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
CaMKII is essential for long-term potentiation(LTP),a process in which synaptic strength is increased following the acquisition of information.Among the four CaMKII isoforms,γCaMKII is the one that mediates the LTP o...CaMKII is essential for long-term potentiation(LTP),a process in which synaptic strength is increased following the acquisition of information.Among the four CaMKII isoforms,γCaMKII is the one that mediates the LTP of excitatory synapses onto inhibitory interneurons(LTPE→I).However,the molecular mechanism underlying howγCaMKII mediates LTPE→I remains unclear.Here,we show thatγCaMKII is highly enriched in cultured hippocampal inhibitory interneurons and opts to be activated by higher stimulating frequencies in the 10–30 Hz range.Following stimulation,γCaMKII is translocated to the synapse and becomes co-localized with the postsynaptic protein PSD-95.Knocking downγCaMKII prevents the chemical LTP-induced phosphorylation and trafficking of AMPA receptors(AMPARs)in putative inhibitory interneurons,which are restored by overexpression ofγCaMKII but not its kinase-dead form.Taken together,these data suggest thatγCaMKII decodes NMDAR-mediated signaling and in turn regulates AMPARs for expressing LTP in inhibitory interneurons.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This work was supported by Science and Technology Innovation 2030-Major Project(2021ZD0203501)the National Natural Science Foundation of China(81930030,31771109,and 31722023)+5 种基金the National Key R&D Program of China(2019YFA0508603)CAMS Innovation Fund for Medical Sciences(2019-I2M-5-057)Project for Hangzhou Medical Disciplines of ExcellenceKey Project for Hangzhou Medical Disciplinesthe Fundamental Research Funds for the Central Universities of China(2018XZZX002-02,2019XZZX001-01-04,and 2019FZA7009)the National Postdoctoral Program for Innovative Talents(BX2021263).
文摘CaMKII is essential for long-term potentiation(LTP),a process in which synaptic strength is increased following the acquisition of information.Among the four CaMKII isoforms,γCaMKII is the one that mediates the LTP of excitatory synapses onto inhibitory interneurons(LTPE→I).However,the molecular mechanism underlying howγCaMKII mediates LTPE→I remains unclear.Here,we show thatγCaMKII is highly enriched in cultured hippocampal inhibitory interneurons and opts to be activated by higher stimulating frequencies in the 10–30 Hz range.Following stimulation,γCaMKII is translocated to the synapse and becomes co-localized with the postsynaptic protein PSD-95.Knocking downγCaMKII prevents the chemical LTP-induced phosphorylation and trafficking of AMPA receptors(AMPARs)in putative inhibitory interneurons,which are restored by overexpression ofγCaMKII but not its kinase-dead form.Taken together,these data suggest thatγCaMKII decodes NMDAR-mediated signaling and in turn regulates AMPARs for expressing LTP in inhibitory interneurons.
