Epoxyeicosatrienoic acids(EETs)have pleiotropic endogenous cardiovascular protective effects and can be hydrolyzed to the corresponding dihydroxyeicosatrienoic acids by soluble epoxide hydrolase(sEH).Heart failure wit...Epoxyeicosatrienoic acids(EETs)have pleiotropic endogenous cardiovascular protective effects and can be hydrolyzed to the corresponding dihydroxyeicosatrienoic acids by soluble epoxide hydrolase(sEH).Heart failure with preserved ejection fraction(HFpEF)has shown an increased prevalence and worse prognosis over the decades.However,the role of sEH activ-ity in HFpEF remains unclear.We enrolled 500 patients with HFpEF and 500 healthy controls between February 2010 and March 2016.Eight types of sEH-related eicosanoids were measured according to target metabolomics,and their correlation with clinical endpoints was also analyzed.The primary endpoint was cardiac mortality,and the secondary endpoint was a composite of cardiac events,including heart failure(HF)readmission,cardiogenic hospitalization,and all-cause mortal-ity.Furthermore,the effect of sEH inhibitors on cardiac diastolic function in HFpEF was investigated in vivo and in vitro.Patients with HFpEF showed significantly enhanced EET degradation by the sEH enzyme compared with healthy controls.More importantly,sEH activity was positively correlated with cardiac mortality in patients with HFpEF,especially in older patients with arrhythmia.A consistent result was obtained in the multiple adjusted models.Decreased sEH activity by the sEH inhibitor showed a significant effective effect on the improvement of cardiac diastolic function by ameliorating lipid disorders in cardiomyocytes of HFpEF mouse model.This study demonstrated that increased sEH activity was associated with cardiac mortality in patients with HFpEF and suggested that sEH inhibition could be a promising therapeutic strategy to improve diastolic cardiac function.Clinical trial identifier:NCT03461107(https://clini caltr ials.gov).展开更多
Multiple sclerosis(MS)is a predominantly T-cell-mediated autoimmune inflammatory disease of the central nervous system(CNS)characterized by multifocal areas of immune cell infiltration,demyelination,axonal damage,and ...Multiple sclerosis(MS)is a predominantly T-cell-mediated autoimmune inflammatory disease of the central nervous system(CNS)characterized by multifocal areas of immune cell infiltration,demyelination,axonal damage,and disruption of neuronal signal.1,2 It is now widely accepted that MS is a heterogeneous,multifactorial disease influenced by genetic,epigenetic,and environmental factors.3 Now,subsequent studies have identified and highlighted an important pathogenic role for Th17 cells in autoimmunity,a kind of CD4+T-cell subset that secrete signature cytokine interleukin IL-17A.4,5 However,the treatment for MS still remains a great challenge.Thus,the current prompted us to find a more effective disease-modifying treatment.Here,we found that small-molecule TPN10456 potently suppressed Th17 cell differentiation.Interestingly,TPN10456 inhibited pathogenic Th17 cells differentiation,but not conventional Th17 cells.Meanwhile,TPN10456 also inhibited human Th17 cells differentiation in vitro.Moreover,compared with the vehicle group,TPN10456-treated EAE mice showed less severe EAE symptoms,including lower clinical scores,reduced inflammatory cells infiltration,and less extensive demyelination in CNS.These results suggest that TPN10456 may represent a promising therapeutic agent for the treatment of MS.展开更多
基金supported by grants from the National Natural Science Foundation of China(81790624[to D.W.W.],81900342[to L.P.]and 81790621[to Y.Z.]).
文摘Epoxyeicosatrienoic acids(EETs)have pleiotropic endogenous cardiovascular protective effects and can be hydrolyzed to the corresponding dihydroxyeicosatrienoic acids by soluble epoxide hydrolase(sEH).Heart failure with preserved ejection fraction(HFpEF)has shown an increased prevalence and worse prognosis over the decades.However,the role of sEH activ-ity in HFpEF remains unclear.We enrolled 500 patients with HFpEF and 500 healthy controls between February 2010 and March 2016.Eight types of sEH-related eicosanoids were measured according to target metabolomics,and their correlation with clinical endpoints was also analyzed.The primary endpoint was cardiac mortality,and the secondary endpoint was a composite of cardiac events,including heart failure(HF)readmission,cardiogenic hospitalization,and all-cause mortal-ity.Furthermore,the effect of sEH inhibitors on cardiac diastolic function in HFpEF was investigated in vivo and in vitro.Patients with HFpEF showed significantly enhanced EET degradation by the sEH enzyme compared with healthy controls.More importantly,sEH activity was positively correlated with cardiac mortality in patients with HFpEF,especially in older patients with arrhythmia.A consistent result was obtained in the multiple adjusted models.Decreased sEH activity by the sEH inhibitor showed a significant effective effect on the improvement of cardiac diastolic function by ameliorating lipid disorders in cardiomyocytes of HFpEF mouse model.This study demonstrated that increased sEH activity was associated with cardiac mortality in patients with HFpEF and suggested that sEH inhibition could be a promising therapeutic strategy to improve diastolic cardiac function.Clinical trial identifier:NCT03461107(https://clini caltr ials.gov).
基金supported by grants from the National Natural Science Foundation of China(32070768,31871404,31900658)the Strategic Priority Research Program of Chinese Academy of Sciences(No.XDA12040327)+1 种基金the Shanghai Municipal Science and Technology Major Project(Grant No.2017SHZDZX01)the State Key Laboratory of Drug Research.
文摘Multiple sclerosis(MS)is a predominantly T-cell-mediated autoimmune inflammatory disease of the central nervous system(CNS)characterized by multifocal areas of immune cell infiltration,demyelination,axonal damage,and disruption of neuronal signal.1,2 It is now widely accepted that MS is a heterogeneous,multifactorial disease influenced by genetic,epigenetic,and environmental factors.3 Now,subsequent studies have identified and highlighted an important pathogenic role for Th17 cells in autoimmunity,a kind of CD4+T-cell subset that secrete signature cytokine interleukin IL-17A.4,5 However,the treatment for MS still remains a great challenge.Thus,the current prompted us to find a more effective disease-modifying treatment.Here,we found that small-molecule TPN10456 potently suppressed Th17 cell differentiation.Interestingly,TPN10456 inhibited pathogenic Th17 cells differentiation,but not conventional Th17 cells.Meanwhile,TPN10456 also inhibited human Th17 cells differentiation in vitro.Moreover,compared with the vehicle group,TPN10456-treated EAE mice showed less severe EAE symptoms,including lower clinical scores,reduced inflammatory cells infiltration,and less extensive demyelination in CNS.These results suggest that TPN10456 may represent a promising therapeutic agent for the treatment of MS.
