Neuronal injury in glaucoma persists despite effective intraocular pressure(IOP)control,necessitating neuroprotective strategies for retinal ganglion cells(RGCs).In this study,we investigated the neuroprotective role ...Neuronal injury in glaucoma persists despite effective intraocular pressure(IOP)control,necessitating neuroprotective strategies for retinal ganglion cells(RGCs).In this study,we investigated the neuroprotective role of theγ-hydroxybutyrate analog HOCPCA in a glaucoma model,focusing on its effects on CaMKII signaling,oxidative stress,and neuroinflammatory responses.Retinal tissue from high IOP animal models was analyzed via proteomics.In vitro mouse retinal explants were subjected to elevated pressure and oxidative stress,followed by HOCPCA treatment.HOCPCA significantly mitigated the RGC loss induced by oxidative stress and elevated pressure,preserving neuronal function.It restored CaMKIIαandβlevels,preserving RGC integrity,while also modulating oxidative stress and neuroinflammatory responses.These findings suggest that HOCPCA,through its interaction with CaMKII,holds promise as a neuroprotective therapy for glaucoma.展开更多
AIM:To investigate the role of Forkhead box protein P3(FOXP3)in choroidal melanoma(CM)metastases and elucidate its underlying mechanisms.METHODS:FOXP3 protein expression was analyzed in CM clinical specimens and cell ...AIM:To investigate the role of Forkhead box protein P3(FOXP3)in choroidal melanoma(CM)metastases and elucidate its underlying mechanisms.METHODS:FOXP3 protein expression was analyzed in CM clinical specimens and cell lines.A stable FOXP3 knockout cell line and a transient FOXP3-overexpressing cell line were established,with transfection efficiencies confirmed by Western blotting(WB).Functional assays,including monoclonal formation,cell counting kit-8(CCK-8)proliferation,migration,invasion,and in vivo tumorigenesis assays in nude mice,were performed to assess the biological effects of FOXP3.Additionally,WB was employed to evaluate epithelial-mesenchymal transition(EMT)markers and the activation of the Wnt5a/CaMKII signaling pathway.RESULTS:FOXP3 expression was significantly elevated in both CM clinical specimens and cell lines.Functional analyses revealed that FOXP3 enhanced CM cell proliferation,migration,and invasion in vitro and promoted tumorigenesis in vivo.Mechanistically,FOXP3 upregulated EMT-related proteins and activated the Wnt5a/CaMKII signaling pathway.Rescue experiments further confirmed that the oncogenic effects of FOXP3 were mediated via modulation of the Wnt5a/CaMKII axis.CONCLUSION:This study identifies FOXP3 as an oncogenic driver in CM,promoting tumor progression through the Wnt5a/CaMKII signaling pathway.These findings provide new insights into the molecular mechanisms of CM pathogenesis and highlight FOXP3 as a potential therapeutic target.展开更多
Netrin-G2 is a membrane-anchored protein known to play critical roles in neuronal circuit development and synaptic organization.In this study,we identify compound heterozygous mutations of c.547delC p.(Arg183Alafs*186...Netrin-G2 is a membrane-anchored protein known to play critical roles in neuronal circuit development and synaptic organization.In this study,we identify compound heterozygous mutations of c.547delC p.(Arg183Alafs*186)and c.605G>A,p.(Trp202X)in NTNG2 causing a syndrome exhibiting developmenta delay,intellectual disability,hypotonia,and facial dysmorphism.To elucidate the underlying cellular and molecular mechanisms,CRISPR-Cas9 technology is employed to generate a knock-in mouse mode expressing the R183Afs and W202X mutations.We report that the Ntng2^(R183Afs/W202X)mice exhibit hypo tonia and impaired learning and memory.We find that the levels of CaMKII and p-GluA1^(Ser831)are decreased,and excitatory postsynaptic transmission and long-term potentiation are impaired.To increase the activity of CaMKII,the mutant mice receive intraperitoneal injections of DCP-LA,a CaMKII agonist,and show improved cognitive function.Together,our findings reveal molecular mechanisms of how NTNG2deficiency leads to impairments of cognitive ability and synaptic plasticity.展开更多
Calcium/calmodulin-dependent protein kinase II (CaMKII) is a key regulator of heart function. While some CaMKII activity is beneficial, excessive, or persistent, CaMKII can lead to heart damage. CaMKII is often elevat...Calcium/calmodulin-dependent protein kinase II (CaMKII) is a key regulator of heart function. While some CaMKII activity is beneficial, excessive, or persistent, CaMKII can lead to heart damage. CaMKII is often elevated in conditions like diabetes and heart disease, contributing to various cardiovascular problems. Therefore, CaMKII is considered a potential target for drug therapy, although its complex nature poses challenges. This review summarizes the structure, regulation, and roles of CaMKII in both normal and disease states, mainly focusing on its involvement in heart problems.展开更多
基金The position of M.H.was funded by grants from the state of North-Rhine-Westphalia,Germany(AZ:323-8.04.10.02-141905)the German Center for Infection Research,DZIF(TTU 08.927 and TTU 08.928)+1 种基金the Deutsche Forschungsgemeinschaft(DFG),SFB 670 procured by Prof.Dr.Martin Krönkesupported by the Deutsche Forschungsgemeinschaft(DFG)with grants PR1569/1-1 and PR 1569/1-3.
文摘Neuronal injury in glaucoma persists despite effective intraocular pressure(IOP)control,necessitating neuroprotective strategies for retinal ganglion cells(RGCs).In this study,we investigated the neuroprotective role of theγ-hydroxybutyrate analog HOCPCA in a glaucoma model,focusing on its effects on CaMKII signaling,oxidative stress,and neuroinflammatory responses.Retinal tissue from high IOP animal models was analyzed via proteomics.In vitro mouse retinal explants were subjected to elevated pressure and oxidative stress,followed by HOCPCA treatment.HOCPCA significantly mitigated the RGC loss induced by oxidative stress and elevated pressure,preserving neuronal function.It restored CaMKIIαandβlevels,preserving RGC integrity,while also modulating oxidative stress and neuroinflammatory responses.These findings suggest that HOCPCA,through its interaction with CaMKII,holds promise as a neuroprotective therapy for glaucoma.
基金Supported by the National Natural Science Foundation of China(No.81873345,No.82274585)Qingdao Key Health Discipline Development Fund.
文摘AIM:To investigate the role of Forkhead box protein P3(FOXP3)in choroidal melanoma(CM)metastases and elucidate its underlying mechanisms.METHODS:FOXP3 protein expression was analyzed in CM clinical specimens and cell lines.A stable FOXP3 knockout cell line and a transient FOXP3-overexpressing cell line were established,with transfection efficiencies confirmed by Western blotting(WB).Functional assays,including monoclonal formation,cell counting kit-8(CCK-8)proliferation,migration,invasion,and in vivo tumorigenesis assays in nude mice,were performed to assess the biological effects of FOXP3.Additionally,WB was employed to evaluate epithelial-mesenchymal transition(EMT)markers and the activation of the Wnt5a/CaMKII signaling pathway.RESULTS:FOXP3 expression was significantly elevated in both CM clinical specimens and cell lines.Functional analyses revealed that FOXP3 enhanced CM cell proliferation,migration,and invasion in vitro and promoted tumorigenesis in vivo.Mechanistically,FOXP3 upregulated EMT-related proteins and activated the Wnt5a/CaMKII signaling pathway.Rescue experiments further confirmed that the oncogenic effects of FOXP3 were mediated via modulation of the Wnt5a/CaMKII axis.CONCLUSION:This study identifies FOXP3 as an oncogenic driver in CM,promoting tumor progression through the Wnt5a/CaMKII signaling pathway.These findings provide new insights into the molecular mechanisms of CM pathogenesis and highlight FOXP3 as a potential therapeutic target.
基金National Key R&D Program of China(2022YFC2703400 to Y.G.Y.)National Natural Science Foundation of China(82001209 to S.S.D.,82271904 and 82070914 to Y.G.Y.)+2 种基金Shanghai Municipal Commission of Health and Family Planning(20204Y0451 to S.S.D.)Shanghai Scientific and Technological Innovation Action Plan(20YF1440600 to S.S.D.)Shanghai Natural Science Foundation of China(21ZR1452700 to Y.K.Z.)。
文摘Netrin-G2 is a membrane-anchored protein known to play critical roles in neuronal circuit development and synaptic organization.In this study,we identify compound heterozygous mutations of c.547delC p.(Arg183Alafs*186)and c.605G>A,p.(Trp202X)in NTNG2 causing a syndrome exhibiting developmenta delay,intellectual disability,hypotonia,and facial dysmorphism.To elucidate the underlying cellular and molecular mechanisms,CRISPR-Cas9 technology is employed to generate a knock-in mouse mode expressing the R183Afs and W202X mutations.We report that the Ntng2^(R183Afs/W202X)mice exhibit hypo tonia and impaired learning and memory.We find that the levels of CaMKII and p-GluA1^(Ser831)are decreased,and excitatory postsynaptic transmission and long-term potentiation are impaired.To increase the activity of CaMKII,the mutant mice receive intraperitoneal injections of DCP-LA,a CaMKII agonist,and show improved cognitive function.Together,our findings reveal molecular mechanisms of how NTNG2deficiency leads to impairments of cognitive ability and synaptic plasticity.
文摘Calcium/calmodulin-dependent protein kinase II (CaMKII) is a key regulator of heart function. While some CaMKII activity is beneficial, excessive, or persistent, CaMKII can lead to heart damage. CaMKII is often elevated in conditions like diabetes and heart disease, contributing to various cardiovascular problems. Therefore, CaMKII is considered a potential target for drug therapy, although its complex nature poses challenges. This review summarizes the structure, regulation, and roles of CaMKII in both normal and disease states, mainly focusing on its involvement in heart problems.
