ZOOLOGICAL RESEARCH
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2025
·Vol. 46
·期 4
·733
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IF 4.7
Bao-Guo Shen,Yuan Wen,Sheng-Jian Lu,Hong-Yuan Wei,Shu-Rui Huang,Guang-Ming Zhou,Wen-Tao Yan,Wen-Can Wu,Yi-Kui Zhang
In adult mammals, optic nerve injury leads to irreversible vision loss due to its extremely limited regenerative capacity. In contrast, adult zebrafish possess a robust capacity for spontaneous visual system regeneration, although the spatiotemporal coordination of recovery across the retina, optic nerve, and brain remains poorly understood. In the present study, the regenerative dynamics following optic nerve transection were systematically characterized in adult zebrafish over a 5 week period using hematoxylin-eosin staining, immunohistochemistry, transmission electron microscopy, single-cell RNA sequencing, and optokinetic response (OKR) behavioral assessments. At 1 week post-injury (1 wpi), retinal ganglion cell depletion was evident but showed significant recovery by 2 wpi. Concurrently, the injured optic nerve displayed a marked increase in diameter and cell number at 2 wpi, including widespread expression of proliferating cell nuclear antigen, consistent with heightened proliferative activity. Single-cell transcriptomic profiling at 2 wpi revealed five principal cell populations: fibroblasts, mural cells, immune cells, mature oligodendrocytes, and myelin-forming oligodendrocytes. By 4–5 wpi, remyelination within the optic nerve and re-establishment of synaptic architecture in the optic tectum were strongly correlated with functional restoration of OKR behavior. These findings provide a comprehensive spatiotemporal framework of visual pathway regeneration in zebrafish, establishing a valuable model for elucidating conserved mechanisms of neural repair with translational potential for human vision restoration.
研究领域:
神经再生
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发育生物学
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分子神经科学
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视觉系统
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转化医学研究
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DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2024
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IF 10
Yueqi Ni,Yuanyuan Hu,Lijia Zhu,Xulin Jiang,Hong Zhang,Jia Liu,Yin Zhao
Retinal ischemia‒reperfusion (IR) is a major contributor to vision impairment and irreversible vision loss due to retinal ganglion cell (RGC) injury or loss. Contemporary therapeutic approaches predominantly focus on the amelioration of symptoms rather than addressing the fundamental etiological factors. Oxidative stress is a notable feature and an important mediator of IR damage. Lycium barbarum polysaccharide (LBP), the main active ingredient of Lycium barbarum, has various pharmacological effects, including antioxidation, immunoregulation, and neuroprotective effects. In this study, the ROS-consumable moiety phenylboronic acid pinacol ester (PBA) is introduced to LBP molecules, which can self-assemble into nanoparticles in aqueous solution. This nanoparticle (termed PLBP) can reduce the cellular ROS levels and enhance the antioxidant capability of RGCs by activating the NRF2 pathway, thus protecting RGCs from ferroptosis and preserving visual function in response to IR injury. PLBP also reduces neuroinflammation by inhibiting the ability of microglia to phagocytose, migrate, secrete inflammatory cytokines, and activate the NF-κB pathway. In conclusion, this approach can be used as an inspiration for the future development of neuroprotective drugs.
研究领域:
眼科学
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神经科学
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药理学
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纳米技术
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产品关联
DOI
PubMed
高影响因子
SENSORS AND ACTUATORS B-CHEMICAL
·
2024
·
IF 8
Yu Lan,Haixia Zhang,Ruichen Xie,Kecheng Li,Feiran Xie,Peihong Xiao,Li Jiang
Glaucoma is a leading cause of irreversible blindness worldwide and characterized by progressive loss of retinal ganglion cells (RGCs). As glaucoma progresses asymptomatically and the lack of specific biomarkers or noninvasive imaging tools during the early stage, it is often discovered at a relatively late stage without cure. Development of an effective tool for early diagnosis remains a necessity. As well known, endoplasmic reticulum (ER) stress and subsequent accumulation of reactive oxygen species (ROS) play a vital role in the development of glaucoma, with peroxynitrite (ONOO − ) as one of the most abundant cytotoxic ROS. In this work, we constructed a novel near-infrared (NIR) fluorescent nanoprobe named ER-ONOO-NPs. It specifically and sensitively targets ER-associated ONOO − with low biotoxicity in cultured RGCs. Systematically applied to the NMDA-induced mouse model of glaucoma, ER-ONOO-NPs performs well for real-time dynamic monitoring of ONOO − fluctuations at the Ganglion cell layer of mice prior to RGCs apoptosis. Thus, our results suggest that the ER-targeted NIR fluorescent nanoprobe could be a noninvasive imaging tool for early diagnosis of glaucoma in high-risk population.
研究领域:
眼科学
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纳米技术
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生物医学工程
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分子生物学
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神经科学
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产品关联
DOI
高影响因子
DRUG DELIVERY
·
2020
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IF 4.902
Dongmei Wang,Mengmeng Luo,Baoshan Huang,Wa Gao,Yan Jiang,Qing Li,Kaihui Nan,Sen Lin
Following the traumatic axonal injury in the optic nerve, the failure of retrograde axonal transport to continuously supply neurotrophins from the brain to retina results in deprivation of neurotrophins in retinal ganglion cells (RGCs), which in turn can modulate the fate of RGCs toward apoptosis and thereby impede axon regeneration. In this study, a ciliary neurotrophic factor (CNTF) loaded thermo-sensitive hydrogel was designed and developed as a localized drug depot to restore neurotrophins supply following axon injury. Besides, following traumatic axon injury, overactive immune responses cause neurotoxicity and induce scar formation which together constitutes the major hindrances for axon regeneration. Thus, the FK506, a hydrophobic macrolide immunosuppressant, was co-loaded into the hydrogel after encapsulating it into a polymeric micelle. The materials can undergo sol-to-gel transition within minutes under a physiological pH of 37 °C. The release of drugs from the hydrogel exhibited a sustainable profile in vitro. The optic nerve was exposed by surgical procedure and the animal model was prepared by crushing the nerve with a reverse clamp. For the localized delivery to the optic nerve, a pre-hydrogel liquid containing chitosan, FK506 (in micelle), CNTF, and the gelling agent was directly smeared on the injured site, which gelled under physiological condition. This co-delivery system exhibited in vivo RGCs protective effect against the adverse effects caused by traumatic optic nerve injury, indicating the potential of this drug delivery system for effective optic nerve repair and this strategy may provide promising platforms for localized drug delivery in various other therapies.
研究领域:
神经科学
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药学
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生物医学工程
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DOI
PubMed
高影响因子
ACS Omega
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2025
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IF 4.3
Suyun Rao,Ke Xiao,Xuhui Chen,Xufang Sun
Diabetic retinopathy (DR) is a major cause of vision impairment, with diabetic retinal neurodegeneration (DRN) identified as an early pathological feature. Although dopamine (DA) has demonstrated protective effects in various neurodegenerative diseases, its role in DRN is inadequately understood. This study provides evidence that DA can alleviate DRN impairment and elucidates the underlying mechanisms. Diabetes was induced in C57BL/6 mice through a single large dose injection of streptozotocin, and the dopamine precursor l-DOPA was administered via intraperitoneal injection daily for 2 weeks to therapeutically supplement dopamine levels. The results indicated that l-DOPA treatment significantly restored retinal thickness, enhanced the amplitude of oscillatory potentials, and alleviated retinal glial cell activation compared to diabetic mice. In vitro, DA treatment of SH-SY5Y cells under high-glucose stress led to a significant increase in superoxide dismutase activity, with a reduction in malondialdehyde levels, lipid peroxide, and iron ion concentration. Additionally, the expression of GPX4, SLC7A11, ferritin, Nrf2, and HO-1 proteins was upregulated, while the expression of NCOA4 was downregulated. Importantly, the protective effects of DA were significantly attenuated by the Nrf2 inhibitor ML385, confirming the involvement of the Nrf2/HO-1 pathway in DA’s protective mechanism. These findings suggest that DA alleviates oxidative stress, reduces ferroptosis, and improves the retinal function in DRN through the activation of the Nrf2/HO-1 pathway, indicating that DA may represent a novel therapeutic strategy for treating DRN.
研究领域:
神经科学
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眼科学
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分子生物学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2025
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IF 10.2
Jing Wang,Yixian Liu,Rong Rong,Xiaobo Xia
Glaucoma, a leading cause of irreversible blindness, is characterized by progressive retinal ganglion cell (RGC) degeneration with limited treatment options. The natural flavonoid farrerol exhibits neuroprotective potential through antioxidative and anti-inflammatory effects, but its therapeutic application is limited by poor bioavailability and photodegradation. This study investigates farrerol's neuroprotective mechanisms and develops an optimized nanoformulation for enhanced efficacy. In vitro oxygen-glucose deprivation/reperfusion (OGD/R) and in vivo ischemia-reperfusion (IR) models demonstrate that farrerol significantly improves RGC survival and visual function. Mechanistic studies reveal that farrerol activates the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant pathway, reduces reactive oxygen species (ROS) accumulation, and modulates key ferroptosis markers (glutathione peroxidase 4 (GPX4) and acyl-CoA synthetase long-chain family member 4 (ACSL4)), thereby inhibiting RGC apoptosis. To overcome delivery limitations, farrerol-loaded bilirubin nanoparticles (FB-NPs) are developed, showing enhanced stability and neuroprotective effects in glaucomatous injury models. These findings identify the Nrf2/ferroptosis/apoptosis axis as a novel therapeutic target and present an effective nanodelivery strategy for glaucoma treatment.
研究领域:
眼科学
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纳米医学
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神经科学
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药学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Small
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2024
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IF 13
Gerile Oudeng,Seema Banerjee,Qin Wang,Ding Jiang,Yadi Fan,Honglian Wu,Feng Pan,Mo Yang
Retinitis pigmentosa is the main cause of inherited human blindness and is associated with dysfunctional photoreceptors (PRs). Compared with traditional methods, optoelectronic stimulation can better preserve the structural integrity and genetic content of the retina. However, enhancing the spatiotemporal accuracy of stimulation is challenging. Quantum dot-doped ZnIn 2 S 4 microflowers (MF) are utilized to construct a biomimetic photoelectric interface with a 0D/3D heterostructure, aiming to restore the light response in PR-degenerative mice. The MF bio interface has dimensions similar to those of natural PRs and can be distributed within the curved spatial region of the retina, mimicking cellular dispersion. The soft 2D nano petals of the MF provide a large specific surface area for photoelectric activation and simulate the flexibility interfacing between cells. This bio interface can selectively restore the light responses of seven types of retina ganglion cells that encode brightness. The distribution of responsive cells forms a pattern similar to that of normal mice, which may reflect the generation of the initial “neural code” in the degenerative retina. Patch-clamp recordings indicate that the bio interface can induce spiking and postsynaptic currents at the single-neuron level. The results will shed light on the development of a potential bionic subretinal prosthetic toolkit for visual function restoration.
研究领域:
神经科学
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生物医学工程
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材料科学
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眼科
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产品关联
DOI
PubMed
高影响因子
Neural Regeneration Research
·
2023
·Vol. 18
·期 10
·2307
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IF 6.1
Gan Yi-Jing,Cao Ying,Zhang Zu-Hui,Zhang Jing,Chen Gang,Dong Ling-Qin,Li Tong,Shen Mei-Xiao,Qu Jia,Chi Zai-Long
Slit-Robo GTPase-activating protein 2 ( SRGAP2 ) plays important roles in axon guidance, neuronal migration, synapse formation, and nerve regeneration. However, the role of SRGAP2 in neuroretinal degenerative disease remains unclear. In this study, we found that SRGAP2 protein was first expressed in the retina of normal mice at the embryonic stage and was mainly located in the mature retinal ganglion cell layer and the inner nuclear layer. SRGAP2 protein in the retina and optic nerve increased after optic nerve crush . Then, we established a heterozygous knockout ( Srgap2 +/– ) mouse model of optic nerve crush and found that Srgap2 suppression increased retinal ganglion cell survival, lowered intraocular pressure, inhibited glial cell activation, and partially restored retinal function. In vitro experiments showed that Srgap2 suppression activated the mammalian target of rapamycin signaling pathway. RNA sequencing results showed that the expression of small heat shock protein genes ( Cryaa , Cryba4 , and Crygs ) related to optic nerve injury were upregulated in the retina of Srgap2 +/– mice. These results suggest that Srgap2 suppression reduced the robust activation of glial cells, activated the mammalian target of rapamycin signaling pathway related to nerve protein, increased the expression of small heat shock protein genes, inhibited the degeneration of retinal ganglion cells, and partially restored optic nerve function.
研究领域:
神经科学
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分子生物学
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眼科
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DOI
PubMed
高影响因子
COLLOIDS AND SURFACES A-PHYSICOCHEMICAL AND ENGINEERING ASPECTS
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2023
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IF 5.2
Chenchen Zhu,Shuimiao Wang,Doudou Wang,Mengxia Hua,Sen Lin,Baoshan Huang,Shengjin Xiang,Kaihui Nan
Ciliary neurotrophic factor (CNTF) shows potential for stimulating axon regeneration of retinal ganglion cells (RGCs), whereas unordered regeneration of axons does not have any biological significance. Given the chemotaxis characteristics of RGCs, materials with gradient CNTF distribution can chemically stimulate axon extension based on the CNTF concentration gradient. Therefore, a novel nano-micro-macro multiple-nested hydrogel with gradient CNTF distribution was developed in this study to induce directional axonal outgrowth of RGCs. The CNTF and magnetic nanoparticles (MNPs) were co-loaded into gelatin microspheres (CNTF& [email protected] ), and subsequently suspended in a gelatin methacryloyl (GelMA) solution (viscous). Using a magnet, the CNTF& [email protected] were moved from the far-magnet side toward the near-magnet side forming gradient CNTF& [email protected] distribution inside the GelMA solution. The GelMA was then cross-linked via ultraviolet (365 nm) to form a hydrogel with gradient CNTF distribution. This hydrogel was further applied as the matrix for retinal explant culturing. The results showed that the number of axons in the segments of 200–300 µm and > 300 µm was 10.21 times and 15.02 times of those in the Gradient than those in the Without Gradient. The axons area distribution was 3.28 times and 13.41 times, respectively. 86.1% of the axons area in the Gradient were distributed in the segments > 200 µm, whereas only 56.27% in the Without Gradient. The results suggested that the hydrogel-matrix with gradient CNTF distribution could intensely induce directional axonal extension of RGCs in the retinal explant. The present study provides a new method for CNTF distribution, which could induce directional axonal regeneration of RGCs, and in turn have potential application in optic nerve injury repair to some extent.
研究领域:
神经科学
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生物材料
·
组织工程
·
再生医学
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产品关联
DOI
高影响因子
Neural Regeneration Research
·
2024
·
IF 5.9
Li Tong,Xing Hui-Min,Qian Hai-Dong,Gao Qiao,Xu Sheng-Lan,Ma Hua,Chi Zai-Long
Several studies have found that transplantation of neural progenitor cells (NPCs) promotes the survival of injured neurons. However, a poor integration rate and high risk of tumorigenicity after cell transplantation limits their clinical application. Small extracellular vesicles (sEVs) contain bioactive molecules for neuronal protection and regeneration. Previous studies have shown that stem/progenitor cell-derived sEVs can promote neuronal survival and recovery of neurological function in neurodegenerative eye diseases and other eye diseases. In this study, we intravitreally transplanted sEVs derived from human induced pluripotent stem cells (hiPSCs) and hiPSCs-differentiated NPCs (hiPSC-NPC) in a mouse model of optic nerve crush. Our results show that these intravitreally injected sEVs were ingested by retinal cells, especially those localized in the ganglion cell layer. Treatment with hiPSC-NPC derived sEVs mitigated optic nerve crush-induced retinal ganglion cell degeneration, and regulated the retinal microenvironment by inhibiting excessive activation of microglia. Component analysis further revealed that hiPSC-NPC derived sEVs transported neuroprotective and anti-inflammatory miRNA cargos to target cells, which had protective effects on RGCs after optic nerve injury. These findings suggest that sEVs derived from hiPSC-NPC are a promising cell-free therapeutic strategy for optic neuropathy.
研究领域:
神经科学
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干细胞生物学
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眼科学
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分子生物学
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DOI
PubMed
高影响因子
Journal of Inflammation Research
·
2021
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IF 6.922
Qianxue Mou,Ke Yao,Meng Ye,Bowen Zhao,Yuanyuan Hu,Xiaotong Lou,Huixia Li,Hong Zhang,Yin Zhao
Purpose Optic nerve injury (ONI) causes neuroinflammation and neurodegeneration leading to visual deficits. The response of microglia has emerged as an impactful component of etiology in neurodegeneration. This study aimed to investigate the effect of SIRT1-mTORC1 signaling pathway in microglia regulation after ONI. Methods Cx3Cr1-Cre ERT2 / Raptor F/F and Cx3Cr1-Cre ERT2 / Sirt1 F/F mice were used to delete Raptor and Sirt1 in microglia, respectively. Optic nerve crush (ONC) model was established to mimic ONI. PLX5622, a highly specific inhibitor of the colony-stimulating factor 1 receptor (CSF1R), is used to eliminate microglia in optic nerve. Ionized calcium binding adaptor molecule 1 (Iba1) immunostaining was used to detect microglial activation. Retinal ganglion cells (RGCs) were quantified by Nissl staining and retinal whole-mount immunostaining with RNA-binding protein with multiple splicing (RBPMS). Axonal damage was valued by transmission electron microscopy (TEM). Results Microglial activation emerged on day 3 post ONC and was earlier than RGCs loss which occurred at day 5 after injury. Depleting microglia with PLX5622 could attenuate the loss of RGCs and axon damage after ONC. Gain- and loss-of-function studies revealed that SIRT1 determined the activation of microglia in optic nerve. In addition, microglia-specific deletion of Raptor resulted in decreased microglial activation. Interestingly, activating mTORC1 with CCT007093 could reverse the function of SIRT1 in regulating the process of microglial activation mediated RGCs loss. Conclusion Our study reveals a potential novel mechanism of SIRT1-mTORC1 pathway in microglia regulation, and indicates a therapeutic potential for the protection of RGCs in ONI.
研究领域:
神经科学
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眼科学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Neuroinflammation
·
2023
·Vol. 20
·期 1
·1-18
·
IF 9.3
Yao Ke,Mou Qianxue,Lou Xiaotong,Ye Meng,Zhao Bowen,Hu Yuanyuan,Luo Jing,Zhang Hong,Li Xing,Zhao Yin
Background Optic nerve injury (ONI) is a key cause of irreversible blindness and triggers retinal ganglion cells (RGCs) change and synapse loss. Microglia is the resistant immune cell in brain and retina and has been demonstrated to be highly related with neuron and synapse injury. However, the function of Sirtuin 1 (SIRT1), a neuroprotective molecule, in mediating microglial activation, retinal synapse loss and subsequent retinal ganglion cells death in optic nerve injury model as well as the regulatory mechanism remain unclear.MethodTo this end, optic nerve crush (ONC) model was conducted to mimic optic nerve injury. Resveratrol and EX527, highly specific activator and inhibitor of SIRT1, respectively, were used to explore the function of SIRT1 in vivo and vitro. Cx3Cr1-CreERT2/RaptorF/F mice were used to delete Raptor for inhibiting mammalian target of rapamycin complex 1 (mTORC1) activity in microglia. HEK293 and BV2 cells were transfected with plasmids to explore the regulatory mechanism of SIRT1.Results We discovered that microglial activation and synapse loss in retinal inner plexiform layer (IPL) occurred after optic nerve crush, with later-development retinal ganglion cells death. SIRT1 activation induced by resveratrol inhibited microglial activation and attenuated synapse loss and retinal ganglion cells injury. After injury, microglial phagocytosed synapse and SIRT1 inhibited this process to protect synapse and retinal ganglion cells. Moreover, SIRT1 exhibited neuron protective effects via activating tuberous sclerosis complex 2 (TSC2) through deacetylation, and enhancing the inhibition effect of tuberous sclerosis complex 2 on mammalian target of rapamycin complex 1 activity.Conclusion Our research provides novel insights into microglial SIRT1 in optic nerve injury and suggests a potential strategy for neuroprotective treatment of optic nerve injury disease.
研究领域:
神经科学
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眼科学
·
分子生物学
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
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