Tag: 2025

The emerging role of exosomal LncRNAs in chronic fatigue syndrome: from intercellular communication to disease biomarkers

Abstract:

Chronic fatigue syndrome (CFS) is a complex disease involving multiple systems throughout the body with unknown pathogenesis and is characterized by chronic fatigue. To date, no effective treatment for CFS has been found, as well as biomarkers for early identification of diagnosis. However, exosomes, a subpopulation of extracellular vesicles (EVs), are membranous vesicles secreted by cells into the surrounding environment, and long noncoding RNAs (LncRNAs) in EVs can mediate inter-organ and inter-cellular communication, which maybe associate with CFS.

Therefore, this study aims to review the association between EV-LncRNAs and CFS, and to explore whether LncRNAs can be used as potential biomarkers for early identification and diagnosis of CFS, which put forward new ideas and a theoretical basis for the pathogenesis of CFS, as well as the identification of novel targeted therapies.

Source: Wang Lei , Xu Yujia , Zhong Xiang , Wang Guiping , Shi Zijun , Mei Can , Chen Linwanyue , Zhan Jianbo , Cheng Jing. The emerging role of exosomal LncRNAs in chronic fatigue syndrome: from intercellular communication to disease biomarkers. Frontiers in Molecular Biosciences. Volume 12 – 2025 https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2025.1653627/full (Full text)

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

Abstract:

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

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

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

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

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

Circulating FGF-21 as a Disease-Modifying Factor Associated with Distinct Symptoms and Cognitive Profiles in Myalgic Encephalomyelitis and Fibromyalgia

Abstract:

Myalgic encephalomyelitis (ME) and fibromyalgia (FM) are overlapping syndromes characterized by persistent fatigue, cognitive difficulties, and post-exertional malaise (PEM), yet they lack objective biomarkers for diagnosis and treatment. Fibroblast growth factor 21 (FGF-21), a stress-responsive metabolic hormone, may offer a promising avenue to distinguish subtypes within these patient populations.

In this cross-sectional study, plasma FGF-21 levels were measured in 250 patients (FM = 47; ME = 99; ME + FM = 104) and 54 healthy controls. Participants were categorized based on FGF-21 levels into three groups: low (0-50 pg/mL), normal (51-200 pg/mL), and high (>200 pg/mL). Symptoms burden and cognitive function were assessed using validated questionnaires (SF-36, MFI-20, DSQ, DPEMQ) and the BrainCheck platform. A standardized mechanical provocation maneuver was used to induce PEM.

Results showed that elevated FGF-21 levels were frequently observed in ME and ME + FM but varied widely across all groups. Stratification by circulating FGF-21 levels, rather than diagnosis alone, revealed distinct symptom and cognitive profiles. Low FGF-21 levels were linked to worsened PEM perception in FM, increased PEM severity and immune/autonomic symptoms in ME, and poorer mental health in ME + FM. Conversely, high FGF-21 levels correlated with better cognition in ME but greater fatigue in ME + FM.

These findings suggest that FGF-21 may serve as a valuable biomarker for identifying clinically meaningful subtypes within ME and FM, supporting the development of personalized treatments. Furthermore, discrepancies between DSQ and DPEMQ highlight the need for objective PEM assessment tools. Overall, FGF-21 shows potential as a biomarker to guide precision medicine in these complex conditions.

Source: Azimi G, Elremaly W, Elbakry M, Franco A, Godbout C, Moreau A. Circulating FGF-21 as a Disease-Modifying Factor Associated with Distinct Symptoms and Cognitive Profiles in Myalgic Encephalomyelitis and Fibromyalgia. Int J Mol Sci. 2025 Aug 8;26(16):7670. doi: 10.3390/ijms26167670. PMID: 40868993. https://www.mdpi.com/1422-0067/26/16/7670 (Full text)

Mapping cerebral blood flow in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and orthostatic intolerance: insights from a systematic review

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex and debilitating condition with a large proportion of patients that experience orthostatic intolerance (OI). This systematic review aimed to assess whether cerebral blood flow (CBF) is reduced in ME/CFS and OI, and whether the presence of both conditions leads to an additional decline in CBF.

Methods: PubMed (from 1943), MEDLINE (from 1946), EMBASE (from 1947) and Cochrane were searched from inception to February 14th, 2025, using terms including “chronic fatigue syndrome”, “myalgic encephalomyelitis”, “orthostatic intolerance” and “cerebral blood flow”. Article selection required the following criteria: published in English; CBF measured in participants with either ME/CFS or OI, or both ME/CFS and OI combined. Quality assessment and risk of bias was assessed using the Newcastle-Ottawa Scale and the systematic review was conducted in accordance with the PRISMA 2020 guidelines.

Results: Of 14,928 articles, 118 were included, 26 (22.1%) of which studied CBF in ME/CFS alone, 81 (68.6%) in OI alone and 11 (9.3%) in both ME/CFS and OI. Overall, the articles included 9185 participants, with a mean age of 39.1 years (SD = 8.8), and 73.8% of participants were female. Studies found CBF was significantly reduced in 12 of the articles focused on ME/CFS and in 56 of those focused on OI; compared to controls. Additionally, in 4 out of 11 studies that examined both conditions, CBF was further reduced in participants suffering from both conditions compared to those with ME/CFS alone.

Conclusions: CBF is reduced in ME/CFS and OI alone and having both conditions comorbidly amplifies CBF reductions. Therefore, observing CBF changes in ME/CFS with and without OI may be important in monitoring disease severity. Despite this, few studies focus on the combination of ME/CFS and OI, and OI may be a confounding factor in CBF in a large portion of ME/CFS studies.

Source: Christopoulos EM, Tantanis D, Huang K, Schneider-Futschik EK, Gooley PR, Moneghetti KJ, Armstrong CW. Mapping cerebral blood flow in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and orthostatic intolerance: insights from a systematic review. J Transl Med. 2025 Aug 26;23(1):963. doi: 10.1186/s12967-025-06954-w. PMID: 40859389. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-025-06954-w (Full text)

Protocol for a qualitative study on the online connections of people with ME/CFS and the relationship between these online connections and offline lives

Abstract:

Introduction: Myalgic encephalomyelitis (ME), also known as chronic fatigue syndrome (CFS), is a debilitating chronic illness that affects the central nervous and immune systems, causing core symptoms of extreme fatigue, post-exertional malaise, cognitive issues and sleep disturbance. With reported higher online use than in other chronic illnesses, people with ME/CFS are often housebound and isolated and may struggle to maintain social relationships. Due to a lack of biomarkers, the illness is often contested, causing invalidation and stigma for those affected. This study aims to broaden the knowledge on how people with ME/CFS gain online connections and whether and how these connections integrate into and impact their everyday life.

Methods and analysis: Qualitative interviews will be conducted with adults aged over 18 years with a diagnosis or self-diagnosis of ME or CFS (n=20-25). A semi-structured topic guide will be used to interview participants and explore online connections and relationships between these and everyday life with ME/CFS. Interviews will be recorded and transcribed verbatim. Data will be thematically analysed to gain in-depth insight into this largely unexplored topic.

Ethics and dissemination: The study has ethical approval from the University of Birmingham (reference: RN_1722-Jun2024), and informed written consent will be provided by all participants. Findings will be published in peer-reviewed journals and disseminated to advocacy organisations and health professionals seeking to offer remote support for people with ME/CFS and their families. This study will provide crucial insight into online use and how it can guide the formulation of management plans for people who may currently receive no support from health professionals at all.

Source: Shortland DL, Fazil Q, Lavis A. Protocol for a qualitative study on the online connections of people with ME/CFS and the relationship between these online connections and offline lives. BMJ Open. 2025 Aug 19;15(8):e099557. doi: 10.1136/bmjopen-2025-099557. PMID: 40829849. https://bmjopen.bmj.com/content/15/8/e099557 (Full text)

Accelerated vascular ageing after COVID-19 infection: the CARTESIAN study

Abstract:

Background and Aims: Increasing evidence suggests that COVID-19 survivors experience long-term cardiovascular complications possibly through development of vascular damage. The study aimed to investigate whether accelerated vascular ageing occurs after COVID-19 infection, and if so, identify its determinants.
Methods: This prospective, multicentric, cohort study, included 34 centres in 16 countries worldwide, in 4 groups of participants—COVID-19-negative controls (ⅰ) and three groups of individuals with recent (6 ± 3 months) exposure to SARS-CoV-2: not hospitalized (ⅱ), hospitalized in general wards (ⅲ), and hospitalized in intensive care units (ⅳ). The main outcome was carotid-femoral pulse wave velocity (PWV), an established biomarker of large artery stiffness.
Results: 2390 individuals (age 50 ± 15 years, 49.2% women) were recruited. After adjustment for confounders, all COVID-19-positive groups showed higher PWV (+0.41, +0.37, and +0.40 m/s for groups 2–4, P < .001, P = .001 and P = .003) vs. controls [PWV 7.53 (7.09; 7.97) m/s adjusted mean (95% CI)]. In sex-stratified analyses, PWV differences were significant in women [PWV (+0.55, +0.60, and +1.09 m/s for groups 2–4, P < .001 for all)], but not in men. Among COVID-19 positive women, persistent symptoms were associated with higher PWV, regardless of disease severity and cardiovascular confounders [adjusted PWV 7.52 (95% CI 7.09; 7.96) vs. 7.13 (95% CI 6.67; 7.59) m/s, P < .001]. A stable or improved PWV after 12 months was found in the COVID+ groups, whereas a progression was observed in the COVID− group.
Conclusions: COVID-19 is associated with early vascular ageing in the long term, especially in women.

Source: Rosa Maria Bruno, Smriti Badhwar, Leila Abid, Mohsen Agharazii, Fabio Anastasio, Jeremy Bellien, Otto Burghuber, Luca Faconti, Jan Filipovsky, Lorenzo Ghiadoni, Cristina Giannattasio, Bernhard Hametner, Alun D Hughes, Ana Jeroncic, Ignatios Ikonomidis, Mai Tone Lonnebakken, Alessandro Maloberti, Christopher C Mayer, Maria Lorenza Muiesan, Anna Paini, Andrie Panayiotou, Chloe Park, Chakravarthi Rajkumar, Carlos Ramos Becerra, Bart Spronck, Dimitrios Terentes-Printzios, Yesim Tuncok, Thomas Weber, Pierre Boutouyrie, the CARTESIAN Investigators , Accelerated vascular ageing after COVID-19 infection: the CARTESIAN study, European Heart Journal, 2025;, ehaf430, https://doi.org/10.1093/eurheartj/ehaf430 https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehaf430/8236450 (Full text)

Mitochondrial function is impaired in long COVID patients

Abstract:

Background: The Long COVID syndrome is a major global health problem, affecting approximately 10–20% of individuals infected with SARS-CoV-2 virus with many remaining symptomatic beyond one year. Fatigue, reduced exercise tolerance and hyperlactataemia on minimal exertion have led to the suggestion of a bioenergetic defect. We hypothesised that mitochondrial dysfunction is a pathological feature in Long COVID cases and would correlate with clinical outcome.

Methods: This prospective, case-controlled, observational study recruited 27 participants with an established diagnosis of Long COVID syndrome from a single tertiary clinic together with 16 age-matched controls aged 25–65 years. Seahorse-based mitochondrial flux analysis and bioenergetics profile of isolated peripheral blood mononuclear cells (PBMCs) was performed and correlated with clinical phenotype.

Findings: Long COVID cases had an increased baseline and ATP-induced oxygen consumption rate with a significant attenuation in tetramethylrhodamine methyl ester perchlorate fluorescence response to oligomycin. Correlations were observed between mitochondrial function and autonomic health, quality of life and time from index infection. Sex-specific differences were also observed.

Interpretation: PBMCs from Long COVID subjects exhibit an exceptional and distinctive change in ATP synthase, as it contributes to the mitochondrial membrane potential rather than using it exclusively to generate ATP. The findings suggest that the enzyme runs both forward and reverse reactions, synthesising and hydrolysing ATP. The correlation of mitochondrial function with clinical phenotype in Long COVID may indicate a causal relationship and warrants further validation in larger scale studies.

Source: Macnaughtan, J., Chau, K. Y., Brennan, E., Toffoli, M., Spinazzola, A., Hillman, T., … Schapira, A. H. V. (2025). Mitochondrial function is impaired in long COVID patients. Annals of Medicine, 57(1). https://doi.org/10.1080/07853890.2025.2528167 https://www.tandfonline.com/doi/full/10.1080/07853890.2025.2528167 (Full text)

Approach to nursing diagnoses of people with myalgic encephalomyelitis / chronic fatigue syndrome: a qualitative meta-synthesis

Abstract:

Objective: To identify human responses (diagnostic foci) that shape the experience of living with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and how they manifest throughout the course of the illness.

Methods: A qualitative meta-synthesis was conducted. Original studies exploring the experience of living with ME/CFS in adults with a confirmed diagnosis, published in English or Spanish between 1994 and June 2024, were included. The literature search was carried out in Medline/Medline In-Process, Embase, CINAHL, PsycINFO, SCI-EXPANDED, SSCI, SciELO, Lilacs, and Cuiden. Data analysis was based on the human responses (diagnostic foci) from the NANDA-I Nursing Diagnoses Classification, 2021–2023, with findings structured according to Fennell’s Four-Phase Model.

Results: A total of 42 articles were selected. Twenty human responses (diagnostic foci) and three classes of the NANDA-I Nursing Diagnoses Classification were identified, interwoven across the different phases of the model. Some responses were present throughout all phases, while others, such as Energy Balance and Health Self-Management, became particularly relevant from Phase 2 onwards. Phases 3 and 4 were characterised by losses and processes of subjective reconstruction, with diagnostic foci such as Sorrow, Spiritual Distress, and Personal Identity being predominant.

Conclusions: The identified human responses (diagnostic foci) highlight how the contested and chronic nature of ME/CFS profoundly shapes the lived experience of those affected. The model derived from this review provides a structured framework for targeted nursing interventions, aligned with the phase each individual is experiencing.

Source: Oter-Quintana, C., Esteban-Hernandez, J., Cuellar-Pompa, L., Gil-Carballo, C., Brito-Brito, P. R., Martín-García, A., … Alameda-Cuesta, A. (2025). Approach to nursing diagnoses of people with myalgic encephalomyelitis / chronic fatigue syndrome: a qualitative meta-synthesis. Fatigue: Biomedicine, Health &amp; Behavior, 1–32. https://doi.org/10.1080/21641846.2025.2522028 https://www.tandfonline.com/doi/full/10.1080/21641846.2025.2522028

Biomarkers over Time: From Visual Contrast Sensitivity to Transcriptomics in Differentiating Chronic Inflammatory Response Syndrome and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Chronic inflammatory response syndrome (CIRS) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) are debilitating multisystem illnesses that share overlapping symptoms and molecular patterns, including immune dysregulation, mitochondrial impairment, and vascular dysfunction. This review provides a chronological synthesis of biomarker development in CIRS, tracing its evolution from early functional tests such as visual contrast sensitivity (VCS) to advanced transcriptomic profiling.

Drawing on peer-reviewed studies spanning two decades, we examine the layered integration of neuroendocrine, immunologic, metabolic, and genomic markers that collectively support a multisystem model of innate immune activation specific to environmentally acquired illness. Particular focus is given to the Gene Expression: Inflammation Explained (GENIE) platform’s use of transcriptomics to classify disease stages and distinguish CIRS from other fatiguing conditions.

While ME/CFS research continues to explore overlapping pathophysiologic features, it has yet to establish a unified diagnostic model with validated biomarkers or exposure-linked mechanisms. As a result, many patients labeled with ME/CFS may, in fact, represent unrecognized CIRS cases.

This review underscores the importance of structured biomarker timelines in improving differential diagnosis and guiding treatment in complex chronic illness and highlights the reproducibility of the CIRS framework in contrast to the diagnostic ambiguity surrounding ME/CFS.

Source: Dooley M. Biomarkers over Time: From Visual Contrast Sensitivity to Transcriptomics in Differentiating Chronic Inflammatory Response Syndrome and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Int J Mol Sci. 2025 Jul 28;26(15):7284. doi: 10.3390/ijms26157284. PMID: 40806417. https://www.mdpi.com/1422-0067/26/15/7284 (Full text)

Reframing Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Biological Basis of Disease and Recommendations for Supporting Patients

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a worldwide challenge. There are an estimated 17-24 million patients worldwide, with an estimated 60 percent or more who have not been diagnosed. Without a known cure, no specific curative medication, disability lasting years to being life-long, and disagreement among healthcare providers as to how to most appropriately treat these patients, ME/CFS patients are in need of assistance. Appropriate healthcare provider education would increase the percentage of patients diagnosed and treated; however, in-school healthcare provider education is limited.

To address the latter issue, the New Jersey Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Association (NJME/CFSA) has developed an independent, incentive-driven, learning program for students of the health professions. NJME/CFSA offers a yearly scholarship program in which applicants write a scholarly paper on an ME/CFS-related topic. The efficacy of the program is demonstrated by the 2024-2025 first place scholarship winner’s essay, which addresses the biological basis of ME/CFS and how the healthcare provider can improve the quality of life of ME/CFS patients.

For the reader, the essay provides an update on what is known regarding the biological underpinnings of ME/CFS, as well as a medical student’s perspective as to how the clinician can provide care and support for ME/CFS patients. The original essay has been slightly modified to demonstrate that ME/CFS is a worldwide problem and for publication.

Source: Agarwal P, Friedman KJ. Reframing Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Biological Basis of Disease and Recommendations for Supporting Patients. Healthcare (Basel). 2025 Aug 5;13(15):1917. doi: 10.3390/healthcare13151917. PMID: 40805949. https://www.mdpi.com/2227-9032/13/15/1917 (Full text)