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目的研究藏红花素通过影响Ca^2＋内流对谷氨酸盐诱导的视网膜神经节细胞（RGCs）凋亡的影响及可能机制。方法分离大鼠RGCs,以0.1、1mmol/L的谷氨酸盐刺激RGCs 24、48h,建立RGCs凋亡模型,并用0.1、1.0、3.0μmol/L浓度梯度藏红花素分别处理。Annexin V-FITC/PI双标检测细胞凋亡率,Fluo-3/AM荧光标记Ca^2＋检测胞内钙离子浓度,Western blot检测藏红花素对胞内钙离子介导的凋亡信号分子calpain和CaMKⅡ表达的影响。JC-1荧光染色和Western blot分别检测藏红花素对线粒体膜电位和线粒体凋亡相关信号分子Caspase-3、Caspase-9、Bcl-2/Bax表达的影响。结果 0.1mmol/L谷氨酸盐刺激24h,RGCs细胞凋亡率与对照组差异无统计学意义（P〉0.05）;而当刺激48h时,RGCs的凋亡率达到（43.050±2.616）%,差异有统计学意义（P〈0.01）。高剂量谷氨酸盐（1mmol/L）刺激24、48h的RGCs凋亡率为（46.450±1.061）%和（45.500±3.253）%,较对照组均显著增加,差异有统计学意义（P〈0.01）。用1mmol/L谷氨酸盐刺激RGCs 12h后加入0.1、1.0、3.0μmol/L藏红花素再处理12h,不同浓度藏红花素均可显著抑制细胞凋亡（P〈0.01）,且抑制效率具有剂量依赖性。另外,1.0μmol/L藏红花素组的谷氨酸盐诱导的胞外Ca^2＋内流减少及钙依赖蛋白Calpain1和CaMKⅡ的表达减弱,线粒体膜电位增高,Caspase-3和Caspase-9的表达减少,Bcl-2/Bax表达上调。结论藏红花素抑制谷氨酸盐诱导的RGCs凋亡,其机制可能与阻止胞外Ca^2＋内流,抑制钙依赖的凋亡信号通路和线粒体凋亡信号通路有关。

The optic fissure （OF） is a transient opening on the ventral side of the developing vertebrate eye that closes before nearly all retinal progenitor cell differentiation has occurred. Failure to close the OF results in coloboma, a congenital disease that is a major cause of childhood blindness. Although human genetic studies and animal models have linked a number of genes to coloboma, the cellular and molecular mechanisms driving the closure of the OF are still largely unclear. In this study, we used Cre-LoxP-mediated conditional removal of fibroblast growth factor （FGF） receptors, Fgfrl and Fgfr2, from the developing optic cup （OC） to show that FGF signaling regulates the closing of the OF. Our molecular, cellular and transcriptome analyses of Fgfrl and Fgfr2 double conditional knockout OCs suggest that FGF signaling controls the OF closure through modulation of retinal progenitor cell proliferation, fate specification and morphological changes. Furthermore, Fgfrl and Fgfr2 double conditional mutant retinal progenitor cells fail to initiate retinal ganglion cell （RGC） genesis. Taken together, our mouse genetic studies reveal that FGF signaling is es-sential for OF morphogenesis and RGC development.

Background：Glaucoma is a progressive optic neuropathy characterized by degeneration of neurons due to loss of retinal ganglion cells （RGCs）.High intraocular pressure （HIOP）,the main risk factor,causes the optic nerve damage.However,the precise mechanism of HIOP-induced RGC death is not yet completely understood.This study was conducted to determine apoptosis of RGC-5 cells induced by elevated hydrostatic pressures,explore whether laminin is associated with apoptosis under pressure,whether laminin can protect RGCs from apoptosis and affirm the mechanism that regulates the process of RGCs survival.Methods：RGC-5 cells were exposed to 0,20,40,and 60 mmHg in a pressurized incubator for 6,12,and 24 h,respectively.The effect of elevated hydrostatic pressure on RGC-5 cells was measured by Annexin V-fluorescein isothiocyanate/propidium iodide staining,3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide assay,and Western blotting of cleaved caspase-3 protein.Location and expression oflaminin were detected by immunofluorescence.The expression of β 1-integrin,phosphorylation of focal adhesion kinase （FAK） and protein kinase B （PKB,or AKT） were investigated with real-time polymerase chain reaction and Western blotting analysis.Results：Elevated hydrostatic pressure induced apoptosis in cultured RGC-5 cells.Pressure with 40 mmHg for 24 h induced a maximum apoptosis.Laminin was declined in RGC-5 cells after exposing to 40 mmHg for 24 h.After pretreating with laminin,RGC-5 cells survived from elevated pressure.Furthermore,β1-integrin and phosphorylation of FAK and AKT were increased compared to 40 mmHg group.Conclusions：The data show apoptosis tendency of RGC-5 cells with elevated hydrostatic pressure.Laminin can protect RGC-5 cells against high pressure via β 1-integrin/FAK/AKT signaling pathway.These results suggest that the decreased laminin of RGC-5 cells might be responsible for apoptosis induced by elevated hydrostatic pressure,and laminin or activating β1-integrin/FAK/AKT pathway might be potential treatments to prevent RGC loss in glaucomatous optic neuropathy.

Retinal ganglion cells（RGCs）are located in the innermost layer of the retina and are the only retinal output neurons,conveying light information to the main retinorecipient target regions of the brain responsible for the image-and non-image-forming visual functions.There are well over twenty RGC types,each with its own dendritic morphology and physiological characteristics,

Glaucoma and other optic neuropathies result in optic nerve degeneration and the loss of retinal ganglion cells（RGCs）through complex signaling pathways.Although the mechanisms that regulate RGC development remain unclear,uncovering novel developmental pathways may support new strategies to regenerate the optic nerve or replace RGCs.Here we review recent studies that provide strong evidence that the Sry-related high-mobility-group C（SoxC）subfamily of transcription factors（TFs）are necessary and sufficient for axon guidance and RGC fate specification.These findings also uncover novel SoxC-dependent mechanisms that serve as master regulators during important steps of RGC development.For example,we review work showing that SoxC TFs regulate RGC axon guidance and direction through the optic chiasm towards their appropriate targets in the brain.We also review work demonstrating that Sox11 subcellular localization is,in part,controlled through small ubiquitin-like post-translational modifier（SUMO）and suggest compensatory cross-talk between Sox4 and Sox11.Furthermore,Sox4 overexpression is shown to positively drive RGC differentiation in human induced pluripotent stem cells（hi PSCs）.Finally,we discuss how these findings may contribute to the advancement of regenerative and cell-based therapies to treat glaucoma and other optic nerve neuropathies.

Background：Compound anisodine （CA） is a compound preparation made from hydrobromide anisodine and procaine hydrochloride.The former is an M-choline receptor blocker with the function of regulating the vegetative nervous system,improving microcirculation,and so on.The latter is an antioxidant with the activities ofneuroprotection.This study aimed to investigate the potential neuroprotection of CA,which affects the degeneration of the retinal ganglion cells （RGCs） in an animal model with chronic ocular hypertension.Methods：Female C57BL/6J mice （n =24） were divided randomly into four groups：Normal control group without any treatment （Group A,n =6）;CA control group with feeding the CA solution （Group B,n =6）;microbeads （MBs） control group with injecting MB into the anterior chamber （Group C,n =6）;CA study group with MB injection and with feeding the CA solution （Group D,n =6）.Intraocular pressure （IOP） was measured every 3 days after MB injection.At the 21st day,neurons were retrograde-labeled by Fluoro-Gold （FG）.Animals were sacrificed on the 27th day.Retinal flat mounts were stained immunohistologically by β-Ⅲ-tubulin.FG-retrograde-labeled RGCs,β-Ⅲ-tubulin-positive RGCs,and β-Ⅲ-tubulin-positive nerve fibers were quantified.Results：Mice of Groups C and D expressed the incidence of consistent IOP elevation,which is above the IOP level of Group A with the normal one.There is no significant difference in IOP between Groups A and B （P ＞ 0.05）.On the 27th day,there were distinct loss in stained RGCs and nerve fibers from Groups C and D compared with Group A （all P ＜ 0.00l）.The quantity was significantly higher in Group D as compared to Group C （all P ＜ 0.00l） but lower than Group A （all P ＜ 0.001）.There was no significant difference in the quantity of RGCs and nerve fibers between Groups A and B （all P ＞ 0.05）.Conclusions：These findings suggest that CA plays an importantly neuroprotective role on RGCs in a mouse model with chronic ocular hypertension.

Light is an electromagnetic stimulus that in mammals is sensed by specialized neurons in the retina.The physiological response to light encompasses two fundamental and different functional outputs：image-forming and non-image forming.

In neurodegenerative diseases,neuroinflammatory responses are often activated in resident immune cells in the central nervous system（CNS）（Schroder and Tschopp,2010）.Optic neuropathy refers to dysfunction and degeneration of retinal ganglion cells（RGCs）and their axons,which is often induced by optic nerve injury or glaucomatous insult.Studies,

Many blinding diseases,such as retinitis pigmentosa,age-related macular degeneration,and glaucoma involve the permanent loss of retinal neurons,especially photoreceptors or the centrally projecting retinal ganglion cells.Stem cells have been proposed as a potential source of cells for neuronal transplantation.

Molecular mechanisms of the Kruppel-like family of transcription factors （KLFs） have been studied more in proliferating cells than in post-mitotic cells such as neurons. We recently found that KLFs regulate intrinsic axon growth ability in central nervous system （CNS） neurons in- cluding retinal ganglion cells, and hippocampal and cortical neurons. With at least 15 of 17 KLF family members expressed in neurons and at least 5 structurally unique subfamilies, it is import- ant to determine how this complex family functions in neurons to regulate the intricate genetic programs of axon growth and regeneration. By characterizing the molecular mechanisms of the KLF family in the nervous system, including binding partners and gene targets, and comparing them to defined mechanisms defined outside the nervous system, we may better understand how KLFs regulate neurite growth and axon regeneration.