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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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Waterman A, Doumas SA, Fischer M, Mattar M, Charbel S, Jennings J, Doman DB. Uncovering the Hidden Link Between the Aberrant Intestinal Microbiome and Fibromyalgia. Gastroenterol Hepatol (N Y) 2025; 21:111-121. [PMID: 40115610 PMCID: PMC11920023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/23/2025]
Abstract
Fibromyalgia is a multifaceted syndrome primarily characterized by chronic widespread pain and fatigue. Despite its significant prevalence and incidence, the mechanisms mediating the disease pathogenesis have remained poorly understood; however, increasing evidence suggests a potentially central role of intestinal dysbiosis. Researchers have been examining possible diagnostic biomarkers, such as Helicobacter pylori infection, urine metabolite profiles, and cytokine levels, which reflect these microbiome changes. Additionally, evaluation of therapeutic interventions targeting the gut microbiome, including probiotics, fecal microbiota transplantation, and antibiotics for specific infections, has highlighted their potential in alleviating fibromyalgia symptoms. This article delves into the emerging role of the gut microbiome in fibromyalgia pathogenesis, illustrating how alterations in gut bacterial composition and diversity are implicated in the pathophysiology of the disease through the gut-brain axis, and sets a direction for future research to enhance diagnostic accuracy and therapeutic efficacy of this complex condition.
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Affiliation(s)
- Ade Waterman
- Department of Internal Medicine, MedStar Georgetown University Hospital, Washington, DC
| | - Stavros A Doumas
- Department of Internal Medicine, MedStar Georgetown University Hospital, Washington, DC
| | - Michele Fischer
- Department of Gastroenterology, MedStar Georgetown University Hospital, Washington, DC
| | - Mark Mattar
- Department of Gastroenterology, MedStar Georgetown University Hospital, Washington, DC
| | - Samer Charbel
- Department of Gastroenterology, MedStar Montgomery Medical Center, Olney, Maryland
| | - Joseph Jennings
- Department of Gastroenterology, MedStar Georgetown University Hospital, Washington, DC
| | - David B Doman
- Department of Gastroenterology, MedStar Health Gastroenterology at Silver Spring, Silver Spring, Maryland
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Yi L, Liao T, Yuan M, Chen Q, Xiong W, Zhu H. Single-cell metabolomics profiling of somatosensory neurons in various stages of neuropathic pain. J Biol Chem 2025; 301:108309. [PMID: 39955065 PMCID: PMC11938157 DOI: 10.1016/j.jbc.2025.108309] [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: 06/05/2024] [Revised: 02/07/2025] [Accepted: 02/10/2025] [Indexed: 02/17/2025] Open
Abstract
Metabolic alterations in the somatosensory cortex (S1) play a crucial role in neuropathic pain development, as evidenced by magnetic resonance spectroscopy and mass spectrometry analyses of brain homogenates. However, investigating metabolic changes in specific neuronal subtypes during neuropathic pain development remains challenging. Here, utilizing a recently developed technique called single-cell mass spectrometry (SCMS), we investigated metabolomic alterations within excitatory glutamatergic neurons located in the primary S1 during various stages of neuropathic pain. Specifically, we induced neuropathic pain in mice using a spared nerve injury (SNI) model and observed activation of glutamatergic neurons in layer II/III of S1 through c-Fos staining and electrophysiology. We profiled metabolic changes and performed pathway enrichment analysis in these neurons by single-cell mass spectrometry during both acute and subchronic phases of SNI. Further analyses revealed metabolites whose alterations significantly correlated with changes in pain thresholds, as well as distinct temporal patterns of metabolite expression during pain progression. From these analyses, we identified several key metabolites (homogentisic acid, phosphatidylcholine, phosphorylcholine, and rhein) and validated their causal roles in pain modulation via pharmacological interventions. Thus, our study provides a valuable resource for elucidating the neurometabolic regulatory mechanisms underlying neuropathic pain from a single-cell perspective.
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Affiliation(s)
- Lin Yi
- Hefei National Research Center for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Tiepeng Liao
- Hefei National Research Center for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Anhui Province Key Laboratory of Biomedical Imaging and Intelligent Processing, Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei, China
| | - Man Yuan
- Hefei National Research Center for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Qi Chen
- Hefei National Research Center for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Wei Xiong
- Hefei National Research Center for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Anhui Province Key Laboratory of Biomedical Imaging and Intelligent Processing, Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei, China; CAS Key Laboratory of Brain Function and Disease, University of Science and Technology of China, Hefei, China; Anhui Province Key Laboratory of Biomedical Aging Research, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China.
| | - Hongying Zhu
- Hefei National Research Center for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Anhui Province Key Laboratory of Biomedical Imaging and Intelligent Processing, Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei, China; CAS Key Laboratory of Brain Function and Disease, University of Science and Technology of China, Hefei, China; Anhui Province Key Laboratory of Biomedical Aging Research, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China.
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Mackey S, Aghaeepour N, Gaudilliere B, Kao MC, Kaptan M, Lannon E, Pfyffer D, Weber K. Innovations in acute and chronic pain biomarkers: enhancing diagnosis and personalized therapy. Reg Anesth Pain Med 2025; 50:110-120. [PMID: 39909549 PMCID: PMC11877092 DOI: 10.1136/rapm-2024-106030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 10/17/2024] [Indexed: 02/07/2025]
Abstract
Pain affects millions worldwide, posing significant challenges in diagnosis and treatment. Despite advances in understanding pain mechanisms, there remains a critical need for validated biomarkers to enhance diagnosis, prognostication, and personalized therapy. This review synthesizes recent advancements in identifying and validating acute and chronic pain biomarkers, including imaging, molecular, sensory, and neurophysiological approaches. We emphasize the emergence of composite, multimodal strategies that integrate psychosocial factors to improve the precision and applicability of biomarkers in chronic pain management. Neuroimaging techniques like MRI and positron emission tomography provide insights into structural and functional abnormalities related to pain, while electrophysiological methods like electroencepholography and magnetoencepholography assess dysfunctional processing in the pain neuroaxis. Molecular biomarkers, including cytokines, proteomics, and metabolites, offer diagnostic and prognostic potential, though extensive validation is needed. Integrating these biomarkers with psychosocial factors into clinical practice can revolutionize pain management by enabling personalized treatment strategies, improving patient outcomes, and potentially reducing healthcare costs. Future directions include the development of composite biomarker signatures, advances in artificial intelligence, and biomarker signature integration into clinical decision support systems. Rigorous validation and standardization efforts are also necessary to ensure these biomarkers are clinically useful. Large-scale collaborative research will be vital to driving progress in this field and implementing these biomarkers in clinical practice. This comprehensive review highlights the potential of biomarkers to transform acute and chronic pain management, offering hope for improved diagnosis, treatment personalization, and patient outcomes.
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Affiliation(s)
- Sean Mackey
- Division of Pain Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Nima Aghaeepour
- Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, California, USA
| | - Brice Gaudilliere
- Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, California, USA
| | - Ming-Chih Kao
- Division of Pain Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Merve Kaptan
- Division of Pain Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Edward Lannon
- Division of Pain Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Dario Pfyffer
- Division of Pain Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Kenneth Weber
- Division of Pain Medicine, Stanford University School of Medicine, Stanford, California, USA
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Erdrich S, Harnett JE. Fibromyalgia severity and symptoms are associated with the disorders of gut-brain interaction. Eur J Pain 2025; 29:10.1002/ejp.4766. [PMID: 39665371 PMCID: PMC11635909 DOI: 10.1002/ejp.4766] [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: 07/05/2024] [Revised: 10/31/2024] [Accepted: 11/19/2024] [Indexed: 12/13/2024]
Abstract
INTRODUCTION Fibromyalgia remains an idiopathic common disorder characterised by widespread pain with no universally accepted treatment. Irritable bowel syndrome is prevalent among women living with fibromyalgia. The prevalence of other disorders of gut-brain interaction (DGBI) and associations with fibromyalgia symptoms and severity is unknown. OBJECTIVES To evaluate the prevalence of the range of DGBI and associations with the symptoms and severity of fibromyalgia in women. METHODS A prospective observational study was conducted in New Zealand in 2022. A comprehensive survey included validated measures to identify DGBI (Rome IV) and items assessing the severity of fibromyalgia and pain symptoms, sleep quality, quality of life, mental health and migraine. Analysis was conducted employing Spearman's rho, Mann-Whitney U, Kruskal-Wallis and chi-square tests. RESULTS A total of 111 adult women with fibromyalgia enrolled in the study. Of these, 98 (93%) met the criteria for at least one DGBI, and 67 (68%) satisfied criteria for more than one. All groups of DGBI, and 11 specific DGBI were significantly associated with measures of pain, fibromyalgia severity, sleep problems and migraine (p < 0.05). Severity of pain and symptoms associated with fibromyalgia, including sleep problems, were also significantly associated with the functional bowel disorder severity index. CONCLUSION This study demonstrated that the prevalence of DGBI in women with fibromyalgia extends beyond irritable bowel syndrome. Presence of multiple DGBI correlates with pain, severity indices of fibromyalgia and sleep problems. Further research is required to examine the aetiology of DGBI in this population. SIGNIFICANCE STATEMENT This observational study has identified important relationships between the broader DGBI, fibromyalgia pain and associated symptoms, particularly migraine and sleep disturbance. Notable correlations between the severity indices of each are demonstrated, suggesting that improvements in one domain may reduce pain and improve overall well-being. These findings highlight the importance of addressing each clinical feature of the condition when supporting patients with fibromyalgia.
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Affiliation(s)
- Sharon Erdrich
- School of Pharmacy, Faculty of Medicine and HealthThe University of SydneyCamperdownNew South WalesAustralia
| | - Joanna E. Harnett
- School of Pharmacy, Faculty of Medicine and HealthThe University of SydneyCamperdownNew South WalesAustralia
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Palma-Ordóñez JF, Moreno-Fernández AM, Ramírez-Tejero JA, Durán-González E, Martínez-Lara A, Cotán D. Implication of intestinal microbiota in the etiopathogenesis of fibromyalgia: A systematic review. Int J Rheum Dis 2024; 27:e15021. [PMID: 38287551 DOI: 10.1111/1756-185x.15021] [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: 05/23/2022] [Revised: 10/18/2023] [Accepted: 12/18/2023] [Indexed: 01/31/2024]
Abstract
Fibromyalgia (FM) is a highly prevalent chronic disease. About 4.7% of the world's population suffers from generalized pain and hypersensitivity, in addition to a wide range of physical and psychological symptoms. The etiopathogenesis of this disease is multifactorial, which makes its diagnosis and treatment challenging. Recently, the increase in the number of studies on microbiota has provided new data that can help to understand the onset and development of FM. An updated systematic review of the causes of FM has been carried out in this work. Particularly in the last decade, research has focused on the gut-brain axis, which has emerged as a crucial mechanism for microbiota-host crosstalk. In FM patients, quantitative imbalances of the intestinal microbiota (dysbiosis) and bacterial metabolites with differential relative abundance have been found, especially short-chain fatty acids and lipopolysaccharides. Furthermore, the microbiota has been found to indirectly influence host neurotransmitter mechanisms, mainly through the serotonin precursor, glutamate, and gamma-aminobutyric acid. Thus, all these mechanisms and their influence on the etiopathogenesis of FM are discussed in this review.
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Smeets Y, Soer R, Chatziantoniou E, Preuper RHS, Reneman MF, Wolff AP, Timmerman H. Role of non-invasive objective markers for the rehabilitative diagnosis of central sensitization in patients with fibromyalgia: A systematic review. J Back Musculoskelet Rehabil 2024; 37:525-584. [PMID: 38073369 PMCID: PMC11091570 DOI: 10.3233/bmr-220430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 09/28/2023] [Indexed: 12/19/2023]
Abstract
BACKGROUND Central sensitization cannot be demonstrated directly in humans. Therefore, studies used different proxy markers (signs, symptoms and tools) to identify factors assumed to relate to central sensitization in humans, that is, Human Assumed Central Sensitization (HACS). The aims of this systematic review were to identify non-invasive objective markers of HACS and the instruments to assess these markers in patients with fibromyalgia (FM). METHODS A systematic review was conducted with the following inclusion criteria: (1) adults, (2) diagnosed with FM, and (3) markers and instruments for HACS had to be non-invasive. Data were subsequently extracted, and studies were assessed for risk of bias using the quality assessment tools developed by the National Institute of Health. RESULTS 78 studies (n= 5234 participants) were included and the findings were categorized in markers identified to assess peripheral and central manifestations of HACS. The identified markers for peripheral manifestations of HACS, with at least moderate evidence, were pain after-sensation decline rates, mechanical pain thresholds, pressure pain threshold, sound 'pressure' pain threshold, cutaneous silent period, slowly repeated evoked pain sensitization and nociceptive flexion reflex threshold. The identified markers for central manifestations of HACS were efficacy of conditioned pain modulation with pressure pain conditioning and brain perfusion analysis. Instruments to assess these markers are: pin-prick stimulators, cuff-algometry, repetitive pressure stimulation using a pressure algometer, sound, electrodes and neuroimaging techniques. CONCLUSIONS This review provides an overview of non-invasive markers and instruments for the assessment of HACS in patients with FM. Implementing these findings into clinical settings may help to identify HACS in patients with FM.
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Affiliation(s)
- Yasemin Smeets
- University of Groningen, University Medical Center Groningen, Department of Anesthesiology, Pain Center, Groningen, The Netherlands
| | - Remko Soer
- University of Groningen, University Medical Center Groningen, Department of Anesthesiology, Pain Center, Groningen, The Netherlands
- mProve Hospitals, Zwolle, The Netherlands
| | - Evangelia Chatziantoniou
- University of Groningen, University Medical Center Groningen, Department of Anesthesiology, Pain Center, Groningen, The Netherlands
| | - Rita H.R. Schiphorst Preuper
- University of Groningen, University Medical Center Groningen, Department of Rehabilitation Medicine, Groningen, The Netherlands
| | - Michiel F. Reneman
- University of Groningen, University Medical Center Groningen, Department of Rehabilitation Medicine, Groningen, The Netherlands
| | - André P. Wolff
- University of Groningen, University Medical Center Groningen, Department of Anesthesiology, Pain Center, Groningen, The Netherlands
| | - Hans Timmerman
- University of Groningen, University Medical Center Groningen, Department of Anesthesiology, Pain Center, Groningen, The Netherlands
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Lee C, Chen C. Role of proprioceptors in chronic musculoskeletal pain. Exp Physiol 2024; 109:45-54. [PMID: 37417654 PMCID: PMC10988698 DOI: 10.1113/ep090989] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 06/23/2023] [Indexed: 07/08/2023]
Abstract
Proprioceptors are non-nociceptive low-threshold mechanoreceptors. However, recent studies have shown that proprioceptors are acid-sensitive and express a variety of proton-sensing ion channels and receptors. Accordingly, although proprioceptors are commonly known as mechanosensing neurons that monitor muscle contraction status and body position, they may have a role in the development of pain associated with tissue acidosis. In clinical practice, proprioception training is beneficial for pain relief. Here we summarize the current evidence to sketch a different role of proprioceptors in 'non-nociceptive pain' with a focus on their acid-sensing properties.
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Affiliation(s)
- Cheng‐Han Lee
- Institute of Biomedical SciencesAcademia SinicaTaipeiTaiwan
| | - Chih‐Cheng Chen
- Institute of Biomedical SciencesAcademia SinicaTaipeiTaiwan
- Neuroscience Program of Academia SinicaAcademia SinicaTaipeiTaiwan
- Taiwan Mouse Clinic, Biomedical Translational Research CenterAcademia SinicaTaipeiTaiwan
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Sas D, Gaudel F, Verdier D, Kolta A. Hyperexcitability of muscle spindle afferents in jaw-closing muscles in experimental myalgia: Evidence for large primary afferents involvement in chronic pain. Exp Physiol 2024; 109:100-111. [PMID: 38103003 PMCID: PMC10988680 DOI: 10.1113/ep090769] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Accepted: 11/30/2023] [Indexed: 12/17/2023]
Abstract
The goals of this review are to improve understanding of the aetiology of chronic muscle pain and identify new targets for treatments. Muscle pain is usually associated with trigger points in syndromes such as fibromyalgia and myofascial syndrome, and with small spots associated with spontaneous electrical activity that seems to emanate from fibers inside muscle spindles in EMG studies. These observations, added to the reports that large-diameter primary afferents, such as those innervating muscle spindles, become hyperexcitable and develop spontaneous ectopic firing in conditions leading to neuropathic pain, suggest that changes in excitability of these afferents might make an important contribution to the development of pathological pain. Here, we review evidence that the muscle spindle afferents (MSAs) of the jaw-closing muscles become hyperexcitable in a model of chronic orofacial myalgia. In these afferents, as in other large-diameter primary afferents in dorsal root ganglia, firing emerges from fast membrane potential oscillations that are supported by a persistent sodium current (INaP ) mediated by Na+ channels containing the α-subunit NaV 1.6. The current flowing through NaV 1.6 channels increases when the extracellular Ca2+ concentration decreases, and studies have shown that INaP -driven firing is increased by S100β, an astrocytic protein that chelates Ca2+ when released in the extracellular space. We review evidence of how astrocytes, which are known to be activated in pain conditions, might, through their regulation of extracellular Ca2+ , contribute to the generation of ectopic firing in MSAs. To explain how ectopic firing in MSAs might cause pain, we review evidence supporting the hypothesis that cross-talk between proprioceptive and nociceptive pathways might occur in the periphery, within the spindle capsule.
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Affiliation(s)
- Dar'ya Sas
- Département de NeurosciencesUniversité de MontréalMontréalQuébecCanada
- Centre Interdisciplinaire de Recherche sur le Cerveau et l'Apprentissage (CIRCA)MontréalQuébecCanada
| | - Fanny Gaudel
- Département de NeurosciencesUniversité de MontréalMontréalQuébecCanada
- Centre Interdisciplinaire de Recherche sur le Cerveau et l'Apprentissage (CIRCA)MontréalQuébecCanada
| | - Dorly Verdier
- Département de NeurosciencesUniversité de MontréalMontréalQuébecCanada
- Centre Interdisciplinaire de Recherche sur le Cerveau et l'Apprentissage (CIRCA)MontréalQuébecCanada
| | - Arlette Kolta
- Département de NeurosciencesUniversité de MontréalMontréalQuébecCanada
- Centre Interdisciplinaire de Recherche sur le Cerveau et l'Apprentissage (CIRCA)MontréalQuébecCanada
- Faculté de Médecine DentaireUniversité de MontréalMontréalQuébecCanada
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Rus A, López-Sánchez JA, Martínez-Martos JM, Ramírez-Expósito MJ, Molina F, Correa-Rodríguez M, Aguilar-Ferrándiz ME. Predictive Ability of Serum Amino Acid Levels to Differentiate Fibromyalgia Patients from Healthy Subjects. Mol Diagn Ther 2024; 28:113-128. [PMID: 37843759 DOI: 10.1007/s40291-023-00677-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/19/2023] [Indexed: 10/17/2023]
Abstract
BACKGROUND Fibromyalgia is a complex illness to diagnose and treat. OBJECTIVES To evaluate a broad range of circulating free amino acid (AA) levels in fibromyalgia patients as well as the ability of the AAs to differentiate fibromyalgia patients from healthy subjects. DESIGN We carried out a case-control study to evaluate AA levels in 62 patients with fibromyalgia and 78 healthy subjects. This study adheres to the STROBE guidelines. METHODS AAs content was assayed by HPLC in serum samples. The predictive value of AA levels in fibromyalgia was determined by receiver operating characteristic (ROC) curve and forward binary logistic regression analyses. RESULTS Fibromyalgia patients showed higher serum levels of aspartic acid, glutamic acid, aminoadipic acid, asparagine, histidine, 3-methyl-histidine, 5-methyl-histidine, glycine, threonine, taurine, tyrosine, valine, methionine, isoleucine, phenylalanine, leucine, ornithine, lysine, branched chain AAs (BCAAs), large neutral AAs, essential AAs (EAAs), non-essential AAs (NEAAs), basic AAs, EAAs/NEAAs ratio, phenylalanine/tyrosine ratio, and global arginine bioavailability ratio than the controls. Serum alanine levels were lower in patients than in controls. According to ROC analysis, most of these AAs may be good markers for differentiating individuals with fibromyalgia from healthy subjects. Results of logistic regression showed that the combination of glutamic acid, histidine, and alanine had the greatest predictive ability to diagnose fibromyalgia. CONCLUSIONS Our results show an imbalance in serum levels of most AAs in patients with fibromyalgia, which suggest a metabolic disturbance. The determination of serum levels of these AAs may aid in the diagnosis of fibromyalgia, in combination with clinical data of the patient.
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Affiliation(s)
- Alma Rus
- Department of Cell Biology, University of Granada, Avenida de la Fuentenueva, s/n, 18071, Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012, Granada, Spain
| | - José Alberto López-Sánchez
- Department of Cell Biology, University of Granada, Avenida de la Fuentenueva, s/n, 18071, Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012, Granada, Spain
- Department of Physical Therapy, Faculty of Health Sciences, University of Granada, Avenida de la Ilustración, 60, 18016, Granada, Spain
| | | | | | - Francisco Molina
- Department of Cell Biology, University of Granada, Avenida de la Fuentenueva, s/n, 18071, Granada, Spain
- Department of Physical Therapy, Faculty of Health Sciences, University of Granada, Avenida de la Ilustración, 60, 18016, Granada, Spain
| | - María Correa-Rodríguez
- Department of Nursing, Faculty of Health Sciences, University of Granada, Avenida de la Ilustración, 60, 18016, Granada, Spain.
| | - María Encarnación Aguilar-Ferrándiz
- Department of Cell Biology, University of Granada, Avenida de la Fuentenueva, s/n, 18071, Granada, Spain
- Department of Physical Therapy, Faculty of Health Sciences, University of Granada, Avenida de la Ilustración, 60, 18016, Granada, Spain
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11
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Bäckryd E, Thordeman K, Gerdle B, Ghafouri B. Cerebrospinal Fluid Metabolomics Identified Ongoing Analgesic Medication in Neuropathic Pain Patients. Biomedicines 2023; 11:2525. [PMID: 37760966 PMCID: PMC10526053 DOI: 10.3390/biomedicines11092525] [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: 06/27/2023] [Revised: 09/06/2023] [Accepted: 09/11/2023] [Indexed: 09/29/2023] Open
Abstract
BACKGROUND Cerebrospinal fluid (CSF) can reasonably be hypothesized to mirror central nervous system pathophysiology in chronic pain conditions. Metabolites are small organic molecules with a low molecular weight. They are the downstream products of genes, transcripts and enzyme functions, and their levels can mirror diseased metabolic pathways. The aim of this metabolomic study was to compare the CSF of patients with chronic neuropathic pain (n = 16) to healthy controls (n = 12). METHODS Nuclear magnetic resonance spectroscopy was used for analysis of the CSF metabolome. Multivariate data analysis by projection discriminant analysis (OPLS-DA) was used to separate information from noise and minimize the multiple testing problem. RESULTS The significant OPLS-DA model identified 26 features out of 215 as important for group separation (R2 = 0.70, Q2 = 0.42, p = 0.017 by CV-ANOVA; 2 components). Twenty-one out of twenty-six features were statistically significant when comparing the two groups by univariate statistics and remained significant at a false discovery rate of 10%. For six out of the top ten metabolite features, the features were absent in all healthy controls. However, these features were related to medication, mainly acetaminophen (=paracetamol), and not to pathophysiological processes. CONCLUSION CSF metabolomics was a sensitive method to detect ongoing analgesic medication, especially acetaminophen.
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Affiliation(s)
- Emmanuel Bäckryd
- Pain and Rehabilitation Center, and Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
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12
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Martín F, Blanco-Suárez M, Zambrano P, Cáceres O, Almirall M, Alegre-Martín J, Lobo B, González-Castro AM, Santos J, Domingo JC, Jurek J, Castro-Marrero J. Increased gut permeability and bacterial translocation are associated with fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome: implications for disease-related biomarker discovery. Front Immunol 2023; 14:1253121. [PMID: 37744357 PMCID: PMC10512706 DOI: 10.3389/fimmu.2023.1253121] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 08/25/2023] [Indexed: 09/26/2023] Open
Abstract
Background There is growing evidence of the significance of gastrointestinal complaints in the impairment of the intestinal mucosal barrier function and inflammation in fibromyalgia (FM) and in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). However, data on intestinal permeability and gut barrier dysfunction in FM and ME/CFS are still limited with conflicting results. This study aimed to assess circulating biomarkers potentially related to intestinal barrier dysfunction and bacterial translocation and their association with self-reported symptoms in these conditions. Methods A pilot multicenter, cross-sectional cohort study with consecutive enrolment of 22 patients with FM, 30 with ME/CFS and 26 matched healthy controls. Plasma levels of anti-beta-lactoglobulin antibodies (IgG anti-β-LGB), zonulin-1 (ZO-1), lipopolysaccharides (LPS), soluble CD14 (sCD14) and interleukin-1-beta (IL-1β) were assayed using ELISA. Demographic and clinical characteristics of the participants were recorded using validated self-reported outcome measures. The diagnostic accuracy of each biomarker was assessed using the receiver operating characteristic (ROC) curve analysis. Results FM patients had significantly higher levels of anti-β-LGB, ZO-1, LPS, and sCD14 than healthy controls (all P < 0.0001). In ME/CFS patients, levels of anti-β-LGB, ZO-1, LPS, and sCD14 were significantly higher than controls, but lower than in FM (all P < 0.01), while there was no significant difference in IL-1β level. In the FM and ME/CFS cohorts, both anti-β-LGB and ZO-1 correlated significantly with LPS and sCD14 (P < 0.001 for both). In the FM group, both anti-β-LGB and ZO-1 were correlated significantly with physical and mental health components on the SF-36 scale (P < 0.05); whereas IL-1β negatively correlated with the COMPASS-31 score (P < 0.05). In the ME/CFS cohort, ZO-1 was positively correlated with the COMPASS-31 score (P < 0.05). The ROC curve analysis indicated a strong ability of anti-β-LGB, ZO-1, LPS and sCD14 to predictively distinguish between FM and ME/CFS from healthy controls (P < 0.0001). Conclusion Biomarkers of intestinal barrier function and inflammation were associated with autonomic dysfunction assessed by COMPASS-31 scores in FM and ME/CFS respectively. Anti-β-LGB antibodies, ZO-1, LPS, and sCD14 may be putative predictors of intestinal barrier dysfunction in these cohorts. Further studies are needed to assess whether these findings are causal and can therefore be applied in clinical practice.
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Affiliation(s)
- Franz Martín
- Andalusian Centre of Molecular Biology and Regenerative Medicine (CABIMER), University Pablo Olavide, University of Seville, Seville, Spain
- Biomedical Research Network on Diabetes and Related Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Manuel Blanco-Suárez
- Central Sensitivity Unit (SHC Medical), Hospital Viamed Santa Ángela de la Cruz, Seville, Spain
| | - Paola Zambrano
- Central Sensitivity Unit (SHC Medical), Hospital Viamed Santa Ángela de la Cruz, Seville, Spain
| | - Oscar Cáceres
- Central Sensitivity Unit (SHC Medical), Hospital Viamed Santa Ángela de la Cruz, Seville, Spain
| | - Miriam Almirall
- Division of Rheumatology, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
- Rheumatology Research Group, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Research Unit, Vall d´Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - José Alegre-Martín
- Division of Rheumatology, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
- Rheumatology Research Group, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Research Unit, Vall d´Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Beatriz Lobo
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d’Hebron Research Institute, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Ana Maria González-Castro
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d’Hebron Research Institute, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Javier Santos
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d’Hebron Research Institute, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Joan Carles Domingo
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Barcelona, Spain
| | - Joanna Jurek
- Rheumatology Research Group, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Research Unit, Vall d´Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Jesús Castro-Marrero
- Rheumatology Research Group, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Research Unit, Vall d´Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
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Maroli AS, Powers R. Closing the gap between in vivo and in vitro omics: using QA/QC to strengthen ex vivo NMR metabolomics. NMR IN BIOMEDICINE 2023; 36:e4594. [PMID: 34369014 PMCID: PMC8821733 DOI: 10.1002/nbm.4594] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 06/21/2021] [Accepted: 07/09/2021] [Indexed: 05/08/2023]
Abstract
Metabolomics aims to achieve a global quantitation of the pool of metabolites within a biological system. Importantly, metabolite concentrations serve as a sensitive marker of both genomic and phenotypic changes in response to both internal and external stimuli. NMR spectroscopy greatly aids in the understanding of both in vitro and in vivo physiological systems and in the identification of diagnostic and therapeutic biomarkers. Accordingly, NMR is widely utilized in metabolomics and fluxomics studies due to its limited requirements for sample preparation and chromatography, its non-destructive and quantitative nature, its utility in the structural elucidation of unknown compounds, and, importantly, its versatility in the analysis of in vitro, in vivo, and ex vivo samples. This review provides an overview of the strengths and limitations of in vitro and in vivo experiments for translational research and discusses how ex vivo studies may overcome these weaknesses to facilitate the extrapolation of in vitro insights to an in vivo system. The application of NMR-based metabolomics to ex vivo samples, tissues, and biofluids can provide essential information that is close to a living system (in vivo) with sensitivity and resolution comparable to those of in vitro studies. The success of this extrapolation process is critically dependent on high-quality and reproducible data. Thus, the incorporation of robust quality assurance and quality control checks into the experimental design and execution of NMR-based metabolomics experiments will ensure the successful extrapolation of ex vivo studies to benefit translational medicine.
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Affiliation(s)
- Amith Sadananda Maroli
- Nebraska Center for Integrated Biomolecular Communication, University of Nebraska-Lincoln, Lincoln, Nebraska, USA
- Department of Chemistry, University of Nebraska-Lincoln, Lincoln, Nebraska, USA
| | - Robert Powers
- Nebraska Center for Integrated Biomolecular Communication, University of Nebraska-Lincoln, Lincoln, Nebraska, USA
- Department of Chemistry, University of Nebraska-Lincoln, Lincoln, Nebraska, USA
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14
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Hung CH, Tsai MH, Wang PS, Liang FW, Hsu CY, Lee KW, Fong YO, Han DS, Lee CH, Lai CL, Chen CC. Oxidative stress involves phenotype modulation of morbid soreness symptoms in fibromyalgia. RMD Open 2023; 9:rmdopen-2022-002741. [PMID: 36918228 PMCID: PMC10016302 DOI: 10.1136/rmdopen-2022-002741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 02/27/2023] [Indexed: 03/16/2023] Open
Abstract
OBJECTIVES Muscle soreness occurs after exercise and also in musculoskeletal diseases, such as fibromyalgia (FM). However, the nosography and pathoetiology of morbid soreness in FM remain unknown. This study aimed to investigate the morbid soreness of FM, evaluate its therapeutic responses and probe its pathophysiology with metabolomics profiling. METHODS Patients with newly diagnosed FM were prospectively recruited and completed self-report questionnaires pertaining to musculoskeletal symptoms. The phenotypes and metabotypes were assessed with variance, classification and correlation analyses. RESULTS Fifty-one patients and 41 healthy controls were included. Soreness symptoms were prevalent in FM individuals (92.2%). In terms of manifestations and metabolomic features, phenotypes diverged between patients with mixed pain and soreness symptoms (FM-PS) and those with pain dominant symptoms. Conventional treatment for FM did not ameliorate soreness severity despite its efficacy on pain. Moreover, despite the salient therapeutic efficacy on pain relief in FM-PS cases, conventional treatment did not improve their general disease severity. Metabolomics analyses suggested oxidative metabolism dysregulation in FM, and high malondialdehyde level indicated excessive oxidative stress in FM individuals as compared with controls (p=0.009). Contrary to exercise-induced soreness, lactate levels were significantly lower in FM individuals than controls, especially in FM-PS. Moreover, FM-PS cases exclusively featured increased malondialdehyde level (p=0.008) and a correlative trend between malondialdehyde expression and soreness intensity (r=0.337, p=0.086). CONCLUSIONS Morbid soreness symptoms were prevalent in FM, with the presentation and therapeutic responses different from FM pain conditions. Oxidative stress rather than lactate accumulation involved phenotype modulation of the morbid soreness in FM. TRIAL REGISTRATION NUMBER NCT04832100.
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Affiliation(s)
- Chih-Hsien Hung
- Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Hsien Tsai
- Department of Child Care, National Pingtung University of Science and Technology, Pingtung, Taiwan
| | - Po-Sheng Wang
- Department of Nutrition and Health Sciences, Fooyin University, Kaohsiung, Taiwan
| | - Fu-Wen Liang
- Department of Public Health, College of Health Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Center for Big Data Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chung-Yao Hsu
- Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Kuo-Wei Lee
- Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Department of Neurology, Kaohsiung Municipal Hsiao Kang Hospital, Kaohsiung, Taiwan
| | - Yi-On Fong
- Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Der-Sheng Han
- Department of Physical Medicine and Rehabilitation, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Physical Medicine and Rehabilitation, National Taiwan UniversityHospital, Bei-Hu Branch, Taipei, Taiwan
| | - Cheng-Han Lee
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Chiou-Lian Lai
- Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan .,School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chih-Cheng Chen
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan .,Taiwan Mouse Clinic - National Comprehensive Mouse Phenotyping and DrugTesting Center, Academia Sinica, Taipei, Taiwan
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15
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Yao S, Bao H, Nuguri SM, Yu L, Mikulik Z, Osuna-Diaz MM, Sebastian KR, Hackshaw KV, Rodriguez-Saona L. Rapid Biomarker-Based Diagnosis of Fibromyalgia Syndrome and Related Rheumatologic Disorders by Portable FT-IR Spectroscopic Techniques. Biomedicines 2023; 11:712. [PMID: 36979691 PMCID: PMC10044908 DOI: 10.3390/biomedicines11030712] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 02/20/2023] [Accepted: 02/24/2023] [Indexed: 03/02/2023] Open
Abstract
Fibromyalgia syndrome (FM), one of the most common illnesses that cause chronic widespread pain, continues to present significant diagnostic challenges. The objective of this study was to develop a rapid vibrational biomarker-based method for diagnosing fibromyalgia syndrome and related rheumatologic disorders (systemic lupus erythematosus (SLE), osteoarthritis (OA) and rheumatoid arthritis (RA)) through portable FT-IR techniques. Bloodspot samples were collected from patients diagnosed with FM (n = 122) and related rheumatologic disorders (n = 70), including SLE (n = 17), RA (n = 43), and OA (n = 10), and stored in conventional protein saver bloodspot cards. The blood samples were prepared by four different methods (blood aliquots, protein-precipitated extraction, and non-washed and water-washed semi-permeable membrane filtration extractions), and spectral data were collected with a portable FT-IR spectrometer. Pattern recognition analysis, OPLS-DA, was able to identify the signature profile and classify the spectra into corresponding classes (Rcv > 0.93) with excellent sensitivity and specificity. Peptide backbones and aromatic amino acids were predominant for the differentiation and might serve as candidate biomarkers for syndromes such as FM. This research evaluated the feasibility of portable FT-IR combined with chemometrics as an accurate and high-throughput tool for distinct spectral signatures of biomarkers related to the human syndrome (FM), which could allow for real-time and in-clinic diagnostics of FM.
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Affiliation(s)
- Siyu Yao
- Department of Food Science and Technology, Ohio State University, Columbus, OH 43210, USA
| | - Haona Bao
- Department of Food Science and Technology, Ohio State University, Columbus, OH 43210, USA
| | - Shreya Madhav Nuguri
- Department of Food Science and Technology, Ohio State University, Columbus, OH 43210, USA
| | - Lianbo Yu
- Center of Biostatistics and Bioinformatics, Ohio State University, Columbus, OH 43210, USA
| | - Zhanna Mikulik
- Department of Internal Medicine, Division of Rheumatology, The Ohio State University, 480 Medical Center Drive, Columbus, OH 43210, USA
| | - Michelle M. Osuna-Diaz
- Department of Internal Medicine, Dell Medical School, The University of Texas, 1601 Trinity St., Austin, TX 78712, USA
| | - Katherine R. Sebastian
- Department of Internal Medicine, Dell Medical School, The University of Texas, 1601 Trinity St., Austin, TX 78712, USA
| | - Kevin V. Hackshaw
- Department of Internal Medicine, Division of Rheumatology, Dell Medical School, The University of Texas, 1601 Trinity St., Austin, TX 78712, USA
| | - Luis Rodriguez-Saona
- Department of Food Science and Technology, Ohio State University, Columbus, OH 43210, USA
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16
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Gut microbiota in chronic pain: Novel insights into mechanisms and promising therapeutic strategies. Int Immunopharmacol 2023. [DOI: 10.1016/j.intimp.2023.109685] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
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17
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Ghafouri B, Thordeman K, Hadjikani R, Bay Nord A, Gerdle B, Bäckryd E. An investigation of metabolome in blood in patients with chronic peripheral, posttraumatic/postsurgical neuropathic pain. Sci Rep 2022; 12:21714. [PMID: 36522472 PMCID: PMC9755304 DOI: 10.1038/s41598-022-26405-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
Neuropathic pain (NP) is a chronic pain condition resulting from a lesion or disease in the somatosensory nervous system. The aim of this study was to investigate the metabolome in plasma from patients with chronic peripheral, posttraumatic/postsurgical NP compared to healthy controls. Further, we aimed to investigate the correlation between pain intensity and the metabolome in plasma. The metabolic profile in plasma samples from 16 patients with chronic NP and 12 healthy controls was analyzed using a nuclear magnetic resonance spectroscopy method. Information about pain intensity, pain duration, body mass index (BMI), age, sex, and blood pressure were obtained through a questionnaire and clinical examination. Multivariate data analysis was used to identify metabolites significant for group separation and their correlation with pain intensity and duration, BMI, and age. We found 50 out of 326 features in plasma significantly contributing to group discrimination between NP and controls. Several of the metabolites that significantly differed were involved in inflammatory processes, while others were important for central nervous system functioning and neural signaling. There was no correlation between pain intensity and levels of metabolite in NP. These findings indicate that there seems to be peripheral/systemic differences in the metabolic profile between patients with chronic NP and healthy individuals.
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Affiliation(s)
- Bijar Ghafouri
- grid.5640.70000 0001 2162 9922Pain and Rehabilitation Center, and Department of Health, Medicine and Caring Sciences, Linköping University, 581 85 Linköping, Sweden
| | - Katarina Thordeman
- grid.5640.70000 0001 2162 9922Pain and Rehabilitation Center, and Department of Health, Medicine and Caring Sciences, Linköping University, 581 85 Linköping, Sweden
| | - Romina Hadjikani
- grid.5640.70000 0001 2162 9922Pain and Rehabilitation Center, and Department of Health, Medicine and Caring Sciences, Linköping University, 581 85 Linköping, Sweden
| | - Anders Bay Nord
- grid.8761.80000 0000 9919 9582Swedish NMR Centre at the University of Gothenburg, Gothenburg, Sweden
| | - Björn Gerdle
- grid.5640.70000 0001 2162 9922Pain and Rehabilitation Center, and Department of Health, Medicine and Caring Sciences, Linköping University, 581 85 Linköping, Sweden
| | - Emmanuel Bäckryd
- grid.5640.70000 0001 2162 9922Pain and Rehabilitation Center, and Department of Health, Medicine and Caring Sciences, Linköping University, 581 85 Linköping, Sweden
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18
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Ricci M, Cimini A, Grivet Fojaja MR, Ullo M, Carabellese B, Frantellizzi V, Lubrano E. Novel Approaches in Molecular Imaging and Neuroimaging of Fibromyalgia. Int J Mol Sci 2022; 23:ijms232415519. [PMID: 36555158 PMCID: PMC9778683 DOI: 10.3390/ijms232415519] [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: 11/10/2022] [Revised: 12/05/2022] [Accepted: 12/06/2022] [Indexed: 12/13/2022] Open
Abstract
Fibromyalgia (FM) represents a condition that is still controversial in its entity, pathophysiology, diagnosis and management. The aim of this review is to focus on imaging aspects of FM, especially on novel approaches in molecular imaging, with a special focus on neuroimaging. Novel functional and molecular imaging findings may represent, eventually, future biomarkers both in research settings and in terms of clinical practice. Several imaging techniques have already been tested in clinical trials in the FM field, including functional MRI, positron emission tomography (PET) imaging with 18F-FDG in FM, PET imaging of the dopaminergic system, PET imaging of the GABAergic system, PET imaging with neuroinflammation and neuroimmune parameters, PET imaging of the opioid system and H215O-PET activation studies. Therefore, the potential role in the FM field of fMRI and different PET tracers has been discussed in different settings, serving as a comprehensive guide of novel imaging options both in research and in the clinical field.
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Affiliation(s)
- Maria Ricci
- Nuclear Medicine Unit, Cardarelli Hospital, 86100 Campobasso, Italy
- Correspondence: or
| | - Andrea Cimini
- Nuclear Medicine Unit, St. Salvatore Hospital, 67100 L’Aquila, Italy
| | | | | | | | - Viviana Frantellizzi
- Department of Radiological Sciences, Oncology and Anatomo-Pathology, Sapienza University of Rome, 00161 Rome, Italy
| | - Ennio Lubrano
- Department of Rheumatology, University of Molise, 86100 Campobasso, Italy
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Zhang D, Jiang L, Li L, Li X, Zheng W, Gui L, Yang Y, Liu Y, Yang L, Wang J, Xiong Y, Ji L, Deng Y, Liu X, He Q, Hu X, Liu X, Fan R, Lu Y, Liu J, Cheng J, Yang H, Li T, Gong M. Integrated metabolomics revealed the fibromyalgia-alleviation effect of Mo 2C nanozyme through regulated homeostasis of oxidative stress and energy metabolism. Biomaterials 2022; 287:121678. [PMID: 35853361 DOI: 10.1016/j.biomaterials.2022.121678] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 07/02/2022] [Accepted: 07/09/2022] [Indexed: 02/08/2023]
Abstract
Fibromyalgia (FM), the most common cause of chronic musculoskeletal pain in the general public, lacks advanced therapeutic methodology and detailed bioinformation. However, acting as a newly developed and important transition metal carbide or carbonitride, the Mo2C nanozyme has provided a novel iatrotechnique with excellent bioactivity in a cell/animal model, which also exhibits potential prospects for future clinical applications. In addition, high-content and high-throughput integrated metabolomics (including aqueous metabolomics, lipidomics, and desorption electrospray ionization-mass spectrometry imaging) also specializes in qualitative and quantitative analysis of metabolic shifts at the molecular level. In this work, the FM-alleviation effect of Mo2C nanozyme was investigated through integrated metabolomics in a mouse model. An advanced platform combining gas chromatography-mass spectrometry, liquid chromatography-mass spectrometry and bioinformatics was utilized to study the variation in the mouse metabolome and lipidome. The results revealed that Mo2C treatment could effectively enhance energy metabolism-related biological events impaired by FM, leading to homeostasis of oxidative stress and energy metabolism toward the control levels. During this process, Mo2C facilitated the elimination of ROS in plasma and cells and the rehabilitation of mice from oxidative stress and mitochondrial dysfunction. It was believed that such an integrated metabolomics study on the FM-alleviation effect of Mo2C nanozyme could provide another excellent alternative to traditional Mo2C-based research with numerous pieces of bioinformation, further supporting research area innovation, material modification, and clinical application.
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Affiliation(s)
- Dingkun Zhang
- Laboratory of Clinical Proteomics and Metabolomics, Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, PR China
| | - Ling Jiang
- Laboratory of Mitochondrial and Metabolism, Department of Anesthesiology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Li Li
- Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xin Li
- Metabolomics and Proteomics Technology Platform, West China Hospital, Sichuan University, Chengdu, PR China
| | - Wen Zheng
- Metabolomics and Proteomics Technology Platform, West China Hospital, Sichuan University, Chengdu, PR China
| | - Luolan Gui
- Metabolomics and Proteomics Technology Platform, West China Hospital, Sichuan University, Chengdu, PR China
| | - Yin Yang
- Department of Clinical Research Management, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yueqiu Liu
- Laboratory of Clinical Proteomics and Metabolomics, Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, PR China
| | - Linghui Yang
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jing Wang
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yixiao Xiong
- Laboratory of Mitochondrial and Metabolism, Department of Anesthesiology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Liwei Ji
- Laboratory of Mitochondrial and Metabolism, Department of Anesthesiology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yan Deng
- Laboratory of Mitochondrial and Metabolism, Department of Anesthesiology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xin Liu
- Laboratory of Mitochondrial and Metabolism, Department of Anesthesiology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Qinqin He
- Laboratory of Mitochondrial and Metabolism, Department of Anesthesiology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xinyi Hu
- Laboratory of Clinical Proteomics and Metabolomics, Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, PR China
| | - Xin Liu
- Laboratory of Clinical Proteomics and Metabolomics, Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, PR China
| | - Rong Fan
- Department of Mechanical Engineering, City University of Hong Kong, Kowloon, Hong Kong; Chengdu Research Institute, City University of Hong Kong, Chengdu, PR China
| | - Yang Lu
- Department of Mechanical Engineering, City University of Hong Kong, Kowloon, Hong Kong; Chengdu Research Institute, City University of Hong Kong, Chengdu, PR China
| | - Jingping Liu
- Key Laboratory of Transplant Engineering and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Jingqiu Cheng
- Laboratory of Clinical Proteomics and Metabolomics, Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, PR China
| | - Hao Yang
- Laboratory of Clinical Proteomics and Metabolomics, Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, PR China
| | - Tao Li
- Laboratory of Mitochondrial and Metabolism, Department of Anesthesiology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Meng Gong
- Laboratory of Clinical Proteomics and Metabolomics, Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, PR China.
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Lysophosphatidylcholine: Potential Target for the Treatment of Chronic Pain. Int J Mol Sci 2022; 23:ijms23158274. [PMID: 35955410 PMCID: PMC9368269 DOI: 10.3390/ijms23158274] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 07/22/2022] [Accepted: 07/23/2022] [Indexed: 12/26/2022] Open
Abstract
The bioactive lipid lysophosphatidylcholine (LPC), a major phospholipid component of oxidized low-density lipoprotein (Ox-LDL), originates from the cleavage of phosphatidylcholine by phospholipase A2 (PLA2) and is catabolized to other substances by different enzymatic pathways. LPC exerts pleiotropic effects mediated by its receptors, G protein-coupled signaling receptors, Toll-like receptors, and ion channels to activate several second messengers. Lysophosphatidylcholine (LPC) is increasingly considered a key marker/factor positively in pathological states, especially inflammation and atherosclerosis development. Current studies have indicated that the injury of nervous tissues promotes oxidative stress and lipid peroxidation, as well as excessive accumulation of LPC, enhancing the membrane hyperexcitability to induce chronic pain, which may be recognized as one of the hallmarks of chronic pain. However, findings from lipidomic studies of LPC have been lacking in the context of chronic pain. In this review, we focus in some detail on LPC sources, biochemical pathways, and the signal-transduction system. Moreover, we outline the detection methods of LPC for accurate analysis of each individual LPC species and reveal the pathophysiological implication of LPC in chronic pain, which makes it an interesting target for biomarkers and the development of medicine regarding chronic pain.
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21
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Baldi S, Pagliai G, Dinu M, Di Gloria L, Nannini G, Curini L, Pallecchi M, Russo E, Niccolai E, Danza G, Benedettelli S, Ballerini G, Colombini B, Bartolucci G, Ramazzotti M, Sofi F, Amedei A. Effect of ancient Khorasan wheat on gut microbiota, inflammation, and short-chain fatty acid production in patients with fibromyalgia. World J Gastroenterol 2022; 28:1965-1980. [PMID: 35664958 PMCID: PMC9150053 DOI: 10.3748/wjg.v28.i18.1965] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 01/19/2022] [Accepted: 03/27/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Fibromyalgia (FM) syndrome is mainly characterized by widespread pain, sleeping disorders, fatigue, and cognitive dysfunction. In many cases, gastrointestinal distress is also reported, suggesting the potential pathogenic role of the gut microbiota (GM). The GM is deeply influenced by several environmental factors, especially the diet, and recent findings highlighted significant symptom improvement in FM patients following various nutritional interventions such as vegetarian diet, low-fermentable oligosaccharides, disaccharides, monosaccharides, and polyols based diets, gluten-free diet, and especially an ancient grain supplementation. In particular, a recent study reported that a replacement diet with ancient Khorasan wheat led to an overall improvement in symptom severity of FM patients. AIM To examine the effects of ancient Khorasan wheat on the GM, inflammation, and short-chain fatty acid production in FM patients. METHODS After a 2-wk run-in period, 20 FM patients were enrolled in this randomized, double-blind crossover trial. In detail, they were assigned to consume either Khorasan or control wheat products for 8 wk and then, following an 8-wk washout period, crossed. Before and after treatments, GM characterization was performed by 16S rRNA sequencing while the fecal molecular inflammatory response and the short-chain fatty acids (SCFAs) were respectively determined with the Luminex MAGPIX detection system and a mass chromatography-mass spectrometry method. RESULTS The Khorasan wheat replacement diet, in comparison with the control wheat diet, had more positive effects on intestinal microbiota composition and on both the fecal immune and SCFAs profiles such as the significant increase of butyric acid levels (P = 0.054), candidatus Saccharibacteria (P = 9.95e-06) and Actinobacteria, and the reduction of Enterococcaceae (P = 4.97e-04). Moreover, the improvement of various FM symptoms along with the variation of some gut bacteria after the Khorasan wheat diet have been documented; in fact we reported positive correlations between Actinobacteria and both Tiredness Symptoms Scale (P < 0.001) and Functional Outcome of Sleep Questionnaire (P < 0.05) scores, between Verrucomicrobiae and both Widespread Pain Index (WPI) + Symptom Severity scale (SS) (P < 0.05) and WPI (P < 0.05) scores, between candidatus Saccharibacteria and SS score (P < 0.05), and between Bacteroidales and Sleep-Related and Safety Behaviour Questionnaire score (P < 0.05). CONCLUSION The replacement diet based on ancient Khorasan wheat results in beneficial GM compositional and functional modifications that positively correlate with an improvement of FM symptomatology.
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Affiliation(s)
- Simone Baldi
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Giuditta Pagliai
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
- Unit of Clinical Nutrition, Careggi University Hospital, Florence 50134, Italy
| | - Monica Dinu
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
- Unit of Clinical Nutrition, Careggi University Hospital, Florence 50134, Italy
| | - Leandro Di Gloria
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Giulia Nannini
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Lavinia Curini
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Marco Pallecchi
- Department of Neurosciences, Psychology, Drug Research and Child Health, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Sesto Fiorentino 50019, Italy
| | - Edda Russo
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Elena Niccolai
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Giovanna Danza
- Department of Biomedical, Experimental and Clinical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Stefano Benedettelli
- Department of Agriculture, Food, Environment and Forestry, University of Florence, Florence 50144, Italy
| | - Giovanna Ballerini
- Multidisciplinary Center for Pain Therapy, Reference Center for Fibromyalgia, Piero Palagi Hospital, USL Toscana Centro, Florence 50122, Italy
| | - Barbara Colombini
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Gianluca Bartolucci
- Department of Neurosciences, Psychology, Drug Research and Child Health, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Sesto Fiorentino 50019, Italy
| | - Matteo Ramazzotti
- Department of Biomedical, Experimental and Clinical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Francesco Sofi
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
- Unit of Clinical Nutrition, Careggi University Hospital, Florence 50134, Italy
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
- SOD of Interdisciplinary Internal Medicine, Careggi University Hospital, Florence 50134, Italy
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Diaz MM, Caylor J, Strigo I, Lerman I, Henry B, Lopez E, Wallace MS, Ellis RJ, Simmons AN, Keltner JR. Toward Composite Pain Biomarkers of Neuropathic Pain-Focus on Peripheral Neuropathic Pain. FRONTIERS IN PAIN RESEARCH 2022; 3:869215. [PMID: 35634449 PMCID: PMC9130475 DOI: 10.3389/fpain.2022.869215] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 04/21/2022] [Indexed: 01/09/2023] Open
Abstract
Chronic pain affects ~10-20% of the U.S. population with an estimated annual cost of $600 billion, the most significant economic cost of any disease to-date. Neuropathic pain is a type of chronic pain that is particularly difficult to manage and leads to significant disability and poor quality of life. Pain biomarkers offer the possibility to develop objective pain-related indicators that may help diagnose, treat, and improve the understanding of neuropathic pain pathophysiology. We review neuropathic pain mechanisms related to opiates, inflammation, and endocannabinoids with the objective of identifying composite biomarkers of neuropathic pain. In the literature, pain biomarkers typically are divided into physiological non-imaging pain biomarkers and brain imaging pain biomarkers. We review both types of biomarker types with the goal of identifying composite pain biomarkers that may improve recognition and treatment of neuropathic pain.
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Affiliation(s)
- Monica M. Diaz
- Department of Neurology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, United States
| | - Jacob Caylor
- Department of Anesthesiology, University of California, San Diego, San Diego, CA, United States
| | - Irina Strigo
- Department of Psychiatry, San Francisco Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States
| | - Imanuel Lerman
- Department of Anesthesiology, University of California, San Diego, San Diego, CA, United States
| | - Brook Henry
- Department of Psychiatry, University of California, San Diego, San Diego, CA, United States
| | - Eduardo Lopez
- Department of Psychiatry, San Francisco Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States
| | - Mark S. Wallace
- Department of Anesthesiology, University of California, San Diego, San Diego, CA, United States
| | - Ronald J. Ellis
- Department of Neurosciences, University of California, San Diego, San Diego, CA, United States
| | - Alan N. Simmons
- Department of Psychiatry, San Diego & Center of Excellence in Stress and Mental Health, Veteran Affairs Health Care System, University of California, San Diego, San Diego, CA, United States
| | - John R. Keltner
- Department of Psychiatry, San Diego & San Diego VA Medical Center, University of California, San Diego, San Diego, CA, United States
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23
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Miettinen T, Nieminen AI, Mäntyselkä P, Kalso E, Lötsch J. Machine Learning and Pathway Analysis-Based Discovery of Metabolomic Markers Relating to Chronic Pain Phenotypes. Int J Mol Sci 2022; 23:5085. [PMID: 35563473 PMCID: PMC9099732 DOI: 10.3390/ijms23095085] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 04/28/2022] [Accepted: 04/28/2022] [Indexed: 11/19/2022] Open
Abstract
Recent scientific evidence suggests that chronic pain phenotypes are reflected in metabolomic changes. However, problems associated with chronic pain, such as sleep disorders or obesity, may complicate the metabolome pattern. Such a complex phenotype was investigated to identify common metabolomics markers at the interface of persistent pain, sleep, and obesity in 71 men and 122 women undergoing tertiary pain care. They were examined for patterns in d = 97 metabolomic markers that segregated patients with a relatively benign pain phenotype (low and little bothersome pain) from those with more severe clinical symptoms (high pain intensity, more bothersome pain, and co-occurring problems such as sleep disturbance). Two independent lines of data analysis were pursued. First, a data-driven supervised machine learning-based approach was used to identify the most informative metabolic markers for complex phenotype assignment. This pointed primarily at adenosine monophosphate (AMP), asparagine, deoxycytidine, glucuronic acid, and propionylcarnitine, and secondarily at cysteine and nicotinamide adenine dinucleotide (NAD) as informative for assigning patients to clinical pain phenotypes. After this, a hypothesis-driven analysis of metabolic pathways was performed, including sleep and obesity. In both the first and second line of analysis, three metabolic markers (NAD, AMP, and cysteine) were found to be relevant, including metabolic pathway analysis in obesity, associated with changes in amino acid metabolism, and sleep problems, associated with downregulated methionine metabolism. Taken together, present findings provide evidence that metabolomic changes associated with co-occurring problems may play a role in the development of severe pain. Co-occurring problems may influence each other at the metabolomic level. Because the methionine and glutathione metabolic pathways are physiologically linked, sleep problems appear to be associated with the first metabolic pathway, whereas obesity may be associated with the second.
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Affiliation(s)
- Teemu Miettinen
- Pain Clinic, Department of Perioperative Medicine, Intensive Care and Pain Medicine, Helsinki University Hospital and SleepWell Research Programme, University of Helsinki, 00014 Helsinki, Finland; (T.M.); (E.K.)
| | - Anni I. Nieminen
- Metabolomics Unit, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00014 Helsinki, Finland;
| | - Pekka Mäntyselkä
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio Finland, and Primary Health Care Unit, Kuopio University Hospital, 70211 Kuopio, Finland;
| | - Eija Kalso
- Pain Clinic, Department of Perioperative Medicine, Intensive Care and Pain Medicine, Helsinki University Hospital and SleepWell Research Programme, University of Helsinki, 00014 Helsinki, Finland; (T.M.); (E.K.)
| | - Jörn Lötsch
- Institute of Clinical Pharmacology, Goethe—University, Theodor—Stern—Kai 7, 60590 Frankfurt am Main, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany
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24
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Piras C, Pintus BM, Noto A, Evangelista M, Fanos V, Musu M, Mussap M, Atzori L, Sardo S, Finco G. Metabolomics and Microbiomics: New Potential Strategies in Chronic Pain Syndrome. J Pain Res 2022; 15:723-731. [PMID: 35310896 PMCID: PMC8923834 DOI: 10.2147/jpr.s354516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 03/02/2022] [Indexed: 11/23/2022] Open
Affiliation(s)
- Cristina Piras
- Department of Biomedical Sciences, University of Cagliari, Monserrato, 09042, Italy
| | - Bruno Maria Pintus
- Department of Medical Sciences and Public Health, University of Cagliari, Monserrato, 09042, Italy
| | - Antonio Noto
- Department of Biomedical Sciences, University of Cagliari, Monserrato, 09042, Italy
- Correspondence: Antonio Noto, Email
| | - Maurizio Evangelista
- Department of Anesthesiology and Pain Medicine, Cattolica University, Rome, 00168, Italy
| | - Vassilios Fanos
- Department of Surgical Science, University of Cagliari, Monserrato, 09042, Italy
| | - Mario Musu
- Department of Medical Sciences and Public Health, University of Cagliari, Monserrato, 09042, Italy
| | - Michele Mussap
- Department of Surgical Science, University of Cagliari, Monserrato, 09042, Italy
| | - Luigi Atzori
- Department of Biomedical Sciences, University of Cagliari, Monserrato, 09042, Italy
| | - Salvatore Sardo
- Department of Medical Sciences and Public Health, University of Cagliari, Monserrato, 09042, Italy
| | - Gabriele Finco
- Department of Medical Sciences and Public Health, University of Cagliari, Monserrato, 09042, Italy
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25
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Gut microbiota and its role in stress-induced hyperalgesia: gender-specific responses linked to different changes in serum metabolites. Pharmacol Res 2022; 177:106129. [DOI: 10.1016/j.phrs.2022.106129] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 01/31/2022] [Accepted: 02/08/2022] [Indexed: 12/13/2022]
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Role of Creatine Supplementation in Conditions Involving Mitochondrial Dysfunction: A Narrative Review. Nutrients 2022; 14:nu14030529. [PMID: 35276888 PMCID: PMC8838971 DOI: 10.3390/nu14030529] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/24/2022] [Accepted: 01/24/2022] [Indexed: 12/14/2022] Open
Abstract
Creatine monohydrate (CrM) is one of the most widely used nutritional supplements among active individuals and athletes to improve high-intensity exercise performance and training adaptations. However, research suggests that CrM supplementation may also serve as a therapeutic tool in the management of some chronic and traumatic diseases. Creatine supplementation has been reported to improve high-energy phosphate availability as well as have antioxidative, neuroprotective, anti-lactatic, and calcium-homoeostatic effects. These characteristics may have a direct impact on mitochondrion's survival and health particularly during stressful conditions such as ischemia and injury. This narrative review discusses current scientific evidence for use or supplemental CrM as a therapeutic agent during conditions associated with mitochondrial dysfunction. Based on this analysis, it appears that CrM supplementation may have a role in improving cellular bioenergetics in several mitochondrial dysfunction-related diseases, ischemic conditions, and injury pathology and thereby could provide therapeutic benefit in the management of these conditions. However, larger clinical trials are needed to explore these potential therapeutic applications before definitive conclusions can be drawn.
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27
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Castelo-Branco L, Cardenas-Rojas A, Pacheco-Barrios K, Teixeira PEP, Gonzalez-Mego P, Vasquez-Avila K, Cortez PC, Marduy A, Rebello-Sanchez I, Parente J, Marzouk S, Fregni F. Can neural markers be used for fibromyalgia clinical management? PRINCIPLES AND PRACTICE OF CLINICAL RESEARCH (2015) 2022; 8:28-33. [PMID: 35677778 PMCID: PMC9172964 DOI: 10.21801/ppcrj.2022.81.5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Luis Castelo-Branco
- Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. 79/96 13th Street, Charlestown – MA 02129
| | - Alejandra Cardenas-Rojas
- Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. 79/96 13th Street, Charlestown – MA 02129
| | - Kevin Pacheco-Barrios
- Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. 79/96 13th Street, Charlestown – MA 02129
- Universidad San Ignacio de Loyola, Vicerrectorado de Investigación, Unidad de Investigación para la Generación y Síntesis de Evidencias en Salud. Lima, Peru. La Fontana 550, La Molina – Peru 15024
| | - Paulo E. P. Teixeira
- Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. 79/96 13th Street, Charlestown – MA 02129
- MGH Institute of Health Professions, 36 1st Ave, Boston, MA 02129, USA
| | - Paola Gonzalez-Mego
- Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. 79/96 13th Street, Charlestown – MA 02129
| | - Karen Vasquez-Avila
- Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. 79/96 13th Street, Charlestown – MA 02129
| | - Pablo Costa Cortez
- Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. 79/96 13th Street, Charlestown – MA 02129
- Instituto de Ciencias Biologicas, Departamento de Imunologia Basica e Aplicada. Av. General Rodrigo Octavio Jordão Ramos, 1200 - Coroado I, Manaus - AM, Brazil- 69067-005
| | - Anna Marduy
- Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. 79/96 13th Street, Charlestown – MA 02129
| | - Ingrid Rebello-Sanchez
- Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. 79/96 13th Street, Charlestown – MA 02129
| | - Joao Parente
- Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. 79/96 13th Street, Charlestown – MA 02129
| | | | - Felipe Fregni
- Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. 79/96 13th Street, Charlestown – MA 02129
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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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Marino C, Grimaldi M, Sabatini P, Amato P, Pallavicino A, Ricciardelli C, D’Ursi AM. Fibromyalgia and Depression in Women: An 1H-NMR Metabolomic Study. Metabolites 2021; 11:429. [PMID: 34209136 PMCID: PMC8304744 DOI: 10.3390/metabo11070429] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 06/15/2021] [Accepted: 06/23/2021] [Indexed: 12/18/2022] Open
Abstract
Fibromyalgia is a chronic and systemic syndrome characterized by muscle, bone, and joint pain. It is a gender-specific condition with a 9:1 incidence ratio between women and men. Fibromyalgia is frequently associated with psychic disorders affecting the cognitive and emotional spheres. In the reported work, we compared 31 female fibromyalgia patients to 31 female healthy controls. They were analyzed for biochemical clinical parameters, for autoimmune markers, and were subjected to 1H-NMR metabolomics analysis. To identify a correlation between the metabolomic profile and the psychic condition, a subset of 19 fibromyalgia patients was subjected to HAM-A and HAM-D Hamilton depression tests. Multivariate statistical analysis showed the dysmetabolism of several metabolites involved in energy balance that are associated with systemic inflammatory conditions. The severity of depression worsens dysmetabolic conditions; conversely, glycine and glutamate, known for their critical role as neuromodulators, appear to be potential biomarkers of fibromyalgia and are associated with different severity depression conditions.
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Affiliation(s)
- Carmen Marino
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, Italy; (C.M.); (M.G.); (A.P.); (C.R.)
| | - Manuela Grimaldi
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, Italy; (C.M.); (M.G.); (A.P.); (C.R.)
| | - Paola Sabatini
- U.O.C. Clinical Pathology D.E.A. III Umberto I, Viale S. Francesco D’Assisi, 84014 Nocera Inferiore, Italy;
| | - Patrizia Amato
- ASL Ser. T Cava de’ Tirreni, Piazza Matteo Galdi 1/3, 84013 Pregiato, Italy;
| | - Arianna Pallavicino
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, Italy; (C.M.); (M.G.); (A.P.); (C.R.)
| | - Carmen Ricciardelli
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, Italy; (C.M.); (M.G.); (A.P.); (C.R.)
| | - Anna Maria D’Ursi
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, Italy; (C.M.); (M.G.); (A.P.); (C.R.)
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30
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Fibromyalgia: Pathogenesis, Mechanisms, Diagnosis and Treatment Options Update. Int J Mol Sci 2021; 22:ijms22083891. [PMID: 33918736 PMCID: PMC8068842 DOI: 10.3390/ijms22083891] [Citation(s) in RCA: 258] [Impact Index Per Article: 64.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 04/06/2021] [Accepted: 04/07/2021] [Indexed: 12/13/2022] Open
Abstract
Fibromyalgia is a syndrome characterized by chronic and widespread musculoskeletal pain, often accompanied by other symptoms, such as fatigue, intestinal disorders and alterations in sleep and mood. It is estimated that two to eight percent of the world population is affected by fibromyalgia. From a medical point of view, this pathology still presents inexplicable aspects. It is known that fibromyalgia is caused by a central sensitization phenomenon characterized by the dysfunction of neuro-circuits, which involves the perception, transmission and processing of afferent nociceptive stimuli, with the prevalent manifestation of pain at the level of the locomotor system. In recent years, the pathogenesis of fibromyalgia has also been linked to other factors, such as inflammatory, immune, endocrine, genetic and psychosocial factors. A rheumatologist typically makes a diagnosis of fibromyalgia when the patient describes a history of pain spreading in all quadrants of the body for at least three months and when pain is caused by digital pressure in at least 11 out of 18 allogenic points, called tender points. Fibromyalgia does not involve organic damage, and several diagnostic approaches have been developed in recent years, including the analysis of genetic, epigenetic and serological biomarkers. Symptoms often begin after physical or emotional trauma, but in many cases, there appears to be no obvious trigger. Women are more prone to developing the disease than men. Unfortunately, the conventional medical therapies that target this pathology produce limited benefits. They remain largely pharmacological in nature and tend to treat the symptomatic aspects of various disorders reported by the patient. The statistics, however, highlight the fact that 90% of people with fibromyalgia also turn to complementary medicine to manage their symptoms.
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Livshits G, Kalinkovich A. Specialized, pro-resolving mediators as potential therapeutic agents for alleviating fibromyalgia symptomatology. PAIN MEDICINE 2021; 23:977-990. [PMID: 33565588 DOI: 10.1093/pm/pnab060] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVE To present a hypothesis on a novel strategy in the treatment of fibromyalgia (FM). DESIGN A narrative review. SETTING FM as a disease remains a challenging concept for numerous reasons, including undefined etiopathogenesis, unclear triggers and unsuccessful treatment modalities. We hypothesize that the inflammatome, the entire set of molecules involved in inflammation, acting as a common pathophysiological instrument of gut dysbiosis, sarcopenia, and neuroinflammation, is one of the major mechanisms underlying FM pathogenesis. In this setup, dysbiosis is proposed as the primary trigger of the inflammatome, sarcopenia as the peripheral nociceptive source, and neuroinflammation as the central mechanism of pain sensitization, transmission and symptomatology of FM. Whereas neuroinflammation is highly-considered as a critical deleterious element in FM pathogenesis, the presumed pathogenic roles of sarcopenia and systemic inflammation remain controversial. Nevertheless, sarcopenia-associated processes and dysbiosis have been recently detected in FM individuals. The prevalence of pro-inflammatory factors in the cerebrospinal fluid and blood has been repeatedly observed in FM individuals, supporting an idea on the role of inflammatome in FM pathogenesis. As such, failed inflammation resolution might be one of the underlying pathogenic mechanisms. In accordance, the application of specialized, inflammation pro-resolving mediators (SPMs) seems most suitable for this goal. CONCLUSIONS The capability of various SPMs to prevent and attenuate pain has been repeatedly demonstrated in laboratory animal experiments. Since SPMs suppress inflammation in a manner that does not compromise host defense, they could be attractive and safe candidates for the alleviation of FM symptomatology, probably in combination with anti-dysbiotic medicine.
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Affiliation(s)
- Gregory Livshits
- Adelson School of Medicine, Ariel University, Ariel, Israel.,Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Alexander Kalinkovich
- Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
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Ostojic SM. Diagnostic and Pharmacological Potency of Creatine in Post-Viral Fatigue Syndrome. Nutrients 2021; 13:nu13020503. [PMID: 33557013 PMCID: PMC7913646 DOI: 10.3390/nu13020503] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 01/27/2021] [Accepted: 01/28/2021] [Indexed: 12/14/2022] Open
Abstract
Post-viral fatigue syndrome (PVFS) is a widespread chronic neurological disease with no definite etiological factor(s), no actual diagnostic test, and no approved pharmacological treatment, therapy, or cure. Among other features, PVFS could be accompanied by various irregularities in creatine metabolism, perturbing either tissue levels of creatine in the brain, the rates of phosphocreatine resynthesis in the skeletal muscle, or the concentrations of the enzyme creatine kinase in the blood. Furthermore, supplemental creatine and related guanidino compounds appear to impact both patient- and clinician-reported outcomes in syndromes and maladies with chronic fatigue. This paper critically overviews the most common disturbances in creatine metabolism in various PVFS populations, summarizes human trials on dietary creatine and creatine analogs in the syndrome, and discusses new frontiers and open questions for using creatine in a post-COVID-19 world.
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Affiliation(s)
- Sergej M. Ostojic
- FSPE Applied Bioenergetics Lab, University of Novi Sad, 21000 Novi Sad, Serbia;
- Faculty of Health Sciences, University of Pecs, H-7621 Pecs, Hungary
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Kreider RB, Stout JR. Creatine in Health and Disease. Nutrients 2021; 13:nu13020447. [PMID: 33572884 PMCID: PMC7910963 DOI: 10.3390/nu13020447] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/22/2021] [Accepted: 01/27/2021] [Indexed: 12/14/2022] Open
Abstract
Although creatine has been mostly studied as an ergogenic aid for exercise, training, and sport, several health and potential therapeutic benefits have been reported. This is because creatine plays a critical role in cellular metabolism, particularly during metabolically stressed states, and limitations in the ability to transport and/or store creatine can impair metabolism. Moreover, increasing availability of creatine in tissue may enhance cellular metabolism and thereby lessen the severity of injury and/or disease conditions, particularly when oxygen availability is compromised. This systematic review assesses the peer-reviewed scientific and medical evidence related to creatine's role in promoting general health as we age and how creatine supplementation has been used as a nutritional strategy to help individuals recover from injury and/or manage chronic disease. Additionally, it provides reasonable conclusions about the role of creatine on health and disease based on current scientific evidence. Based on this analysis, it can be concluded that creatine supplementation has several health and therapeutic benefits throughout the lifespan.
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Affiliation(s)
- Richard B. Kreider
- Human Clinical Research Facility, Exercise & Sport Nutrition Lab, Department of Health & Kinesiology, Texas A&M University, College Station, TX 77843, USA
- Correspondence:
| | - Jeffery R. Stout
- Physiology of Work and Exercise Response (POWER) Laboratory, Institute of Exercise Physiology and Rehabilitation Science, School of Kinesiology and Physical Therapy, University of Central Florida, 12494 University Blvd., Orlando, FL 32816, USA;
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Hackshaw KV. The Search for Biomarkers in Fibromyalgia. Diagnostics (Basel) 2021; 11:diagnostics11020156. [PMID: 33494476 PMCID: PMC7911687 DOI: 10.3390/diagnostics11020156] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 01/18/2021] [Indexed: 12/12/2022] Open
Abstract
Fibromyalgia is the most common of the central sensitivity syndromes affecting 2–5% of the adult population in the United States. This pain amplification syndrome has enormous societal impact as measured by work absenteeism, decreased work productivity, disability and injury compensation and over-utilization of healthcare resources. Multiple studies have shown that early diagnosis of this condition can improve patient outlook and redirect valuable healthcare resources towards more appropriate targeted therapy. Efforts have been made towards improving diagnostic accuracy through updated criteria. The search for biomarkers for diagnosis and verification of Fibromyalgia is an ongoing process. Inadequacies with current diagnostic criteria for this condition have fueled these efforts for identification of a reproducible marker that can verify this disease in a highly sensitive, specific and reproducible manner. This review focuses on areas of research for biomarkers in fibromyalgia and suggests that future efforts might benefit from approaches that utilize arrays of biomarkers to identify this disorder that presents with a diverse clinical phenotype.
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Affiliation(s)
- Kevin V Hackshaw
- Department of Internal Medicine, Division of Rheumatology, Dell Medical School at the University of Texas at Austin, 1601 Trinity St, Austin, TX 78712, USA
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35
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Baraniuk JN, Kern G, Narayan V, Cheema A. Exercise modifies glutamate and other metabolic biomarkers in cerebrospinal fluid from Gulf War Illness and Myalgic encephalomyelitis / Chronic Fatigue Syndrome. PLoS One 2021; 16:e0244116. [PMID: 33440400 PMCID: PMC7806361 DOI: 10.1371/journal.pone.0244116] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Accepted: 12/02/2020] [Indexed: 12/21/2022] Open
Abstract
Myalgic encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) and Gulf War Illness (GWI) share many symptoms of fatigue, pain, and cognitive dysfunction that are not relieved by rest. Patterns of serum metabolites in ME/CFS and GWI are different from control groups and suggest potential dysfunction of energy and lipid metabolism. The metabolomics of cerebrospinal fluid was contrasted between ME/CFS, GWI and sedentary controls in 2 sets of subjects who had lumbar punctures after either (a) rest or (b) submaximal exercise stress tests. Postexercise GWI and control subjects were subdivided according to acquired transient postexertional postural tachycardia. Banked cerebrospinal fluid specimens were assayed using Biocrates AbsoluteIDQ® p180 kits for quantitative targeted metabolomics studies of amino acids, amines, acylcarnitines, sphingolipids, lysophospholipids, alkyl and ether phosphocholines. Glutamate was significantly higher in the subgroup of postexercise GWI subjects who did not develop postural tachycardia after exercise compared to nonexercise and other postexercise groups. The only difference between nonexercise groups was higher lysoPC a C28:0 in GWI than ME/CFS suggesting this biochemical or phospholipase activities may have potential as a biomarker to distinguish between the 2 diseases. Exercise effects were suggested by elevation of short chain acylcarnitine C5-OH (C3-DC-M) in postexercise controls compared to nonexercise ME/CFS. Limitations include small subgroup sample sizes and absence of postexercise ME/CFS specimens. Mechanisms of glutamate neuroexcitotoxicity may contribute to neuropathology and “neuroinflammation” in the GWI subset who did not develop postural tachycardia after exercise. Dysfunctional lipid metabolism may distinguish the predominantly female ME/CFS group from predominantly male GWI subjects.
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Affiliation(s)
- James N Baraniuk
- Department of Medicine, Georgetown University, Washington, DC, United States of America
| | - Grant Kern
- Department of Medicine, Georgetown University, Washington, DC, United States of America
| | - Vaishnavi Narayan
- Department of Medicine, Georgetown University, Washington, DC, United States of America
| | - Amrita Cheema
- Department of Oncology, Georgetown Lombardi Comprehensive Cancer Centre, Georgetown University, Washington, DC, United States of America
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Silva AR, Bernardo MA, Mesquita MF, Vaz Patto J, Moreira P, Padrão P, Silva ML. Dysbiosis, Small Intestinal Bacterial Overgrowth, and Chronic Diseases. ADVANCES IN MEDICAL DIAGNOSIS, TREATMENT, AND CARE 2021:334-362. [DOI: 10.4018/978-1-7998-4808-0.ch015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
Abstract
Dysbiosis is characterized by an alteration in quantity and quality of intestinal microbiota composition. In the presence of dysbiosis, enterocytes will have difficulty in maintaining the integrity of the mucosal barrier, leading to increased intestinal permeability. These events are recognised to be linked to several chronic diseases. One of the consequences of dysbiosis is the manifestation of small intestinal bacterial overgrowth (SIBO), which is associated to a variety of chronic diseases. Single food nutrients and bioactive molecules, food additives, pre- and probiotics, and different dietary patterns may change the composition of the intestinal microbiota. Low FODMAPs diet has been a reference in SIBO treatment. This chapter intends to describe how the intestinal microbiota, dysbiosis, and SIBO can be related; to define dysbiosis food and nutrients influence; and to offer some nutritional therapy strategies for applying the low FODMAPs protocol, enabling better adherence by patients in order to increase their wellbeing.
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Affiliation(s)
- Ana Rita Silva
- Centro de Investigação Interdisciplinar Egas Moniz, Portugal
| | | | | | | | - Pedro Moreira
- Faculdade de Ciências da Nutrição e Alimentação, Universidade do Porto, Portugal
| | - Patrícia Padrão
- Faculdade de Ciências da Nutrição e Alimentação, Universidade do Porto, Portugal
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Arfuch VM, Caballol Angelats R, Aguilar Martín C, Carrasco-Querol N, Sancho Sol MC, González Serra G, Fusté Anguera I, Gonçalves AQ, Berenguera A. Assessing the benefits on quality of life of a multicomponent intervention for fibromyalgia syndrome in primary care: patients' and health professionals' appraisals: a qualitative study protocol. BMJ Open 2020; 10:e039873. [PMID: 33177139 PMCID: PMC7661363 DOI: 10.1136/bmjopen-2020-039873] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 10/07/2020] [Accepted: 10/23/2020] [Indexed: 11/04/2022] Open
Abstract
INTRODUCTION Fibromyalgia syndrome (FMS) is a complex condition still scarcely understood and with ambiguity when prescribing treatment. Both patients and healthcare providers can supply valuable information for the development of new treatment strategies. The qualitative narrative analysis of participant's accounts is potentially helpful to reveal new insights about their opinions, needs, and experiences and, consequently, to model healthcare interventions accurately. International treatment guidelines suggest a promising future for multicomponent intervention (MI) approaches for FMS. This study aims to assess the benefits of a MI for patients with FMS in the context of primary care (PC) in Terres de L'Ebre, Catalonia (Spain). Furthermore, it is intended to detect the overall perception of effectiveness and to understand patients' lived experience and its impact on the quality of life. METHOD AND ANALYSIS Qualitative research from a socioconstructivism paradigm perspective and a Hermeneutic Phenomenological method. For data collection, four focus group discussions (FGDs) of 8-12 people (2 FGDs of patients and 2 of professionals) and 10-12 key informant interviews with the participants in the MI group will be carried out. All the information will be recorded and verbatim transcribed to perform an interpretive thematic analysis. ETHICS AND DISSEMINATION This study protocol has been approved by the Clinical Research Ethics Committee from the IDIAPJGol Institute, on 25 April 2018 (code P18/068), according to the Declaration of Helsinki/Tokyo. All participants will receive oral/written information about the study, and they will be required to sign an informed consent sheet. Data anonymity will be guaranteed. Dissemination will be carried out through publications in scientific journals, presentations in academic meetings, workshops and through the local and national media. TRIAL REGISTRATION NUMBER ClinicalTrials.gov: NCT04049006; Pre-results.
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Affiliation(s)
- Victoria Mailen Arfuch
- Unitat de Suport a la Recerca Terres de l'Ebre, IDIAP Jordi Gol, Barcelona, Catalunya, Spain
- Department of Pediatrics, Obstetrics and Gynecology, and Preventive Medicine, Universitat Autonoma de Barcelona, Barcelona, Catalunya, Spain
| | - Rosa Caballol Angelats
- Equip d'Atenció Primària Tortosa Est, Institut Català de la Salut, Tortosa, Catalunya, Spain
- Unitat d'Expertesa en Sindromes de Sensibilització Central Terres de l'Ebre, Institut Català de la Salut, Tortosa, Catalunya, Spain
| | - Carina Aguilar Martín
- Unitat de Suport a la Recerca Terres de l'Ebre, IDIAP Jordi Gol, Barcelona, Catalunya, Spain
- Unitat d'Avaluació, Direcció d'Atenció Primària Terres de l'Ebre, Institut Català de la Salut, Tortosa, Catalunya, Spain
| | - Noèlia Carrasco-Querol
- Unitat de Suport a la Recerca Terres de l'Ebre, IDIAP Jordi Gol, Barcelona, Catalunya, Spain
| | - Maria Cinta Sancho Sol
- Unitat de Suport a la Recerca Terres de l'Ebre, IDIAP Jordi Gol, Barcelona, Catalunya, Spain
- Unitat d'Expertesa en Sindromes de Sensibilització Central Terres de l'Ebre, Institut Català de la Salut, Tortosa, Catalunya, Spain
| | - Gemma González Serra
- Unitat de Suport a la Recerca Terres de l'Ebre, IDIAP Jordi Gol, Barcelona, Catalunya, Spain
- Unitat d'Expertesa en Sindromes de Sensibilització Central Terres de l'Ebre, Institut Català de la Salut, Tortosa, Catalunya, Spain
| | - Immaculada Fusté Anguera
- Equip d'Atenció Primària Tortosa Est, Institut Català de la Salut, Tortosa, Catalunya, Spain
- Unitat d'Expertesa en Sindromes de Sensibilització Central Terres de l'Ebre, Institut Català de la Salut, Tortosa, Catalunya, Spain
| | - Alessandra Queiroga Gonçalves
- Unitat de Suport a la Recerca Terres de l'Ebre, IDIAP Jordi Gol, Barcelona, Catalunya, Spain
- Unitat Docent de Medicina de Família i Comunitària Tortosa-Terres de L'Ebre, Institut Català de la Salut, Tortosa, Catalunya, Spain
| | - Anna Berenguera
- Department of Pediatrics, Obstetrics and Gynecology, and Preventive Medicine, Universitat Autonoma de Barcelona, Barcelona, Catalunya, Spain
- Central Research Unit, IDIAP Jordi Gol, Barcelona, Catalunya, Spain
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Evidence of Mitochondrial Dysfunction in Fibromyalgia: Deviating Muscle Energy Metabolism Detected Using Microdialysis and Magnetic Resonance. J Clin Med 2020; 9:jcm9113527. [PMID: 33142767 PMCID: PMC7693920 DOI: 10.3390/jcm9113527] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 10/28/2020] [Accepted: 10/30/2020] [Indexed: 12/14/2022] Open
Abstract
In fibromyalgia (FM) muscle metabolism, studies are sparse and conflicting associations have been found between muscle metabolism and pain aspects. This study compared alterations in metabolic substances and blood flow in erector spinae and trapezius of FM patients and healthy controls. FM patients (n = 33) and healthy controls (n = 31) underwent a clinical examination that included pressure pain thresholds and physical tests, completion of a health questionnaire, participation in microdialysis investigations of the etrapezius and erector spinae muscles, and also underwent phosphorus-31 magnetic resonance spectroscopy of the erector spinae muscle. At the baseline, FM had significantly higher levels of pyruvate in both muscles. Significantly lower concentrations of phosphocreatine (PCr) and nucleotide triphosphate (mainly adenosine triphosphate) in erector spinae were found in FM. Blood flow in erector spinae was significantly lower in FM. Significant associations between metabolic variables and pain aspects (pain intensity and pressure pain threshold PPT) were found in FM. Our results suggest that FM has mitochondrial dysfunction, although it is unclear whether inactivity, obesity, aging, and pain are causes of, the results of, or coincidental to the mitochondrial dysfunction. The significant regressions of pain intensity and PPT in FM agree with other studies reporting associations between peripheral biological factors and pain aspects.
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Teckchandani S, Nagana Gowda GA, Raftery D, Curatolo M. Metabolomics in chronic pain research. Eur J Pain 2020; 25:313-326. [PMID: 33065770 DOI: 10.1002/ejp.1677] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 09/22/2020] [Accepted: 10/11/2020] [Indexed: 01/26/2023]
Abstract
BACKGROUND AND OBJECTIVE Metabolomics deals with the identification and quantification of small molecules (metabolites) in biological samples. As metabolite levels can reflect normal or altered metabolic pathways, their measurement provides information to improve the understanding, diagnosis and management of diseases. Despite its immense potential, metabolomics applications to pain research have been sparse. This paper describes current metabolomics techniques, reviews published human metabolomics pain research and compares successful metabolomics research in other areas of medicine with the goal of highlighting opportunities offered by metabolomics to advance pain medicine. DATABASES AND DATA TREATMENT Non-systematic review. RESULTS Our search identified 19 studies that adopted a metabolomics approach in: fibromyalgia (7), chronic widespread pain (4), other musculoskeletal pain conditions (5), neuropathic pain (1), complex regional pain syndrome (1) and pelvic pain (1). The studies used either mass spectrometry or nuclear magnetic resonance. Most are characterized by small sample sizes. Some consistency has been found for alterations in glutamate and testosterone metabolism, and metabolic imbalances caused by the gut microbiome. CONCLUSIONS Metabolomics research in chronic pain is in its infancy. Most studies are at the pilot stage. Metabolomics research has been successful in other areas of medicine. These achievements should motivate investigators to expand metabolomics research to improve the understanding of the basic mechanisms of human pain, as well as provide tools to diagnose, predict and monitor chronic pain conditions. Metabolomics research can lead to the identification of biomarkers to support the development and testing of treatments, thereby facilitating personalized pain medicine.
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Affiliation(s)
- Shweta Teckchandani
- Department of Anesthesiology & Pain Medicine, University of Washington, Seattle, WA, USA
| | - G A Nagana Gowda
- Department of Anesthesiology & Pain Medicine, University of Washington, Seattle, WA, USA.,Northwest Metabolomics Research Center, Mitochondria and Metabolism Center, University of Washington, Seattle, WA, USA
| | - Daniel Raftery
- Department of Anesthesiology & Pain Medicine, University of Washington, Seattle, WA, USA.,Northwest Metabolomics Research Center, Mitochondria and Metabolism Center, University of Washington, Seattle, WA, USA
| | - Michele Curatolo
- Department of Anesthesiology & Pain Medicine, University of Washington, Seattle, WA, USA.,Harborview Injury Prevention and Research Center, University of Washington, Seattle, WA, USA.,CLEAR Research Center for Musculoskeletal Disorders, University of Washington, Seattle, WA, USA
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Chen YL, He ZG, Wang Q, Xiang HB, Fan L, Xiong J. Specific Patterns of Spinal Metabolite Ratio Underlying α-Me-5-HT-evoked Pruritus Compared with Compound 48/80 Based on Proton Nuclear Magnetic Resonance Spectroscopy. Curr Med Sci 2020; 40:761-766. [PMID: 32862388 DOI: 10.1007/s11596-020-2233-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 06/12/2020] [Indexed: 01/03/2023]
Abstract
Mechanisms of pruritus are implicated in the dysregulation of the metabolites in the spinal cord. We investigated pruritus behavioral testing in three groups of young adult male C57Bl/6 mice, including one group treated with normal saline, while the other groups intradermally injected with α-Me-5-HT (histamine-independent pruritogen), compound 48/80 (histamine-dependent pruritogen) at the nape skin of the neck, respectively. Proton nuclear magnetic resonance spectroscopy (MRS) was used to compare spinal metabolites from the vertebral cervical among three groups, and to study the association of spinal metabolite ratio and pruritus intensity. The MRS-measured N-acetylaspartate-to-myoinositol ratio (NAA/Ins) was significantly correlated with the number of scratches between normal saline group and 48/80 group or α-Me-5-HT group (both P<0.0001), indicating that NAA/Ins may be a robust surrogate marker of histamine-independent/dependent pruritogen. There was significant difference in Glu/Ins between normal saline group and 48/80 group (P=0.017), indicating that Glu/Ins may be a surrogate marker of histamine-dependent pruritogen, while GABA/Ins was highly significantly different between normal saline group and α-Me-5-HT group (P=0.008), suggesting that GABA/Ins may be a surrogate marker of histamine-independent pruritogen. MRS may reflect the extent of pruritus intensity elicited by α-Me-5-HT and compound 48/80 with sensitivity similar to the number of scratches, and above potential markers need to be further validated in pre-clinical and clinical treatment trials.
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Affiliation(s)
- Ying-le Chen
- Department of Anesthesiology, the First Affiliated Quanzhou Hospital of Fujian Medical University, Quanzhou, 362000, China
| | - Zhi-Gang He
- Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Qian Wang
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Hong-Bing Xiang
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Li Fan
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Jun Xiong
- Hepatobiliary Surgery Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Affiliation(s)
- Sergej M Ostojic
- FSPE Applied Bioenergetics Lab, University of Novi Sad, Novi Sad, Serbia
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Ahmed S, Lawrence A. PATHOGENESIS OF FIBROMYALGIA IN PATIENTS WITH AUTOIMMUNE DISEASES: SCOPING REVIEW FOR HYPOTHESIS GENERATION. CENTRAL ASIAN JOURNAL OF MEDICAL HYPOTHESES AND ETHICS 2020. [DOI: 10.47316/cajmhe.2020.1.1.06] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Introduction: Fibromyalgia (FM) prevalence is much higher in patients with other rheumatic diseases than in the general population. This leads to increase in the perceived disease activity scores and prevents patients from reaching remission. Elucidating the pathogenesis of such “secondary” FM can help alleviate some unmet needs in these diseases.
Methods: MEDLINE and Scopus databases were searched for a scoping review for hypothesis generation regarding the genesis of secondary FM.
Results: FM has been postulated to be due to cytokine dysfunction, neurogenic neuroinflammation, stress, including social defeat, sleep disturbances, sympathetic overactivity, and small fibre neuropathy. These factors increase in most autoimmune and autoinflammatory diseases. Further the evidence for the role of these factors in the pathogenesis of FM is seems strong. Metabolic syndrome and mitochondrial dysfunction are also associated with FM, but it is difficult to distinguish between cause and effect.
Conclusion: FM is the common phenotype arising from the amalgamation of various aetiologies. Recruitment or amplification of the above 6 factors by various rheumatic diseases may thus lead precipitation of secondary FM in susceptible individuals.
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Stanhope J, Breed MF, Weinstein P. Exposure to greenspaces could reduce the high global burden of pain. ENVIRONMENTAL RESEARCH 2020; 187:109641. [PMID: 32447087 PMCID: PMC7207132 DOI: 10.1016/j.envres.2020.109641] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 05/04/2020] [Accepted: 05/04/2020] [Indexed: 05/17/2023]
Abstract
Painful conditions are among the leading causes of years lived with disability, and may increase following the coronavirus pandemic, which has led to temporary closure of some healthcare services for people with chronic pain. To reduce this burden, novel, cost-effective and accessible interventions are required. We propose that greenspace exposure may be one such intervention. Drawing on evidence from neuroscience, physiology, microbiology, and psychology, we articulate how and why exposure to greenspaces could improve pain outcomes and reduce the high global burden of pain. Greenspace exposure potentially provides opportunities to benefit from known or proposed health-enhancing components of nature, such as environmental microbiomes, phytoncides, negative air ions, sunlight, and the sights and sounds of nature itself. We review the established and potential links between these specific exposures and pain outcomes. While further research is required to determine possible causal links between greenspace exposure and pain outcomes, we suggest that there is already sufficient evidence to help reduce the global burden of pain by improving access and exposure to quality greenspaces.
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Affiliation(s)
- Jessica Stanhope
- School of Biological Sciences, The University of Adelaide, North Tce, Adelaide, South Australia, 5005, Australia; School of Allied Health Science and Practice, The University of Adelaide, North Tce, Adelaide, South Australia, 5005, Australia.
| | - Martin F Breed
- College of Science and Engineering, Flinders University of South Australia, Sturt Rd, Bedford Park, South Australia, 5042, Australia; Healthy Urban Microbiome Initiative (HUMI), Adelaide, South Australia, Australia.
| | - Philip Weinstein
- School of Biological Sciences, The University of Adelaide, North Tce, Adelaide, South Australia, 5005, Australia; Healthy Urban Microbiome Initiative (HUMI), Adelaide, South Australia, Australia; School of Public Health, The University of Adelaide, North Tce, Adelaide, South Australia, 5005, Australia.
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Aroke EN, Powell-Roach KL. The Metabolomics of Chronic Pain Conditions: A Systematic Review. Biol Res Nurs 2020; 22:458-471. [PMID: 32666804 DOI: 10.1177/1099800420941105] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND Chronic pain is a significant public health problem in the United States, affecting approximately 100 million people. Yet there is a lack of robust biomarkers for clinical use in chronic pain conditions. Downstream effects of environmental, genomic, and proteomic variations in individuals with chronic pain conditions can be identified and quantified using a metabolomic approach. AIM/DESIGN The purpose of this systematic review was to examine the literature for reports of potential metabolomic signatures associated with chronic pain conditions. METHODS We searched relevant electronic databases for published studies that used various metabolomic approaches to investigate chronic pain conditions among subjects of all ages. RESULTS Our search identified a total of 586 articles, 18 of which are included in this review. The reviewed studies used metabolomics to investigate fibromyalgia (n = 5), osteoarthritis (n = 4), migraine (n = 3), musculoskeletal pain (n = 2), and other chronic pain conditions (n = 1/condition). Results show that several known and newly identified metabolites differ in individuals with chronic pain conditions compared to those without these conditions. These include amino acids (e.g., glutamine, serine, and phenylalanine) and intermediate products (e.g., succinate, citrate, acetylcarnitine, and N-acetylornithine) of pathways that metabolize various macromolecules. CONCLUSION Though more high-quality research is needed, this review provides insights into potential biomarkers for future metabolomics studies in people with chronic pain conditions.
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Affiliation(s)
- Edwin N Aroke
- School of Nursing, University of Alabama at Birmingham, AL, USA
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Wang H, Tian Q, Zhang J, Liu H, Zhang X, Cao W, Zhang J, Anto EO, Li X, Wang X, Liu D, Zheng Y, Guo Z, Wu L, Song M, Wang Y, Wang W. Population-based case-control study revealed metabolomic biomarkers of suboptimal health status in Chinese population-potential utility for innovative approach by predictive, preventive, and personalized medicine. EPMA J 2020; 11:147-160. [PMID: 32549914 PMCID: PMC7272523 DOI: 10.1007/s13167-020-00200-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Accepted: 03/06/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND Suboptimal health status (SHS) is a subclinical stage of chronic diseases, and the identification of SHS provides an opportunity for the predictive, preventive, and personalized medicine (PPPM) of chronic diseases. Previous studies have reported the associations between metabolic signatures and early signs of chronic diseases. METHODS This study aimed to detect the metabolic biomarkers for the identification of SHS in a case-control study. SHS questionnaire-25 (SHSQ-25) was used in a population-based health survey to measure the SHS levels of participants. The liquid chromatography-mass spectrometry-based untargeted metabolomics analysis was conducted on plasma samples collected from 50 SHS participants and 50 age- and sex-matched healthy controls. RESULTS After adjusting for the confounders, 24 significantly differential metabolites, such as sphingomyelin, sphingosine, sphinganine, progesterone, pregnanolone, and bilirubin, were identified as the candidate biomarkers for SHS. Pathway analysis revealed that sphingolipid metabolism, taurine metabolism, and steroid hormone biosynthesis are the disturbed metabolic pathways related to SHS. A combination of four metabolic biomarkers (sphingosine, pregnanolone, taurolithocholate sulfate, cervonyl carnitine) can distinguish SHS individuals from the controls with a sensitivity of 94.0%, a specificity of 90.0%, and an area under the receiver operating characteristic curve of 0.977. CONCLUSION Plasma metabolites are valuable biomarkers for SHS identification, and meanwhile, SHSQ-25 can be used as an alternative health screening tool in the population-based health survey. SHS-related metabolic disturbances could be detected at the early onset of SHS, and SHS-related metabolites could create a window opportunity for PPPM of chronic diseases.
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Affiliation(s)
- Hao Wang
- Beijing Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, China
- School of Medical and Health Sciences, Edith Cowan University, Perth, WA Australia
| | - Qiuyue Tian
- Beijing Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, China
| | - Jie Zhang
- Beijing Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, China
| | - Hongqi Liu
- Student Health Center, Weifang University, Weifang, China
| | - Xiaoyu Zhang
- Beijing Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, China
| | - Weijie Cao
- Beijing Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, China
| | - Jinxia Zhang
- Beijing Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, China
| | - Enoch Odame Anto
- School of Medical and Health Sciences, Edith Cowan University, Perth, WA Australia
| | - Xingang Li
- School of Medical and Health Sciences, Edith Cowan University, Perth, WA Australia
| | - Xueqing Wang
- School of Medical and Health Sciences, Edith Cowan University, Perth, WA Australia
| | - Di Liu
- Beijing Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, China
| | - Yulu Zheng
- School of Medical and Health Sciences, Edith Cowan University, Perth, WA Australia
| | - Zheng Guo
- School of Medical and Health Sciences, Edith Cowan University, Perth, WA Australia
| | - Lijuan Wu
- Beijing Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, China
| | - Manshu Song
- Beijing Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, China
- School of Medical and Health Sciences, Edith Cowan University, Perth, WA Australia
| | - Youxin Wang
- Beijing Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, China
| | - Wei Wang
- Beijing Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, China
- School of Medical and Health Sciences, Edith Cowan University, Perth, WA Australia
- School of Public Health, Shandong First Medical University, Taian, China
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Gerdle B, Wåhlén K, Ghafouri B. Plasma protein patterns are strongly correlated with pressure pain thresholds in women with chronic widespread pain and in healthy controls-an exploratory case-control study. Medicine (Baltimore) 2020; 99:e20497. [PMID: 32481465 DOI: 10.1097/md.0000000000020497] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Chronic widespread pain (CWP) is a complex pain condition characterized by generalized musculoskeletal pain and often associated with other symptoms. An important clinical feature is widespread increased pain sensitivity such as lowered pain thresholds for mechanical stimuli (pressure pain thresholds [PPT]). There is a growing interest in investigating the activated neurobiological mechanisms in CWP, which includes fibromyalgia. In CWP, strong significant correlations have been found between muscle protein patterns and PPT. This explorative proteomic study investigates the multivariate correlation pattern between plasma proteins and PPT in CWP and in healthy controls (CON). In addition, this study analyses whether the important proteins for PPT differ between the 2 groups.Using 2-dimensional gel electrophoresis, we analyzed the plasma proteome of the CWP (n = 15) and the CON (n = 23) and proteins were identified using mass spectrometry. For both the CWP and the CON, the associations between the identified proteins and PPT were analyzed using orthogonal partial least square in 2 steps.Significant associations between certain plasma proteins and PPT existed both in CWP (R = 0.95; P = .006) and in CON (R = 0.89; P < .001). For both groups of subjects, we found several proteins involved in PPT that reflect different biological processes. The plasma proteins as well as the biological processes involved in PPT differed markedly between the 2 groups of subjects.This study suggests that plasma protein patterns are associated with pain thresholds in CWP. Using the plasma proteome profile of CWP to study potential biomarker candidates could provide a snapshot of ongoing systemic mechanisms in CWP.
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Affiliation(s)
- Björn Gerdle
- Pain and Rehabilitation Centre, and Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
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Bliziotis NG, Engelke UFH, Aspers RLEG, Engel J, Deinum J, Timmers HJLM, Wevers RA, Kluijtmans LAJ. A comparison of high-throughput plasma NMR protocols for comparative untargeted metabolomics. Metabolomics 2020; 16:64. [PMID: 32358672 PMCID: PMC7196944 DOI: 10.1007/s11306-020-01686-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Accepted: 04/23/2020] [Indexed: 12/15/2022]
Abstract
INTRODUCTION When analyzing the human plasma metabolome with Nuclear Magnetic Resonance (NMR) spectroscopy, the Carr-Purcell-Meiboom-Gill (CPMG) experiment is commonly employed for large studies. However, this process can lead to compromised statistical analyses due to residual macromolecule signals. In addition, the utilization of Trimethylsilylpropanoic acid (TSP) as an internal standard often leads to quantification issues, and binning, as a spectral summarization step, can result in features not clearly assignable to metabolites. OBJECTIVES Our aim was to establish a new complete protocol for large plasma cohorts collected with the purpose of describing the comparative metabolic profile of groups of samples. METHODS We compared the conventional CPMG approach to a novel procedure that involves diffusion NMR, using the Longitudinal Eddy-Current Delay (LED) experiment, maleic acid (MA) as the quantification reference and peak picking for spectral reduction. This comparison was carried out using the ultrafiltration method as a gold standard in a simple sample classification experiment, with Partial Least Squares-Discriminant Analysis (PLS-DA) and the resulting metabolic signatures for multivariate data analysis. In addition, the quantification capabilities of the method were evaluated. RESULTS We found that the LED method applied was able to detect more metabolites than CPMG and suppress macromolecule signals more efficiently. The complete protocol was able to yield PLS-DA models with enhanced classification accuracy as well as a more reliable set of important features than the conventional CPMG approach. Assessment of the quantitative capabilities of the method resulted in good linearity, recovery and agreement with an established amino acid assay for the majority of the metabolites tested. Regarding repeatability, ~ 85% of all peaks had an adequately low coefficient of variation (< 30%) in replicate samples. CONCLUSION Overall, our comparison yielded a high-throughput untargeted plasma NMR protocol for optimized data acquisition and processing that is expected to be a valuable contribution in the field of metabolic biomarker discovery.
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Affiliation(s)
- Nikolaos G. Bliziotis
- Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboudumc, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands
| | - Udo F. H. Engelke
- Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboudumc, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands
| | - Ruud L. E. G. Aspers
- Institute for Molecules and Materials, Radboud University, Houtlaan 4, 6525 XZ Nijmegen, The Netherlands
| | - Jasper Engel
- Institute for Molecules and Materials, Radboud University, Houtlaan 4, 6525 XZ Nijmegen, The Netherlands
- Present Address: Biometris, Wageningen UR, Droevendaalsesteeg 1, 6708 PB Wageningen, The Netherlands
| | - Jaap Deinum
- Department of Internal Medicine, Radboudumc, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands
| | - Henri J. L. M. Timmers
- Department of Internal Medicine, Radboudumc, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands
| | - Ron A. Wevers
- Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboudumc, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands
| | - Leo A. J. Kluijtmans
- Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboudumc, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands
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Miller JS, Rodriguez-Saona L, Hackshaw KV. Metabolomics in Central Sensitivity Syndromes. Metabolites 2020; 10:E164. [PMID: 32344505 PMCID: PMC7240948 DOI: 10.3390/metabo10040164] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 04/11/2020] [Accepted: 04/19/2020] [Indexed: 01/09/2023] Open
Abstract
Central sensitization syndromes are a collection of frequently painful disorders that contribute to decreased quality of life and increased risk of opiate abuse. Although these disorders cause significant morbidity, they frequently lack reliable diagnostic tests. As such, technologies that can identify key moieties in central sensitization disorders may contribute to the identification of novel therapeutic targets and more precise treatment options. The analysis of small molecules in biological samples through metabolomics has improved greatly and may be the technology needed to identify key moieties in difficult to diagnose diseases. In this review, we discuss the current state of metabolomics as it relates to central sensitization disorders. From initial literature review until Feb 2020, PubMed, Embase, and Scopus were searched for applicable studies. We included cohort studies, case series, and interventional studies of both adults and children affected by central sensitivity syndromes. The majority of metabolomic studies addressing a CSS found significantly altered metabolites that allowed for differentiation of CSS patients from healthy controls. Therefore, the published literature overwhelmingly supports the use of metabolomics in CSS. Further research into these altered metabolites and their respective metabolic pathways may provide more reliable and effective therapeutics for these syndromes.
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Affiliation(s)
- Joseph S. Miller
- Department of Medicine, Ohio University Heritage College of Osteopathic Medicine, Dublin, OH 43016, USA;
| | - Luis Rodriguez-Saona
- Department of Food Science and Technology, Ohio State University, Columbus, OH 43210, USA;
| | - Kevin V. Hackshaw
- Department of Internal Medicine, Division of Rheumatology, Dell Medical School, The University of Texas, 1701 Trinity St, Austin, TX 78712, USA
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Erdrich S, Hawrelak JA, Myers SP, Harnett JE. Determining the association between fibromyalgia, the gut microbiome and its biomarkers: A systematic review. BMC Musculoskelet Disord 2020; 21:181. [PMID: 32192466 PMCID: PMC7083062 DOI: 10.1186/s12891-020-03201-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Accepted: 03/11/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The association between fibromyalgia and irritable bowel syndrome is well-established. Alterations in the composition and diversity of the gut microbiome in irritable bowel syndrome have been reported, however, this association is poorly understood in fibromyalgia. Our aim was to summarise the research reporting on the gastrointestinal microbiome and its biomarkers in people with fibromyalgia. METHODS A systematic review of published original research reporting on the gastrointestinal microbiota and its biomarkers in adults with a diagnosis of fibromyalgia was undertaken. RESULTS From 4771 studies, 11 met our inclusion criteria and were separated into four main groups: papers reporting Helicobacter pylori; other gut bacterial markers; metabolomics and other biomarkers, which included intestinal permeability and small intestinal bacterial overgrowth. CONCLUSION The results suggest there is a paucity of quality research in this area, with indications that the gut microbiota may play a role in fibromyalgia within the emerging field of the gut-musculoskeletal axis. Further investigations into the relationship between the gut microbiota, gut dysfunction and fibromyalgia are warranted.
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Affiliation(s)
- Sharon Erdrich
- Faculty of Medicine and Health, School of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia.
| | - Jason A Hawrelak
- College of Health and Medicine, University of Tasmania, Hobart, Tasmania, Australia
| | - Stephen P Myers
- NatMed Research Unit, Division of Research, Southern Cross University, Lismore, New South Wales, Australia
| | - Joanna E Harnett
- Faculty of Medicine and Health, School of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia
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Andretta A, Schieferdecker MEM, Petterle RR, Dos Santos Paiva E, Boguszewski CL. Relations between serum magnesium and calcium levels and body composition and metabolic parameters in women with fibromyalgia. Adv Rheumatol 2020; 60:18. [PMID: 32171334 DOI: 10.1186/s42358-020-0122-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 02/17/2020] [Indexed: 12/25/2022] Open
Abstract
OBJECTIVE Correlate serum magnesium (Mg) and Calcium (Ca) levels with body composition and metabolic parameters in women with fibromyalgia (FM). PATIENTS AND METHODS Cross-sectional study compared with a control group paired by age and body mass index (BMI) of adult women diagnosed with fibromyalgia. All participants went through assessment of their body composition through dual-energy X-ray absorptiometry (DXA) and had blood samples collected for dosing of Mg, Ca, C-reactive Protein (CRP), lipidogram and glycemia. RESULTS 53 women with FM (average age 48.1 ± 8.2 years, average BMI 26.6 ± 4.5 kg/m2) and 50 control women (average age 47.1 ± 9.9 years, average BMI 25.6 ± 3.6 kg/m2) participated in the study. Serum levels turned out to have inverse correlation with CRP in the FM group (r = - 0.29, p = 0.03) and with BMI and glycemia in the control group (r = 0.31; p = 0.02 and r = 0.48; p = 0.0004 respectively). Serum levels of calcium correlated with triglycerides (r = 0.29; p = 0.03) in the FM group and with glycemia in the control group (r = 0.64; p = 0.0001). CONCLUSIONS In patients with FM, magnesemia turned out to have inverse correlation with CRP and calcemia had positive association with triglycerides.
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Affiliation(s)
- Aline Andretta
- Department of Internal Medicine, Federal University of Parana (UFPR), Curitiba, PR, Brazil. Rua General Carneiro, 181, Curitiba, PR, 80060-900, Brazil.
| | | | | | | | - César Luiz Boguszewski
- Endocrine Division (SEMPR), Department of Internal Medicine, Federal University of Parana (UFPR), Curitiba, PR, Brazil
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