Parkinson's disease(PD)is the most common neurodegenerative movement disease.It is featured by abnormal alphα-synuclein(α-syn)aggregation in dopaminergic neurons in the substantia nigra.Macroautophagy(autophagy)...Parkinson's disease(PD)is the most common neurodegenerative movement disease.It is featured by abnormal alphα-synuclein(α-syn)aggregation in dopaminergic neurons in the substantia nigra.Macroautophagy(autophagy)is an evolutionarily conserved cellular process for degradation of cellular contents,including protein aggregates,to maintain cellular homeostasis.Corynoxine B(Cory B),a natural alkaloid isolated from Uncaria rhynchophylla(Miq.)Jacks.,has been reported to promote the clearance ofα-syn in cell models by inducing autophagy.However,the molecular mechanism by which Cory B induces autophagy is not known,and theα-syn-lowering activity of Cory B has not been verified in animal models.Here,we report that Cory B enhanced the activity of Beclin 1/VPS34 complex and increased autophagy by promoting the interaction between Beclin 1 and HMGB1/2.Depletion of HMGB1/2 impaired Cory B-induced autophagy.We showed for the first time that,similar to HMGB1,HMGB2 is also required for autophagy and depletion of HMGB2 decreased autophagy levels and phosphatidylinositol 3-kinaseⅢactivity both under basal and stimulated conditions.By applying cellular thermal shift assay,surface plasmon resonance,and molecular docking,we confirmed that Cory B directly binds to HMGB1/2 near the C106 site.Furthermore,in vivo studies with a wild-typeα-syn transgenic drosophila model of PD and an A53Tα-syn transgenic mouse model of PD,Cory B enhanced autophagy,promotedα-syn clearance and improved behavioral abnormalities.Taken together,the results of this study reveal that Cory B enhances phosphatidylinositol 3-kinaseⅢactivity/autophagy by binding to HMGB1/2 and that this enhancement is neuroprotective against PD.展开更多
DearEditor,The Arenaviridae family(recently assigned to the Bunyavirales order)is a group of emerging viruses that include causative agents of severe hemorrhagic fevers with high mortality in humans(de la Torre,2009)....DearEditor,The Arenaviridae family(recently assigned to the Bunyavirales order)is a group of emerging viruses that include causative agents of severe hemorrhagic fevers with high mortality in humans(de la Torre,2009).Lymphocytic choriomeningitis virus(LCMV)is the prototypic member of the Arenaviridae family and belongs to the Old World(OW)arenavirus together with Lassa virus(LASV),which are distinct from the New World(NW)arenavirus[e.g.Machupo virus(MACV)and Junin virus(JUNV)].LCMV infection in the fetus and newborm results in severe impairment of brain development associated with sensory loss and mental retardation and is also known to be associated with severe systemic infection with high mortality in transplantation patients(Palacios et al.,2008).展开更多
Dear Editor,Takeda G protein-coupled receptor 5(TGR5),also known as G protein-coupled bile acids(BAs)receptor 1(GPBAR1),1 belongs to the class A GPCR subfamily.The major TGR5-dependent actions of BAs include maintaini...Dear Editor,Takeda G protein-coupled receptor 5(TGR5),also known as G protein-coupled bile acids(BAs)receptor 1(GPBAR1),1 belongs to the class A GPCR subfamily.The major TGR5-dependent actions of BAs include maintaining energy homeostasis,regulating glucose/lipids metabolism,as well as immunosuppressive properties.2 TGR5 is identified as a potential therapeutic target for protecting hepatocytes from bile acid overload,preventing atherosclerosis,and inhibiting macrophage inflammation due to its critical role in bile acid sensitization.Thus,elucidation of structural characteristics of TGR5 and its activation mechanism would benefit the discovery of therapeutic drugs for these metabolic disorders.展开更多
Neuropsychiatric disorders are multifactorial disorders with diverse aetiological factors.Identifying treatment targets is challenging because the diseases are resulting from heterogeneous biological,genetic,and envir...Neuropsychiatric disorders are multifactorial disorders with diverse aetiological factors.Identifying treatment targets is challenging because the diseases are resulting from heterogeneous biological,genetic,and environmental factors.Nevertheless,the increasing understanding of G protein-coupled receptor(GPCR)opens a new possibility in drug discovery.Harnessing our knowledge of molecular mechanisms and structural information of GPCRs will be advantageous for developing effective drugs.This review provides an overview of the role of GPCRs in various neurodegenerative and psychiatric diseases.Besides,we highlight the emerging opportunities of novel GPCR targets and address recent progress in GPCR drug development.展开更多
As a cellular bulk degradation and survival mechanism,autophagy is implicated in diverse biological processes.Genome-wide association studies have revealed the link between autophagy gene polymorphisms and susceptibil...As a cellular bulk degradation and survival mechanism,autophagy is implicated in diverse biological processes.Genome-wide association studies have revealed the link between autophagy gene polymorphisms and susceptibility of autoimmune diseases including systemic lupus erythematosus(SLE)and inflammatory bowel disease(IBD),indicating that autophagy dysregulation may be involved in the development of autoimmune diseases.A series of autophagy modulators have displayed protective effects on autoimmune disease models,highlighting the emerging role of autophagy modulators in treating autoimmune diseases.This review explores the roles of autophagy in the autoimmune diseases,with emphasis on four major autoimmune diseases[SLE,rheumatoid arthritis(RA),IBD,and experimental autoimmune encephalomyelitis(EAE)].More importantly,the therapeutic potentials of small molecular autophagy modulators(including autophagy inducers and inhibitors)on autoimmune diseases are comprehensively analyzed.展开更多
Inflammatory bowel disease(IBD)is a chronic,non-specific,recurrent inflammatory disease,majorly affecting the gastrointestinal tract.Due to its unclear pathogenesis,the current therapeutic strategy for IBD is focused ...Inflammatory bowel disease(IBD)is a chronic,non-specific,recurrent inflammatory disease,majorly affecting the gastrointestinal tract.Due to its unclear pathogenesis,the current therapeutic strategy for IBD is focused on symptoms alleviation.Autophagy is a lysosome-mediated catabolic process for maintaining cellular homeostasis.Genome-wide association studies and subsequent functional studies have highlighted the critical role of autophagy in IBD via a number of mechanisms,including modulating macrophage function.Macrophages are the gatekeepers of intestinal immune homeostasis,especially involved in regulating inflammation remission and tissue repair.Interestingly,many autophagic proteins and IBD-related genes have been revealed to regulate macrophage function,suggesting that macrophage autophagy is a potentially important process implicated in IBD regulation.Here,we have summarized current understanding of macrophage autophagy function in pathogen and apoptotic cell clearance,inflammation remission and tissue repair regulation in IBD,and discuss how this knowledge can be used as a strategy for IBD treatment.展开更多
基金supported by the National Natural Science Foundation of China(No.82271455)the Guangdong Basic and Applied Basic Research Foundation(No.2022A1515012416,China)+5 种基金the Science and Technology Development Fund,Macao SAR(No.0128/2019/A3,China)the Shenzhen Fundamental Research Program(No.SGDX20210823103804030,China)the University of Macao grants(No.MYRG2022-00094-ICMS,China)awarded to Jia-hong Lupartly supported by Hong Kong Health and Medical Research Fund(HMRF/17182551,HMRF/09203776,China)the Hong Kong General Research Fund(HKBU 12100618,HKBU 12101022,China)from Hong Kong Governmentthe Research Fund from Hong Kong Baptist University(HKBU/RC-IRCs/17-18/03,IRCMS/19-20/H02,China)awarded to Min Li。
文摘Parkinson's disease(PD)is the most common neurodegenerative movement disease.It is featured by abnormal alphα-synuclein(α-syn)aggregation in dopaminergic neurons in the substantia nigra.Macroautophagy(autophagy)is an evolutionarily conserved cellular process for degradation of cellular contents,including protein aggregates,to maintain cellular homeostasis.Corynoxine B(Cory B),a natural alkaloid isolated from Uncaria rhynchophylla(Miq.)Jacks.,has been reported to promote the clearance ofα-syn in cell models by inducing autophagy.However,the molecular mechanism by which Cory B induces autophagy is not known,and theα-syn-lowering activity of Cory B has not been verified in animal models.Here,we report that Cory B enhanced the activity of Beclin 1/VPS34 complex and increased autophagy by promoting the interaction between Beclin 1 and HMGB1/2.Depletion of HMGB1/2 impaired Cory B-induced autophagy.We showed for the first time that,similar to HMGB1,HMGB2 is also required for autophagy and depletion of HMGB2 decreased autophagy levels and phosphatidylinositol 3-kinaseⅢactivity both under basal and stimulated conditions.By applying cellular thermal shift assay,surface plasmon resonance,and molecular docking,we confirmed that Cory B directly binds to HMGB1/2 near the C106 site.Furthermore,in vivo studies with a wild-typeα-syn transgenic drosophila model of PD and an A53Tα-syn transgenic mouse model of PD,Cory B enhanced autophagy,promotedα-syn clearance and improved behavioral abnormalities.Taken together,the results of this study reveal that Cory B enhances phosphatidylinositol 3-kinaseⅢactivity/autophagy by binding to HMGB1/2 and that this enhancement is neuroprotective against PD.
基金facility support.This work was supported by the National Natural Science Foundation of China(32188101 and U20A20135)the National Program on Key Research Project of China(2020YFA0707500),and Tsinghua University Spring Breeze Fund.
文摘DearEditor,The Arenaviridae family(recently assigned to the Bunyavirales order)is a group of emerging viruses that include causative agents of severe hemorrhagic fevers with high mortality in humans(de la Torre,2009).Lymphocytic choriomeningitis virus(LCMV)is the prototypic member of the Arenaviridae family and belongs to the Old World(OW)arenavirus together with Lassa virus(LASV),which are distinct from the New World(NW)arenavirus[e.g.Machupo virus(MACV)and Junin virus(JUNV)].LCMV infection in the fetus and newborm results in severe impairment of brain development associated with sensory loss and mental retardation and is also known to be associated with severe systemic infection with high mortality in transplantation patients(Palacios et al.,2008).
基金supported by the National Natural Science Foundation of China(Project No.31971218)Shenzhen Science and Technology Innovation Committee(Projects No.JCYJ20180307151618765 and JCYJ20180508163206306).R.R.was also supported in part by Kobilka Institute of Innovative Drug Discovery and Presidential Fellowship at the Chinese University of Hong Kong,Shenzhen.G.C.was supported in part by Ganghong Young Scholar Fund.
文摘Dear Editor,Takeda G protein-coupled receptor 5(TGR5),also known as G protein-coupled bile acids(BAs)receptor 1(GPBAR1),1 belongs to the class A GPCR subfamily.The major TGR5-dependent actions of BAs include maintaining energy homeostasis,regulating glucose/lipids metabolism,as well as immunosuppressive properties.2 TGR5 is identified as a potential therapeutic target for protecting hepatocytes from bile acid overload,preventing atherosclerosis,and inhibiting macrophage inflammation due to its critical role in bile acid sensitization.Thus,elucidation of structural characteristics of TGR5 and its activation mechanism would benefit the discovery of therapeutic drugs for these metabolic disorders.
基金supported by grants from Science,Technology and Innovation Commission of Shenzhen Municipality(Project code JCYJ20200109150019113,GXWD20201231105722002)the Kobilka Institute of Innovative Drug Discovery and Presidential Fellowship at the Chinese University of Hong Kong,Shenzhen,China+1 种基金National Natural Science Foundation of China(Project code 32271263 to Y.D.,Project code 82173690 to S.L.,81825020 and 82150208 to H.L.)the Lingang Laboratory(Project code LG-QS-202206-02 to S.L.)。
文摘Neuropsychiatric disorders are multifactorial disorders with diverse aetiological factors.Identifying treatment targets is challenging because the diseases are resulting from heterogeneous biological,genetic,and environmental factors.Nevertheless,the increasing understanding of G protein-coupled receptor(GPCR)opens a new possibility in drug discovery.Harnessing our knowledge of molecular mechanisms and structural information of GPCRs will be advantageous for developing effective drugs.This review provides an overview of the role of GPCRs in various neurodegenerative and psychiatric diseases.Besides,we highlight the emerging opportunities of novel GPCR targets and address recent progress in GPCR drug development.
基金supported by the Science and Technology Development Fund,Macao SAR(Nos.0110/2018/A3,0128/2019/A3,China)the University of Macao grants(No.MYRG201900129-ICMS,China)awarded to Jia-Hong Lu。
文摘As a cellular bulk degradation and survival mechanism,autophagy is implicated in diverse biological processes.Genome-wide association studies have revealed the link between autophagy gene polymorphisms and susceptibility of autoimmune diseases including systemic lupus erythematosus(SLE)and inflammatory bowel disease(IBD),indicating that autophagy dysregulation may be involved in the development of autoimmune diseases.A series of autophagy modulators have displayed protective effects on autoimmune disease models,highlighting the emerging role of autophagy modulators in treating autoimmune diseases.This review explores the roles of autophagy in the autoimmune diseases,with emphasis on four major autoimmune diseases[SLE,rheumatoid arthritis(RA),IBD,and experimental autoimmune encephalomyelitis(EAE)].More importantly,the therapeutic potentials of small molecular autophagy modulators(including autophagy inducers and inhibitors)on autoimmune diseases are comprehensively analyzed.
基金supported by the Shenzhen Fundamental Research Program(No.SGDX20210823103804030)Science and Technology Development Fund,Macao SAR(No.0025/2022/A1)+3 种基金the 2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund(Guangdong-Hong Kong-Macao Joint Lab)(No.2020B1212030006)Guangdong Basic and Applied Basic Research Foundation(No.2022A1515012416)National Natural Science Foundation of China(No.31871024)the University of Macao grants(No.MYRG2019-00129-ICMS)awarded to JHL.
文摘Inflammatory bowel disease(IBD)is a chronic,non-specific,recurrent inflammatory disease,majorly affecting the gastrointestinal tract.Due to its unclear pathogenesis,the current therapeutic strategy for IBD is focused on symptoms alleviation.Autophagy is a lysosome-mediated catabolic process for maintaining cellular homeostasis.Genome-wide association studies and subsequent functional studies have highlighted the critical role of autophagy in IBD via a number of mechanisms,including modulating macrophage function.Macrophages are the gatekeepers of intestinal immune homeostasis,especially involved in regulating inflammation remission and tissue repair.Interestingly,many autophagic proteins and IBD-related genes have been revealed to regulate macrophage function,suggesting that macrophage autophagy is a potentially important process implicated in IBD regulation.Here,we have summarized current understanding of macrophage autophagy function in pathogen and apoptotic cell clearance,inflammation remission and tissue repair regulation in IBD,and discuss how this knowledge can be used as a strategy for IBD treatment.