Background:Neuronal structure is disrupted after spinal cord injury(SCl),causing functional impairment.The effectiveness of exercise therapy(ET)in clinical settings for nerve remodeling post-SCI and its underlying mec...Background:Neuronal structure is disrupted after spinal cord injury(SCl),causing functional impairment.The effectiveness of exercise therapy(ET)in clinical settings for nerve remodeling post-SCI and its underlying mechanisms remain unclear.This study aims to explore the effects and related mechanisms of ET on nerve remodeling in SCI rats.Methods:We randomly assigned rats to various groups:sham-operated group,sham-operated+ET,SCI alone,SCI+H89,SCI+ET,and SCI+ET+H89.Techniques including motor-evoked potential(MEP),video capture and analysis,the Basso-Beattie-Bresnahan(BBB)scale,western blotting,transmission electron microscopy,hematoxylin and eosin staining,Nissl staining,glycine silver staining,immunofluorescence,and Golgi staining were utilized to assess signal conduction capabilities,neurological deficits,hindlimb performance,protein expression levels,neuron ultrastructure,and tissue morphology.H89-an inhibitor that targets the protein kinase A(PKA)/cAMP response element-binding(CREB)signaling pathway-was employed to investigate molecular mechanisms.Results:This study found that ET can reduce neuronal damage in rats with SCl,protect residual tissue,promote the remodeling of motor neurons,neurofilaments,dendrites/axons,synapses,and myelin sheaths,reorganize neural circuits,and promote motor function recovery.In terms of mechanism,ET mainly works by mediating the PKA/CREB signaling pathway in neurons.Conclusions:Our findings indicated that:(1)ET counteracted the H89-induced suppression of the PKA/CREB signaling pathway following SCl;(2)ET significantly alleviated neuronal injury and improved motor dysfunction;(3)ET facilitated neuronal regeneration by mediating the PKA/CREB signaling pathway;(4)ET enhanced synaptic and dendritic spine plasticity,as well as myelin sheath remodeling,post-SCI through the PKA/CREB signaling pathway.展开更多
Despite extensive studies on CD4^＋CD25^＋ regulatory T cells （Tregs） during the past decade, the progress on their clinical translation remains stagnant. Mounting evidence suggests that naturally occurring CD8^＋CD...Despite extensive studies on CD4^＋CD25^＋ regulatory T cells （Tregs） during the past decade, the progress on their clinical translation remains stagnant. Mounting evidence suggests that naturally occurring CD8^＋CD122^＋ T cells are also Tregs with the capacity to inhibit T-cell responses and suppress autoimmunity as well as alloimmunity. In fact, they are memory-like Tregs that resemble a central memory T cell （TcM） phenotype. The mechanisms underlying their suppression are still not well understood, although they may include IL-IO production. We have recently demonstrated that programmed death-1 （PD-1） expression distinguishes between regulatory and memory CD8^＋CD122^＋ T cells and that CD8^＋CD122^＋ Tregs undergo faster homeostatic proliferation and are more potent in the suppression of allograft rejection than conventional CD4^＋CD25^＋ Tregs. These findings may open a new line of investigation for accelerating effective Treg therapies in the clinic. In this review, we summarize the significant progress in this promising field of CD8^＋CD122^＋ Treg research and discuss their phenotypes, suppressive roles in autoimmunity and alloimmunity, functional requirements, mechanisms of action and potential applications in the clinic.展开更多
CD8^(+)T cells are regulatory T cells(Tregs)that suppress both alloimmunity and autoimmunity in many animal models.This class of regulatory cells includes the CD8^(+)CD28^(-),CD8^(+)CD103^(+),CD8^(+)FoxP3^(+)and CD8^(...CD8^(+)T cells are regulatory T cells(Tregs)that suppress both alloimmunity and autoimmunity in many animal models.This class of regulatory cells includes the CD8^(+)CD28^(-),CD8^(+)CD103^(+),CD8^(+)FoxP3^(+)and CD8^(+)CD122^(+)subsets.The mechanisms of action of these regulatory cells are not fully understood;however,the secretion of immunosuppressive cytokines,such as interleukin(IL)-4,IL-10 and transforming growth factor beta(TGF-β)as well as the direct killing of target cells via Fas L/Fas and the perforin/granzyme B pathways have been demonstrated in various models.Further studies are necessary to fully understand the mechanisms underlying the suppressive effects of Tregs and to provide experimental support for potential clinical trials.We recently observed that CD8^(+)CD122^(+)Tregs more potently suppressed allograft rejection compared to their CD4^(+)CD25^(+)counterparts,supporting the hypothesis that CD8^(+)Tregs may represent a new and promising Treg family that can be targeted to prevent allograft rejection in the clinic.In this review,we summarize the progress in the field during the past 7-10 years and discuss CD8^(+)Treg phenotypes,mechanisms of action,and their potential clinical applications;particularly in composite tissue transplants in burn and trauma patients.展开更多
Dear Editor,The transcription factor nuclear factor erythroid 2-related factor 2(Nrf2)plays a crucial role in human antioxidant defense response against environmental insults.Small molecular chemical activators of Nrf...Dear Editor,The transcription factor nuclear factor erythroid 2-related factor 2(Nrf2)plays a crucial role in human antioxidant defense response against environmental insults.Small molecular chemical activators of Nrf2 can confer protection against oxidative insults and inhibit the progression of diseases related to oxidative stress.Here,we identified oba-cunone as a novel activator of Nrf2 by decreasing Nrf2 ubiquitination and increasing its stability.In support of these findings,the systemic administration of obacunone strongly inhibits bleomycin-induced lung fibrosis in mice.展开更多
基金supported by National Natural Science Foundation of China(No.82302856,No.82271629 and No.81873376)China Postdoctoral Science Foundation under Grant Number 2024M762443+3 种基金Priority-Funded Postdoctoral Research Project,Zhejiang Province(ZJ2024133)Postdoctoral Fellowshiprogram of CPSF under Grant Number Grant Number GZC20241252Zhejiang Provincial Natural Science Foundation of China(No.LQ21H170003)Science Technology Bureau of Wenzhou funded project(No.Y20210164).
文摘Background:Neuronal structure is disrupted after spinal cord injury(SCl),causing functional impairment.The effectiveness of exercise therapy(ET)in clinical settings for nerve remodeling post-SCI and its underlying mechanisms remain unclear.This study aims to explore the effects and related mechanisms of ET on nerve remodeling in SCI rats.Methods:We randomly assigned rats to various groups:sham-operated group,sham-operated+ET,SCI alone,SCI+H89,SCI+ET,and SCI+ET+H89.Techniques including motor-evoked potential(MEP),video capture and analysis,the Basso-Beattie-Bresnahan(BBB)scale,western blotting,transmission electron microscopy,hematoxylin and eosin staining,Nissl staining,glycine silver staining,immunofluorescence,and Golgi staining were utilized to assess signal conduction capabilities,neurological deficits,hindlimb performance,protein expression levels,neuron ultrastructure,and tissue morphology.H89-an inhibitor that targets the protein kinase A(PKA)/cAMP response element-binding(CREB)signaling pathway-was employed to investigate molecular mechanisms.Results:This study found that ET can reduce neuronal damage in rats with SCl,protect residual tissue,promote the remodeling of motor neurons,neurofilaments,dendrites/axons,synapses,and myelin sheaths,reorganize neural circuits,and promote motor function recovery.In terms of mechanism,ET mainly works by mediating the PKA/CREB signaling pathway in neurons.Conclusions:Our findings indicated that:(1)ET counteracted the H89-induced suppression of the PKA/CREB signaling pathway following SCl;(2)ET significantly alleviated neuronal injury and improved motor dysfunction;(3)ET facilitated neuronal regeneration by mediating the PKA/CREB signaling pathway;(4)ET enhanced synaptic and dendritic spine plasticity,as well as myelin sheath remodeling,post-SCI through the PKA/CREB signaling pathway.
文摘Despite extensive studies on CD4^＋CD25^＋ regulatory T cells （Tregs） during the past decade, the progress on their clinical translation remains stagnant. Mounting evidence suggests that naturally occurring CD8^＋CD122^＋ T cells are also Tregs with the capacity to inhibit T-cell responses and suppress autoimmunity as well as alloimmunity. In fact, they are memory-like Tregs that resemble a central memory T cell （TcM） phenotype. The mechanisms underlying their suppression are still not well understood, although they may include IL-IO production. We have recently demonstrated that programmed death-1 （PD-1） expression distinguishes between regulatory and memory CD8^＋CD122^＋ T cells and that CD8^＋CD122^＋ Tregs undergo faster homeostatic proliferation and are more potent in the suppression of allograft rejection than conventional CD4^＋CD25^＋ Tregs. These findings may open a new line of investigation for accelerating effective Treg therapies in the clinic. In this review, we summarize the significant progress in this promising field of CD8^＋CD122^＋ Treg research and discuss their phenotypes, suppressive roles in autoimmunity and alloimmunity, functional requirements, mechanisms of action and potential applications in the clinic.
文摘CD8^(+)T cells are regulatory T cells(Tregs)that suppress both alloimmunity and autoimmunity in many animal models.This class of regulatory cells includes the CD8^(+)CD28^(-),CD8^(+)CD103^(+),CD8^(+)FoxP3^(+)and CD8^(+)CD122^(+)subsets.The mechanisms of action of these regulatory cells are not fully understood;however,the secretion of immunosuppressive cytokines,such as interleukin(IL)-4,IL-10 and transforming growth factor beta(TGF-β)as well as the direct killing of target cells via Fas L/Fas and the perforin/granzyme B pathways have been demonstrated in various models.Further studies are necessary to fully understand the mechanisms underlying the suppressive effects of Tregs and to provide experimental support for potential clinical trials.We recently observed that CD8^(+)CD122^(+)Tregs more potently suppressed allograft rejection compared to their CD4^(+)CD25^(+)counterparts,supporting the hypothesis that CD8^(+)Tregs may represent a new and promising Treg family that can be targeted to prevent allograft rejection in the clinic.In this review,we summarize the progress in the field during the past 7-10 years and discuss CD8^(+)Treg phenotypes,mechanisms of action,and their potential clinical applications;particularly in composite tissue transplants in burn and trauma patients.
基金supported by a grant from the National Basic ResearchProgram(973 Program)(No.2013CB966900)Guangdong Provin-cial Key Laboratory of Cancer Immunotherapy and Guangzhou KeyLaboratory of Tumor Immunology Researchthe National Natural Science Foundation of China(No.81473294).
文摘Dear Editor,The transcription factor nuclear factor erythroid 2-related factor 2(Nrf2)plays a crucial role in human antioxidant defense response against environmental insults.Small molecular chemical activators of Nrf2 can confer protection against oxidative insults and inhibit the progression of diseases related to oxidative stress.Here,we identified oba-cunone as a novel activator of Nrf2 by decreasing Nrf2 ubiquitination and increasing its stability.In support of these findings,the systemic administration of obacunone strongly inhibits bleomycin-induced lung fibrosis in mice.
