Myalgic encephalomyelitis/chronic fatigue syndrome-an insidious disease:The recent COVID-19 pandemic has brought substantial attention to the overlapping symptoms between long COVID and myalgic encephalomyelitis/chron...Myalgic encephalomyelitis/chronic fatigue syndrome-an insidious disease:The recent COVID-19 pandemic has brought substantial attention to the overlapping symptoms between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome(ME/CFS),a chronic and poorly understood neurological disorder(Shankar et al.,2024).展开更多
Objectives:People living with myalgic encephalomyelitis/chronic fatigue syndrome(ME/CFS)may face unique barriers to physical activity.Active video games may overcome these barriers and increase physical activity.The p...Objectives:People living with myalgic encephalomyelitis/chronic fatigue syndrome(ME/CFS)may face unique barriers to physical activity.Active video games may overcome these barriers and increase physical activity.The primary aim of this pilot study was to determine the feasibility and acceptability of active video games to increase physical activity levels of people with ME/CFS.Methods:A mixed method design was employed.Adults living with ME/CFS were randomised to a six-month intervention of(1)pacing,(2)pacing and conventional physical activity,or(3)pacing and active video gaming.Feasibility and acceptability were determined through semi-structured interviews.Health-related outcomes(e.g.,physical activity,blood samples,quality of life,and functioning)were also collected.Results:Fifteen people were assigned an intervention group with 12 completing.Three themes were identified from post-intervention interviews(1)positivity led to overall acceptability,(2)flexibility enabled participant autonomy,and(3)knowledge was gained about the self.No changes were seen in physical activity levels.An active video gaming intervention is acceptable but not feasible for people living with ME/CFS.Conclusions:Taken together,results suggest that physical activity can be managed safely by some people living with ME/CFS.Trial registration ACTRN12616000285459.展开更多
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...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 indepth 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.展开更多
Kindling might represent a heuristic model for understanding the etiology of Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS). Kindling occurs when an organism is exposed repeatedly to an initially sub-thre...Kindling might represent a heuristic model for understanding the etiology of Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS). Kindling occurs when an organism is exposed repeatedly to an initially sub-threshold stimulus re-sulting in hypersensitivity and spontaneous seizure-like activity. Among patients with ME/CFS, chronically repeated low-intensity stimulation due to an infectious illness might cause kindling of the limbic-hypothalamic-pituitary axis. Kindling might also occur by high-intensity stimulation (e.g., brain trauma) of the limbic-hypothalamic-pituitary axis. Once this system is charged or kindled, it can sustain a high level of arousal with little or no external stimulus and eventually this could lead to hypocortisolism. Seizure activity may spread to adjacent structures of the limbic-hypothalamic-pituitary axis in the brain, which might be responsible for the varied symptoms that occur among patients with ME/CFS. In addition, kindling may also be responsible for high levels of oxidative stress, which has been found in patients with ME/CFS.展开更多
BACKGROUND The literature is mixed about the occurrence of alcohol intolerance among patients with myalgic encephalomyelitis/chronic fatigue syndrome(ME/CFS).Surveys that asked respondents with ME/CFS whether they exp...BACKGROUND The literature is mixed about the occurrence of alcohol intolerance among patients with myalgic encephalomyelitis/chronic fatigue syndrome(ME/CFS).Surveys that asked respondents with ME/CFS whether they experienced alcohol intolerance within a recent time frame might produce inaccurate results because respondents may indicate that the symptom was not present if they avoid alcohol due to alcohol intolerance.AIM To overcome this methodologic problem,participants in the current study were asked whether they have avoided alcohol in the past 6 mo,and if they had,how severe their alcohol intolerance would be if they were to drink alcohol.METHODS The instrument used was a validated scale called the DePaul symptom questionnaire.Independent t-tests were performed among the alcohol intolerant or not alcohol intolerant group.The alcohol intolerant group had 208 participants,and the not alcohol intolerant group had 96 participants.RESULTS Using specially designed questions to properly identify those with alcohol intolerance,those who experienced alcohol intolerance vs those who did not experience alcohol intolerance experienced more frequent/severe symptoms and domains.In addition,using a multiple regression analysis,the orthostatic intolerance symptom domain was related to alcohol intolerance.CONCLUSION The findings from the current study indicated that those with ME/CFS are more likely to experience alcohol intolerance.In addition,those with this symptom have more overall symptoms than those without alcohol intolerance.展开更多
Highlights Fatiguing syndromes affect millions of patients in the United States and globally,but are grossly underserved in the clinic and in the contemplative design of basic research.
Although myalgic encephalomyelitis(ME) and chronic fatigue syndrome(CFS) are considered to be synonymous,the definitional criteria for ME and CFS define two distinct,partially overlapping,clinical entities.ME,whether ...Although myalgic encephalomyelitis(ME) and chronic fatigue syndrome(CFS) are considered to be synonymous,the definitional criteria for ME and CFS define two distinct,partially overlapping,clinical entities.ME,whether defined by the original criteria or by the recently proposed criteria,is not equivalent to CFS,let alone a severe variant of incapacitating chronic fatigue.Distinctive features of ME are:muscle weaknessand easy muscle fatigability,cognitive impairment,circulatory deficits,a marked variability of the symptoms in presence and severity,but above all,post-exertional "malaise":a(delayed) prolonged aggravation of symptoms after a minor exertion.In contrast,CFS is primarily defined by(unexplained) chronic fatigue,which should be accompanied by four out of a list of 8 symptoms,e.g.,headaches.Due to the subjective nature of several symptoms of ME and CFS,researchers and clinicians have questioned the physiological origin of these symptoms and qualified ME and CFS as functional somatic syndromes.However,various characteristic symptoms,e.g.,post-exertional "malaise" and muscle weakness,can be assessed objectively using wellaccepted methods,e.g.,cardiopulmonary exercise tests and cognitive tests.The objective measures acquired by these methods should be used to accurately diagnose patients,to evaluate the severity and impact of the illness objectively and to assess the positive and negative effects of proposed therapies impartially.展开更多
A significant number of SARS-CoV-2 (COVID-19) pandemic patients have developed chronic symptoms lasting weeks or months which are very similar to those described for myalgic encephalomyelitis/chronic fatigue syndrome....A significant number of SARS-CoV-2 (COVID-19) pandemic patients have developed chronic symptoms lasting weeks or months which are very similar to those described for myalgic encephalomyelitis/chronic fatigue syndrome. This study reviews the current literature and understanding of the role that mitochondria, oxidative stress and antioxidants may play in the understanding of the pathophysiology and treatment of chronic fatigue. It describes what is known about the dysfunctional pathways which can develop in mitochondria and their relationship to chronic fatigue. It also reviews what is known about oxidative stress and how this can be related to the pathophysiology of fatigue, as well as examining the potential for specific therapy directed at mitochondria for the treatment of chronic fatigue in the form of antioxidants. This study identifies areas which require urgent, further research in order to fully elucidate the clinical and therapeutic potential of these approaches.展开更多
Chronic migraine(CM)is a prevalent and highly debilitating neurological disorder.Functional magnetic resonance imaging(fMRI)studies have demonstrated associations between abnormal brain region activation and CM,yet th...Chronic migraine(CM)is a prevalent and highly debilitating neurological disorder.Functional magnetic resonance imaging(fMRI)studies have demonstrated associations between abnormal brain region activation and CM,yet the underlying complex neural circuitry mechanisms remain unclear.The spinal trigeminal nucleus caudalis(Sp5C)serves as the primary central hub for orofacial nociceptive input,receiving trigeminal pain signals and projecting to higher-order centers such as the thalamus.Therefore,we sought to investigate whether the Sp5C region and its associated circuits were involved in CM pathogenesis.In this study,we established a CM mouse model through repeated intraperitoneal injections of nitroglycerin(NTG).Using a combination of in vivo fiber photometry and in vitro c-Fos immunohistochemistry,we found a marked periorbital and plantar mechanical allodynia in CM mice,accompanied by increased glutamatergic neuronal activity in Sp5C.Chemogenetic manipulation of Sp5C glutamatergic neurons(Sp5CV^(glut2))bidirectionally modulated migraine-like behaviors and induced pain-related affective states,as evidenced by conditioned place preference/aversion(CPP/CPA)paradigms.Anterograde viral tracing revealed dense projections from Sp5C^(Vglut2)to the subthalamic nucleus(STN),which was activated in CM mice.Optogenetic activation of the Sp5C-STN pathway similarly produced migraine-like behaviors and pain-related aversive memory in mice.Altogether,we revealed a critical role of the Sp5CVglut2-STN circuit in the development and modulation of CM.Our findings provide novel mechanistic insights into the central mechanisms underlying CM,establishing potential theoretical foundations for clinical diagnosis and therapeutic development.展开更多
BACKGROUND Acute disseminated encephalomyelitis(ADEM),which is rare,primarily affects children.It usually manifests as acute encephalopathy and multifocal neurological impairments after infection or vaccination.Diagno...BACKGROUND Acute disseminated encephalomyelitis(ADEM),which is rare,primarily affects children.It usually manifests as acute encephalopathy and multifocal neurological impairments after infection or vaccination.Diagnosis is still difficult due to the clinical and radiological similarity to other central nervous system disorders.Adult-onset ADEM calls for thorough reporting in order to improve diagnosis and treatment.CASE SUMMARY A 55-year-old man with hypertension had a high fever,intense headache and a steady decline in his neurological function after two weeks.Left facial paralysis was the initial symptom,which progressed to left hemiparesis,reduced consciousness level,photophobia,phonophobia,vomiting,and a focal seizure in the right leg.He had no history of autoimmune disease,vaccinations,or infections.Investigations showed negative infectious/autoimmune serology,mild cerebrospinal fluid lymphocytic pleocytosis(protein 76 mg/dL),and lymphopenia.Brain magnetic resonance imaging without contrast revealed bilateral,symmetrical T2/fluid-attenuated inversion recovery hyperintensities,primarily in the middle cerebellar peduncles,with minor involvement in the pontine and periventricular regions.Neoplastic,metabolic,vascular,and infectious conditions were not included.The patient showed spontaneous neurological improvement by Week 3 with near-complete motor recovery(limb strength 4/5)after methylprednisolone and rehabilitation,despite logistical delays in starting immunotherapy.The monophasic course and radiological/clinical remission were supported by idiopathic ADEM.CONCLUSION This case shows an uncommon,idiopathic,cerebellar-predominant ADEM variation in an adult without conventional triggers.It emphasizes the diagnostic difficulty in distinguishing ADEM from mimics(such as stroke or infection)in adults.Spontaneous improvement before treatment,although early detection is still crucial,should be highlighted,although early detection is still crucial.Increased clinician awareness,fair access to neuroimaging,and focused research on adult ADEM are crucial to fill these gaps and improve outcomes in places with limited resources.展开更多
Lyme disease is the most common vector-borne illness in the United States and has been causing significant morbidity since its discovery in 1977.It is well-documented that about 10%of patients properly treated with an...Lyme disease is the most common vector-borne illness in the United States and has been causing significant morbidity since its discovery in 1977.It is well-documented that about 10%of patients properly treated with antibiotics never fully recover,but instead go on to develop a chronic illness dubbed,posttreatment Lyme disease syndrome(PTLDS)characterized by severe fatigue,cognitive slowing,chronic pain,and sleep difficulties.This review includes 18 studies that detail the symptoms of patients with PTLDS and uses qualitative analysis to compare them to myalgic encephalitis/chronic fatigue syndrome(ME/CFS),a strikingly similar syndrome.In the majority of the PTLDS studies,at least four of the six major symptoms of ME/CFS were also noted,including substantial impairment in activity level and fatigue for more than 6 months,post-exertional malaise,and unrefreshing sleep.In one of the included PTLDS articles,26 of the 29 ME/CFS symptoms were noted.This study adds to the expanding literature on the post-active phase of infection syndromes,which suggests that chronic illnesses such as PTLDS and ME/CFS have similar pathogenesis despite different infectious origins.展开更多
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), recently renamed as systemic exertion intolerance disease (SEID), is a chronic and often disabling disease. Although the exact pathophysiological mechanism ...Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), recently renamed as systemic exertion intolerance disease (SEID), is a chronic and often disabling disease. Although the exact pathophysiological mechanism of ME/CFS is unknown, immunological abnormalities may play an important role. Curcumin is a herb with powerful anti-oxidative, and anti-inflammatory properties. Therefore, we hypothesized that curcumin has favorable effects on symptomatology in ME/CFS patients. In total 52 patients participated, nine stopped the use of curcumin because of side effects. All remaining patients (n = 43) met the criteria for CFS;72% met the criteria for ME. Before and 8 weeks after the use of curcumin complexed with phosphatidyl choline, 500 mg bid, the CDC inventory for assessment of Chronic Fatigue Syndrome was filled in. The CDC questions (n = 19) were scored and divided into 2 parts: the first being specific for CFS complaints (n = 9), the second being scores of less specific symptoms (n = 10);denoted as CDC rest score. Results showed that 8 weeks curcumin use significantly decreased the CFS related symptom scores, but not the CDC rest scores. Analyzing the data separately for ME and CFS patients, the same significance for the CFS symptom scores was present. Conclusion: in this open-labeled study, 8 weeks curcumin use in a phosphatidyl choline complex reduced ME/CFS symptomatology. Therefore, a randomized placebo controlled study is warranted to assess its efficacy in ME/CFS patients.展开更多
Chronic fatigue syndrome and myalgic encephalomyelitis (CFS/ME) are, amongst others, characterized by exercise intolerance, pain, post exertional malaise and orthostatic intolerance. It has been shown in venous diseas...Chronic fatigue syndrome and myalgic encephalomyelitis (CFS/ME) are, amongst others, characterized by exercise intolerance, pain, post exertional malaise and orthostatic intolerance. It has been shown in venous disease and sport participation that compression stockings may improve exercise performance and reduce post exercise muscle soreness. Moreover, its use is advocated in orthostatic hypotension. Therefore, it was hypothesized that compression stockings may reduce symptomatology in CFS/ME patients. Methods: 100 patients used compression stockings class II for minimally 3 weeks and thereafter filled in a questionnaire, based on the Rand 36 physical activity questions (n = 9), whether compression stockings changed perceived symptoms or not. Moreover, 7 questions referring to prolonged standing and sitting, to recovery post exercise, muscle pain during or immediately post exercise, and to dizziness/light-headedness during or immediately post exercise, while standing and during prolonged sitting were added. Questions were scored as 1: able to perform activity much less while wearing the stockings, 2: perform activity somewhat less, 3: no perceived change in activity, 4: perform activity slightly better, 5: able to perform activity much better while wearing the stockings. Results: In patients able to answer the question, all mean scores per activity were significantly higher than 3, being no perceived change in activity while wearing the stockings. Subgroup analysis showed that patients with orthostatic intolerance reported higher effects than patients without orthostatic intolerance. Conclusion: This pilot study suggests that compression stockings may be useful to reduce symptomatology of physical activities in CFS/ME patients, especially in patients with orthostatic intolerance. Larger prospective studies with hard endpoints are warranted.展开更多
Introduction: Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is often associated with gastrointestinal disturbance and inflammatory markers;however, there have been no histological studies performed in th...Introduction: Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is often associated with gastrointestinal disturbance and inflammatory markers;however, there have been no histological studies performed in the small intestine from CFS/ME patients. The aim of this investigation was to assess the expression of certain inflammatory markers and inflammatory receptors, namely transient receptor potential melastin 3 (TRPM3) ion channels and muscarinic acetylcholine M3 (mAChRM3) receptors, in small intestinal tissues in a case controlled study comprising a CFS/ME patient and a healthy non-fatigued control. Method: Immunohistochemistry was performed on a small intestinal biopsy from a CFS/ME patient (age = 50;female) with self-reported symptoms of gastrointestinal disturbance and a non-fatigued control (NFC), (age = 28;female). Semi-quantitative analysis of expression was undertaken for interferon-gamma (IFNy), interleukin-1 alpha (IL-1α), tumour necrosis factor-alpha (TNFα), TRPM3 ion channels and mAChRM3 acetylcholine receptors. Results: There was significantly decreased expression of TRPM3 in the CFS/ME patient (35% ±9%) and a significant decrease in mAChRM3 in the CFS/ME patient (54% ±9%). There was no difference in IL-1α between CFS/ME patient and NFC, however;there was an increase in IFNy (13% ±6%) in the CFS/ME patient compared to NFC. There was a difference observed in TNFα in CFS/ME compared to NFC. Conclusion: Differences were noted in the expression of specific TRP ion channels and cholinergic receptors in CFS/ME compared with NFC, with CFS/ME demonstrating decreased TRPM3 and mAChRM3. Further, IFNy was increased, and TNFα decreased, in the small intestine of the CFS/ME patient with reported gastrointestinal disturbance.展开更多
Infiltration and activation of peripheral immune cells are critical in the progression of multiple sclerosis and its experimental animal model,experimental autoimmune encephalomyelitis(EAE).This study investigates the...Infiltration and activation of peripheral immune cells are critical in the progression of multiple sclerosis and its experimental animal model,experimental autoimmune encephalomyelitis(EAE).This study investigates the role of high mobility group box 1(HMGB1)in oligodendrocyte precursor cells(OPCs)in modulating pathogenic T cells infiltrating the central nervous system through the blood-brain barrier(BBB)by using OPC-specific HMGB1 knockout(KO)mice.We found that HMGB1 released from OPCs promotes BBB disruption,subsequently allowing increased immune cell infiltration.The migration of CD4+T cells isolated from EAE-induced mice was enhanced when co-cultured with OPCs compared to oligodendrocytes(OLs).OPC-specific HMGB1 KO mice exhibited lower BBB permeability and reduced immune cell infiltration into the CNS,leading to less damage to the myelin sheath and mitigated EAE progression.CD4+T cell migration was also reduced when co-cultured with HMGB1 knock-out OPCs.Our findings reveal that HMGB1 secretion from OPCs is crucial for regulating immune cell infiltration and provides insights into the immunomodulatory function of OPCs in autoimmune diseases.展开更多
Background:Multiple sclerosis(MS)is a chronic disease of the central nervous system(CNS),exhibiting hallmarks of both inflammation and neurodegeneration and with limited treatment options.The intricate nature of MS pa...Background:Multiple sclerosis(MS)is a chronic disease of the central nervous system(CNS),exhibiting hallmarks of both inflammation and neurodegeneration and with limited treatment options.The intricate nature of MS pathophysiology and its variable progression pose severe challenges for the development of effective therapies.The experimental autoimmune encephalomyelitis(EAE)MS model,in its most common form,is an aggressive disease,which is not representative of the MS course and offers a limited time window for drug evaluation.This study aimed to generate an attenuated EAE variant,which extends the clinical testing window while preserving the high incidence of the standard EAE model.Methods:Components of the EAE induction protocol were titrated to develop a milder disease profile.In a subsequent drug trial using the MS medication fingolimod hydrochloride(FTY,Gilenya),the new variant was validated under prophylactic and therapeutic treatment regimens.Results:The attenuated EAE variant retains the standard hallmarks of neuroinflammation and,crucially,significantly extends the time frame for clinical drug testing.Unlike the standard variant,where FTY efficacy could only be demonstrated by prophylactic treatment,the attenuated variant facilitated differentiation of drug effects by therapeutic treatment initiated early in the acute phase of disease.Conclusion:The new EAE variant is suitable for use in preclinical assessment of candidate therapeutics and the identification of targetable molecular mechanisms underpinning disease development and progression.This study illustrates the importance of optimizing and refining the experimental tool to enhance the translational success of the candidate therapeutics for MS.展开更多
Coronaviruses(CoVs)are a large family of human and animal pathogens that cause significant health and economic burdens worldwide.Thapsigargin(Tg)is a plant-derived sesquiterpene lactone with potent antiviral effects;h...Coronaviruses(CoVs)are a large family of human and animal pathogens that cause significant health and economic burdens worldwide.Thapsigargin(Tg)is a plant-derived sesquiterpene lactone with potent antiviral effects;however,the underlying mechanism remains unclear.Here,we show that Tg exhibited strong antiviral activity against the neurotropic swine CoV porcine hemagglutinating encephalomyelitis virus(PHEV)both in vivo and in vitro.Tg also exhibited inhibitory activity against other three swine coronaviruses in cell lines.Specifically,Tg treatment significantly inhibited the replication and transcription of genomic RNA in the viral life cycle but did not directly inactivate PHEV.Transcriptome analysis and glycolysis/mitochondrial stress testing confirmed that Tg alters intracellular metabolic flux,and suppresses glycolysis and oxidative phosphorylation(OXPHOS).Furthermore,metabolic reprogramming is associated with the antiviral effect of Tg and is required for productive PHEV infection.Overall,our findings highlight that Tg plays a crucial role in combating viral infections by targeting host energy metabolism shared by pathogenic microorganisms,suggesting that targeting key nodes of host metabolic processes may be a strategy for designing antiviral drugs against coronaviruses.展开更多
High mobility group box 1(HMGB1),when released extracellularly,plays a pivotal role in the development of spinal cord synapses and exacerbates autoimmune diseases within the central nervous system.In experimental auto...High mobility group box 1(HMGB1),when released extracellularly,plays a pivotal role in the development of spinal cord synapses and exacerbates autoimmune diseases within the central nervous system.In experimental autoimmune encephalomyelitis(EAE),a condition that models multiple sclerosis,the levels of extracellular HMGB1 and interleukin-33(IL-33)have been found to be inversely correlated.However,the mechanism by which IL-33 deficiency enhances HMGB1 release during EAE remains elusive.Our study elucidates a potential signaling pathway whereby the absence of IL-33 leads to increased binding of P300/CBP-associated factor with HMGB1 in the nuclei of astrocytes,upregulating HMGB1 acetylation and promoting its release from astrocyte nuclei in the spinal cord of EAE mice.Conversely,the addition of IL-33 counteracts the TNF-α-induced increase in HMGB1 and acetylated HMGB1 levels in primary astrocytes.These findings underscore the potential of IL-33-associated signaling pathways as a therapeutic target for EAE treatment.展开更多
Vaccines have been shown to cause differential expression of genes and increase antibody titers against antigens. Influenza vaccines may have an effect on unexplained disorders such as Chronic Fatigue Syndrome/Myalgic...Vaccines have been shown to cause differential expression of genes and increase antibody titers against antigens. Influenza vaccines may have an effect on unexplained disorders such as Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). Immunological changes have been identified following immunization with trivalent influenza vaccine (TIV). The objective of this pilot study was to examine the consequences of TIV on cytokine and cytotoxic genes in CFS/ME. Peripheral blood mononuclear cells were preferentially isolated from whole blood of 7 CFS/ME patients and 8 controls. Following total RNA extraction and synthesis of cDNA, reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) was used to determine the expression levels of mRNAs for cytotoxic genes (perforin (PRF1), granzyme A (GZMA), granzyme B (GZMB) and cytokine genes. GZMB was significantly increased overall in the CFS/ME patients compared to the controls. GZMA was significantly increased 28 days after vaccination while PRF1 was reduced prevaccination but increased 14 days post-vaccination in the CFS/ME patients. There were no significant changes in cytokine genes pre or post vaccination. Administration of TIV may increase the expression of lytic genes in CFS/ME and this may contribute to the increase in cytotoxic activity we observed in these patients post vaccination.展开更多
Background: Chronic Fatigue Syndrome, also known as Myalgic Encephalomyelitis (CFS/ME), is a debilitating condition that presents with a range of symptoms, including fatigue, cognitive dysfunction, muscular and joint ...Background: Chronic Fatigue Syndrome, also known as Myalgic Encephalomyelitis (CFS/ME), is a debilitating condition that presents with a range of symptoms, including fatigue, cognitive dysfunction, muscular and joint pain, and may be immune-mediated. In particular, patients exhibit abnormal cytokine expression. Similarly, in Multiple Sclerosis (MS), patients display neuroimmunological symptoms, and abnormal cytokine expression, with some overlap in symptomology with CFS/ME. The purpose of this study was to compare Th1, Th2, Th17 cytokines, inflammatory cytokines and chemokines, in healthy controls, CFS/ME and MS patients. Methods: Serum samples were collected from healthy controls (n = 16, mean age = 50 ± 11.85 years), CFS/ME patients (n = 16, mean age = 49.88 ± 9.54 years) and MS patients (n = 11, mean age = 52.75 ± 12.81 years). The concentrations of 27 cytokines (IFN-γ, TNF-α, IL-12, IL-2, IL-1β, IL-4, IL-6, IL-10, IL-13, IL-5, IL-17, IL-1ra, IL-7, IL-8, IL-9, eotaxin, IP-10, MCP-1, MIP1α, MIP1β, PDGF-bb, RANTES, basic FGF, GCSF, GMCSF, VEGF and IL-15) were measured using a Bio-Plex Pro™ kit. Results: IFN-γ, IL-10 and IL-5 were significantly higher in the serum of both CFS/ME and MS patients compared to the healthy controls (p ≤ 0.041). However, only the MS patients had significantly elevated levels of IL-12, IL-1β, IL-4, IL-13, IL-6, IL-17, IL-1ra, IL-7, IL-9, eotaxin, IL-10, MIP1α, basic FGF, GCSF and VEGF compared to the CFS/ME patients and controls (p ≤ 0.04). There were no significant differences between groups for IL-8, MCP-1, MIP1β, RANTES, GMCSF, TNF-α, and IL-2. Conclusion: CFS/ME and MS patients both displayed abnormal cytokine levels, with dual expression of Th1 and Th2 cytokines. Further research into cytokines such as IFN-γ, IL-10 and IL-5, with the use of a specific CFS/ME case definition and sensitive cytokine assays, is required to improve the understanding of the pathophysiology of CFS/ME.展开更多
基金supported by the Judith Jane Mason and Harold Stannett Williams Memorial Foundation National Medical Program(#Mason2210)to JX。
文摘Myalgic encephalomyelitis/chronic fatigue syndrome-an insidious disease:The recent COVID-19 pandemic has brought substantial attention to the overlapping symptoms between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome(ME/CFS),a chronic and poorly understood neurological disorder(Shankar et al.,2024).
基金funded by the Mason Foundation National Medical Program(MAS2015F053).
文摘Objectives:People living with myalgic encephalomyelitis/chronic fatigue syndrome(ME/CFS)may face unique barriers to physical activity.Active video games may overcome these barriers and increase physical activity.The primary aim of this pilot study was to determine the feasibility and acceptability of active video games to increase physical activity levels of people with ME/CFS.Methods:A mixed method design was employed.Adults living with ME/CFS were randomised to a six-month intervention of(1)pacing,(2)pacing and conventional physical activity,or(3)pacing and active video gaming.Feasibility and acceptability were determined through semi-structured interviews.Health-related outcomes(e.g.,physical activity,blood samples,quality of life,and functioning)were also collected.Results:Fifteen people were assigned an intervention group with 12 completing.Three themes were identified from post-intervention interviews(1)positivity led to overall acceptability,(2)flexibility enabled participant autonomy,and(3)knowledge was gained about the self.No changes were seen in physical activity levels.An active video gaming intervention is acceptable but not feasible for people living with ME/CFS.Conclusions:Taken together,results suggest that physical activity can be managed safely by some people living with ME/CFS.Trial registration ACTRN12616000285459.
文摘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 indepth 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.
文摘Kindling might represent a heuristic model for understanding the etiology of Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS). Kindling occurs when an organism is exposed repeatedly to an initially sub-threshold stimulus re-sulting in hypersensitivity and spontaneous seizure-like activity. Among patients with ME/CFS, chronically repeated low-intensity stimulation due to an infectious illness might cause kindling of the limbic-hypothalamic-pituitary axis. Kindling might also occur by high-intensity stimulation (e.g., brain trauma) of the limbic-hypothalamic-pituitary axis. Once this system is charged or kindled, it can sustain a high level of arousal with little or no external stimulus and eventually this could lead to hypocortisolism. Seizure activity may spread to adjacent structures of the limbic-hypothalamic-pituitary axis in the brain, which might be responsible for the varied symptoms that occur among patients with ME/CFS. In addition, kindling may also be responsible for high levels of oxidative stress, which has been found in patients with ME/CFS.
文摘BACKGROUND The literature is mixed about the occurrence of alcohol intolerance among patients with myalgic encephalomyelitis/chronic fatigue syndrome(ME/CFS).Surveys that asked respondents with ME/CFS whether they experienced alcohol intolerance within a recent time frame might produce inaccurate results because respondents may indicate that the symptom was not present if they avoid alcohol due to alcohol intolerance.AIM To overcome this methodologic problem,participants in the current study were asked whether they have avoided alcohol in the past 6 mo,and if they had,how severe their alcohol intolerance would be if they were to drink alcohol.METHODS The instrument used was a validated scale called the DePaul symptom questionnaire.Independent t-tests were performed among the alcohol intolerant or not alcohol intolerant group.The alcohol intolerant group had 208 participants,and the not alcohol intolerant group had 96 participants.RESULTS Using specially designed questions to properly identify those with alcohol intolerance,those who experienced alcohol intolerance vs those who did not experience alcohol intolerance experienced more frequent/severe symptoms and domains.In addition,using a multiple regression analysis,the orthostatic intolerance symptom domain was related to alcohol intolerance.CONCLUSION The findings from the current study indicated that those with ME/CFS are more likely to experience alcohol intolerance.In addition,those with this symptom have more overall symptoms than those without alcohol intolerance.
文摘Highlights Fatiguing syndromes affect millions of patients in the United States and globally,but are grossly underserved in the clinic and in the contemplative design of basic research.
文摘Although myalgic encephalomyelitis(ME) and chronic fatigue syndrome(CFS) are considered to be synonymous,the definitional criteria for ME and CFS define two distinct,partially overlapping,clinical entities.ME,whether defined by the original criteria or by the recently proposed criteria,is not equivalent to CFS,let alone a severe variant of incapacitating chronic fatigue.Distinctive features of ME are:muscle weaknessand easy muscle fatigability,cognitive impairment,circulatory deficits,a marked variability of the symptoms in presence and severity,but above all,post-exertional "malaise":a(delayed) prolonged aggravation of symptoms after a minor exertion.In contrast,CFS is primarily defined by(unexplained) chronic fatigue,which should be accompanied by four out of a list of 8 symptoms,e.g.,headaches.Due to the subjective nature of several symptoms of ME and CFS,researchers and clinicians have questioned the physiological origin of these symptoms and qualified ME and CFS as functional somatic syndromes.However,various characteristic symptoms,e.g.,post-exertional "malaise" and muscle weakness,can be assessed objectively using wellaccepted methods,e.g.,cardiopulmonary exercise tests and cognitive tests.The objective measures acquired by these methods should be used to accurately diagnose patients,to evaluate the severity and impact of the illness objectively and to assess the positive and negative effects of proposed therapies impartially.
基金This study was support by a grant from Otago Medical School Scholarship for Ms Wood.
文摘A significant number of SARS-CoV-2 (COVID-19) pandemic patients have developed chronic symptoms lasting weeks or months which are very similar to those described for myalgic encephalomyelitis/chronic fatigue syndrome. This study reviews the current literature and understanding of the role that mitochondria, oxidative stress and antioxidants may play in the understanding of the pathophysiology and treatment of chronic fatigue. It describes what is known about the dysfunctional pathways which can develop in mitochondria and their relationship to chronic fatigue. It also reviews what is known about oxidative stress and how this can be related to the pathophysiology of fatigue, as well as examining the potential for specific therapy directed at mitochondria for the treatment of chronic fatigue in the form of antioxidants. This study identifies areas which require urgent, further research in order to fully elucidate the clinical and therapeutic potential of these approaches.
基金supported by the National Natural Science Foundation of China(No.32571336 and 32271048)Research Funds of Centre for Leading Medicine and Advanced Technologies of IHM(No.2025IHM01100)。
文摘Chronic migraine(CM)is a prevalent and highly debilitating neurological disorder.Functional magnetic resonance imaging(fMRI)studies have demonstrated associations between abnormal brain region activation and CM,yet the underlying complex neural circuitry mechanisms remain unclear.The spinal trigeminal nucleus caudalis(Sp5C)serves as the primary central hub for orofacial nociceptive input,receiving trigeminal pain signals and projecting to higher-order centers such as the thalamus.Therefore,we sought to investigate whether the Sp5C region and its associated circuits were involved in CM pathogenesis.In this study,we established a CM mouse model through repeated intraperitoneal injections of nitroglycerin(NTG).Using a combination of in vivo fiber photometry and in vitro c-Fos immunohistochemistry,we found a marked periorbital and plantar mechanical allodynia in CM mice,accompanied by increased glutamatergic neuronal activity in Sp5C.Chemogenetic manipulation of Sp5C glutamatergic neurons(Sp5CV^(glut2))bidirectionally modulated migraine-like behaviors and induced pain-related affective states,as evidenced by conditioned place preference/aversion(CPP/CPA)paradigms.Anterograde viral tracing revealed dense projections from Sp5C^(Vglut2)to the subthalamic nucleus(STN),which was activated in CM mice.Optogenetic activation of the Sp5C-STN pathway similarly produced migraine-like behaviors and pain-related aversive memory in mice.Altogether,we revealed a critical role of the Sp5CVglut2-STN circuit in the development and modulation of CM.Our findings provide novel mechanistic insights into the central mechanisms underlying CM,establishing potential theoretical foundations for clinical diagnosis and therapeutic development.
文摘BACKGROUND Acute disseminated encephalomyelitis(ADEM),which is rare,primarily affects children.It usually manifests as acute encephalopathy and multifocal neurological impairments after infection or vaccination.Diagnosis is still difficult due to the clinical and radiological similarity to other central nervous system disorders.Adult-onset ADEM calls for thorough reporting in order to improve diagnosis and treatment.CASE SUMMARY A 55-year-old man with hypertension had a high fever,intense headache and a steady decline in his neurological function after two weeks.Left facial paralysis was the initial symptom,which progressed to left hemiparesis,reduced consciousness level,photophobia,phonophobia,vomiting,and a focal seizure in the right leg.He had no history of autoimmune disease,vaccinations,or infections.Investigations showed negative infectious/autoimmune serology,mild cerebrospinal fluid lymphocytic pleocytosis(protein 76 mg/dL),and lymphopenia.Brain magnetic resonance imaging without contrast revealed bilateral,symmetrical T2/fluid-attenuated inversion recovery hyperintensities,primarily in the middle cerebellar peduncles,with minor involvement in the pontine and periventricular regions.Neoplastic,metabolic,vascular,and infectious conditions were not included.The patient showed spontaneous neurological improvement by Week 3 with near-complete motor recovery(limb strength 4/5)after methylprednisolone and rehabilitation,despite logistical delays in starting immunotherapy.The monophasic course and radiological/clinical remission were supported by idiopathic ADEM.CONCLUSION This case shows an uncommon,idiopathic,cerebellar-predominant ADEM variation in an adult without conventional triggers.It emphasizes the diagnostic difficulty in distinguishing ADEM from mimics(such as stroke or infection)in adults.Spontaneous improvement before treatment,although early detection is still crucial,should be highlighted,although early detection is still crucial.Increased clinician awareness,fair access to neuroimaging,and focused research on adult ADEM are crucial to fill these gaps and improve outcomes in places with limited resources.
文摘Lyme disease is the most common vector-borne illness in the United States and has been causing significant morbidity since its discovery in 1977.It is well-documented that about 10%of patients properly treated with antibiotics never fully recover,but instead go on to develop a chronic illness dubbed,posttreatment Lyme disease syndrome(PTLDS)characterized by severe fatigue,cognitive slowing,chronic pain,and sleep difficulties.This review includes 18 studies that detail the symptoms of patients with PTLDS and uses qualitative analysis to compare them to myalgic encephalitis/chronic fatigue syndrome(ME/CFS),a strikingly similar syndrome.In the majority of the PTLDS studies,at least four of the six major symptoms of ME/CFS were also noted,including substantial impairment in activity level and fatigue for more than 6 months,post-exertional malaise,and unrefreshing sleep.In one of the included PTLDS articles,26 of the 29 ME/CFS symptoms were noted.This study adds to the expanding literature on the post-active phase of infection syndromes,which suggests that chronic illnesses such as PTLDS and ME/CFS have similar pathogenesis despite different infectious origins.
文摘Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), recently renamed as systemic exertion intolerance disease (SEID), is a chronic and often disabling disease. Although the exact pathophysiological mechanism of ME/CFS is unknown, immunological abnormalities may play an important role. Curcumin is a herb with powerful anti-oxidative, and anti-inflammatory properties. Therefore, we hypothesized that curcumin has favorable effects on symptomatology in ME/CFS patients. In total 52 patients participated, nine stopped the use of curcumin because of side effects. All remaining patients (n = 43) met the criteria for CFS;72% met the criteria for ME. Before and 8 weeks after the use of curcumin complexed with phosphatidyl choline, 500 mg bid, the CDC inventory for assessment of Chronic Fatigue Syndrome was filled in. The CDC questions (n = 19) were scored and divided into 2 parts: the first being specific for CFS complaints (n = 9), the second being scores of less specific symptoms (n = 10);denoted as CDC rest score. Results showed that 8 weeks curcumin use significantly decreased the CFS related symptom scores, but not the CDC rest scores. Analyzing the data separately for ME and CFS patients, the same significance for the CFS symptom scores was present. Conclusion: in this open-labeled study, 8 weeks curcumin use in a phosphatidyl choline complex reduced ME/CFS symptomatology. Therefore, a randomized placebo controlled study is warranted to assess its efficacy in ME/CFS patients.
文摘Chronic fatigue syndrome and myalgic encephalomyelitis (CFS/ME) are, amongst others, characterized by exercise intolerance, pain, post exertional malaise and orthostatic intolerance. It has been shown in venous disease and sport participation that compression stockings may improve exercise performance and reduce post exercise muscle soreness. Moreover, its use is advocated in orthostatic hypotension. Therefore, it was hypothesized that compression stockings may reduce symptomatology in CFS/ME patients. Methods: 100 patients used compression stockings class II for minimally 3 weeks and thereafter filled in a questionnaire, based on the Rand 36 physical activity questions (n = 9), whether compression stockings changed perceived symptoms or not. Moreover, 7 questions referring to prolonged standing and sitting, to recovery post exercise, muscle pain during or immediately post exercise, and to dizziness/light-headedness during or immediately post exercise, while standing and during prolonged sitting were added. Questions were scored as 1: able to perform activity much less while wearing the stockings, 2: perform activity somewhat less, 3: no perceived change in activity, 4: perform activity slightly better, 5: able to perform activity much better while wearing the stockings. Results: In patients able to answer the question, all mean scores per activity were significantly higher than 3, being no perceived change in activity while wearing the stockings. Subgroup analysis showed that patients with orthostatic intolerance reported higher effects than patients without orthostatic intolerance. Conclusion: This pilot study suggests that compression stockings may be useful to reduce symptomatology of physical activities in CFS/ME patients, especially in patients with orthostatic intolerance. Larger prospective studies with hard endpoints are warranted.
文摘Introduction: Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is often associated with gastrointestinal disturbance and inflammatory markers;however, there have been no histological studies performed in the small intestine from CFS/ME patients. The aim of this investigation was to assess the expression of certain inflammatory markers and inflammatory receptors, namely transient receptor potential melastin 3 (TRPM3) ion channels and muscarinic acetylcholine M3 (mAChRM3) receptors, in small intestinal tissues in a case controlled study comprising a CFS/ME patient and a healthy non-fatigued control. Method: Immunohistochemistry was performed on a small intestinal biopsy from a CFS/ME patient (age = 50;female) with self-reported symptoms of gastrointestinal disturbance and a non-fatigued control (NFC), (age = 28;female). Semi-quantitative analysis of expression was undertaken for interferon-gamma (IFNy), interleukin-1 alpha (IL-1α), tumour necrosis factor-alpha (TNFα), TRPM3 ion channels and mAChRM3 acetylcholine receptors. Results: There was significantly decreased expression of TRPM3 in the CFS/ME patient (35% ±9%) and a significant decrease in mAChRM3 in the CFS/ME patient (54% ±9%). There was no difference in IL-1α between CFS/ME patient and NFC, however;there was an increase in IFNy (13% ±6%) in the CFS/ME patient compared to NFC. There was a difference observed in TNFα in CFS/ME compared to NFC. Conclusion: Differences were noted in the expression of specific TRP ion channels and cholinergic receptors in CFS/ME compared with NFC, with CFS/ME demonstrating decreased TRPM3 and mAChRM3. Further, IFNy was increased, and TNFα decreased, in the small intestine of the CFS/ME patient with reported gastrointestinal disturbance.
基金supported by the National Research Foundation of Korea(NRF)funded by the government of the Republic of Korea[2023R1A2C1004955]the Technology Innovation Program funded by the Ministry of Trade,Industry&Energy(Korea)(20009707)+1 种基金the Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Education(2020R1A6A3A01099056)the Korea Institute for Advancement of Technology funded by the Ministry of Trade,Industry and Energy(P0025489).
文摘Infiltration and activation of peripheral immune cells are critical in the progression of multiple sclerosis and its experimental animal model,experimental autoimmune encephalomyelitis(EAE).This study investigates the role of high mobility group box 1(HMGB1)in oligodendrocyte precursor cells(OPCs)in modulating pathogenic T cells infiltrating the central nervous system through the blood-brain barrier(BBB)by using OPC-specific HMGB1 knockout(KO)mice.We found that HMGB1 released from OPCs promotes BBB disruption,subsequently allowing increased immune cell infiltration.The migration of CD4+T cells isolated from EAE-induced mice was enhanced when co-cultured with OPCs compared to oligodendrocytes(OLs).OPC-specific HMGB1 KO mice exhibited lower BBB permeability and reduced immune cell infiltration into the CNS,leading to less damage to the myelin sheath and mitigated EAE progression.CD4+T cell migration was also reduced when co-cultured with HMGB1 knock-out OPCs.Our findings reveal that HMGB1 secretion from OPCs is crucial for regulating immune cell infiltration and provides insights into the immunomodulatory function of OPCs in autoimmune diseases.
基金Private DonationLa Trobe Research Focus AreasMultiple Sclerosis Australia,Grant/Award Number:20-032。
文摘Background:Multiple sclerosis(MS)is a chronic disease of the central nervous system(CNS),exhibiting hallmarks of both inflammation and neurodegeneration and with limited treatment options.The intricate nature of MS pathophysiology and its variable progression pose severe challenges for the development of effective therapies.The experimental autoimmune encephalomyelitis(EAE)MS model,in its most common form,is an aggressive disease,which is not representative of the MS course and offers a limited time window for drug evaluation.This study aimed to generate an attenuated EAE variant,which extends the clinical testing window while preserving the high incidence of the standard EAE model.Methods:Components of the EAE induction protocol were titrated to develop a milder disease profile.In a subsequent drug trial using the MS medication fingolimod hydrochloride(FTY,Gilenya),the new variant was validated under prophylactic and therapeutic treatment regimens.Results:The attenuated EAE variant retains the standard hallmarks of neuroinflammation and,crucially,significantly extends the time frame for clinical drug testing.Unlike the standard variant,where FTY efficacy could only be demonstrated by prophylactic treatment,the attenuated variant facilitated differentiation of drug effects by therapeutic treatment initiated early in the acute phase of disease.Conclusion:The new EAE variant is suitable for use in preclinical assessment of candidate therapeutics and the identification of targetable molecular mechanisms underpinning disease development and progression.This study illustrates the importance of optimizing and refining the experimental tool to enhance the translational success of the candidate therapeutics for MS.
基金supported by the National Key Research and Development Program of China under Grant 2022YFD1801400 to Zi Lithe National Natural Science Foundation of China under Grants 32302851 to Junchao Shi,32272956 to Zi Li,32172828 to Wenqi Hethe Natural Science Foundation Project of Jilin Province under Grant 20240101014JC to Zi Li.
文摘Coronaviruses(CoVs)are a large family of human and animal pathogens that cause significant health and economic burdens worldwide.Thapsigargin(Tg)is a plant-derived sesquiterpene lactone with potent antiviral effects;however,the underlying mechanism remains unclear.Here,we show that Tg exhibited strong antiviral activity against the neurotropic swine CoV porcine hemagglutinating encephalomyelitis virus(PHEV)both in vivo and in vitro.Tg also exhibited inhibitory activity against other three swine coronaviruses in cell lines.Specifically,Tg treatment significantly inhibited the replication and transcription of genomic RNA in the viral life cycle but did not directly inactivate PHEV.Transcriptome analysis and glycolysis/mitochondrial stress testing confirmed that Tg alters intracellular metabolic flux,and suppresses glycolysis and oxidative phosphorylation(OXPHOS).Furthermore,metabolic reprogramming is associated with the antiviral effect of Tg and is required for productive PHEV infection.Overall,our findings highlight that Tg plays a crucial role in combating viral infections by targeting host energy metabolism shared by pathogenic microorganisms,suggesting that targeting key nodes of host metabolic processes may be a strategy for designing antiviral drugs against coronaviruses.
基金supported by the National Natural Science Foundation of China(82001281 and 82371195)Hubei Provincial Natural Science Foundation of China for Distinguished Young Scholars(2022CFA104)the Research Fund of Jianghan University(2022XKZX28).
文摘High mobility group box 1(HMGB1),when released extracellularly,plays a pivotal role in the development of spinal cord synapses and exacerbates autoimmune diseases within the central nervous system.In experimental autoimmune encephalomyelitis(EAE),a condition that models multiple sclerosis,the levels of extracellular HMGB1 and interleukin-33(IL-33)have been found to be inversely correlated.However,the mechanism by which IL-33 deficiency enhances HMGB1 release during EAE remains elusive.Our study elucidates a potential signaling pathway whereby the absence of IL-33 leads to increased binding of P300/CBP-associated factor with HMGB1 in the nuclei of astrocytes,upregulating HMGB1 acetylation and promoting its release from astrocyte nuclei in the spinal cord of EAE mice.Conversely,the addition of IL-33 counteracts the TNF-α-induced increase in HMGB1 and acetylated HMGB1 levels in primary astrocytes.These findings underscore the potential of IL-33-associated signaling pathways as a therapeutic target for EAE treatment.
文摘Vaccines have been shown to cause differential expression of genes and increase antibody titers against antigens. Influenza vaccines may have an effect on unexplained disorders such as Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). Immunological changes have been identified following immunization with trivalent influenza vaccine (TIV). The objective of this pilot study was to examine the consequences of TIV on cytokine and cytotoxic genes in CFS/ME. Peripheral blood mononuclear cells were preferentially isolated from whole blood of 7 CFS/ME patients and 8 controls. Following total RNA extraction and synthesis of cDNA, reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) was used to determine the expression levels of mRNAs for cytotoxic genes (perforin (PRF1), granzyme A (GZMA), granzyme B (GZMB) and cytokine genes. GZMB was significantly increased overall in the CFS/ME patients compared to the controls. GZMA was significantly increased 28 days after vaccination while PRF1 was reduced prevaccination but increased 14 days post-vaccination in the CFS/ME patients. There were no significant changes in cytokine genes pre or post vaccination. Administration of TIV may increase the expression of lytic genes in CFS/ME and this may contribute to the increase in cytotoxic activity we observed in these patients post vaccination.
文摘Background: Chronic Fatigue Syndrome, also known as Myalgic Encephalomyelitis (CFS/ME), is a debilitating condition that presents with a range of symptoms, including fatigue, cognitive dysfunction, muscular and joint pain, and may be immune-mediated. In particular, patients exhibit abnormal cytokine expression. Similarly, in Multiple Sclerosis (MS), patients display neuroimmunological symptoms, and abnormal cytokine expression, with some overlap in symptomology with CFS/ME. The purpose of this study was to compare Th1, Th2, Th17 cytokines, inflammatory cytokines and chemokines, in healthy controls, CFS/ME and MS patients. Methods: Serum samples were collected from healthy controls (n = 16, mean age = 50 ± 11.85 years), CFS/ME patients (n = 16, mean age = 49.88 ± 9.54 years) and MS patients (n = 11, mean age = 52.75 ± 12.81 years). The concentrations of 27 cytokines (IFN-γ, TNF-α, IL-12, IL-2, IL-1β, IL-4, IL-6, IL-10, IL-13, IL-5, IL-17, IL-1ra, IL-7, IL-8, IL-9, eotaxin, IP-10, MCP-1, MIP1α, MIP1β, PDGF-bb, RANTES, basic FGF, GCSF, GMCSF, VEGF and IL-15) were measured using a Bio-Plex Pro™ kit. Results: IFN-γ, IL-10 and IL-5 were significantly higher in the serum of both CFS/ME and MS patients compared to the healthy controls (p ≤ 0.041). However, only the MS patients had significantly elevated levels of IL-12, IL-1β, IL-4, IL-13, IL-6, IL-17, IL-1ra, IL-7, IL-9, eotaxin, IL-10, MIP1α, basic FGF, GCSF and VEGF compared to the CFS/ME patients and controls (p ≤ 0.04). There were no significant differences between groups for IL-8, MCP-1, MIP1β, RANTES, GMCSF, TNF-α, and IL-2. Conclusion: CFS/ME and MS patients both displayed abnormal cytokine levels, with dual expression of Th1 and Th2 cytokines. Further research into cytokines such as IFN-γ, IL-10 and IL-5, with the use of a specific CFS/ME case definition and sensitive cytokine assays, is required to improve the understanding of the pathophysiology of CFS/ME.
