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
The nervous system function requires a precise but plastic neural architecture.The neuronal shape dictates how neurons interact with each other and with other cells,being the morphology of dendrites and axons the cent...The nervous system function requires a precise but plastic neural architecture.The neuronal shape dictates how neurons interact with each other and with other cells,being the morphology of dendrites and axons the central determinant of the functional properties of neurons and neural circuits.The topological and structural morphology of axons and dendrites defines and determines how synapses are conformed.The morphological diversity of axon and dendrite arborization governs the neuron’s inputs,synaptic integration,neuronal computation,signal transmission,and network circuitry,hence defining the particular connectivity and function of the different brain areas.展开更多
Neuropathic pain,often featuring allodynia,imposes significant physical and psychological burdens on patients,with limited treatments due to unclear central mechanisms.Addressing this challenge remains a crucial unsol...Neuropathic pain,often featuring allodynia,imposes significant physical and psychological burdens on patients,with limited treatments due to unclear central mechanisms.Addressing this challenge remains a crucial unsolved issue in pain medicine.Our previous study,using protein kinase C gamma(PKCγ)-tdTomato mice,highlights the spinal feedforward inhibitory circuit involving PKCγ neurons in gating neuropathic allodynia.However,the regulatory mechanisms governing this circuit necessitate further elucidation.We used diverse transgenic mice and advanced techniques to uncover the regulatory role of the descending serotonin(5-HT)facilitation system on spinal PKCγ neurons.Our findings revealed that 5-HT neurons from the rostral ventromedial medulla hyperpolarize spinal inhibitory interneurons via 5-HT_(2C) receptors,disinhibiting the feedforward inhibitory circuit involving PKCγ neurons and exacerbating allodynia.Inhibiting spinal 5-HT_(2C) receptors restored the feedforward inhibitory circuit,effectively preventing neuropathic allodynia.These insights offer promising therapeutic targets for neuropathic allodynia management,emphasizing the potential of spinal 5-HT_(2C) receptors as a novel avenue for intervention.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supported by the Wellcome Trust(grant No.103852).
文摘The nervous system function requires a precise but plastic neural architecture.The neuronal shape dictates how neurons interact with each other and with other cells,being the morphology of dendrites and axons the central determinant of the functional properties of neurons and neural circuits.The topological and structural morphology of axons and dendrites defines and determines how synapses are conformed.The morphological diversity of axon and dendrite arborization governs the neuron’s inputs,synaptic integration,neuronal computation,signal transmission,and network circuitry,hence defining the particular connectivity and function of the different brain areas.
基金supported by the National Natural Science Foundation of China(81971058,82371226,82101295,82301398)the National Funded Postdoctoral Researcher Program(GZC20233585)The Boost Plan of Xijing Hospital(XJZT24QN25,XJZT25CX22).
文摘Neuropathic pain,often featuring allodynia,imposes significant physical and psychological burdens on patients,with limited treatments due to unclear central mechanisms.Addressing this challenge remains a crucial unsolved issue in pain medicine.Our previous study,using protein kinase C gamma(PKCγ)-tdTomato mice,highlights the spinal feedforward inhibitory circuit involving PKCγ neurons in gating neuropathic allodynia.However,the regulatory mechanisms governing this circuit necessitate further elucidation.We used diverse transgenic mice and advanced techniques to uncover the regulatory role of the descending serotonin(5-HT)facilitation system on spinal PKCγ neurons.Our findings revealed that 5-HT neurons from the rostral ventromedial medulla hyperpolarize spinal inhibitory interneurons via 5-HT_(2C) receptors,disinhibiting the feedforward inhibitory circuit involving PKCγ neurons and exacerbating allodynia.Inhibiting spinal 5-HT_(2C) receptors restored the feedforward inhibitory circuit,effectively preventing neuropathic allodynia.These insights offer promising therapeutic targets for neuropathic allodynia management,emphasizing the potential of spinal 5-HT_(2C) receptors as a novel avenue for intervention.
