Chloroquine(CQ)is a weak base that was originally used to treat malaria infection.1 However,recent findings have pinpointed the modulatory effect of CQ in models of chronic inflammation and viral infections.The antivi...Chloroquine(CQ)is a weak base that was originally used to treat malaria infection.1 However,recent findings have pinpointed the modulatory effect of CQ in models of chronic inflammation and viral infections.The antiviral effect of CQ and its derivative hydroxychloroquine has attracted great attention due to the recent Sars-CoV-2 virus outbreak.展开更多
Multiple sclerosis(MS)and its animal model,experimental autoimmune encephalomyelitis(EAE),are chronic neuroinflammatory and demyelinating diseases of the central nervous system(CNS).1 Here,we provide compelling eviden...Multiple sclerosis(MS)and its animal model,experimental autoimmune encephalomyelitis(EAE),are chronic neuroinflammatory and demyelinating diseases of the central nervous system(CNS).1 Here,we provide compelling evidence of the novel anti-inflammatory and neuroprotective therapeutic effects of P7C3 in a CNS autoimmune disease.P7C3 treatment effectively reduces disease severity and improves clinical recovery before,at the onset,and at the peak stage of EAE.These effects,together with direct protection of oligodendrocyte survival,can work synergistically to achieve desirable therapeutic effects in EAE,in which the CNS pathology involves both inflammation and demyelination.The anti-inflammatory and neuroprotective capacity of P7C3 gives it a great therapeutic advantage among current therapies for MS,which is in urgent need of a more effective disease-modifying treatment.展开更多
Environmental cues provided by products from the diet,gut microbiota metabolism,and exposure to sunlight are sensed by specific receptors that drive a specific genomic profile in immune cells and influence the outcome...Environmental cues provided by products from the diet,gut microbiota metabolism,and exposure to sunlight are sensed by specific receptors that drive a specific genomic profile in immune cells and influence the outcome of multiple sclerosis(MS),an autoimmune disease of the central nervous system(CNS),1 which affects approximately 2.3 million people worldwide.2 Among these receptors,the ligand-activated transcription factor retinoic acid receptorα(RAR-α)senses retinoic acid and other ligands to promote the transcription of genes that have retinoic acid receptor elements in their promoter region.3 Supplementation with all-trans retinoic acid(ATRA),a metabolite of vitamin A,ameliorates inflammation in MS and the corresponding animal model,experimental autoimmune encephalomyelitis(EAE),by shifting the balance between Th17/regulatory T cells(Tregs)and inducing tolerogenic dendritic cells.4,5 To overcome the weaknesses associated with ATRA agonists,e.g.,instability,poor bioavailability and nonselective binding to a broad range of retinoid receptors,a variety of synthetic agonists specifically targeting RAR have been developed.6 One of them,AM80,inhibits Th17 cells and suppress acute neuroinflammation;however,continuous AM80 treatment is ineffective,most likely because AM80 also inhibits Tregs and IL-10 production.6 AM580,a stable benzoic derivative of retinoic acid and a selective RAR-αagonist,has been recently shown to significantly reduce the production of Th1 cytokines but promote Th2 cytokines in human PBMCs7 and to inhibit microglial activation,thus acting beneficially in Alzheimer’s disease treatment.8 In addition,AM580 protects retinal cells against diabetes-induced apoptosis by inducing neurotrophic factors.9 However,whether it has a protective effect on neuroinflammation is unknown.展开更多
基金This work has been supported by the National Natural Science Foundation of China(NSFC)[39900154,30170339]Shanghai Education and Development Foundation(SEDF)[03SG32].We thank Katherine Regan for excellent editorial assistance.
文摘Chloroquine(CQ)is a weak base that was originally used to treat malaria infection.1 However,recent findings have pinpointed the modulatory effect of CQ in models of chronic inflammation and viral infections.The antiviral effect of CQ and its derivative hydroxychloroquine has attracted great attention due to the recent Sars-CoV-2 virus outbreak.
基金supported by the NIH(Grants All35601 and NS099594)USA.X.L.and Y.Z.were partially supported by the Chinese National Natural Science Foundation(Grant nos.31970771 and 81771345).
文摘Multiple sclerosis(MS)and its animal model,experimental autoimmune encephalomyelitis(EAE),are chronic neuroinflammatory and demyelinating diseases of the central nervous system(CNS).1 Here,we provide compelling evidence of the novel anti-inflammatory and neuroprotective therapeutic effects of P7C3 in a CNS autoimmune disease.P7C3 treatment effectively reduces disease severity and improves clinical recovery before,at the onset,and at the peak stage of EAE.These effects,together with direct protection of oligodendrocyte survival,can work synergistically to achieve desirable therapeutic effects in EAE,in which the CNS pathology involves both inflammation and demyelination.The anti-inflammatory and neuroprotective capacity of P7C3 gives it a great therapeutic advantage among current therapies for MS,which is in urgent need of a more effective disease-modifying treatment.
基金supported by the NIH grants NS099594 and AI135601.Q.W.and C.G.M.supported by grants from the National Natural Science Foundation of China(No.81371414 and 81473577)。
文摘Environmental cues provided by products from the diet,gut microbiota metabolism,and exposure to sunlight are sensed by specific receptors that drive a specific genomic profile in immune cells and influence the outcome of multiple sclerosis(MS),an autoimmune disease of the central nervous system(CNS),1 which affects approximately 2.3 million people worldwide.2 Among these receptors,the ligand-activated transcription factor retinoic acid receptorα(RAR-α)senses retinoic acid and other ligands to promote the transcription of genes that have retinoic acid receptor elements in their promoter region.3 Supplementation with all-trans retinoic acid(ATRA),a metabolite of vitamin A,ameliorates inflammation in MS and the corresponding animal model,experimental autoimmune encephalomyelitis(EAE),by shifting the balance between Th17/regulatory T cells(Tregs)and inducing tolerogenic dendritic cells.4,5 To overcome the weaknesses associated with ATRA agonists,e.g.,instability,poor bioavailability and nonselective binding to a broad range of retinoid receptors,a variety of synthetic agonists specifically targeting RAR have been developed.6 One of them,AM80,inhibits Th17 cells and suppress acute neuroinflammation;however,continuous AM80 treatment is ineffective,most likely because AM80 also inhibits Tregs and IL-10 production.6 AM580,a stable benzoic derivative of retinoic acid and a selective RAR-αagonist,has been recently shown to significantly reduce the production of Th1 cytokines but promote Th2 cytokines in human PBMCs7 and to inhibit microglial activation,thus acting beneficially in Alzheimer’s disease treatment.8 In addition,AM580 protects retinal cells against diabetes-induced apoptosis by inducing neurotrophic factors.9 However,whether it has a protective effect on neuroinflammation is unknown.
