimens. Recent technological developments in these areas enable high-throughput analysis of thousands of metabolites and proteins from a variety of biological samples and model systems, that provides a powerful approach to unraveling the metabolic phenotypes associated with these complex diseases. Emerging evidence suggests that ME/CFS, GWS, and FM are all characterized by disturbances in metabolic pathways, particularly those related to energy production, lipid metabolism, and oxidative stress. Altered levels of key metabolites in these pathways have been reported in studies highlighting potential common biochemical abnormalities. The precise mechanisms driving altered metabolic pathways in ME/CFS, GWS, and FM remain to be elucidated; however, the elevated oxidative stress observed across these illnesses may contribute to symptoms and offer a potential target for therapeutic intervention. Investigating the mechanisms, and their role in the disease process, could provide insights into disease pathogenesis and reveal novel treatment targets. As such, comprehensive metabolomic and proteomic analyses are crucial for advancing the understanding of these conditions in-order to identify both common, and unique, metabolic alterations that could serve as diagnostic markers or therapeutic targets.
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Affiliation(s)
- Leah Davis
- The Nuffield Department of Women's and Reproductive Health, The Women Centre, The John Radcliffe Hospital, The University of Oxford, Oxford, United Kingdom
| | - Maisy Higgs
- The Nuffield Department of Women's and Reproductive Health, The Women Centre, The John Radcliffe Hospital, The University of Oxford, Oxford, United Kingdom
| | - Ailsa Snaith
- Veterans and Families Institute for Military Social Research, Anglia Ruskin University, Chelmsford, United Kingdom
| | - Tiffany A. Lodge
- The Nuffield Department of Women's and Reproductive Health, The Women Centre, The John Radcliffe Hospital, The University of Oxford, Oxford, United Kingdom
| | - James Strong
- The Nuffield Department of Women's and Reproductive Health, The Women Centre, The John Radcliffe Hospital, The University of Oxford, Oxford, United Kingdom
| | - Jose A. Espejo-Oltra
- Department of Pathology, Catholic University of Valencia Saint Vincent Martyr, Valencia, Spain
| | - Sławomir Kujawski
- Department of Exercise Physiology and Functional Anatomy, Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland, Nicolaus Copernicus University in Torun, Torun, Poland
| | - Paweł Zalewski
- Department of Exercise Physiology and Functional Anatomy, Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland, Nicolaus Copernicus University in Torun, Torun, Poland
- Department of Experimental and Clinical Physiology, Warsaw Medical University, Warszawa, Poland
| | - Etheresia Pretorius
- Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, South Africa
- Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Michael Hoerger
- Departments of Psychology, Psychiatry, and Medicine, Tulane Cancer Center, Tulane University, New Orleans, LA, United States
| | - Karl J. Morten
- The Nuffield Department of Women's and Reproductive Health, The Women Centre, The John Radcliffe Hospital, The University of Oxford, Oxford, United Kingdom
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Nakayama M, Watanabe K, Sato E, Ito Y, Kadota N, Konishi K, Aizawa C, Maruyama Y, Fujimaru T, Nagahama M, Taki F, Suzuki M. Hemodialysis employing molecular hydrogen (H 2) enriched dialysis solution may improve dialysis related fatigue through impact on energy metabolism. Sci Rep 2025; 15:5039. [PMID: 39934143 PMCID: PMC11814270 DOI: 10.1038/s41598-025-88827-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 01/31/2025] [Indexed: 02/13/2025] Open
Abstract
Hemodialysis employing molecular hydrogen (H2)-enriched dialysis solution rendered by water electrolysis (E-HD), has been reported to alleviate dialysis-related fatigue, but its association with metabolic profiles remains unclear. Eighty-one patients undergoing standard HD were classified into 3 groups [Group A (n = 25, 30.9%): fatigue with activity reduction-subgroups A1: chronic persistent fatigue (n = 11), A2: fatigue only on dialysis days (n = 14); Group B: fatigue without activity reduction (n = 24, 29.6%); Group C (n = 32, 39.5%): no fatigue], and their changes in fatigue, body composition, and metabolic profiles were studied following 12 months of E-HD. There were no significant differences in baseline characteristics among the groups. Over the 12 months after E-HD initiation, fatigue in Group A significantly decreased, while no changes in Group-B and C. Bio-impedance analysis revealed no significant changes in A1, but significant reductions in body fat and increases in skeletal muscle mass were observed despite no significant weight change in A2. Enrichment analysis suggested significant differences in metabolic pathways such as fatty acid metabolism, citric acid cycle, and glycolysis between Groups A and C at baseline, and these differences were mitigated by E-HD. E-HD could suppress dialysis-related fatigue, through possible involvement of altered energy metabolism of patients. E-HD may represent a new paradigm for uremia treatment beyond traditional solute removal-based dialysis therapies.
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Affiliation(s)
- Masaaki Nakayama
- Kidney Center, St Luke's International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japan.
- Department of Research Management, St Luke's International University, Tokyo, Japan.
- Head Office for Open Innovation Business Development Strategy, Tohoku University, Sendai, Japan.
| | - Kimio Watanabe
- Kidney Center, St Luke's International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japan
| | - Emiko Sato
- Division of Clinical Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Yugo Ito
- Kidney Center, St Luke's International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japan
| | - Nozomi Kadota
- Kidney Center, St Luke's International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japan
| | - Kasumi Konishi
- Kidney Center, St Luke's International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japan
| | - Chiharu Aizawa
- Kidney Center, St Luke's International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japan
| | - Yukio Maruyama
- Department of Kidney and Hypertension, The Tokyo Jikei University School of Medicine, Tokyo, Japan
| | - Takuya Fujimaru
- Kidney Center, St Luke's International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japan
| | - Masahiko Nagahama
- Kidney Center, St Luke's International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japan
| | - Fumika Taki
- Kidney Center, St Luke's International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japan
| | - Michiko Suzuki
- Kidney Center, St Luke's International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japan
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Clarke KSP, Kingdon CC, Hughes MP, Lacerda EM, Lewis R, Kruchek EJ, Dorey RA, Labeed FH. The search for a blood-based biomarker for Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS): from biochemistry to electrophysiology. J Transl Med 2025; 23:149. [PMID: 39905423 PMCID: PMC11792299 DOI: 10.1186/s12967-025-06146-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 01/16/2025] [Indexed: 02/06/2025] Open
Abstract
BACKGROUND Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease of unknown aetiology characterised by symptoms of post-exertional malaise (PEM) and fatigue leading to substantial impairment in functioning. Other key symptoms include cognitive impairment and unrefreshing sleep, with many experiencing pain. To date there is no complete understanding of the triggering pathomechanisms of disease, and no quantitative biomarker available with sufficient sensitivity, specificity, and adoptability to provide conclusive diagnosis. Clinicians thus eliminate differential diagnoses, and rely on subjective, unspecific, and disputed clinical diagnostic criteria-a process that often takes years with patients being misdiagnosed and receiving inappropriate and sometimes detrimental care. Without a quantitative biomarker, trivialisation, scepticism, marginalisation, and misunderstanding of ME/CFS continues despite the significant disability for many. One in four individuals are bed-bound for long periods of time, others have difficulties maintaining a job/attending school, incurring individual income losses of thousands, while few participate in social activities. MAIN BODY Recent studies have reported promising quantifiable differences in the biochemical and electrophysiological properties of blood cells, which separate ME/CFS and non-ME/CFS participants with high sensitivities and specificities-demonstrating potential development of an accessible and relatively non-invasive diagnostic biomarker. This includes profiling immune cells using Raman spectroscopy, measuring the electrical impedance of blood samples during hyperosmotic challenge using a nano-electronic assay, use of metabolomic assays, and certain techniques which assess mitochondrial dysfunction. However, for clinical application, the specificity of these biomarkers to ME/CFS needs to be explored in more disease controls, and their practicality/logistics considered. Differences in cytokine profiles in ME/CFS are also well documented, but finding a consistent, stable, and replicable cytokine profile may not be possible. Increasing evidence demonstrates acetylcholine receptor and transient receptor potential ion channel dysfunction in ME/CFS, though how these findings could translate to a diagnostic biomarker are yet to be explored. CONCLUSION Different biochemical and electrophysiological properties which differentiate ME/CFS have been identified across studies, holding promise as potential blood-based quantitative diagnostic biomarkers for ME/CFS. However, further research is required to determine their specificity to ME/CFS and adoptability for clinical use.
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Affiliation(s)
- Krista S P Clarke
- Centre for Biomedical Engineering, School of Engineering, University of Surrey, Guildford, UK
| | - Caroline C Kingdon
- Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK
| | - Michael Pycraft Hughes
- Department of Biomedical Engineering and Biotechnology/Healthcare Engineering Innovation Center, Khalifa University, Abu Dhabi, UAE
| | - Eliana Mattos Lacerda
- Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK
| | - Rebecca Lewis
- Department of Comparative Biomedical Sciences, School of Veterinary Medicine, University of Surrey, Guildford, Surrey, GU2 7XH, UK
| | - Emily J Kruchek
- Centre for Biomedical Engineering, School of Engineering, University of Surrey, Guildford, UK
| | - Robert A Dorey
- Centre for Biomedical Engineering, School of Engineering, University of Surrey, Guildford, UK
| | - Fatima H Labeed
- Department of Biology, United Arab Emirates University, Al Ain, UAE.
- Centre for Biomedical Engineering, School of Engineering, University of Surrey, Guildford, UK.
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Baraniuk JN. Exertional Exhaustion (Post-Exertional Malaise, PEM) Evaluated by the Effects of Exercise on Cerebrospinal Fluid Metabolomics-Lipidomics and Serine Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Int J Mol Sci 2025; 26:1282. [PMID: 39941050 PMCID: PMC11818353 DOI: 10.3390/ijms26031282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 01/25/2025] [Accepted: 01/28/2025] [Indexed: 02/16/2025] Open
Abstract
Post-exertional malaise (PEM) is a defining condition of myalgic encephalomyelitis (ME/CFS). The concept requires that a provocation causes disabling limitation of cognitive and functional effort ("fatigue") that does not respond to rest. Cerebrospinal fluid was examined as a proxy for brain metabolite and lipid flux and to provide objective evidence of pathophysiological dysfunction. Two cohorts of ME/CFS and sedentary control subjects had lumbar punctures at baseline (non-exercise) or after submaximal exercise (post-exercise). Cerebrospinal fluid metabolites and lipids were quantified by targeted Biocrates mass spectrometry methods. Significant differences between ME/CFS and control, non-exercise vs. post-exercise, and by gender were examined by multivariate general linear regression and Bayesian regression methods. Differences were found at baseline between ME/CFS and control groups indicating disease-related pathologies, and between non-exercise and post-exercise groups implicating PEM-related pathologies. A new, novel finding was elevated serine and its derivatives sarcosine and phospholipids with a decrease in 5-methyltetrahydrofolate (5MTHF), which suggests general dysfunction of folate and one-carbon metabolism in ME/CFS. Exercise led to consumption of lipids in ME/CFS and controls while metabolites were consumed in ME/CFS but generated in controls. In general, the frequentist and Bayesian analyses generated complementary but not identical sets of analytes that matched the metabolic modules and pathway analysis. Cerebrospinal fluid is unique because it samples the choroid plexus, brain interstitial fluid, and cells of the brain parenchyma. The quantitative outcomes were placed into the context of the cell danger response hypothesis to explain shifts in serine and phospholipid synthesis; folate and one-carbon metabolism that affect sarcosine, creatine, purines, and thymidylate; aromatic and anaplerotic amino acids; glucose, TCA cycle, trans-aconitate, and coenzyme A in energy metabolism; and vitamin activities that may be altered by exertion. The metabolic and phospholipid profiles suggest the additional hypothesis that white matter dysfunction may contribute to the cognitive dysfunction in ME/CFS.
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Affiliation(s)
- James N Baraniuk
- Department of Medicine and Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, 3900 Reservoir Rd NW, Washington, DC 20007, USA
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Wang K, Shen M, Tang H, Zhou J, Liu Y, Niu D, Zeng Z, Pan L, Yao J, Sun C. Jingfang Granule promotes the tricarboxylic acid cycle to improve chronic fatigue syndrome by increasing the expression of Idh1 and Idh2. JOURNAL OF ETHNOPHARMACOLOGY 2025; 340:119241. [PMID: 39689747 DOI: 10.1016/j.jep.2024.119241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 12/08/2024] [Accepted: 12/13/2024] [Indexed: 12/19/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Chronic fatigue syndrome (CFS), as a complex, multisystemic, and multisystemic disorder affecting multiple organs and systems, often accompanies by symptoms such as post-exercise discomfort, sleep disorders, cognitive difficulties, and orthostatic intolerance. Jingfang Granule (JFG) is a traditional Chinese medicine that have significant protective effects on CFS, but the mechanism is still vague. AIM OF STUDY This study was designed to evaluate the protective mechanism of JFG on mice with CFS. MATERIALS AND METHODS The combined stimuli method was used to establish the mice CFS model, and JFG was orally administered. The body weight, exhaustion swimming training and tail suspension test were assayed every 7 days to evaluate the improvement of JFG on CFS. Lactic acid, adenosine triphosphate (ATP), malondialdehyde (MDA), superoxide dismutase (SOD), reactive oxygen species (ROS), IL-1β, TNF-α, IL-6 in serum and liver glycogen, muscle glycogen in muscle were analyzed. Transmission electron microscopy was used to detect mitochondrial morphology. The regulatory networks were investigated by proteomics and central carbon metabolomics, which were verified by Western blot. RESULTS JFG reversed the loss of weight and reduce of exhaust swimming time (P < 0.05) induced by CFS in mice, and increased the tail suspension time (P < 0.05), indicating that JFG has an improving effect on CFS. Meanwhile, JFG increased the spleen index (P < 0.05), decreased the thymus index (P < 0.05) and cardiac index (P < 0.05), inhibited the secretion of Lactic acid (P < 0.05), and increased the content of liver glycogen (P < 0.05), muscle glycogen (P < 0.05), and ATP (P < 0.05), and improved mitochondrial morphology in mice with CFS. JFG also inhibited the release of TNF-α (P < 0.05), IL-1β (P < 0.05) and IL-6 (P < 0.05) in serum by inhibiting TLR4/NF-κB signaling pathway and NLRP3 inflammasome signaling pathway, and inhibited oxidative stress by activating Nrf2/HO-1/NQO1 axis. Integrated central carbon metabolomics, proteomics and Western blot showed that JFG intervened in CFS by increasing the expression of Idh1 (P < 0.05) and Idh2 (P < 0.01) to promote tricarboxylic acid (TCA) cycle. CONCLUSIONS This study confirmed that JFG promoted the TCA cycle by increasing the expression of Idh1 and Idh2, and then inhibited inflammation and oxidative stress to prevent CFS injury, which provided a potential drug candidate for CFS treatment.
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Affiliation(s)
- Kun Wang
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Ji'nan, 250355, China.
| | - Mengmeng Shen
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Lunan Pharmaceutical Group Co. Ltd., Linyi, 276005, China.
| | - Hongguang Tang
- College of Pharmacy, Jiangsu Ocean University, Lianyungang, 222005, China.
| | - Jidong Zhou
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Lunan Pharmaceutical Group Co. Ltd., Linyi, 276005, China.
| | - Yan Liu
- School of Pharmacy, Qingdao University, Qingdao, 266071, China.
| | - Dejun Niu
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Lunan Pharmaceutical Group Co. Ltd., Linyi, 276005, China.
| | - Zhen Zeng
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Lunan Pharmaceutical Group Co. Ltd., Linyi, 276005, China.
| | - Lihong Pan
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Lunan Pharmaceutical Group Co. Ltd., Linyi, 276005, China.
| | - Jingchun Yao
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Ji'nan, 250355, China; State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Lunan Pharmaceutical Group Co. Ltd., Linyi, 276005, China.
| | - Chenghong Sun
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Lunan Pharmaceutical Group Co. Ltd., Linyi, 276005, China; College of Food Science and Pharmaceutical Engineering, Zaozhuang University, Zaozhuang, 277160, China.
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Tsoukalas D, Sarandi E, Fragoulakis V, Xenidis S, Mhliopoulou M, Charta M, Paramera E, Papakonstantinou E, Tsatsakis A. Metabolomics-based treatment for chronic diseases: results from a multidisciplinary clinical study. BMJ Nutr Prev Health 2024; 7:e000883. [PMID: 39882279 PMCID: PMC11773651 DOI: 10.1136/bmjnph-2024-000883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 11/20/2024] [Indexed: 01/31/2025] Open
Abstract
Background Non-communicable diseases (NCDs), known as chronic diseases, significantly impact patients' quality of life (QoL) and increase medical expenses. The majority of risk factors are modifiable, and metabolomics has been suggested as a promising strategy for their evaluation, though real-world data are scarce. This study evaluated the QoL improvement and cost-effectiveness of a metabolomics-based treatment for NCDs, aiming to restore metabolic dysfunctions and nutritional deficiencies. Methods We performed a pre-post intervention analysis using clinical, metabolomics, QoL and economic data obtained from the electronic health records of 765 patients visiting a private practice. The intervention consisted of personalised treatment to restore metabolic dysfunctions and nutritional deficiencies identified by metabolomics alongside the standard treatment for their condition. The mean intervention duration was 401 days. Results Significant improvement was identified in energy levels, sleep quality, gastrointestinal function and physical activity (p<0.001). 67.9% of participants reported significant improvement in the overall QoL, and the average quality-adjusted life-years (QALYs) increased by 0.064 (95% uncertainty interval 0.050 to 0.078) post-treatment. The incremental cost-effectiveness ratio was estimated at €49.774/QALY (95% CI €40.110 to €61.433). Metabolic profiling demonstrated that 16/35 organic acids and 11/24 total fatty acids were significantly changed post-treatment (p<0.001), participating in key pathways such as energy metabolism, microbiome and neurotransmitter turnover. Vitamin D and 5-methyltetrahydrofolate insufficiency was significantly restored (p=0.036). Conclusion This is the first study providing evidence that the integration of metabolomics in clinical practice can have a clinical benefit for patients' QoL and may be a cost-effective method.
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Affiliation(s)
- Dimitris Tsoukalas
- European Institute of Molecular Medicine, Rome, Italy
- Metabolomic Medicine, Athens, Greece
| | - Evangelia Sarandi
- Metabolomic Medicine, Athens, Greece
- Laboratory of Toxicology and Forensic Sciences, Medical School of the University of Crete, Crete, Greece
| | - Vassilleios Fragoulakis
- The Golden Helix Foundation, London, UK
- Laboratory of Health Economics and Management (LabHEM), Economics Department, University of Piraeus, Athens, Greece
| | | | | | | | | | | | - Aristidis Tsatsakis
- Laboratory of Toxicology and Forensic Sciences, Medical School of the University of Crete, Crete, Greece
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Garbsch R, Schäfer H, Mooren FC, Schmitz B. Analysis of fat oxidation capacity during cardiopulmonary exercise testing indicates long-lasting metabolic disturbance in patients with post-covid-19 syndrome. Clin Nutr 2024; 43:26-35. [PMID: 39423759 DOI: 10.1016/j.clnu.2024.10.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 10/01/2024] [Accepted: 10/07/2024] [Indexed: 10/21/2024]
Abstract
BACKGROUND & AIMS Post-COVID-19 Syndrome (PCS) is characterized by symptoms including fatigue, reduced physical performance, dyspnea, cognitive impairment, and psychological distress. The mechanisms underlying the onset and severity of PCS point to mitochondrial dysfunction as significant contributor. This study examined fat oxidation as a function of mitochondrial capacity during exercise. METHODS Single-center prospective cohort study during inpatient rehabilitation. Cardiopulmonary exercise testing and assessment of fatigue using questionnaires were performed at admission and discharge. Detailed spirometric breath-by-breath data were used to calculate substrate oxidation rates. RESULTS Patients (N = 187; 38 % women; 49.7 ± 11.4 years) were referred to rehabilitation 253.4 ± 130.6 days after infection. Lead symptoms included fatigue/exercise intolerance (79.9 %), shortness of breath (77.0 %), and cognitive dysfunction (55.1 %). Fat oxidation capacity was disturbed in PCS patients overall (AUC: 11.3 [10.7-11.9]) compared to healthy controls (p < 0.0001), with hospitalization during acute infection predicting the level of disturbance (p < 0.0001). Low exercise capacity and high fatigue scores resulted in reduced fat oxidation (both p < 0.0001). In particular, younger males were affected by significantly reduced fat oxidation capacity (sex: p = 0.002; age: p < 0.001). Metabolic disturbance was significantly improved during exercise-based rehabilitation (AUC: 14.9 [14.4-15.4]; p < 0.0001), even for the group of younger impaired males (+44.2 %; p < 0.0001). Carbohydrate oxidation was not impaired. CONCLUSIONS PCS-specific restrictions in fat oxidation may indicate persistent mitochondrial dysfunction. Clinical assessment of PCS patients should include detailed breath-by-breath analysis during exercise to identify metabolic alterations especially in the group of younger males identified in this report. Exercise-based rehabilitation results in improved exercise capacity and fat oxidation and thus likely mitochondrial function. CLINICAL TRIALS NCT06468722.
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Affiliation(s)
- René Garbsch
- Department of Rehabilitation Sciences, Faculty of Health, University of Witten/Herdecke, Witten, Germany; DRV Clinic Königsfeld, Center for Medical Rehabilitation, Ennepetal, Germany
| | - Hendrik Schäfer
- Department of Rehabilitation Sciences, Faculty of Health, University of Witten/Herdecke, Witten, Germany; DRV Clinic Königsfeld, Center for Medical Rehabilitation, Ennepetal, Germany
| | - Frank C Mooren
- Department of Rehabilitation Sciences, Faculty of Health, University of Witten/Herdecke, Witten, Germany; DRV Clinic Königsfeld, Center for Medical Rehabilitation, Ennepetal, Germany
| | - Boris Schmitz
- Department of Rehabilitation Sciences, Faculty of Health, University of Witten/Herdecke, Witten, Germany; DRV Clinic Königsfeld, Center for Medical Rehabilitation, Ennepetal, Germany.
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9
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Huang K, G C de Sá A, Thomas N, Phair RD, Gooley PR, Ascher DB, Armstrong CW. Discriminating Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and comorbid conditions using metabolomics in UK Biobank. COMMUNICATIONS MEDICINE 2024; 4:248. [PMID: 39592839 PMCID: PMC11599898 DOI: 10.1038/s43856-024-00669-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Accepted: 11/06/2024] [Indexed: 11/28/2024] Open
Abstract
BACKGROUND Diagnosing complex illnesses like Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is complicated due to the diverse symptomology and presence of comorbid conditions. ME/CFS patients often present with multiple health issues, therefore, incorporating comorbidities into research can provide a more accurate understanding of the condition's symptomatology and severity, to better reflect real-life patient experiences. METHODS We performed association studies and machine learning on 1194 ME/CFS individuals with blood plasma nuclear magnetic resonance (NMR) metabolomics profiles, and seven exclusive comorbid cohorts: hypertension (n = 13,559), depression (n = 2522), asthma (n = 6406), irritable bowel syndrome (n = 859), hay fever (n = 3025), hypothyroidism (n = 1226), migraine (n = 1551) and a non-diseased control group (n = 53,009). RESULTS We present a lipoprotein perspective on ME/CFS pathophysiology, highlighting gender-specific differences and identifying overlapping associations with comorbid conditions, specifically surface lipids, and ketone bodies from 168 significant individual biomarker associations. Additionally, we searched for, trained, and optimised a machine learning algorithm, resulting in a predictive model using 19 baseline characteristics and nine NMR biomarkers which could identify ME/CFS with an AUC of 0.83 and recall of 0.70. A multi-variable score was subsequently derived from the same 28 features, which exhibited ~2.5 times greater association than the top individual biomarker. CONCLUSIONS This study provides an end-to-end analytical workflow that explores the potential clinical utility that association scores may have for ME/CFS and other difficult to diagnose conditions.
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Affiliation(s)
- Katherine Huang
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC, Australia
| | - Alex G C de Sá
- School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane City, QLD, Australia
- Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
- Baker Department of Cardiometabolic Health, University of Melbourne, Parkville, VIC, Australia
| | - Natalie Thomas
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC, Australia
| | - Robert D Phair
- Integrative Bioinformatics, Inc., Mountain View, CA, USA
| | - Paul R Gooley
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC, Australia
| | - David B Ascher
- School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane City, QLD, Australia
- Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
- Baker Department of Cardiometabolic Health, University of Melbourne, Parkville, VIC, Australia
| | - Christopher W Armstrong
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC, Australia.
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10
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Liu T, Sun W, Guo S, Chen T, Zhu M, Yuan Z, Li B, Lu J, Shao Y, Qu Y, Sun Z, Feng C, Yang T. Research progress on pathogenesis of chronic fatigue syndrome and treatment of traditional Chinese and Western medicine. Auton Neurosci 2024; 255:103198. [PMID: 39047501 DOI: 10.1016/j.autneu.2024.103198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Revised: 06/11/2024] [Accepted: 06/30/2024] [Indexed: 07/27/2024]
Abstract
Chronic Fatigue Syndrome (CFS) is a complex and perplexing medical disorder primarily characterized by persistent and debilitating fatigue, often accompanied by a constellation of symptoms, including weakness, dyspnea, arthromyalgia, sore throat, and disrupted sleep patterns. CFS is defined by its persistent or recurrent manifestation for a minimum duration of six months, marked by an enduring and unrelenting fatigue that remains refractory to rest. In recent decades, this condition has garnered significant attention within the medical community. While the precise etiology of CFS remains elusive, it is postulated to be multifactorial. CFS is potentially associated with various contributory factors such as infections, chronic stress, genetic predisposition, immune dysregulation, and psychosocial influences. The pathophysiological underpinnings of CFS encompass viral infections, immune system dysregulation, neuroendocrine aberrations, heightened oxidative stress, and perturbations in gut microbiota. Presently, clinical management predominantly relies on pharmaceutical interventions or singular therapeutic modalities, offering alleviation of specific symptoms but exhibiting inherent limitations. Traditional Chinese Medicine (TCM) interventions have emerged as a promising paradigm, demonstrating notable efficacy through their multimodal, multi-target, multi-pathway approach, and holistic regulatory mechanisms. These interventions effectively address the lacunae in contemporary medical interventions. This comprehensive review synthesizes recent advancements in the understanding of the etiological factors, pathophysiological mechanisms, and interventional strategies for CFS, drawing from a corpus of domestic and international literature. Its aim is to furnish valuable insights for clinicians actively involved in diagnosing and treating CFS, as well as for pharmaceutical researchers delving into innovative drug development pathways. Moreover, it seeks to address the intricate challenges confronted by clinical practitioners in managing this incapacitating condition.
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Affiliation(s)
- Tingting Liu
- Heilongjiang University of Chinese Medicine, Harbin, China
| | - Weibo Sun
- Harbin Medical University, Harbin, China
| | - Shuhao Guo
- Heilongjiang University of Chinese Medicine, Harbin, China
| | - Tao Chen
- Heilongjiang University of Chinese Medicine, Harbin, China
| | - Minghang Zhu
- Heilongjiang University of Chinese Medicine, Harbin, China
| | - Zhiying Yuan
- Heilongjiang University of Chinese Medicine, Harbin, China
| | - Binbin Li
- Heilongjiang University of Chinese Medicine, Harbin, China
| | - Jing Lu
- Heilongjiang University of Chinese Medicine, Harbin, China
| | - Yuying Shao
- Heilongjiang University of Chinese Medicine, Harbin, China
| | - Yuanyuan Qu
- Heilongjiang University of Chinese Medicine, Harbin, China
| | - Zhongren Sun
- Heilongjiang University of Chinese Medicine, Harbin, China
| | - Chuwen Feng
- Heilongjiang University of Chinese Medicine, Harbin, China; Rehabilitation Medicine Department, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China; Key Laboratory of Chinese Medicine Informotics in Heilongjiang Province, 24 Heping Road, Harbin, China
| | - Tiansong Yang
- Heilongjiang University of Chinese Medicine, Harbin, China; Rehabilitation Medicine Department, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China; Key Laboratory of Chinese Medicine Informotics in Heilongjiang Province, 24 Heping Road, Harbin, China.
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11
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Sakurai M, Motoike IN, Hishinuma E, Aoki Y, Tadaka S, Kogure M, Orui M, Ishikuro M, Obara T, Nakaya N, Kumada K, Hozawa A, Kuriyama S, Yamamoto M, Koshiba S, Kinoshita K. Identifying critical age and gender-based metabolomic shifts in a Japanese population of the Tohoku Medical Megabank cohort. Sci Rep 2024; 14:15681. [PMID: 38977808 PMCID: PMC11231361 DOI: 10.1038/s41598-024-66180-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 06/27/2024] [Indexed: 07/10/2024] Open
Abstract
Understanding the physiological changes associated with aging and the associated disease risks is essential to establish biomarkers as indicators of biological aging. This study used the NMR-measured plasma metabolome to calculate age-specific metabolite indices. In doing so, the scope of the study was deliberately simplified to capture general trends and insights into age-related changes in metabolic patterns. In addition, changes in metabolite concentrations with age were examined in detail, with the period from 55-59 to 60-64 years being a period of significant metabolic change, particularly in men, and from 45-49 to 50-54 years in females. These results illustrate the different variations in metabolite concentrations by sex and provide new insights into the relationship between age and metabolic diseases.
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Affiliation(s)
- Miyuki Sakurai
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - Ikuko N Motoike
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
- Graduate School of Information Sciences, Tohoku University, Sendai, Japan
| | - Eiji Hishinuma
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
- Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, Sendai, Japan
| | - Yuichi Aoki
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
- Graduate School of Information Sciences, Tohoku University, Sendai, Japan
| | - Shu Tadaka
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - Mana Kogure
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
- Graduate School of Medicine, Tohoku University, Sendai, Japan
| | - Masatsugu Orui
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
- Graduate School of Medicine, Tohoku University, Sendai, Japan
| | - Mami Ishikuro
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
- Graduate School of Medicine, Tohoku University, Sendai, Japan
| | - Taku Obara
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
- Graduate School of Medicine, Tohoku University, Sendai, Japan
- Tohoku University Hospital, Tohoku University, Sendai, Japan
| | - Naoki Nakaya
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
- Graduate School of Medicine, Tohoku University, Sendai, Japan
| | - Kazuki Kumada
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - Atsushi Hozawa
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
- Graduate School of Medicine, Tohoku University, Sendai, Japan
| | - Shinichi Kuriyama
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
- Graduate School of Medicine, Tohoku University, Sendai, Japan
- International Research Institute of Disaster Science, Tohoku University, Sendai, Japan
| | - Masayuki Yamamoto
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - Seizo Koshiba
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
- Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, Sendai, Japan
| | - Kengo Kinoshita
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
- Graduate School of Information Sciences, Tohoku University, Sendai, Japan.
- Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, Sendai, Japan.
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12
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Apostolou E, Rosén A. Epigenetic reprograming in myalgic encephalomyelitis/chronic fatigue syndrome: A narrative of latent viruses. J Intern Med 2024; 296:93-115. [PMID: 38693641 DOI: 10.1111/joim.13792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/03/2024]
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic disease presenting with severe fatigue, post-exertional malaise, and cognitive disturbances-among a spectrum of symptoms-that collectively render the patient housebound or bedbound. Epigenetic studies in ME/CFS collectively confirm alterations and/or malfunctions in cellular and organismal physiology associated with immune responses, cellular metabolism, cell death and proliferation, and neuronal and endothelial cell function. The sudden onset of ME/CFS follows a major stress factor that, in approximately 70% of cases, involves viral infection, and ME/CFS symptoms overlap with those of long COVID. Viruses primarily linked to ME/CFS pathology are the symbiotic herpesviruses, which follow a bivalent latent-lytic lifecycle. The complex interaction between viruses and hosts involves strategies from both sides: immune evasion and persistence by the viruses, and immune activation and viral clearance by the host. This dynamic interaction is imperative for herpesviruses that facilitate their persistence through epigenetic regulation of their own and the host genome. In the current article, we provide an overview of the epigenetic signatures demonstrated in ME/CFS and focus on the potential strategies that latent viruses-particularly Epstein-Barr virus-may employ in long-term epigenetic reprograming in ME/CFS. Epigenetic studies could aid in elucidating relevant biological pathways impacted in ME/CFS and reflect the physiological variations among the patients that stem from environmental triggers, including exogenous viruses and/or altered viral activity.
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Affiliation(s)
- Eirini Apostolou
- Division of Cell and Neurobiology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Anders Rosén
- Division of Cell and Neurobiology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
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13
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Arron HE, Marsh BD, Kell DB, Khan MA, Jaeger BR, Pretorius E. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: the biology of a neglected disease. Front Immunol 2024; 15:1386607. [PMID: 38887284 PMCID: PMC11180809 DOI: 10.3389/fimmu.2024.1386607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Accepted: 04/11/2024] [Indexed: 06/20/2024] Open
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic, debilitating disease characterised by a wide range of symptoms that severely impact all aspects of life. Despite its significant prevalence, ME/CFS remains one of the most understudied and misunderstood conditions in modern medicine. ME/CFS lacks standardised diagnostic criteria owing to variations in both inclusion and exclusion criteria across different diagnostic guidelines, and furthermore, there are currently no effective treatments available. Moving beyond the traditional fragmented perspectives that have limited our understanding and management of the disease, our analysis of current information on ME/CFS represents a significant paradigm shift by synthesising the disease's multifactorial origins into a cohesive model. We discuss how ME/CFS emerges from an intricate web of genetic vulnerabilities and environmental triggers, notably viral infections, leading to a complex series of pathological responses including immune dysregulation, chronic inflammation, gut dysbiosis, and metabolic disturbances. This comprehensive model not only advances our understanding of ME/CFS's pathophysiology but also opens new avenues for research and potential therapeutic strategies. By integrating these disparate elements, our work emphasises the necessity of a holistic approach to diagnosing, researching, and treating ME/CFS, urging the scientific community to reconsider the disease's complexity and the multifaceted approach required for its study and management.
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Affiliation(s)
- Hayley E. Arron
- Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, South Africa
| | - Benjamin D. Marsh
- MRCPCH Consultant Paediatric Neurodisability, Exeter, Devon, United Kingdom
| | - Douglas B. Kell
- Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, South Africa
- Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, United Kingdom
- The Novo Nordisk Foundation Centre for Biosustainability, Technical University of Denmark, Lyngby, Denmark
| | - M. Asad Khan
- Directorate of Respiratory Medicine, Manchester University Hospitals, Wythenshawe Hospital, Manchester, United Kingdom
| | - Beate R. Jaeger
- Long COVID department, Clinic St Georg, Bad Aibling, Germany
| | - Etheresia Pretorius
- Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, South Africa
- Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, United Kingdom
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14
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Okinaka Y, Kageyama S, Goto T, Sugimoto M, Tomita A, Aizawa Y, Kobayashi K, Wada A, Kawauchi A, Kataoka Y. Metabolomic profiling of cancer-related fatigue involved in cachexia and chemotherapy. Sci Rep 2024; 14:8329. [PMID: 38594321 PMCID: PMC11004174 DOI: 10.1038/s41598-024-57747-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 03/21/2024] [Indexed: 04/11/2024] Open
Abstract
Patients with advanced cancer are frequently burdened with a severe sensation of fatigue called cancer-related fatigue (CRF). CRF is induced at various stages and treatments, such as cachexia and chemotherapy, and reduces the overall survival of patients. Objective and quantitative assessment of CRF could contribute to the diagnosis and prediction of treatment efficacy. However, such studies have not been intensively performed, particularly regarding metabolic profiles. Here, we conducted plasma metabolomics of 15 patients with urological cancer. The patients with and without fatigue, including those with cachexia or chemotherapy-induced fatigue, were compared. Significantly lower concentrations of valine and tryptophan were observed in fatigued patients than in non-fatigued patients. In addition, significantly higher concentrations of polyamine pathway metabolites were observed in patients with fatigue and cachexia than in those without cachexia. Patients with exacerbated fatigue due to chemotherapy showed significantly decreased cysteine and methionine metabolism before chemotherapy compared with those without fatigue exacerbation. These findings suggest that plasma metabolic profiles could help improve the diagnosis and monitoring of CRF.
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Affiliation(s)
- Yuki Okinaka
- Department of Urology, Shiga University of Medical Science, Shiga, 520-2192, Japan
- RIKEN Center for Biosystems Dynamics Research, Hyogo, 650-0047, Japan
| | - Susumu Kageyama
- Department of Urology, Shiga University of Medical Science, Shiga, 520-2192, Japan
| | - Toshiyuki Goto
- RIKEN Center for Biosystems Dynamics Research, Hyogo, 650-0047, Japan
- Graduate School of Science, Technology and Innovation, Kobe University, Hyogo, 650-0047, Japan
| | - Masahiro Sugimoto
- Institute of Medical Science, Tokyo Medical University, Tokyo, 160-8402, Japan
- Institute for Advanced Biosciences, Keio University, Yamagata, 997-0052, Japan
| | - Atsumi Tomita
- Institute of Medical Science, Tokyo Medical University, Tokyo, 160-8402, Japan
| | - Yumi Aizawa
- Institute of Medical Science, Tokyo Medical University, Tokyo, 160-8402, Japan
| | - Kenichi Kobayashi
- Department of Urology, Shiga University of Medical Science, Shiga, 520-2192, Japan
| | - Akinori Wada
- Department of Urology, Shiga University of Medical Science, Shiga, 520-2192, Japan
| | - Akihiro Kawauchi
- Department of Urology, Shiga University of Medical Science, Shiga, 520-2192, Japan
| | - Yosky Kataoka
- RIKEN Center for Biosystems Dynamics Research, Hyogo, 650-0047, Japan.
- Graduate School of Science, Technology and Innovation, Kobe University, Hyogo, 650-0047, Japan.
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15
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Ren W, Wang M, Wang Q, Huang Q, Feng S, Tao J, Wen C, Xu M, He J, Yang C, Zhao K, Yu X. Altered functional connectivity in patients with post-stroke fatigue: A resting-state fMRI study. J Affect Disord 2024; 350:468-475. [PMID: 38224743 DOI: 10.1016/j.jad.2024.01.129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Revised: 11/24/2023] [Accepted: 01/12/2024] [Indexed: 01/17/2024]
Abstract
BACKGROUND Post-stroke fatigue (PSF) was a common complication after stroke. This study aimed to explore the neuroimaging mechanism of PSF, which was rarely studied. METHODS Patients with the first episode of ischemic stroke were recruited from the First Affiliated Hospital of Wenzhou Medical University between March 2021 and December 2022. The fatigue severity scale (FSS) was used to assess fatigue symptoms. PSF was diagnosed by a neurologist based on the FSS score and PSF diagnostic criteria. All the patients were scanned by resting-state functional MRI (rs-fMRI). Precuneus, the posterior node of default-mode network (pDMN), was related to fatigue. Therefore, imaging data were further analyzed by the seed-based resting-state functional connectivity (FC) approach, with the left (PCUN.L) and right precuneus (PCUN.R) being the seeds. RESULTS A total of 70 patients with acute ischemic stroke were finally recruited, comprising 40 patients with PSF and 30 patients without PSF. Both the PCUN.L and PCUN.R seeds (pDMN) exhibited decreased FC with the prefrontal lobes located at the anterior part of DMN (aDMN), and the FC values were negatively correlated with FSS scores (both p < 0.001). These two seeds also exhibited increased FC with the right insula, and the FC values were positively correlated with FSS scores (both p < 0.05). CONCLUSION The abnormal FC between the aDMN and pDMN was associated with PSF. Besides, the insula, related to interoception, might also play an important role in PSF.
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Affiliation(s)
- Wenwei Ren
- Department of Psychiatry, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; School of Mental Health, Wenzhou Medical University, Wenzhou, China
| | - Mengpu Wang
- School of Mental Health, The Affiliated Wenzhou Kangning Hospital, Wenzhou Medical University, Wenzhou, China; School of Mental Health, Wenzhou Medical University, Wenzhou, China
| | - Qiongzhang Wang
- School of Mental Health, Wenzhou Medical University, Wenzhou, China
| | - Qiqi Huang
- Pediatric nursing unit, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Shengchuang Feng
- Centre for Lifelong Learning and Individualised Cognition, Nanyang Technological University, Singapore
| | - Jiejie Tao
- Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Caiyun Wen
- Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Minjie Xu
- Lishui Second People's Hospital Affiliated to Wenzhou Medical University, Lishui, China
| | - Jincai He
- Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Chuang Yang
- Department of Psychiatry, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ke Zhao
- School of Mental Health, Wenzhou Medical University, Wenzhou, China; Lishui Second People's Hospital Affiliated to Wenzhou Medical University, Lishui, China; The Affiliated Kangning Hospital of Wenzhou Medical University, Wenzhou, China.
| | - Xin Yu
- School of Mental Health, Wenzhou Medical University, Wenzhou, China; Peking University Institute of Mental Health (Sixth Hospital), Beijing, China; National Clinical Research Center for Mental Disorders and Key Laboratory of Mental Health, Ministry of Health, Peking University, Beijing, China; Beijing Municipal Key Laboratory for Translational Research on Diagnosis and Treatment of Dementia, Beijing, China.
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16
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Gil A, Hoag GE, Salerno JP, Hornig M, Klimas N, Selin LK. Identification of CD8 T-cell dysfunction associated with symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID and treatment with a nebulized antioxidant/anti-pathogen agent in a retrospective case series. Brain Behav Immun Health 2024; 36:100720. [PMID: 38327880 PMCID: PMC10847863 DOI: 10.1016/j.bbih.2023.100720] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 11/29/2023] [Accepted: 12/18/2023] [Indexed: 02/09/2024] Open
Abstract
Background Patients with post-acute sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection (PASC, i.e., Long COVID) have a symptom complex highly analogous to many features of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), suggesting they may share some aspects of pathogenesis in these similar disorders. ME/CFS is a complex disease affecting numerous organ systems and biological processes and is often preceded by an infection-like episode. It is postulated that the chronic manifestations of illness may result from an altered host response to infection or inability to resolve inflammation, as is being reported in Long COVID. The immunopathogenesis of both disorders is still poorly understood. Here, we show data that suggest Long COVID and ME/CFS may be due to an aberrant response to an immunological trigger-like infection, resulting in a dysregulated immune system with CD8 T-cell dysfunction reminiscent of some aspects of T-cell clonal exhaustion, a phenomenon associated with oxidative stress. As there is an urgent need for diagnostic tools and treatment strategies for these two related disabling disorders, here, in a retrospective case series, we have also identified a potential nebulized antioxidant/anti-pathogen treatment that has evidence of a good safety profile. This nebulized agent is comprised of five ingredients previously reported individually to relieve oxidative stress, attenuate NF-κB signaling, and/or to act directly to inhibit pathogens, including viruses. Administration of this treatment by nebulizer results in rapid access of small doses of well-studied antioxidants and agents with anti-pathogen potential to the lungs; components of this nebulized agent are also likely to be distributed systemically, with potential to enter the central nervous system. Methods and Findings: We conducted an analysis of CD8 T-cell function and severity of symptoms by self-report questionnaires in ME/CFS, Long COVID and healthy controls. We developed a CD8 T-cell functional assay, assessing CD8 T-cell dysfunction by intracellular cytokine staining (ICS) in a group of ME/CFS (n = 12) and Long COVID patients (n = 8), comparing to healthy controls (HC) with similar age and sex (n = 10). Magnet-enriched fresh CD8 T-cells in both patient groups had a significantly diminished capacity to produce both cytokines, IFNγ or TNFα, after PMA stimulation when compared to HC. The symptom severity questionnaire showed similar symptom profiles for the two disorders. Fortuitously, through a retrospective case series, we were able to examine the ICS and questionnaire data of 4 ME/CFS and 4 Long COVID patients in conjunction with their treatment (3-15 months). In parallel with the treatment pursued electively by participants in this retrospective case series, there was an increase in CD8 T-cell IFNγ and TNFα production and a decrease in overall self-reported symptom severity score by 54%. No serious treatment-associated side effects or laboratory anomalies were noted in these patients. Conclusions Here, in this small study, we present two observations that appear potentially fundamental to the pathogenesis and treatment of Long COVID and ME/CFS. The first is that both disorders appear to be characterized by dysfunctional CD8 T-cells with severe deficiencies in their abilities to produce IFNγ and TNFα. The second is that in a small retrospective Long COVID and ME/CFS case series, this immune dysfunction and patient health improved in parallel with treatment with an immunomodulatory, antioxidant pharmacological treatment with anticipated anti-pathogen activity. This work provides evidence of the potential utility of a biomarker, CD8 T-cell dysfunction, and suggests the potential for benefit from a new nebulized antioxidant/anti-pathogen treatment. These immune biomarker data may help build capacity for improved diagnosis and tracking of treatment outcomes during clinical trials for both Long COVID and ME/CFS while providing clues to new treatment avenues that suggest potential efficacy for both conditions.
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Affiliation(s)
- Anna Gil
- University of Massachusetts Chan Medical School, Department of Pathology, Worcester, MA, USA
| | | | - John P. Salerno
- Inspiritol, Inc., Fairfield, CT, USA
- The Salerno Center for Complementary Medicine, New York, USA
| | - Mady Hornig
- Columbia University Mailman School of Public Health, New York, USA
| | - Nancy Klimas
- Nova Southeastern University, Fort Lauderdale, Florida, USA
| | - Liisa K. Selin
- University of Massachusetts Chan Medical School, Department of Pathology, Worcester, MA, USA
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17
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Sumida Y, Tsunoda M. Development of a Two-Dimensional Liquid Chromatographic Method for Analysis of Urea Cycle Amino Acids. Molecules 2024; 29:700. [PMID: 38338444 PMCID: PMC10856254 DOI: 10.3390/molecules29030700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 01/22/2024] [Accepted: 01/29/2024] [Indexed: 02/12/2024] Open
Abstract
The urea cycle has been found to be closely associated with certain types of cancers and other diseases such as cardiovascular disease and chronic kidney disease. An analytical method for the precise quantification of urea cycle amino acids (arginine, ornithine, citrulline, and argininosuccinate) by off-line two-dimensional liquid chromatography (2D-LC) combined with fluorescence-based detection was developed. Before analysis, the amino acids were derivatised with 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F) to obtain NBD-amino acids. The first dimension involved the reversed-phase separation, in which NBD derivatives of urea cycle amino acids were completely separated from each other and mostly separated from the 18 NBD-proteinogenic amino acids. The samples were eluted with stepwise gradient using 0.02% trifluoroacetic acid in water-acetonitrile as the mobile phase. In the second dimension, an amino column was used for the separation of NBD-ornithine, -citrulline, and -argininosuccinate, while a sulfonic acid column was used to separate NBD-arginine. The developed 2D-LC system was used to analyse human plasma samples. The fractions of NBD-urea cycle amino acids obtained in the first dimension were collected manually and introduced into the second dimension. By choosing appropriate mobile phases for the second dimension, each NBD-urea cycle amino acid eluted in the first dimension was well separated from the other proteinogenic amino acids and interference from endogenous substance. This could not be achieved in the first dimension. The urea cycle amino acids in human plasma sample were quantified, and the method was well validated. The calibration curves for each NBD-urea cycle amino acid showed good linearity from 3 (ASA) or 15 (Orn, Cit, and Arg) to 600 nM, with correlation coefficients higher than 0.9969. The intraday and interday precisions were less than 7.9% and 15%, respectively. The 2D-LC system is expected to be useful for understanding the involvement of the urea cycle in disease progression.
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Affiliation(s)
| | - Makoto Tsunoda
- Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan
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18
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Vanrusselt D, Sleurs C, Arif M, Lemiere J, Verschueren S, Uyttebroeck A. Biomarkers of fatigue in oncology: A systematic review. Crit Rev Oncol Hematol 2024; 194:104245. [PMID: 38141868 DOI: 10.1016/j.critrevonc.2023.104245] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 12/18/2023] [Accepted: 12/18/2023] [Indexed: 12/25/2023] Open
Abstract
Cancer-related fatigue (CRF) is a distressing side effect of cancer and treatment, affecting both patients during active treatment and survivors, negatively impacting quality of life. While its exact cause remains uncertain, various mechanisms such as immune dysfunction, HPA-axis dysfunction, and treatment toxicity are proposed. Inflammatory biomarkers of CRF have been explored in previous research, but non-inflammatory markers have not been comprehensively studied. This systematic review analysed 33 studies to identify non-inflammatory peripheral blood biomarkers associated with CRF. Promising markers included Hb, blood coagulation factors, BDNF, tryptophan, GAA, mtDNA, platinum, CA125, and cystatin-C. Inconsistent findings were observed for other markers like VEGF, leptin, and stress hormones. Most studies focused on adults. Research in pediatrics is limited. This review showed partial evidence for the inflammaging hypothesis (neurotoxicity due to neuro-inflammation) laying at the basis of CRF. Further research, especially in pediatrics, is needed to confirm this hypothesis and guide future biomarker studies.
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Affiliation(s)
- Deveny Vanrusselt
- Pediatric Hematology and Oncology, University Hospitals Leuven, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium.
| | - Charlotte Sleurs
- Pediatric Hematology and Oncology, University Hospitals Leuven, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium; Department of Social and Behavioral Sciences, Tilburg University, Tilburg, the Netherlands
| | - Mahnoor Arif
- Department of Oncology, KU Leuven, Leuven, Belgium
| | - Jurgen Lemiere
- Pediatric Hematology and Oncology, University Hospitals Leuven, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium
| | | | - Anne Uyttebroeck
- Pediatric Hematology and Oncology, University Hospitals Leuven, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium
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19
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Kaczmarek MP. Heterogenous circulating miRNA changes in ME/CFS converge on a unified cluster of target genes: A computational analysis. PLoS One 2023; 18:e0296060. [PMID: 38157384 PMCID: PMC10756525 DOI: 10.1371/journal.pone.0296060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 12/02/2023] [Indexed: 01/03/2024] Open
Abstract
Myalgic Encephalomyelitis / Chronic Fatigue Syndrome is a debilitating, multisystem disease of unknown mechanism, with a currently ongoing search for its endocrine mediators. Circulating microRNAs (miRNA) are a promising candidate for such a mediator and have been reported as significantly different in the patient population versus healthy controls by multiple studies. None of these studies, however, agree with each other on which specific miRNA are under- or over-expressed. This discrepancy is the subject of the computational study presented here, in which a deep dive into the predicted gene targets and their functional interactions is conducted, revealing that the aberrant circulating miRNAs in ME/CFS, although different between patients, seem to mainly target the same specific set of genes (p ≈ 0.0018), which are very functionally related to each other (p ≲ 0.0001). Further analysis of these functional relations, based on directional pathway information, points to impairments in exercise hyperemia, angiogenic adaptations to hypoxia, antioxidant defenses, and TGF-β signaling, as well as a shift towards mitochondrial fission, corroborating and explaining previous direct observations in ME/CFS. Many transcription factors and epigenetic modulators are implicated as well, with currently uncertain downstream combinatory effects. As the results show significant similarity to previous research on latent herpesvirus involvement in ME/CFS, the possibility of a herpesvirus origin of these miRNA changes is also explored through further computational analysis and literature review, showing that 8 out of the 10 most central miRNAs analyzed are known to be upregulated by various herpesviruses. In total, the results establish an appreciable and possibly central role for circulating microRNAs in ME/CFS etiology that merits further experimental research.
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20
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Xu J, Lodge T, Kingdon C, Strong JWL, Maclennan J, Lacerda E, Kujawski S, Zalewski P, Huang WE, Morten KJ. Developing a Blood Cell-Based Diagnostic Test for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Using Peripheral Blood Mononuclear Cells. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2302146. [PMID: 37653608 PMCID: PMC10602530 DOI: 10.1002/advs.202302146] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 07/12/2023] [Indexed: 09/02/2023]
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by debilitating fatigue that profoundly impacts patients' lives. Diagnosis of ME/CFS remains challenging, with most patients relying on self-report, questionnaires, and subjective measures to receive a diagnosis, and many never receiving a clear diagnosis at all. In this study, a single-cell Raman platform and artificial intelligence are utilized to analyze blood cells from 98 human subjects, including 61 ME/CFS patients of varying disease severity and 37 healthy and disease controls. These results demonstrate that Raman profiles of blood cells can distinguish between healthy individuals, disease controls, and ME/CFS patients with high accuracy (91%), and can further differentiate between mild, moderate, and severe ME/CFS patients (84%). Additionally, specific Raman peaks that correlate with ME/CFS phenotypes and have the potential to provide insights into biological changes and support the development of new therapeutics are identified. This study presents a promising approach for aiding in the diagnosis and management of ME/CFS and can be extended to other unexplained chronic diseases such as long COVID and post-treatment Lyme disease syndrome, which share many of the same symptoms as ME/CFS.
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Affiliation(s)
- Jiabao Xu
- Department of Engineering ScienceUniversity of OxfordParks RoadOxfordOX1 3PJUK
- Division of Biomedical Engineering, James Watt School of EngineeringUniversity of GlasgowGlasgowG12 8LTUK
| | - Tiffany Lodge
- Nuffield Department of Women's and Reproductive HealthUniversity of OxfordThe Women CentreJohn Radcliffe HospitalHeadley Way, HeadingtonOxfordOX3 9DUUK
| | - Caroline Kingdon
- Faculty of Infectious DiseasesLondon School of Hygiene and Tropical MedicineKeppel StLondonWC1E 7HTUK
| | - James W. L. Strong
- Nuffield Department of Women's and Reproductive HealthUniversity of OxfordThe Women CentreJohn Radcliffe HospitalHeadley Way, HeadingtonOxfordOX3 9DUUK
| | - John Maclennan
- Soft Cell Biological ResearchAttwood Innovation Center453 S 600 ESt. GeorgeUT84770USA
| | - Eliana Lacerda
- Faculty of Infectious DiseasesLondon School of Hygiene and Tropical MedicineKeppel StLondonWC1E 7HTUK
| | - Slawomir Kujawski
- Department of Exercise Physiology and Functional AnatomyCollegium Medicum in BydgoszczNicolaus Copernicus University in TorunSwietojanska 20Bydgoszcz85‐077Poland
| | - Pawel Zalewski
- Department of Exercise Physiology and Functional AnatomyCollegium Medicum in BydgoszczNicolaus Copernicus University in TorunSwietojanska 20Bydgoszcz85‐077Poland
- Department of Experimental and Clinical PhysiologyWarsaw Medical UniversityStefana Banacha 2aWarszawa02‐097Poland
| | - Wei E. Huang
- Department of Engineering ScienceUniversity of OxfordParks RoadOxfordOX1 3PJUK
| | - Karl J. Morten
- Nuffield Department of Women's and Reproductive HealthUniversity of OxfordThe Women CentreJohn Radcliffe HospitalHeadley Way, HeadingtonOxfordOX3 9DUUK
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21
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Raizen DM, Mullington J, Anaclet C, Clarke G, Critchley H, Dantzer R, Davis R, Drew KL, Fessel J, Fuller PM, Gibson EM, Harrington M, Ian Lipkin W, Klerman EB, Klimas N, Komaroff AL, Koroshetz W, Krupp L, Kuppuswamy A, Lasselin J, Lewis LD, Magistretti PJ, Matos HY, Miaskowski C, Miller AH, Nath A, Nedergaard M, Opp MR, Ritchie MD, Rogulja D, Rolls A, Salamone JD, Saper C, Whittemore V, Wylie G, Younger J, Zee PC, Craig Heller H. Beyond the symptom: the biology of fatigue. Sleep 2023; 46:zsad069. [PMID: 37224457 PMCID: PMC10485572 DOI: 10.1093/sleep/zsad069] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 05/24/2023] [Indexed: 05/26/2023] Open
Abstract
A workshop titled "Beyond the Symptom: The Biology of Fatigue" was held virtually September 27-28, 2021. It was jointly organized by the Sleep Research Society and the Neurobiology of Fatigue Working Group of the NIH Blueprint Neuroscience Research Program. For access to the presentations and video recordings, see: https://neuroscienceblueprint.nih.gov/about/event/beyond-symptom-biology-fatigue. The goals of this workshop were to bring together clinicians and scientists who use a variety of research approaches to understand fatigue in multiple conditions and to identify key gaps in our understanding of the biology of fatigue. This workshop summary distills key issues discussed in this workshop and provides a list of promising directions for future research on this topic. We do not attempt to provide a comprehensive review of the state of our understanding of fatigue, nor to provide a comprehensive reprise of the many excellent presentations. Rather, our goal is to highlight key advances and to focus on questions and future approaches to answering them.
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Affiliation(s)
- David M Raizen
- Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA
| | - Janet Mullington
- Department of Neurology, Harvard Medical School, Boston, MA, USA
| | - Christelle Anaclet
- Department of Neurological Surgery, University of California, Davis School of Medicine, Sacramento, CA, USA
| | - Gerard Clarke
- Department of Psychiatry and Neurobehavioural Science, and APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Hugo Critchley
- Brighton and Sussex Medical School Department of Neuroscience, University of Sussex, Brighton, UK
| | - Robert Dantzer
- Department of Symptom Research, Division of Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ronald Davis
- Department of Biochemistry and Genetics, Stanford University, Palo Alto, CA, USA
| | - Kelly L Drew
- Department of Chemistry and Biochemistry, Institute of Arctic Biology, Center for Transformative Research in Metabolism, University of Alaska Fairbanks, Fairbanks, AK, USA
| | - Josh Fessel
- Division of Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA
| | - Patrick M Fuller
- Department of Neurological Surgery, University of California, Davis School of Medicine, Sacramento, CA, USA
| | - Erin M Gibson
- Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA, USA
| | - Mary Harrington
- Department of Psychology, Neuroscience Program, Smith College, Northampton, MA, USA
| | - W Ian Lipkin
- Center for Infection and Immunity, and Departments of Neurology and Pathology, Columbia University, New York City, NY, USA
| | - Elizabeth B Klerman
- Division of Sleep Medicine, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
| | - Nancy Klimas
- Department of Clinical Immunology, College of Osteopathic Medicine, Nova Southeastern University, Ft. Lauderdale, FL, USA
| | - Anthony L Komaroff
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
| | - Walter Koroshetz
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
| | - Lauren Krupp
- Department of Neurology, NYU Grossman School of Medicine, NYC, NY, USA
| | - Anna Kuppuswamy
- University College London, Queen Square Institute of Neurology, London, England
| | - Julie Lasselin
- Department of Psychology, Stockholm University, Stockholm, Sweden
| | - Laura D Lewis
- Center for Systems Neuroscience, Department of Biomedical Engineering, Boston University, Boston, MA, USA
| | - Pierre J Magistretti
- Biological and Environmental Science and Engineering Division, King Abdullah University of Science and Technology, Thuwal, Kingdom of Saudi Arabia
| | - Heidi Y Matos
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
| | - Christine Miaskowski
- Department of Physiological Nursing, School of Nursing, University of California, San Francisco, CA, USA
| | - Andrew H Miller
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA
| | - Avindra Nath
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
| | - Maiken Nedergaard
- Departments of Neurology and Neurosurgery, University of Rochester Medical Center, Rochester, NY, USA
| | - Mark R Opp
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA
| | - Marylyn D Ritchie
- Department of Genetics, Institute for Biomedical Informatics, Penn Center for Precision Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Dragana Rogulja
- Department of Neurobiology, Harvard University, Boston, MA, USA
| | - Asya Rolls
- Rappaport Institute for Medical Research, Technion, Israel Institute of Technology, Haifa, Israel
| | - John D Salamone
- Department of Psychological Sciences, University of Connecticut, Storrs, CT, USA
| | - Clifford Saper
- Department of Neurology, Harvard Medical School, Boston, MA, USA
| | - Vicky Whittemore
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
| | - Glenn Wylie
- Rocco Ortenzio Neuroimaging Center at Kessler Foundation, East Hanover, NJ, USA
| | - Jarred Younger
- Department of Psychology, University of Alabama, Birmingham, Birmingham, AL, USA
| | - Phyllis C Zee
- Center for Circadian and Sleep Medicine, Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - H Craig Heller
- Department of Biology, Stanford University and Sleep Research Society, Stanford, CA, USA
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22
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López-Hernández Y, Monárrez-Espino J, López DAG, Zheng J, Borrego JC, Torres-Calzada C, Elizalde-Díaz JP, Mandal R, Berjanskii M, Martínez-Martínez E, López JA, Wishart DS. The plasma metabolome of long COVID patients two years after infection. Sci Rep 2023; 13:12420. [PMID: 37528111 PMCID: PMC10394026 DOI: 10.1038/s41598-023-39049-x] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Accepted: 07/19/2023] [Indexed: 08/03/2023] Open
Abstract
One of the major challenges currently faced by global health systems is the prolonged COVID-19 syndrome (also known as "long COVID") which has emerged as a consequence of the SARS-CoV-2 epidemic. It is estimated that at least 30% of patients who have had COVID-19 will develop long COVID. In this study, our goal was to assess the plasma metabolome in a total of 100 samples collected from healthy controls, COVID-19 patients, and long COVID patients recruited in Mexico between 2020 and 2022. A targeted metabolomics approach using a combination of LC-MS/MS and FIA MS/MS was performed to quantify 108 metabolites. IL-17 and leptin were measured in long COVID patients by immunoenzymatic assay. The comparison of paired COVID-19/long COVID-19 samples revealed 53 metabolites that were statistically different. Compared to controls, 27 metabolites remained dysregulated even after two years. Post-COVID-19 patients displayed a heterogeneous metabolic profile. Lactic acid, lactate/pyruvate ratio, ornithine/citrulline ratio, and arginine were identified as the most relevant metabolites for distinguishing patients with more complicated long COVID evolution. Additionally, IL-17 levels were significantly increased in these patients. Mitochondrial dysfunction, redox state imbalance, impaired energy metabolism, and chronic immune dysregulation are likely to be the main hallmarks of long COVID even two years after acute COVID-19 infection.
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Affiliation(s)
- Yamilé López-Hernández
- CONAHCyT-Metabolomics and Proteomics Laboratory, Academic Unit of Biological Sciences, Autonomous University of Zacatecas, 98000, Zacatecas, Mexico.
| | - Joel Monárrez-Espino
- Department of Health Research, Christus Muguerza del Parque Hospital - University of Monterrey, 31125, Chihuahua, Mexico
| | | | - Jiamin Zheng
- The Metabolomics Innovation Centre, University of Alberta, Edmonton, AB, T6G 1C9, Canada
| | - Juan Carlos Borrego
- Departamento de Epidemiología, Hospital General de Zona #1 "Emilio Varela Luján", Instituto Mexicano del Seguro Social, Zacatecas, 98000, México
| | | | - José Pedro Elizalde-Díaz
- Laboratory of Cell Communication & Extracellular Vesicles, Division of Basic Science, Instituto Nacional de Medicina Genómica, 14610, Ciudad de México, Mexico
| | - Rupasri Mandal
- The Metabolomics Innovation Centre, University of Alberta, Edmonton, AB, T6G 1C9, Canada
| | - Mark Berjanskii
- The Metabolomics Innovation Centre, University of Alberta, Edmonton, AB, T6G 1C9, Canada
| | - Eduardo Martínez-Martínez
- Laboratory of Cell Communication & Extracellular Vesicles, Division of Basic Science, Instituto Nacional de Medicina Genómica, 14610, Ciudad de México, Mexico
| | - Jesús Adrián López
- MicroRNAs and Cancer Laboratory, Academic Unit of Biological Sciences, Autonomous University of Zacatecas, 98000, Zacatecas, Mexico
| | - David S Wishart
- The Metabolomics Innovation Centre, University of Alberta, Edmonton, AB, T6G 1C9, Canada.
- Department of Biological Sciences, University of Alberta, Edmonton, AB, T6G 1C9, Canada.
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23
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Maya J. Surveying the Metabolic and Dysfunctional Profiles of T Cells and NK Cells in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Int J Mol Sci 2023; 24:11937. [PMID: 37569313 PMCID: PMC10418326 DOI: 10.3390/ijms241511937] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 07/20/2023] [Accepted: 07/24/2023] [Indexed: 08/13/2023] Open
Abstract
Millions globally suffer from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The inflammatory symptoms, illness onset, recorded outbreak events, and physiological variations provide strong indications that ME/CFS, at least sometimes, has an infectious origin, possibly resulting in a chronic unidentified viral infection. Meanwhile, studies exposing generalized metabolic disruptions in ME/CFS have stimulated interest in isolated immune cells with an altered metabolic state. As the metabolism dictates the cellular function, dissecting the biomechanics of dysfunctional immune cells in ME/CFS can uncover states such as exhaustion, senescence, or anergy, providing insights into the consequences of these phenotypes in this disease. Despite the similarities that are seen metabolically between ME/CFS and other chronic viral infections that result in an exhausted immune cell state, immune cell exhaustion has not yet been verified in ME/CFS. This review explores the evidence for immunometabolic dysfunction in ME/CFS T cell and natural killer (NK) cell populations, comparing ME/CFS metabolic and functional features to dysfunctional immune cell states, and positing whether anergy, exhaustion, or senescence could be occurring in distinct immune cell populations in ME/CFS, which is consistent with the hypothesis that ME/CFS is a chronic viral disease. This comprehensive review of the ME/CFS immunometabolic literature identifies CD8+ T cell exhaustion as a probable contender, underscores the need for further investigation into the dysfunctional state of CD4+ T cells and NK cells, and explores the functional implications of molecular findings in these immune-cell types. Comprehending the cause and impact of ME/CFS immune cell dysfunction is critical to understanding the physiological mechanisms of ME/CFS, and developing effective treatments to alleviate the burden of this disabling condition.
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Affiliation(s)
- Jessica Maya
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14850, USA
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24
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Gamer J, Van Booven DJ, Zarnowski O, Arango S, Elias M, Kurian A, Joseph A, Perez M, Collado F, Klimas N, Oltra E, Nathanson L. Sex-Dependent Transcriptional Changes in Response to Stress in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Pilot Project. Int J Mol Sci 2023; 24:10255. [PMID: 37373402 PMCID: PMC10299261 DOI: 10.3390/ijms241210255] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 05/23/2023] [Accepted: 06/04/2023] [Indexed: 06/29/2023] Open
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, multi-symptom illness characterized by debilitating fatigue and post-exertional malaise (PEM). Numerous studies have reported sex differences at the epidemiological, cellular, and molecular levels between male and female ME/CFS patients. To gain further insight into these sex-dependent changes, we evaluated differential gene expression by RNA-sequencing (RNA-Seq) in 33 ME/CFS patients (20 female, 13 male) and 34 matched healthy controls (20 female and 14 male) before, during, and after an exercise challenge intended to provoke PEM. Our findings revealed that pathways related to immune-cell signaling (including IL-12) and natural killer cell cytotoxicity were activated as a result of exertion in the male ME/CFS cohort, while female ME/CFS patients did not show significant enough changes in gene expression to meet the criteria for the differential expression. Functional analysis during recovery from an exercise challenge showed that male ME/CFS patients had distinct changes in the regulation of specific cytokine signals (including IL-1β). Meanwhile, female ME/CFS patients had significant alterations in gene networks related to cell stress, response to herpes viruses, and NF-κβ signaling. The functional pathways and differentially expressed genes highlighted in this pilot project provide insight into the sex-specific pathophysiology of ME/CFS.
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Affiliation(s)
- Jackson Gamer
- Institute for Neuro-Immune Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.G.); (N.K.)
- Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (O.Z.); (S.A.); (M.E.); (A.K.); (A.J.); (M.P.)
| | - Derek J. Van Booven
- Dr. J.P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA;
| | - Oskar Zarnowski
- Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (O.Z.); (S.A.); (M.E.); (A.K.); (A.J.); (M.P.)
| | - Sebastian Arango
- Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (O.Z.); (S.A.); (M.E.); (A.K.); (A.J.); (M.P.)
| | - Mark Elias
- Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (O.Z.); (S.A.); (M.E.); (A.K.); (A.J.); (M.P.)
| | - Asha Kurian
- Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (O.Z.); (S.A.); (M.E.); (A.K.); (A.J.); (M.P.)
| | - Andrew Joseph
- Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (O.Z.); (S.A.); (M.E.); (A.K.); (A.J.); (M.P.)
| | - Melanie Perez
- Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (O.Z.); (S.A.); (M.E.); (A.K.); (A.J.); (M.P.)
| | - Fanny Collado
- Department of Veterans Affairs, Miami VA Healthcare System, Geriatric Research Education and Clinical Center (GRECC), Miami, FL 33125, USA;
- South Florida Veterans Affairs Foundation for Research and Education Inc., Fort Lauderdale, FL 33125, USA
| | - Nancy Klimas
- Institute for Neuro-Immune Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.G.); (N.K.)
- Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (O.Z.); (S.A.); (M.E.); (A.K.); (A.J.); (M.P.)
- Department of Veterans Affairs, Miami VA Healthcare System, Geriatric Research Education and Clinical Center (GRECC), Miami, FL 33125, USA;
- South Florida Veterans Affairs Foundation for Research and Education Inc., Fort Lauderdale, FL 33125, USA
| | - Elisa Oltra
- School Medicine, Universidad Católica de Valencia San Vicente Mártir, 46001 Valencia, Spain;
| | - Lubov Nathanson
- Institute for Neuro-Immune Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.G.); (N.K.)
- Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (O.Z.); (S.A.); (M.E.); (A.K.); (A.J.); (M.P.)
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25
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Komaroff AL, Lipkin WI. ME/CFS and Long COVID share similar symptoms and biological abnormalities: road map to the literature. Front Med (Lausanne) 2023; 10:1187163. [PMID: 37342500 PMCID: PMC10278546 DOI: 10.3389/fmed.2023.1187163] [Citation(s) in RCA: 127] [Impact Index Per Article: 63.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 05/09/2023] [Indexed: 06/23/2023] Open
Abstract
Some patients remain unwell for months after "recovering" from acute COVID-19. They develop persistent fatigue, cognitive problems, headaches, disrupted sleep, myalgias and arthralgias, post-exertional malaise, orthostatic intolerance and other symptoms that greatly interfere with their ability to function and that can leave some people housebound and disabled. The illness (Long COVID) is similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) as well as to persisting illnesses that can follow a wide variety of other infectious agents and following major traumatic injury. Together, these illnesses are projected to cost the U.S. trillions of dollars. In this review, we first compare the symptoms of ME/CFS and Long COVID, noting the considerable similarities and the few differences. We then compare in extensive detail the underlying pathophysiology of these two conditions, focusing on abnormalities of the central and autonomic nervous system, lungs, heart, vasculature, immune system, gut microbiome, energy metabolism and redox balance. This comparison highlights how strong the evidence is for each abnormality, in each illness, and helps to set priorities for future investigation. The review provides a current road map to the extensive literature on the underlying biology of both illnesses.
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Affiliation(s)
- Anthony L. Komaroff
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - W. Ian Lipkin
- Center for Infection and Immunity, Mailman School of Public Health, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY, United States
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26
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Vernon SD, Hartle M, Sullivan K, Bell J, Abbaszadeh S, Unutmaz D, Bateman L. Post-exertional malaise among people with long COVID compared to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Work 2023; 74:1179-1186. [PMID: 36911963 DOI: 10.3233/wor-220581] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/12/2023] Open
Abstract
BACKGROUND Long COVID describes a condition with symptoms that linger for months to years following acute COVID-19. Many of these Long COVID symptoms are like those experienced by patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). OBJECTIVE We wanted to determine if people with Long COVID experienced post-exertional malaise (PEM), the hallmark symptom of ME/CFS, and if so, how it compared to PEM experienced by patients with ME/CFS. METHODS A questionnaire that asked about the domains of PEM including triggers, experience, recovery, and prevention was administered to 80 people seeking care for Long COVID at Bateman Horne Center. Their responses were compared to responses about PEM given by 151 patients with ME/CFS using chi-square tests of independence. RESULTS All but one Long COVID respondent reported having PEM. There were many significant differences in the types of PEM triggers, symptoms experienced during PEM, and ways to recover and prevent PEM between Long COVID and ME/CFS. Similarities between Long COVID and ME/CFS included low and medium physical and cognitive exertion to trigger PEM, symptoms of fatigue, pain, immune reaction, neurologic, orthostatic intolerance, and gastrointestinal symptoms during PEM, rest to recover from PEM, and pacing to prevent PEM. CONCLUSION People with Long COVID experience PEM. There were significant differences in PEM experienced by people with Long COVID compared to patients with ME/CFS. This may be due to the newness of Long COVID, not knowing what exertional intolerance is or how to manage it.
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Affiliation(s)
| | | | - Karen Sullivan
- The Bateman Horne Center of Excellence, Salt Lake City, UT, USA
| | - Jennifer Bell
- The Bateman Horne Center of Excellence, Salt Lake City, UT, USA
| | | | - Derya Unutmaz
- Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.,University of Connecticut School of Medicine, Farmington, CT, USA
| | - Lucinda Bateman
- The Bateman Horne Center of Excellence, Salt Lake City, UT, USA
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27
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Glass KA, Germain A, Huang YV, Hanson MR. Urine Metabolomics Exposes Anomalous Recovery after Maximal Exertion in Female ME/CFS Patients. Int J Mol Sci 2023; 24:3685. [PMID: 36835097 PMCID: PMC9958671 DOI: 10.3390/ijms24043685] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 02/06/2023] [Accepted: 02/09/2023] [Indexed: 02/16/2023] Open
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease with unknown etiology or effective treatments. Post-exertional malaise (PEM) is a key symptom that distinguishes ME/CFS patients. Investigating changes in the urine metabolome between ME/CFS patients and healthy subjects following exertion may help us understand PEM. The aim of this pilot study was to comprehensively characterize the urine metabolomes of eight female healthy sedentary control subjects and ten female ME/CFS patients in response to a maximal cardiopulmonary exercise test (CPET). Each subject provided urine samples at baseline and 24 h post-exercise. A total of 1403 metabolites were detected via LC-MS/MS by Metabolon® including amino acids, carbohydrates, lipids, nucleotides, cofactors and vitamins, xenobiotics, and unknown compounds. Using a linear mixed effects model, pathway enrichment analysis, topology analysis, and correlations between urine and plasma metabolite levels, significant differences were discovered between controls and ME/CFS patients in many lipid (steroids, acyl carnitines and acyl glycines) and amino acid subpathways (cysteine, methionine, SAM, and taurine; leucine, isoleucine, and valine; polyamine; tryptophan; and urea cycle, arginine and proline). Our most unanticipated discovery is the lack of changes in the urine metabolome of ME/CFS patients during recovery while significant changes are induced in controls after CPET, potentially demonstrating the lack of adaptation to a severe stress in ME/CFS patients.
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Affiliation(s)
| | | | | | - Maureen R. Hanson
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA
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28
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Maya J, Leddy SM, Gottschalk CG, Peterson DL, Hanson MR. Altered Fatty Acid Oxidation in Lymphocyte Populations of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Int J Mol Sci 2023; 24:2010. [PMID: 36768336 PMCID: PMC9916395 DOI: 10.3390/ijms24032010] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/14/2023] [Accepted: 01/16/2023] [Indexed: 01/20/2023] Open
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling multisystem illness in which individuals are plagued with fatigue, inflammatory symptoms, cognitive dysfunction, and the hallmark symptom, post-exertional malaise. While the cause of this disease remains unknown, there is evidence of a potential infectious component that, along with patient symptoms and common onsets of the disease, implicates immune system dysfunction. To further our understanding of the state of ME/CFS lymphocytes, we characterized the role of fatty acids in isolated Natural Killer cells, CD4+ T cells, and CD8+ T cells in circulation and after overnight stimulation, through implicit perturbations to fatty acid oxidation. We examined samples obtained from at least 8 and as many as 20 subjects for immune cell fatty acid characterization in a variety of experiments and found that all three isolated cell types increased their utilization of lipids and levels of pertinent proteins involved in this metabolic pathway in ME/CFS samples, particularly during higher energy demands and activation. In T cells, we characterized the cell populations contributing to these metabolic shifts, which included CD4+ memory cells, CD4+ effector cells, CD8+ naïve cells, and CD8+ memory cells. We also discovered that patients with ME/CFS and healthy control samples had significant correlations between measurements of CD4+ T cell fatty acid metabolism and demographic data. These findings provide support for metabolic dysfunction in ME/CFS immune cells. We further hypothesize about the consequences that these altered fuel dependencies may have on T and NK cell effector function, which may shed light on the illness's mechanism of action.
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Affiliation(s)
- Jessica Maya
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14850, USA
| | - Sabrina M. Leddy
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14850, USA
| | | | - Daniel L. Peterson
- Simmaron Research, Incline Village, NV 89451, USA
- Sierra Internal Medicine, Incline Village, NV 89451, USA
| | - Maureen R. Hanson
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14850, USA
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29
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Metabolomic Profiling of Plasma, Urine, and Saliva of Kidney Transplantation Recipients. Int J Mol Sci 2022; 23:ijms232213938. [PMID: 36430414 PMCID: PMC9695205 DOI: 10.3390/ijms232213938] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 11/05/2022] [Accepted: 11/08/2022] [Indexed: 11/16/2022] Open
Abstract
Kidney biopsy is commonly used to diagnose kidney transplant dysfunction after transplantation. Therefore, the development of minimally invasive and quantitative methods to evaluate kidney function in transplant recipients is necessary. Here, we used capillary electrophoresis-mass spectrometry to analyze the biofluids collected from transplant recipients with impaired (Group I, n = 31) and stable (Group S, n = 19) kidney function and from donors (Group D, n = 9). Metabolomics analyses identified and quantified 97 metabolites in plasma, 133 metabolites in urine, and 108 metabolites in saliva. Multivariate analyses revealed apparent differences in the metabolomic profiles of the three groups. In plasma samples, arginine biosynthesis and purine metabolism between the I and S Groups differed. In addition, considerable differences in metabolomic profiles were observed between samples collected from participants with T cell-mediated rejection (TCR), antibody-mediated rejection, and other kidney disorders (KD). The metabolomic profiles in the three types of biofluids showed different patterns between TCR and KD, wherein 3-indoxyl sulfate showed a significant increase in TCR consistently in both plasma and urine samples. These results suggest that each biofluid has different metabolite features to evaluate kidney function after transplantation and that 3-indoxyl sulfate could predict acute rejection.
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30
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Long-Term Mastication Changed Salivary Metabolomic Profiles. Metabolites 2022; 12:metabo12070660. [PMID: 35888784 PMCID: PMC9322701 DOI: 10.3390/metabo12070660] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/08/2022] [Accepted: 07/15/2022] [Indexed: 11/29/2022] Open
Abstract
Saliva is an ideal biofluid for monitoring oral and systemic health. Repeated mastication is a typical physical stimulus that improves salivary flow and oral hygiene. Recent metabolomic studies have shown the potential of salivary metabolomic components for various disease monitoring systems. Here, we evaluated the effect of long-term mastication on salivary metabolomic profiles. Young women with good oral hygiene (20.8 ± 0.3 years, n = 17) participated. They were prohibited from chewing gum during control periods (4 weeks each) and were instructed to chew a piece of gum base seven times a day for 10 min each time during the intervention period. Paired samples of unstimulated whole saliva collected on the last day of the control and intervention period were compared. Liquid chromatography−time-of-flight mass spectrometry successfully quantified 85 metabolites, of which 41 showed significant differences (p < 0.05, Wilcoxon paired test corrected by false discovery rate). Except for a few metabolites, such as citrate, most metabolites showed lower concentrations after the intervention. The pathways related to glycogenic amino acids, such as alanine, arginine, and glutamine, altered considerably. This study suggests that long-term mastication induces unstimulated salivary component-level changes.
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31
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Metabolomic Evidence for Peroxisomal Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Int J Mol Sci 2022; 23:ijms23147906. [PMID: 35887252 PMCID: PMC9320121 DOI: 10.3390/ijms23147906] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 07/14/2022] [Accepted: 07/16/2022] [Indexed: 12/04/2022] Open
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease characterized by unexplained physical fatigue, cognitive and sensory dysfunction, sleeping disturbances, orthostatic intolerance, and gastrointestinal problems. People with ME/CFS often report a prodrome consistent with infections. Using regression, Bayesian and enrichment analyses, we conducted targeted and untargeted metabolomic analysis of plasma from 106 ME/CFS cases and 91 frequency-matched healthy controls. Subjects in the ME/CFS group had significantly decreased levels of plasmalogens and phospholipid ethers (p < 0.001), phosphatidylcholines (p < 0.001) and sphingomyelins (p < 0.001), and elevated levels of dicarboxylic acids (p = 0.013). Using machine learning algorithms, we were able to differentiate ME/CFS or subgroups of ME/CFS from controls with area under the receiver operating characteristic curve (AUC) values up to 0.873. Our findings provide the first metabolomic evidence of peroxisomal dysfunction, and are consistent with dysregulation of lipid remodeling and the tricarboxylic acid cycle. These findings, if validated in other cohorts, could provide new insights into the pathogenesis of ME/CFS and highlight the potential use of the plasma metabolome as a source of biomarkers for the disease.
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32
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Tamura Y, Yamato M, Kataoka Y. Animal Models for Neuroinflammation and Potential Treatment Methods. Front Neurol 2022; 13:890217. [PMID: 35832182 PMCID: PMC9271866 DOI: 10.3389/fneur.2022.890217] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Accepted: 06/03/2022] [Indexed: 11/25/2022] Open
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic disease of unknown etiology and without effective treatment options. The onset of ME/CFS is often associated with neuroinflammation following bacterial or viral infection. A positron emission tomography imaging study revealed that the degree of neuroinflammation was correlated with the severity of several symptoms in patients with ME/CFS. In animal studies, lipopolysaccharide- and polyinosinic-polycytidylic acid-induced models are thought to mimic the pathological features of ME/CFS and provoke neuroinflammation, characterized by increased levels of proinflammatory cytokines and activation of microglia. In this review, we described the anti-inflammatory effects of three compounds on neuroinflammatory responses utilizing animal models. The findings of the included studies suggest that anti-inflammatory substances may be used as effective therapies to ameliorate disease symptoms in patients with ME/CFS.
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Affiliation(s)
- Yasuhisa Tamura
- Laboratory for Cellular Function Imaging, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan
- Multi-Modal Microstructure Analysis Unit, RIKEN-JEOL Collaboration Center, RIKEN, Kobe, Japan
| | - Masanori Yamato
- Laboratory for Cellular Function Imaging, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan
- Multi-Modal Microstructure Analysis Unit, RIKEN-JEOL Collaboration Center, RIKEN, Kobe, Japan
| | - Yosky Kataoka
- Laboratory for Cellular Function Imaging, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan
- Multi-Modal Microstructure Analysis Unit, RIKEN-JEOL Collaboration Center, RIKEN, Kobe, Japan
- *Correspondence: Yosky Kataoka
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33
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Umeda K, Shindo D, Somekawa S, Nishitani S, Sato W, Toyoda S, Karakawa S, Kawasaki M, Mine T, Suzuki K. Effects of Five Amino Acids (Serine, Alanine, Glutamate, Aspartate, and Tyrosine) on Mental Health in Healthy Office Workers: A Randomized, Double-Blind, Placebo-Controlled Exploratory Trial. Nutrients 2022; 14:nu14112357. [PMID: 35684157 PMCID: PMC9183184 DOI: 10.3390/nu14112357] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 05/24/2022] [Accepted: 05/27/2022] [Indexed: 12/04/2022] Open
Abstract
Background: The importance of maintaining good mental health with overall well-being has recently drawn attention from various spheres of academics and the working population. Amino acid intake has been reported to reduce depression symptoms and other mental health problems. However, the effectiveness of amino acid intake (i.e., single or combined) remains unknown. In this study, we assessed a combination of five amino acids (serine, alanine, glutamate, aspartate, and tyrosine; SAGAT) reported to regulate mental health. Methods: A randomized, double-blind, placebo-controlled exploratory trial was conducted. Participants, aged between 20 and 65 years with fatigue sensation, were randomized to receive either SAGAT or the placebo and ingested them for four weeks. A transient mental work was loaded at day 0 and after four weeks of intervention. As the primary outcomes, the fatigue sensation was assessed. The mood status, cognitive function, work efficiency, and blood marker were also measured as secondary outcomes. Results: The number of participants analyzed for the efficacy evaluation were 20 in SAGAT and 22 in the placebo. There were no significant differences in the primary outcomes. However, as the secondary outcomes, the SAGAT group showed a significant improvement in motivation and cognitive function in the recovery period after mental work loaded in a four-week intervention compared to the placebo. Conclusion: The current findings suggest that SAGAT contributes to maintaining proper motivation and cognitive function. Clinical Trial Registration: University Hospital Medical Information Network Clinical Trial Registry (ID: UMIN 000041221).
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Affiliation(s)
- Kentaro Umeda
- Institute of Food Sciences and Technologies, Ajinomoto Co., Inc., Kawasaki 210-8681, Japan; (D.S.); (S.S.); (S.N.)
- Correspondence: (K.U.); (K.S.)
| | - Daichi Shindo
- Institute of Food Sciences and Technologies, Ajinomoto Co., Inc., Kawasaki 210-8681, Japan; (D.S.); (S.S.); (S.N.)
| | - Shinji Somekawa
- Institute of Food Sciences and Technologies, Ajinomoto Co., Inc., Kawasaki 210-8681, Japan; (D.S.); (S.S.); (S.N.)
| | - Shinobu Nishitani
- Institute of Food Sciences and Technologies, Ajinomoto Co., Inc., Kawasaki 210-8681, Japan; (D.S.); (S.S.); (S.N.)
| | - Wataru Sato
- Research Institute for Bioscience Products & Fine Chemicals, Ajinomoto Co., Inc., Kawasaki 210-8681, Japan; (W.S.); (S.T.); (S.K.); (M.K.)
| | - Sakiko Toyoda
- Research Institute for Bioscience Products & Fine Chemicals, Ajinomoto Co., Inc., Kawasaki 210-8681, Japan; (W.S.); (S.T.); (S.K.); (M.K.)
| | - Sachise Karakawa
- Research Institute for Bioscience Products & Fine Chemicals, Ajinomoto Co., Inc., Kawasaki 210-8681, Japan; (W.S.); (S.T.); (S.K.); (M.K.)
| | - Mika Kawasaki
- Research Institute for Bioscience Products & Fine Chemicals, Ajinomoto Co., Inc., Kawasaki 210-8681, Japan; (W.S.); (S.T.); (S.K.); (M.K.)
| | - Tomoyuki Mine
- Research & Business Planning Department, Ajinomoto Co., Inc., Tokyo 104-8315, Japan;
| | - Katsuya Suzuki
- Institute of Food Sciences and Technologies, Ajinomoto Co., Inc., Kawasaki 210-8681, Japan; (D.S.); (S.S.); (S.N.)
- Correspondence: (K.U.); (K.S.)
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Germain A, Giloteaux L, Moore GE, Levine SM, Chia JK, Keller BA, Stevens J, Franconi CJ, Mao X, Shungu DC, Grimson A, Hanson MR. Plasma metabolomics reveals disrupted response and recovery following maximal exercise in myalgic encephalomyelitis/chronic fatigue syndrome. JCI Insight 2022; 7:e157621. [PMID: 35358096 PMCID: PMC9090259 DOI: 10.1172/jci.insight.157621] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 03/23/2022] [Indexed: 11/17/2022] Open
Abstract
Post-exertional malaise (PEM) is a hallmark symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We monitored the evolution of 1157 plasma metabolites in 60 ME/CFS (45 female, 15 male) and 45 matched healthy control participants (30 female, 15 male) before and after 2 maximal cardiopulmonary exercise test (CPET) challenges separated by 24 hours, with the intent of provoking PEM in patients. Four time points allowed exploration of the metabolic response to maximal energy-producing capacity and the recovery pattern of participants with ME/CFS compared with the healthy control group. Baseline comparison identified several significantly different metabolites, along with an enriched percentage of yet-to-be identified compounds. Additionally, temporal measures demonstrated an increased metabolic disparity between cohorts, including unknown metabolites. The effects of exertion in the ME/CFS cohort predominantly highlighted lipid-related as well as energy-related pathways and chemical structure clusters, which were disparately affected by the first and second exercise sessions. The 24-hour recovery period was distinct in the ME/CFS cohort, with over a quarter of the identified pathways statistically different from the controls. The pathways that are uniquely different 24 hours after an exercise challenge provide clues to metabolic disruptions that lead to PEM. Numerous altered pathways were observed to depend on glutamate metabolism, a crucial component of the homeostasis of many organs in the body, including the brain.
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Affiliation(s)
- Arnaud Germain
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, USA
| | - Ludovic Giloteaux
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, USA
| | - Geoffrey E. Moore
- Department of Exercise Science and Athletic Training, Ithaca College, Ithaca, New York, USA
| | - Susan M. Levine
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, USA
| | | | - Betsy A. Keller
- Department of Exercise Science and Athletic Training, Ithaca College, Ithaca, New York, USA
| | | | - Carl J. Franconi
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, USA
| | - Xiangling Mao
- Department of Neuroradiology, Weill Cornell Medical College, New York, New York, USA
| | - Dikoma C. Shungu
- Department of Neuroradiology, Weill Cornell Medical College, New York, New York, USA
| | - Andrew Grimson
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, USA
| | - Maureen R. Hanson
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, USA
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Hirano SI, Ichikawa Y, Sato B, Takefuji Y, Satoh F. Molecular Hydrogen as a Medical Gas for the Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Possible Efficacy Based on a Literature Review. Front Neurol 2022; 13:841310. [PMID: 35493814 PMCID: PMC9042428 DOI: 10.3389/fneur.2022.841310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 03/15/2022] [Indexed: 11/17/2022] Open
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disorder that is characterized by fatigue that persists for more than 6 months, weakness, sleep disturbances, and cognitive dysfunction. There are multiple possible etiologies for ME/CFS, among which mitochondrial dysfunction plays a major role in abnormal energy metabolism. The potential of many substances for the treatment of ME/CFS has been examined; however, satisfactory outcomes have not yet been achieved. The development of new substances for curative, not symptomatic, treatments is desired. Molecular hydrogen (H2) ameliorates mitochondrial dysfunction by scavenging hydroxyl radicals, the most potent oxidant among reactive oxygen species. Animal experiments and clinical trials reported that H2 exerted ameliorative effects on acute and chronic fatigue. Therefore, we conducted a literature review on the mechanism by which H2 improves acute and chronic fatigue in animals and healthy people and showed that the attenuation of mitochondrial dysfunction by H2 may be involved in the ameliorative effects. Although further clinical trials are needed to determine the efficacy and mechanism of H2 gas in ME/CFS, our literature review suggested that H2 gas may be an effective medical gas for the treatment of ME/CFS.
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Affiliation(s)
- Shin-ichi Hirano
- Department of Research and Development, MiZ Company Limited, Kamakura, Japan
| | - Yusuke Ichikawa
- Department of Research and Development, MiZ Company Limited, Kamakura, Japan
- MiZ Inc., Newark, CA, United States
| | - Bunpei Sato
- Department of Research and Development, MiZ Company Limited, Kamakura, Japan
- MiZ Inc., Newark, CA, United States
| | - Yoshiyasu Takefuji
- Professor Emeritus, Keio University, Tokyo, Japan
- Faculty of Data Science, Musashino University, Tokyo, Japan
| | - Fumitake Satoh
- Department of Research and Development, MiZ Company Limited, Kamakura, Japan
- MiZ Inc., Newark, CA, United States
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36
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Hernandez-Baixauli J, Abasolo N, Palacios-Jordan H, Foguet-Romero E, Suñol D, Galofré M, Caimari A, Baselga-Escudero L, Del Bas JM, Mulero M. Imbalances in TCA, Short Fatty Acids and One-Carbon Metabolisms as Important Features of Homeostatic Disruption Evidenced by a Multi-Omics Integrative Approach of LPS-Induced Chronic Inflammation in Male Wistar Rats. Int J Mol Sci 2022; 23:ijms23052563. [PMID: 35269702 PMCID: PMC8910732 DOI: 10.3390/ijms23052563] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 02/21/2022] [Accepted: 02/23/2022] [Indexed: 12/02/2022] Open
Abstract
Chronic inflammation is an important risk factor in a broad variety of physical and mental disorders leading to highly prevalent non-communicable diseases (NCDs). However, there is a need for a deeper understanding of this condition and its progression to the disease state. For this reason, it is important to define metabolic pathways and complementary biomarkers associated with homeostatic disruption in chronic inflammation. To achieve that, male Wistar rats were subjected to intraperitoneal and intermittent injections with saline solution or increasing lipopolysaccharide (LPS) concentrations (0.5, 5 and 7.5 mg/kg) thrice a week for 31 days. Biochemical and inflammatory parameters were measured at the end of the study. To assess the omics profile, GC-qTOF and UHPLC-qTOF were performed to evaluate plasma metabolome; 1H-NMR was used to evaluate urine metabolome; additionally, shotgun metagenomics sequencing was carried out to characterize the cecum microbiome. The chronicity of inflammation in the study was evaluated by the monitoring of monocyte chemoattractant protein-1 (MCP-1) during the different weeks of the experimental process. At the end of the study, together with the increased levels of MCP-1, levels of interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-α) and prostaglandin E2 (PGE2) along with 8-isoprostanes (an indicative of oxidative stress) were significantly increased (p-value < 0.05). The leading features implicated in the current model were tricarboxylic acid (TCA) cycle intermediates (i.e., alpha-ketoglutarate, aconitic acid, malic acid, fumaric acid and succinic acid); lipids such as specific cholesterol esters (ChoEs), lysophospholipids (LPCs) and phosphatidylcholines (PCs); and glycine, as well as N, N-dimethylglycine, which are related to one-carbon (1C) metabolism. These metabolites point towards mitochondrial metabolism through TCA cycle, β-oxidation of fatty acids and 1C metabolism as interconnected pathways that could reveal the metabolic effects of chronic inflammation induced by LPS administration. These results provide deeper knowledge concerning the impact of chronic inflammation on the disruption of metabolic homeostasis.
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Affiliation(s)
- Julia Hernandez-Baixauli
- Eurecat, Centre Tecnològic de Catalunya, Unitat de Nutrició i Salut, 43204 Reus, Spain; (J.H.-B.); (A.C.); (L.B.-E.)
| | - Nerea Abasolo
- Eurecat, Centre Tecnològic de Catalunya, Centre for Omic Sciences (COS), Joint Unit Universitat Rovira i Virgili-EURECAT, 43204 Reus, Spain; (N.A.); (H.P.-J.); (E.F.-R.)
| | - Hector Palacios-Jordan
- Eurecat, Centre Tecnològic de Catalunya, Centre for Omic Sciences (COS), Joint Unit Universitat Rovira i Virgili-EURECAT, 43204 Reus, Spain; (N.A.); (H.P.-J.); (E.F.-R.)
| | - Elisabet Foguet-Romero
- Eurecat, Centre Tecnològic de Catalunya, Centre for Omic Sciences (COS), Joint Unit Universitat Rovira i Virgili-EURECAT, 43204 Reus, Spain; (N.A.); (H.P.-J.); (E.F.-R.)
| | - David Suñol
- Eurecat, Centre Tecnològic de Catalunya, Digital Health, 08005 Barcelona, Spain; (D.S.); (M.G.)
| | - Mar Galofré
- Eurecat, Centre Tecnològic de Catalunya, Digital Health, 08005 Barcelona, Spain; (D.S.); (M.G.)
| | - Antoni Caimari
- Eurecat, Centre Tecnològic de Catalunya, Unitat de Nutrició i Salut, 43204 Reus, Spain; (J.H.-B.); (A.C.); (L.B.-E.)
| | - Laura Baselga-Escudero
- Eurecat, Centre Tecnològic de Catalunya, Unitat de Nutrició i Salut, 43204 Reus, Spain; (J.H.-B.); (A.C.); (L.B.-E.)
| | - Josep M Del Bas
- Eurecat, Centre Tecnològic de Catalunya, Unitat de Nutrició i Salut, 43204 Reus, Spain; (J.H.-B.); (A.C.); (L.B.-E.)
- Correspondence: (J.M.D.B.); (M.M.)
| | - Miquel Mulero
- Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili, 43007 Tarragona, Spain
- Nutrigenomics Research Group, Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili, 43007 Tarragona, Spain
- Correspondence: (J.M.D.B.); (M.M.)
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Che X, Brydges CR, Yu Y, Price A, Joshi S, Roy A, Lee B, Barupal DK, Cheng A, Palmer DM, Levine S, Peterson DL, Vernon SD, Bateman L, Hornig M, Montoya JG, Komaroff AL, Fiehn O, Lipkin WI. Evidence for Peroxisomal Dysfunction and Dysregulation of the CDP-Choline Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2022. [PMID: 35043127 PMCID: PMC8764736 DOI: 10.1101/2021.06.14.21258895] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Background Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease that is characterized by unexplained physical fatigue unrelieved by rest. Symptoms also include cognitive and sensory dysfunction, sleeping disturbances, orthostatic intolerance, and gastrointestinal problems. A syndrome clinically similar to ME/CFS has been reported following well-documented infections with the coronaviruses SARS-CoV and MERS-CoV. At least 10% of COVID-19 survivors develop post acute sequelae of SARS-CoV-2 infection (PASC). Although many individuals with PASC have evidence of structural organ damage, a subset have symptoms consistent with ME/CFS including fatigue, post exertional malaise, cognitive dysfunction, gastrointestinal disturbances, and postural orthostatic intolerance. These common features in ME/CFS and PASC suggest that insights into the pathogenesis of either may enrich our understanding of both syndromes, and could expedite the development of strategies for identifying those at risk and interventions that prevent or mitigate disease. Methods Using regression, Bayesian and enrichment analyses, we conducted targeted and untargeted metabolomic analysis of 888 metabolic analytes in plasma samples of 106 ME/CFS cases and 91 frequency-matched healthy controls. Results In ME/CFS cases, regression, Bayesian and enrichment analyses revealed evidence of peroxisomal dysfunction with decreased levels of plasmalogens. Other findings included decreased levels of several membrane lipids, including phosphatidylcholines and sphingomyelins, that may indicate dysregulation of the cytidine-5’-diphosphocholine pathway. Enrichment analyses revealed decreased levels of choline, ceramides and carnitines, and increased levels of long chain triglycerides (TG) and hydroxy-eicosapentaenoic acid. Elevated levels of dicarboxylic acids were consistent with abnormalities in the tricarboxylic acid cycle. Using machine learning algorithms with selected metabolites as predictors, we were able to differentiate female ME/CFS cases from female controls (highest AUC=0.794) and ME/CFS cases without self-reported irritable bowel syndrome (sr-IBS) from controls without sr-IBS (highest AUC=0.873). Conclusion Our findings are consistent with earlier ME/CFS work indicating compromised energy metabolism and redox imbalance, and highlight new abnormalities that may provide insights into the pathogenesis of ME/CFS. Plasma levels of plasmalogens are decreased in patients with myalgic encephalomyelitis/chronic fatigue syndrome suggesting peroxisome dysfunction.
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Hara Y, Kume S, Kataoka Y, Watanabe N. Changes in TCA cycle and TCA cycle-related metabolites in plasma upon citric acid administration in rats. Heliyon 2021; 7:e08501. [PMID: 34934832 PMCID: PMC8654791 DOI: 10.1016/j.heliyon.2021.e08501] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 10/28/2021] [Accepted: 11/25/2021] [Indexed: 11/28/2022] Open
Abstract
Recent studies have reported that plasma levels of tricarboxylic acid (TCA) cycle metabolites and TCA cycle-related metabolite change in patients with chronic fatigue syndrome (CFS) and in healthy humans after exercise. Exogenous dietary citric acid has been reported to alleviate fatigue during daily activities and after exercise. However, it is unknown whether dietary citric acid affects the plasma levels of these metabolites. Therefore, the present study aimed to investigate the effects of exogenously administered citric acid on TCA cycle metabolites and TCA cycle-related metabolites in plasma. Sprague-Dawley rats were divided into control and citric acid groups. We evaluated the effect of exogenous dietary citric acid on the plasma TCA cycle and TCA cycle-related metabolites by metabolome analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS). TCA cycle metabolites, including plasma citrate, cis-aconitate, and isocitrate, were significantly elevated after exogenous administration of citric acid. Anaplerotic amino acids, which are converted to TCA cycle metabolites, such as serine, glycine, tryptophan, lysine, leucine, histidine, glutamine, arginine, isoleucine, methionine, valine, and phenylalanine, also showed significantly elevated levels. Citric acid administration significantly increased the levels of initial TCA cycle metabolites in the plasma. This increase after administration of citric acid was shown to be opposite to the metabolic changes observed in patients with CFS. These results contribute novel insight into the fatigue alleviation mechanism of citric acid.
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Affiliation(s)
- Yurie Hara
- Department of Advanced Food Sciences, College of Agriculture, Tamagawa University, Tokyo, Japan
| | - Satoshi Kume
- Laboratory for Pathophysiological and Health Science, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan.,Center for Health Science Innovation, Osaka City University, Osaka, Japan.,Laboratory for Cellular Function Imaging, RIKEN Center for Biosystems Dynamics Research, Hyogo, Japan
| | - Yosky Kataoka
- Laboratory for Cellular Function Imaging, RIKEN Center for Biosystems Dynamics Research, Hyogo, Japan.,Multi-modal Microstructure Analysis Unit, RIKEN-JEOL Collaboration Center, RIKEN Baton Zone Program, Hyogo, Japan
| | - Nakamichi Watanabe
- Department of Health Science, Faculty of Food and Health Sciences, Showa Women's University, Tokyo, Japan
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Motoki N, Motoki H, Utsumi M, Yamazaki S, Obinata H, Takei K, Yasukochi S. Identification of metabolomic profile related to adult Fontan pathophysiology. IJC HEART & VASCULATURE 2021; 37:100921. [PMID: 34901379 PMCID: PMC8639334 DOI: 10.1016/j.ijcha.2021.100921] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 11/12/2021] [Accepted: 11/18/2021] [Indexed: 11/29/2022]
Abstract
Background Metabolic disorders are important pathophysiologies that can cause multiple organ dysfunction and worsen prognosis in Fontan patients. This study aimed to comprehensively evaluate the metabolomic profile of adult Fontan patients and characterize its pathophysiology in relation to 2 control groups. Methods and Results We performed metabolomic analysis of 31 plasma samples using capillary electrophoresis time-of-flight mass spectrometry. This observational cross-sectional study compared plasma metabolites of 14 heterogeneous adult Fontan patients with those of control groups, including 9 patients with congenital heart disease after biventricular repair and 8 normal healthy controls. Fontan patients exhibited significant differences in intermediate metabolite concentrations related to glycolysis, the tricarboxylic acid (TCA) cycle, and the urea cycle. The plasma concentrations of lactic acid, 2-oxoglutarate, isocitric acid, malic acid, cis-aconitic acid, arginine, citrulline, and the ratio of ornithine/citrulline showed significantly differences among the groups. Multiple logistic regression analysis with a stepwise selection-elimination method identified 2-oxoglutaric acid (odds ratio [OR] 1.98, 95% confidence interval [CI] 1.05–3.76) and cis-aconitic acid (OR 2.69, 95% CI 1.04–6.99) as independently associated with Fontan patients. After adjustment for the covariates of age and gender, 2-oxoglutaric acid (OR 1.97, 95% CI 0.98–3.93) and cis-aconitic acid (OR 3.88, 95% CI 0.99–15.2) showed remarkable relationships with Fontan patients. Conclusions The present findings suggest that abnormalities in the TCA cycle and amino acid metabolism are distinguishing features in the pathophysiology of Fontan patients. Future metabolomic studies will assist in developing biomarkers for the early prediction of “silent” Fontan pathophysiologies.
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Affiliation(s)
- Noriko Motoki
- Department of Pediatrics, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
| | - Hirohiko Motoki
- Department of Cardiology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
| | - Masafumi Utsumi
- Department of Pediatrics, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
| | - Shoko Yamazaki
- Department of Pediatrics, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
| | - Haruka Obinata
- Department of Cardiology, Nagano Children's Hospital, 3100 Toyoshina, Azumino, Nagano 399-8288, Japan
| | - Kohta Takei
- Department of Cardiology, Nagano Children's Hospital, 3100 Toyoshina, Azumino, Nagano 399-8288, Japan
| | - Satoshi Yasukochi
- Department of Cardiology, Nagano Children's Hospital, 3100 Toyoshina, Azumino, Nagano 399-8288, Japan
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Insights from myalgic encephalomyelitis/chronic fatigue syndrome may help unravel the pathogenesis of postacute COVID-19 syndrome. Trends Mol Med 2021; 27:895-906. [PMID: 34175230 PMCID: PMC8180841 DOI: 10.1016/j.molmed.2021.06.002] [Citation(s) in RCA: 154] [Impact Index Per Article: 38.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 05/25/2021] [Accepted: 06/01/2021] [Indexed: 12/13/2022]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause chronic and acute disease. Postacute sequelae of SARS-CoV-2 infection (PASC) include injury to the lungs, heart, kidneys, and brain that may produce a variety of symptoms. PASC also includes a post-coronavirus disease 2019 (COVID-19) syndrome ('long COVID') with features that can follow other acute infectious diseases and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Here we summarize what is known about the pathogenesis of ME/CFS and of 'acute' COVID-19, and we speculate that the pathogenesis of post-COVID-19 syndrome in some people may be similar to that of ME/CFS. We propose molecular mechanisms that might explain the fatigue and related symptoms in both illnesses, and we suggest a research agenda for both ME/CFS and post-COVID-19 syndrome.
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Monzón-Nomdedeu MB, Morten KJ, Oltra E. Induced pluripotent stem cells as suitable sensors for fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome. World J Stem Cells 2021; 13:1134-1150. [PMID: 34567431 PMCID: PMC8422931 DOI: 10.4252/wjsc.v13.i8.1134] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 04/19/2021] [Accepted: 07/05/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Fibromyalgia (FM) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are devastating metabolic neuroimmune diseases that are difficult to diagnose because of the presence of numerous symptoms and a lack of specific biomarkers. Despite patient heterogeneity linked to patient subgroups and variation in disease severity, anomalies are found in the blood and plasma of these patients when compared with healthy control groups. The seeming specificity of these "plasma factors", as recently reported by Ron Davis and his group at Stanford University, CA, United States, and observations by our group, have led to the proposal that induced pluripotent stem cells (iPSCs) may be used as metabolic sensors for FM and ME/CFS, a hypothesis that is the basis for this in-depth review. AIM To identify metabolic signatures in FM and/or ME/CFS supporting the existence of disease-associated plasma factors to be sensed by iPSCs. METHODS A PRISMA (Preferred Reported Items for Systematic Reviews and Meta-analysis)-based systematic review of the literature was used to select original studies evaluating the metabolite profiles of FM and ME/CFS body fluids. The MeSH terms "metabolomic" or "metabolites" in combination with FM and ME/CFS disease terms were screened against the PubMed database. Only original studies applying omics technologies, published in English, were included. The data obtained were tabulated according to the disease and type of body fluid analyzed. Coincidences across studies were searched and P-values reported by the original studies were gathered to document significant differences found in the disease groups. RESULTS Eighteen previous studies show that some metabolites are commonly altered in ME/CFS and FM body fluids. In vitro cell-based assays have the potential to be developed as screening platforms, providing evidence for the existence of factors in patient body fluids capable of altering morphology, differentiation state and/or growth patterns. Moreover, they can be further developed using approaches aimed at blocking or reversing the effects of specific plasma/serum factors seen in patients. The documented high sensitivity and effective responses of iPSCs to environmental cues suggests that these pluripotent cells could form robust, reproducible reporter systems of metabolic diseases, including ME/CFS and FM. Furthermore, culturing iPSCs, or their mesenchymal stem cell counterparts, in patient-conditioned medium may provide valuable information to predict individual outcomes to stem-cell therapy in the context of precision medicine studies. CONCLUSION This opinion review explains our hypothesis that iPSCs could be developed as a screening platform to provide evidence of a metabolic imbalance in FM and ME/CFS.
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Affiliation(s)
- María B Monzón-Nomdedeu
- School of Biotechnology, Universidad Católica de Valencia San Vicente Mártir, Valencia 46001, Spain
| | - Karl J Morten
- Nuffield Department of Women's and Reproductive Health, The Women Centre, University of Oxford, Oxford OX3 9DU, United Kingdom
| | - Elisa Oltra
- Department of Pathology, Universidad Católica de Valencia San Vicente Mártir, Valencia 46001, Spain
- Centro de Investigación Traslacional San Alberto Magno, Universidad Católica de Valencia San Vicente Mártir, Valencia 46001, Spain.
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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 2021; 118:e2024358118. [PMID: 34400495 PMCID: PMC8403932 DOI: 10.1073/pnas.2024358118] [Citation(s) in RCA: 159] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Although most patients recover from acute COVID-19, some experience postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection (PASC). One subgroup of PASC is a syndrome called "long COVID-19," reminiscent of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS is a debilitating condition, often triggered by viral and bacterial infections, leading to years-long debilitating symptoms including profound fatigue, postexertional malaise, unrefreshing sleep, cognitive deficits, and orthostatic intolerance. Some are skeptical that either ME/CFS or long COVID-19 involves underlying biological abnormalities. However, in this review, we summarize the evidence that people with acute COVID-19 and with ME/CFS have biological abnormalities including redox imbalance, systemic inflammation and neuroinflammation, an impaired ability to generate adenosine triphosphate, and a general hypometabolic state. These phenomena have not yet been well studied in people with long COVID-19, and each of them has been reported in other diseases as well, particularly neurological diseases. We also examine the bidirectional relationship between redox imbalance, inflammation, energy metabolic deficits, and a hypometabolic state. We speculate as to what may be causing these abnormalities. Thus, understanding the molecular underpinnings of both PASC and ME/CFS may lead to the development of novel therapeutics.
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Affiliation(s)
- Bindu D Paul
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205
| | | | - Anthony L Komaroff
- Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02120
| | - Solomon H Snyder
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205
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Hoel F, Hoel A, Pettersen IK, Rekeland IG, Risa K, Alme K, Sørland K, Fosså A, Lien K, Herder I, Thürmer HL, Gotaas ME, Schäfer C, Berge RK, Sommerfelt K, Marti HP, Dahl O, Mella O, Fluge Ø, Tronstad KJ. A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome. JCI Insight 2021; 6:e149217. [PMID: 34423789 PMCID: PMC8409979 DOI: 10.1172/jci.insight.149217] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 07/07/2021] [Indexed: 01/08/2023] Open
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease usually presenting after infection. Emerging evidence supports that energy metabolism is affected in ME/CFS, but a unifying metabolic phenotype has not been firmly established. We performed global metabolomics, lipidomics, and hormone measurements, and we used exploratory data analyses to compare serum from 83 patients with ME/CFS and 35 healthy controls. Some changes were common in the patient group, and these were compatible with effects of elevated energy strain and altered utilization of fatty acids and amino acids as catabolic fuels. In addition, a set of heterogeneous effects reflected specific changes in 3 subsets of patients, and 2 of these expressed characteristic contexts of deregulated energy metabolism. The biological relevance of these metabolic phenotypes (metabotypes) was supported by clinical data and independent blood analyses. In summary, we report a map of common and context-dependent metabolic changes in ME/CFS, and some of them presented possible associations with clinical patient profiles. We suggest that elevated energy strain may result from exertion-triggered tissue hypoxia and lead to systemic metabolic adaptation and compensation. Through various mechanisms, such metabolic dysfunction represents a likely mediator of key symptoms in ME/CFS and possibly a target for supportive intervention.
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Affiliation(s)
| | - August Hoel
- Department of Biomedicine and.,Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | | | - Ingrid G Rekeland
- Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway
| | - Kristin Risa
- Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway
| | - Kine Alme
- Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway
| | - Kari Sørland
- Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway
| | - Alexander Fosså
- Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.,KJ Jebsen Centre for B-cell malignancies, University of Oslo, Oslo, Norway
| | - Katarina Lien
- CFS/ME Center, Division of Medicine, Oslo University Hospital, Oslo, Norway
| | - Ingrid Herder
- CFS/ME Center, Division of Medicine, Oslo University Hospital, Oslo, Norway
| | | | - Merete E Gotaas
- Department of Pain and Complex Disorders, St. Olav's Hospital, Trondheim, Norway
| | - Christoph Schäfer
- Department of Rehabilitation Medicine, University Hospital of North Norway, Tromsø, Norway
| | - Rolf K Berge
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Kristian Sommerfelt
- Department of Clinical Science, University of Bergen, Bergen, Norway.,Department of Pediatrics and
| | - Hans-Peter Marti
- Department of Clinical Medicine, University of Bergen, Bergen, Norway.,Department of Medicine, Haukeland University Hospital, Bergen, Norway
| | - Olav Dahl
- Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway.,Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Olav Mella
- Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway.,Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Øystein Fluge
- Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway.,Department of Clinical Science, University of Bergen, Bergen, Norway
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Rusin A, Li M, Cocchetto A, Seymour C, Mothersill C. Radiation exposure and mitochondrial insufficiency in chronic fatigue and immune dysfunction syndrome. Med Hypotheses 2021; 154:110647. [PMID: 34358921 DOI: 10.1016/j.mehy.2021.110647] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 04/19/2021] [Accepted: 07/25/2021] [Indexed: 12/13/2022]
Abstract
Chronic fatigue and Immune Dysfunction Syndrome (CFIDS) is a heterogeneous disease that may be promoted by various environmental stressors, including viral infection, toxin uptake, and ionizing radiation exposure. Previous studies have identified mitochondrial dysfunction in CFIDS patients, including modulation of mitochondrial respiratory chain activity, deletions in the mitochondrial genome, and upregulation of reactive oxygen species (ROS). This paper focuses on radiation effects and hypothesizes that CFIDS is primarily caused by stressor-induced mitochondrial metabolic insufficiency, which results in decreased energy production and anabolic metabolites required for normal cellular metabolism. Furthermore, tissues neighbouring or distant from directly perturbed tissues compensate for this dysfunction, which causes symptoms associated with CFIDS. This hypothesis is justified by reviewing the links between radiation exposure and CFIDS, cancer, immune dysfunction, and induction of oxidative stress. Moreover, the relevance of mitochondria in cellular responses to radiation and metabolism are discussed and putative mitochondrial biomarkers for CFIDS are introduced. Implications for diagnosis are then described, including a potential urine assay and PCR test for mitochondrial genome mutations. Finally, future research needs are offered with an emphasis on where rapid progress may be made to assist the afflicted.
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Affiliation(s)
- Andrej Rusin
- Department of Biology, McMaster University, Hamilton, ON Canada.
| | - Megan Li
- Department of Physics and Astronomy, McMaster University, Department of Physics and Astronomy, McMaster University, Hamilton, ON Canada
| | - Alan Cocchetto
- National CFIDS Foundation Inc., 103 Aletha Road, Needham, MA USA
| | - Colin Seymour
- Department of Biology, McMaster University, Hamilton, ON Canada
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Blauensteiner J, Bertinat R, León LE, Riederer M, Sepúlveda N, Westermeier F. Altered endothelial dysfunction-related miRs in plasma from ME/CFS patients. Sci Rep 2021; 11:10604. [PMID: 34011981 PMCID: PMC8134566 DOI: 10.1038/s41598-021-89834-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 04/28/2021] [Indexed: 02/08/2023] Open
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease characterized by unexplained debilitating fatigue. Although the etiology is unknown, evidence supports immunological abnormalities, such as persistent inflammation and immune-cell activation, in a subset of patients. Since the interplay between inflammation and vascular alterations is well-established in other diseases, endothelial dysfunction has emerged as another player in ME/CFS pathogenesis. Endothelial nitric oxide synthase (eNOS) generates nitric oxide (NO) that maintains endothelial homeostasis. eNOS is activated by silent information regulator 1 (Sirt1), an anti-inflammatory protein. Despite its relevance, no study has addressed the Sirt1/eNOS axis in ME/CFS. The interest in circulating microRNAs (miRs) as potential biomarkers in ME/CFS has increased in recent years. Accordingly, we analyze a set of miRs reported to modulate the Sirt1/eNOS axis using plasma from ME/CFS patients. Our results show that miR-21, miR-34a, miR-92a, miR-126, and miR-200c are jointly increased in ME/CFS patients compared to healthy controls. A similar finding was obtained when analyzing public miR data on peripheral blood mononuclear cells. Bioinformatics analysis shows that endothelial function-related signaling pathways are associated with these miRs, including oxidative stress and oxygen regulation. Interestingly, histone deacetylase 1, a protein responsible for epigenetic regulations, represented the most relevant node within the network. In conclusion, our study provides a basis to find endothelial dysfunction-related biomarkers and explore novel targets in ME/CFS.
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Affiliation(s)
- J Blauensteiner
- Institute of Biomedical Science, Department of Health Studies, FH Joanneum University of Applied Sciences, Graz, Austria
| | - R Bertinat
- Centro de Microscopía Avanzada, CMA-BIO BIO, Facultad de Ciencias Biológica, Universidad de Concepción, Concepción, Chile
| | - L E León
- Instituto de Ciencias Biomédicas, Facultad de Ciencias de La Salud, Universidad Autónoma de Chile, Santiago, Chile
| | - M Riederer
- Institute of Biomedical Science, Department of Health Studies, FH Joanneum University of Applied Sciences, Graz, Austria
| | - N Sepúlveda
- Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK
- CEAUL - Centro de Estatística e Aplicações da Universidade de Lisboa, Lisbon, Portugal
- Institute of Medical Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität (FU) Berlin, Humboldt-Universität Zu Berlin and Berlin Institute of Health (BIH), Berlin, Germany
| | - F Westermeier
- Institute of Biomedical Science, Department of Health Studies, FH Joanneum University of Applied Sciences, Graz, Austria.
- Centro Integrativo de Biología y Química Aplicada (CIBQA), Universidad Bernardo O´Higgins, Santiago, Chile.
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Study on the Relationship between the miRNA-centered ceRNA Regulatory Network and Fatigue. J Mol Neurosci 2021; 71:1967-1974. [PMID: 33993410 PMCID: PMC8500871 DOI: 10.1007/s12031-021-01845-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 04/13/2021] [Indexed: 10/25/2022]
Abstract
In recent years, the incidence of fatigue has been increasing, and the effective prevention and treatment of fatigue has become an urgent problem. As a result, the genetic research of fatigue has become a hot spot. Transcriptome-level regulation is the key link in the gene regulatory network. The transcriptome includes messenger RNAs (mRNAs) and noncoding RNAs (ncRNAs). MRNAs are common research targets in gene expression profiling. Noncoding RNAs, including miRNAs, lncRNAs, circRNAs and so on, have been developed rapidly. Studies have shown that miRNAs are closely related to the occurrence and development of fatigue. MiRNAs can regulate the immune inflammatory reaction in the central nervous system (CNS), regulate the transmission of nerve impulses and gene expression, regulate brain development and brain function, and participate in the occurrence and development of fatigue by regulating mitochondrial function and energy metabolism. LncRNAs can regulate dopaminergic neurons to participate in the occurrence and development of fatigue. This has certain value in the diagnosis of chronic fatigue syndrome (CFS). CircRNAs can participate in the occurrence and development of fatigue by regulating the NF-κB pathway, TNF-α and IL-1β. The ceRNA hypothesis posits that in addition to the function of miRNAs in unidirectional regulation, mRNAs, lncRNAs and circRNAs can regulate gene expression by competitive binding with miRNAs, forming a ceRNA regulatory network with miRNAs. Therefore, we suggest that the miRNA-centered ceRNA regulatory network is closely related to fatigue. At present, there are few studies on fatigue-related ncRNA genes, and most of these limited studies are on miRNAs in ncRNAs. However, there are a few studies on the relationship between lncRNAs, cirRNAs and fatigue. Less research is available on the pathogenesis of fatigue based on the ceRNA regulatory network. Therefore, exploring the complex mechanism of fatigue based on the ceRNA regulatory network is of great significance. In this review, we summarize the relationship between miRNAs, lncRNAs and circRNAs in ncRNAs and fatigue, and focus on exploring the regulatory role of the miRNA-centered ceRNA regulatory network in the occurrence and development of fatigue, in order to gain a comprehensive, in-depth and new understanding of the essence of the fatigue gene regulatory network.
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Lupo GFD, Rocchetti G, Lucini L, Lorusso L, Manara E, Bertelli M, Puglisi E, Capelli E. Potential role of microbiome in Chronic Fatigue Syndrome/Myalgic Encephalomyelits (CFS/ME). Sci Rep 2021; 11:7043. [PMID: 33782445 PMCID: PMC8007739 DOI: 10.1038/s41598-021-86425-6] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 02/23/2021] [Indexed: 12/17/2022] Open
Abstract
Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is a severe multisystemic disease characterized by immunological abnormalities and dysfunction of energy metabolism. Recent evidences suggest strong correlations between dysbiosis and pathological condition. The present research explored the composition of the intestinal and oral microbiota in CFS/ME patients as compared to healthy controls. The fecal metabolomic profile of a subgroup of CFS/ME patients was also compared with the one of healthy controls. The fecal and salivary bacterial composition in CFS/ME patients was investigated by Illumina sequencing of 16S rRNA gene amplicons. The metabolomic analysis was performed by an UHPLC-MS. The fecal microbiota of CFS/ME patients showed a reduction of Lachnospiraceae, particularly Anaerostipes, and an increased abundance of genera Bacteroides and Phascolarctobacterium compared to the non-CFS/ME groups. The oral microbiota of CFS/ME patients showed an increase of Rothia dentocariosa. The fecal metabolomic profile of CFS/ME patients revealed high levels of glutamic acid and argininosuccinic acid, together with a decrease of alpha-tocopherol. Our results reveal microbial signatures of dysbiosis in the intestinal microbiota of CFS/ME patients. Further studies are needed to better understand if the microbial composition changes are cause or consequence of the onset of CFS/ME and if they are related to any of the several secondary symptoms.
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Affiliation(s)
- Giuseppe Francesco Damiano Lupo
- Department for Sustainable Food Process-DiSTAS, Università Cattolica del Sacro Cuore, Via Emilia Parmense 84, 29122, Piacenza, Italy
- Laboratory of Immunology and Genetic Analysis, Department of Earth and Environmental Science, University of Pavia, 27100, Pavia, Italy
- Centre for Health Technologies, University of Pavia, 27100, Pavia, Italy
| | - Gabriele Rocchetti
- Department for Sustainable Food Process-DiSTAS, Università Cattolica del Sacro Cuore, Via Emilia Parmense 84, 29122, Piacenza, Italy
| | - Luigi Lucini
- Department for Sustainable Food Process-DiSTAS, Università Cattolica del Sacro Cuore, Via Emilia Parmense 84, 29122, Piacenza, Italy
| | - Lorenzo Lorusso
- ASST Lecco, UOC Neurology and Stroke Unit, Merate, LC, Italy
| | - Elena Manara
- MAGI Euregio, Via Maso della Pieve, 60/A, 39100, Bolzano, Italy
| | - Matteo Bertelli
- MAGI Euregio, Via Maso della Pieve, 60/A, 39100, Bolzano, Italy
| | - Edoardo Puglisi
- Department for Sustainable Food Process-DiSTAS, Università Cattolica del Sacro Cuore, Via Emilia Parmense 84, 29122, Piacenza, Italy.
| | - Enrica Capelli
- Laboratory of Immunology and Genetic Analysis, Department of Earth and Environmental Science, University of Pavia, 27100, Pavia, Italy.
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Insights into Metabolite Diagnostic Biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Int J Mol Sci 2021; 22:ijms22073423. [PMID: 33810365 PMCID: PMC8037376 DOI: 10.3390/ijms22073423] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/23/2021] [Accepted: 03/23/2021] [Indexed: 12/23/2022] Open
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a persistent and unexplained pathological state characterized by exertional and severely debilitating fatigue, with/without infectious or neuropsychiatric symptoms, and with a minimum duration of 6 consecutive months. Its pathogenesis is not fully understood. There are no firmly established diagnostic biomarkers or treatment, due to incomplete understanding of the etiology of ME/CFS and diagnostic uncertainty. Establishing a biomarker for the objective diagnosis is urgently needed to treat a lot of patients. Recently, research on ME/CFS using metabolome analysis methods has been increasing. Here, we overview recent findings concerning the metabolic features in patients with ME/CFS and the animal models which contribute to the development of diagnostic biomarkers for ME/CFS and its treatment. In addition, we discuss future perspectives of studies on ME/CFS.
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Feng LR, Barb JJ, Regan J, Saligan LN. Plasma metabolomic profile associated with fatigue in cancer patients. Cancer Med 2021; 10:1623-1633. [PMID: 33534943 PMCID: PMC7940245 DOI: 10.1002/cam4.3749] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 12/18/2020] [Accepted: 01/10/2021] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Metabolomics is the newest -omics methodology and allows for a functional snapshot of the biochemical activity and cellular state. The goal of this study is to characterize metabolomic profiles associated with cancer-related fatigue, a debilitating symptom commonly reported by oncology patients. METHODS Untargeted ultrahigh performance liquid chromatography/mass spectrometry metabolomics approach was used to identify metabolites in plasma samples collected from a total of 197 participants with or without cancer. Partial least squares-discriminant analysis (PLS-DA) was used to identify discriminant metabolite features, and diagnostic performance of selected classifiers was quantified using area under the receiver operating characteristics (AUROC) curve analysis. Pathway enrichment analysis was performed using Fisher's exact test and the Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic pathway database. FINDINGS The global metabolomics approach yielded a total of 1120 compounds of known identity. Significant metabolic pathways unique to fatigued cancer versus control groups included sphingolipid metabolism, histidine metabolism, and cysteine and methionine metabolism. Significant pathways unique to non-fatigued cancer versus control groups included inositol phosphate metabolism, primary bile acid biosynthesis, ascorbate and aldarate metabolism, starch and sucrose metabolism, and pentose and glucuronate interconversions. Pathways shared between the two comparisons included caffeine metabolism, tyrosine metabolism, steroid hormone biosynthesis, sulfur metabolism, and phenylalanine metabolism. CONCLUSIONS We found significant metabolomic profile differences associated with cancer-related fatigue. By comparing metabolic signatures unique to fatigued cancer patients with metabolites associated with, but not unique to, fatigued cancer individuals (overlap pathways) and metabolites associated with cancer but not fatigue, we provided a broad view of the metabolic phenotype of cancer-related fatigue.
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Affiliation(s)
- Li Rebekah Feng
- National Institute of Nursing ResearchNational Institutes of HealthBethesdaMDUSA
| | | | - Jeniece Regan
- The Pennsylvania State University College of MedicineHersheyPAUSA
| | - Leorey N. Saligan
- National Institute of Nursing ResearchNational Institutes of HealthBethesdaMDUSA
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Altered in vivo brain GABA and glutamate levels are associated with multiple sclerosis central fatigue. Eur J Radiol 2021; 137:109610. [PMID: 33657474 DOI: 10.1016/j.ejrad.2021.109610] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 01/31/2021] [Accepted: 02/21/2021] [Indexed: 11/20/2022]
Abstract
PURPOSE Fatigue is a common symptom in patients with multiple sclerosis (MS) with unknown pathophysiology. Dysfunction of the GABAergic/glutamatergic pathways involving inhibitory and excitatory neurotransmitters such as γ-aminobutyric acid (GABA) and glutamine + glutamate pool (Glx) have been implicated in several neurological disorders. This study is aimed to evaluate the potential role of GABA and Glx in the origin of central fatigue in relapse remitting MS (RRMS) patients. METHODS 24 RRMS patients and 16 age- and sex-matched healthy controls (HC) were scanned using Mescher-Garwood point resolved spectroscopy (MEGA-PRESS) with a 3 T system to quantify GABA+ and Glx from prefrontal (PFC) and sensorimotor (SMC) cortices. Self-reported fatigue status was measured on all participants using the Modified Fatigue Impact Scale (MFIS). RESULTS RRMS patients had higher fatigue scores relative to HC (p ≤ 0.05). Compared to HC, Glx levels in RRMS patients were significantly decreased in SMC (p = 0.04). Significant correlations were found between fatigue scores and GABA+ (r = -0.531, p = 0.008) and Glx (r = 0.511, p = 0.018) in PFC. Physical fatigue was negatively correlated with GABA+ in SMC and PFC (r = -0.428 and -0.472 respectively, p ≤ 0.04) and positively with PFC Glx (r = 0.480, p = 0.028). CONCLUSION The associations between fatigue and GABA + and Glx suggest that there might be dysregulation of GABAergic/glutamatergic neurotransmission in the pathophysiological mechanism of central fatigue in MS.
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