Objective:Chronic fatigue syndrome(CFS)is a prevalent symptom of post-coronavirus disease 2019(COVID-19)and is associated with unclear disease mechanisms.The herbal medicine Qingjin Yiqi granules(QJYQ)constitute a cli...Objective:Chronic fatigue syndrome(CFS)is a prevalent symptom of post-coronavirus disease 2019(COVID-19)and is associated with unclear disease mechanisms.The herbal medicine Qingjin Yiqi granules(QJYQ)constitute a clinically approved formula for treating post-COVID-19;however,its potential as a drug target for treating CFS remains largely unknown.This study aimed to identify novel causal factors for CFS and elucidate the potential targets and pharmacological mechanisms of action of QJYQ in treating CFS.Methods:This prospective cohort analysis included 4,212 adults aged≥65 years who were followed up for 7 years with 435 incident CFS cases.Causal modeling and multivariate logistic regression analysis were performed to identify the potential causal determinants of CFS.A proteome-wide,two-sample Mendelian randomization(MR)analysis was employed to explore the proteins associated with the identified causal factors of CFS,which may serve as potential drug targets.Furthermore,we performed a virtual screening analysis to assess the binding affinity between the bioactive compounds in QJYQ and CFS-associated proteins.Results:Among 4,212 participants(47.5%men)with a median age of 69 years(interquartile range:69–70 years)enrolled in 2004,435 developed CFS by 2011.Causal graph analysis with multivariate logistic regression identified frequent cough(odds ratio:1.74,95%confidence interval[CI]:1.15–2.63)and insomnia(odds ratio:2.59,95%CI:1.77–3.79)as novel causal factors of CFS.Proteome-wide MR analysis revealed that the upregulation of endothelial cell-selective adhesion molecule(ESAM)was causally linked to both chronic cough(odds ratio:1.019,95%CI:1.012–1.026,P=2.75 e^(−05))and insomnia(odds ratio:1.015,95%CI:1.008–1.022,P=4.40 e^(−08))in CFS.The major bioactive compounds of QJYQ,ginsenoside Rb2(docking score:−6.03)and RG4(docking score:−6.15),bound to ESAM with high affinity based on virtual screening.Conclusions:Our integrated analytical framework combining epidemiological,genetic,and in silico data provides a novel strategy for elucidating complex disease mechanisms,such as CFS,and informing models of action of traditional Chinese medicines,such as QJYQ.Further validation in animal models is warranted to confirm the potential pharmacological effects of QJYQ on ESAM and as a treatment for CFS.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
基金supported by an internal fund from Macao Polytechnic University(RP/FCSD-02/2022).
文摘Objective:Chronic fatigue syndrome(CFS)is a prevalent symptom of post-coronavirus disease 2019(COVID-19)and is associated with unclear disease mechanisms.The herbal medicine Qingjin Yiqi granules(QJYQ)constitute a clinically approved formula for treating post-COVID-19;however,its potential as a drug target for treating CFS remains largely unknown.This study aimed to identify novel causal factors for CFS and elucidate the potential targets and pharmacological mechanisms of action of QJYQ in treating CFS.Methods:This prospective cohort analysis included 4,212 adults aged≥65 years who were followed up for 7 years with 435 incident CFS cases.Causal modeling and multivariate logistic regression analysis were performed to identify the potential causal determinants of CFS.A proteome-wide,two-sample Mendelian randomization(MR)analysis was employed to explore the proteins associated with the identified causal factors of CFS,which may serve as potential drug targets.Furthermore,we performed a virtual screening analysis to assess the binding affinity between the bioactive compounds in QJYQ and CFS-associated proteins.Results:Among 4,212 participants(47.5%men)with a median age of 69 years(interquartile range:69–70 years)enrolled in 2004,435 developed CFS by 2011.Causal graph analysis with multivariate logistic regression identified frequent cough(odds ratio:1.74,95%confidence interval[CI]:1.15–2.63)and insomnia(odds ratio:2.59,95%CI:1.77–3.79)as novel causal factors of CFS.Proteome-wide MR analysis revealed that the upregulation of endothelial cell-selective adhesion molecule(ESAM)was causally linked to both chronic cough(odds ratio:1.019,95%CI:1.012–1.026,P=2.75 e^(−05))and insomnia(odds ratio:1.015,95%CI:1.008–1.022,P=4.40 e^(−08))in CFS.The major bioactive compounds of QJYQ,ginsenoside Rb2(docking score:−6.03)and RG4(docking score:−6.15),bound to ESAM with high affinity based on virtual screening.Conclusions:Our integrated analytical framework combining epidemiological,genetic,and in silico data provides a novel strategy for elucidating complex disease mechanisms,such as CFS,and informing models of action of traditional Chinese medicines,such as QJYQ.Further validation in animal models is warranted to confirm the potential pharmacological effects of QJYQ on ESAM and as a treatment for CFS.
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.
