CELL PROLIFERATION
·
2023
·
IF 8.5
Zihui Xu,Yanan Guo,Kangjian Xiang,Dongchang Xiao,Mengqing Xiang
Glaucoma and other optic neuropathies lead to progressive and irreversible vision loss by damaging retinal ganglion cells (RGCs) and their axons. Cell replacement therapy is a potential promising treatment. However, current methods to obtain RGCs have inherent limitations, including time-consuming procedures, inefficient yields and complex protocols, which hinder their practical application. Here, we have developed a straightforward, rapid and efficient approach for directly inducing RGCs from mouse embryonic fibroblasts (MEFs) using a combination of triple transcription factors (TFs): ASCL1, BRN3B and PAX6 (ABP). We showed that on the 6th day following ABP induction, neurons with molecular characteristics of RGCs were observed, and more than 60% of induced neurons became iRGCs (induced retinal ganglion cells) in the end. Transplanted iRGCs had the ability to survive and appropriately integrate into the RGC layer of mouse retinal explants and N-methyl- D -aspartic acid (NMDA)-damaged retinas. Moreover, they exhibited electrophysiological properties typical of RGCs, and were able to regrow dendrites and axons and form synaptic connections with host retinal cells. Together, we have established a rapid and efficient approach to acquire functional RGCs for potential cell replacement therapy to treat glaucoma and other optic neuropathies.
研究领域:
神经科学
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细胞生物学
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再生医学
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DOI
PubMed
高影响因子
Asian Journal of Pharmaceutical Sciences
·
2022
·
IF 9.273
Tao Wang,Yunran Zhang,Meiling Chi,Chen Zhao,Linlin Cao,Chutong Tian,K. Kamei,Ying Zheng,Qikun Jiang
Currently commercial fixed-concomitant three agents have multiple problems such as multiple dosing administration, poor efficacy and side effects. Once-daily fixed-combination timolol-netarsudil-latanoprost ophthalmic solution (FC-TNL) has the ability to treat glaucoma by lowering the intraocular pressure (IOP) with great efficacy and improving patient compliance. However, the commercialized netarsudil dimesylate precipitated when the pH of the solution was above 5.4, or when maleic acid, the salt of commercial timolol maleate, was mixed with netarsudil dimesylate. Consequently, the homologous salt engineering strategy was used to make netarsudil dimesylate soluble in pH 4.8–5.2 solution by synthesizing timolol mesylate. Next, the morphology of timolol mesylate was observed by scanning electron microscopy, differential scanning calorimetry, thermogravimetric analysis, and powder X-ray diffraction. The prepared FC-TNL showed good stability during refrigeration storage. Additionally, FC-TNL exerted no influence on the intraocular penetration of each active compounds in the pharmacokinetic study. Importantly, once-daily FC-TNL exerted potent IOP-lowering effect and protective effect on retinal ganglion cells. The FC-TNL was stable, safe and effective, being a promising glaucoma therapeutic.
研究领域:
药理学
·
眼科医学
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DOI
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Bingqing Luo,Tingting Cheng,Ying Xiang,Shengkai Sun,Yuanshan Liu,Jincong Yan,Yajie Zhang,Yi Cao,Xingzhu Liu,Renjun Pei
Optic neuropathy, characterized by the irreversible degeneration of RGCs, leads to vision loss for which treatment options remained limited. Nanoparticle-based therapeutic strategies have been developed to stimulate RGCs regeneration; however, insufficient nanoparticles delivery to RGCs and a lack of robust stimulation of RGCs intrinsic regenerative capacity, have limited their application. Here, we demonstrate that a RGC-targeting Tet1 conjugated to liposome delivery system (Lipo-T) enhances therapeutic agent delivery to RGCs while minimizing off-target effect for activating glial cells. Targeted delivery of a mTOR-specific activator MHY1485 to RGCs via Lipo-T (MHY@Lipo-T) significantly enhances in vivo RGCs survival, neurite outgrowth, and axonal regeneration without retinal inflammation from unwanted glial activation. By conferring sustained MHY1485 to degenerated retina through Lipo-T injection, and with its high target ability potential, the first use of MHY@Lipo-T expands new therapeutic option for optic nerve injury.
研究领域:
神经科学
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药学
·
眼科学
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产品关联
DOI
PubMed
高影响因子
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
·
2021
·Vol. 62
·期 3
·13-13
·
IF 4.799
Ran Zhang,Yuqing Feng,Jinfang Lu,Yanni Ge,Huiling Li
Purpose:Apoptosis of the retinal ganglion cells (RGCs) can cause irreversible damage to visual function after retinal ischemia reperfusion injury (RIR). Using a lncRNA chip assay, we selected lncRNA Ttc-209 and characterized its role in RGCs during ischemia reperfusion (I/R)–induced apoptosis.Methods:We created an ischemic model of RGCs by applying Hank's balanced salt solution containing 10 µM antimycin A and 2 µM calcium ionophore for 2 hours. RIR was induced in mice by elevating the intraocular pressure to 120 mm Hg for 1 hour by cannulation of the cornea; this was followed by reperfusion. Real-time quantitative PCR was used to detect the expression levels of long noncoding RNA (lncRNA), microRNA (miRNA), and target gene mRNA. Western blotting, flow cytometry, immunofluorescent staining, and TUNEL assays were performed to detect cell apoptosis. Dual-luciferase reporter assays and FISH were used to identify endogenous competitive RNA (ceRNA) mechanisms that link lncRNAs, miRNAs, and target genes. We also used scotopic electroretinography examinations to evaluate visual function in treated mice.Results:lncRNA Ttc3-209 was significantly upregulated after I/R injury and played a proapoptotic role in RGCs during I/R-induced apoptosis. Mechanistically, lncRNA Ttc3-209 is a ceRNA that competitively binds to miR-484 and upregulates the translation of its target (Wnt8a mRNA), thus promoting apoptosis in RGCs.Conclusions:Reducing the expression of lncRNA Ttc3-209 had a protective effect against apoptosis in RGCs. This may provide a new therapeutic option for the prevention of RGC apoptosis in response to RIR injury.
研究领域:
眼科学
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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
PubMed
高影响因子
Advanced Healthcare Materials
·
2025
·
IF 9.6
Hai-Dong Qian,Xiang-Yuan Song,Guan-Wen He,Xue-Ni Peng,Ying Chen,Pan Huang,Jing Zhang,Xiao-Yan Lin,Qiao Gao,Sen-Miao Zhu,Tong Li,Zai-Long Chi
Retinal ganglion cell (RGC) degeneration leads to irreversible blindness. Müller glia (MG) play pivotal roles in retinal homeostasis and disease through paracrine signaling. Small extracellular vesicles (sEVs) are bioactive nanomaterials derived from all types of live cells and are recognized as a potential strategy for neuroprotective therapy. The aim of this study is to investigate the potential roles of MG-derived sEVs (MG-sEVs) in a mouse model of optic nerve injury (ONC). It is found that MG-sEVs treatment effectively mitigates RGC degeneration and suppresses microglial activation, thereby improves visual function in ONC mice. Retinal transcriptomic analysis reveals a strong correlation between C-x3-c motif chemokine ligand 1 (Cx3cl1)-mediated glial activation and inflammation. Subsequently, it is confirmed that the expression levels of Cx3cl1 and proinflammatory cytokines are significantly decreased in retinas treated with MG-sEVs. The components analysis of MG-sEVs cargo identifies that miR-125b-5p and miR-16-5p target Cx3cl1 gene to regulate its expression. It is also observed that Cx3cl1 colocalizes on the microglia of transgenic C-x3-c motif chemokine receptor 1 (Cx3Cr1)-GFP mice. In conclusion, MG-sEVs mitigate RGC degeneration by suppressing microglial activation via Cx3cl1-Cx3cr1 signaling. This research provides additional opportunities for the treatment of RGC degeneration.
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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DOI
PubMed
高影响因子
International Journal of Ophthalmology
·
2025
·Vol. 18
·期 1
·39
·
IF 1.8
Lin-Ping Xue,Hai-Song Feng
AIM To explore the neuroprotective effects of high mobility group box 2 ( HMGB2 ) knockdown on retinal ganglion cells (RGCs) in the retinal ischemia-reperfusion injury (RIRI). METHODS Oxygen-glucose deprivation (OGD)-injured RGCs from postnatal three-day C57BL/6 mice pups and high intraocular pressure (IOP)-induced RIRI mice were used as cellular and animal models of RIRI. The expression of HMGB2 in the retina of RIRI mice and OGD-injured RGCs was detected through reverse transcription-polymerase chain reaction (RT-qPCR) and Western blotting. The effects of HMGB2 silencing on the morphological changes, RGCs survival, and cell apoptosis in mouse retinal tissues were observed through H&E staining, immunofluorescence staining with RNA-binding protein with multiple splicing (RBPMS) antibody, and TUNEL staining, respectively. RGC viability and apoptosis were examined by CCK-8 and flow cytometry assays. The levels of proteins associated with NOD-like receptor thermal protein domain associated protein 3 (NLRP3)-mediated pyroptosis [NLRP3, Caspase-1, GSDMD-N, interleukin (IL)-1β, IL-18] in vivo and in vitro were measured by Western blotting. RESULTS HMGB2 protein and NLRP3 were upregulated in the retina of RIRI mice and OGD-injured RGCs ( P <0.001). The retina was edematous, accompanied by disorganized cell arrangement and decreased thickness of all layers, and obvious vacuoles in ganglion cell layer. HMGB2 silencing alleviated the reduction in total retinal thickness and the severity of retinal tissue damage as well as suppressed RGC loss and retinal cell apoptosis in RIRI mice. OGD-induced RGC apoptosis was ameliorated after downregulation of HMGB2 in vitro . Intravitreal injection of the AAV-sh-HMGB2 and si-HMGB2 resulted in significantly decrease of NLRP3, Caspase-1, GSDMD-N, IL-1β, and IL-18 protein levels in the retinal tissues of RIRI mice and OGD-injured RGCs, respectively (all P <0.001). CONCLUSION HMGB2 knockdown protects against RGC apoptosis and pyroptosis after RIRI through suppressing NLRP3 inflammasome activation.
研究领域:
眼科学
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神经科学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2024
·Vol. 15
·期 1
·1-15
·
IF 14.7
Yao Mingyu,Zeng Zhenhai,Li Siheng,Zou Zhilin,Chen Zhongxing,Chen Xinyi,Gao Qingyi,Zhao Guoli,Chen Aodong,Li Zheng,Wang Yiran,Ning Rui,McAlinden Colm,Zhou Xingtao,Huang Jinhai
Glaucoma affects approximately 80 million individuals worldwide, a condition for which current treatment options are inadequate. The primary risk factor for glaucoma is elevated intraocular pressure. Intraocular pressure is determined by the balance between the secretion and outflow of aqueous humor. Here we show that using the RNA interference tool CasRx based on shH10 adenovirus-associated virus can reduce the expression of the aqueous humor circulation related genes Rock1 and Rock2 , as well as aquaporin 1 and β2 adrenergic receptor in female mice. This significantly reduced intraocular pressure in female mice and provided protection to the retina ganglion cells, ultimately delaying disease progression. In addition, we elucidated the mechanisms by which the knockdown of Rock1 and Rock2 , or aquaporin 1 and β2 adrenergic receptor in female mice, reduces the intraocular pressure and secures the retina ganglion cells by single-cell sequencing.
研究领域:
分子生物学
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遗传学
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眼科学
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神经科学
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DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2024
·
IF 6.6
Qi Wang,Jiaxin Dong,Mengxian Du,Xinna Liu,Shiqi Zhang,Di Zhang,Wanyun Qin,Xikun Xu,Xianghui Li,Ruidong Su,Leyi Qiu,Baoqiang Li,Huiping Yuan
Introduction: Glaucoma is a prevalent cause of irreversible vision impairment, characterized by progressive retinal ganglion cells (RGCs) loss, with no currently available effective treatment. Rapamycin (RAPA), an autophagy inducer, has been reported to treat glaucoma in rodent models by promoting RGC survival, but its limited water solubility, systemic toxicity, and pre-treatment requirements hinder its potential clinical applications.Methods: Chitosan (CS)-RAPA carbon dot (CRCD) was synthesized via hydrothermal carbonization of CS and RAPA and characterized by transmission electron microscopy, Fourier transform infrared spectra, and proton nuclear magnetic resonance. In vitro assays on human umbilical cord vein endothelial and rat retinal cell line examined its biocompatibility and anti-oxidative capabilities, while lipopolysaccharide-stimulated murine microglia (BV2) assays measured its effects on microglial polarization. In vivo, using a mouse retinal ischemia/reperfusion (I/R) model by acute intraocular pressure elevation, the effects of CRCD on visual function, RGC apoptosis, oxidative stress, and M2 microglial polarization were examined.Results: CRCD exhibited good water solubility and anti-oxidative capabilities, in the form of free radical scavenging. In vitro, CRCD was bio-compatible and lowered oxidative stress, which was also found in vivo in the retinal I/R model. Additionally, both in vitro with lipopolysaccharide-stimulated BV2 cells and in vivo with the I/R model, CRCD was able to promote M2 microglial polarization by activating autophagy, which, in turn, down-regulated pro-inflammatory cytokines, such as IL-1β and TNF-α, as well as up-regulated anti-inflammatory cytokines, such as IL-4 and TGF-β. All these anti-oxidative and anti-inflammatory effects ultimately aided in preserving RGCs, and subsequently, improved visual function.Discussion: CRCD could serve as a potential novel treatment strategy for glaucoma, via incorporating RAPA into CDs, in turn not only mitigating its toxic side effects but also enhancing its therapeutic efficacy.
研究领域:
眼科
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药学
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神经科学
·
材料科学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR MEDICINE
·
2023
·Vol. 29
·期 1
·1-17
·
IF 5.7
Feng Yuqing,Lu Jinfang,Peng Xujun,Ge Yanni,Zhang Ran,Li Huiling
Background Retinal ganglion cells (RGCs) apoptosis is a vital manifestation of retinal ischemia/reperfusion (I/R) injury, yet the underlying mechanisms are not well understood. The contribution of long noncoding RNAs (lncRNAs) to this cellular process is currently being explored. Based on a lncRNA chip assay, we aimed to investigate the role of lncRNA uc007nnj.1 in the pathological process of ischemia-induced RGCs apoptosis.Methods Hank’s balanced salt solution containing 10 µM antimycin A and 2 µM calcium ionophore for 2 h to construct an ischemic model in RGCs, and elevation of intraocular pressure to 120 mm Hg for 1 h was used to construct a mouse model of retinal I/R injury.Results In this study, lncRNA uc007nnj.1 was highly upregulated in response to I/R injury in RGCs and mouse retinas. In addition, lncRNA uc007nnj.1 knockdown reduced retinal neuronal cell apoptosis in vitro and in vivo and significantly improved retinal function.DiscussionMechanistically, the results demonstrated that lncRNA uc007nnj.1 acts as ceRNA competitively binding miR-155-5p, thereby enhancing the expression levels of Tle4, thus aggravating ischemia-related apoptosis in RGCs.Conclusion sFinally, our study identifies the lncRNA uc007nnj.1/miR-155-5p/Tle4 axis as a potential target for the prevention of I/R-induced retinal neuronal death.
研究领域:
神经科学
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分子生物学
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眼科
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Ginseng Research
·
2022
·
IF 5.735
Ye-ying Jiang,Rong-yun Wei,Kai Tang,Zhen Wang,Ning-hua Tan
Background Mechanisms of synaptic plasticity in retinal ganglion cells (RGCs) are complex and the current knowledge cannot explain. Growth and regeneration of dendrites together with synaptic formation are the most important parameters for evaluating the cellular protective effects of various molecules. The effect of ginsenoside Rg1 (Rg1) on the growth of retinal ganglion cell processes has been poorly understood. Therefore, we investigated the effect of ginsenoside Rg1 on the neurite growth of RGCs. Methods Expression of proteins and mRNA were detected by Western blot and qPCR. cAMP levels were determined by ELISA. In vivo effects of Rg1 on RGCs were evaluated by hematoxylin and eosin, and immunohistochemistry staining. Results This study found that Rg1 promoted the growth and synaptic plasticity of RGCs neurite by activating the cAMP/PKA/CREB pathways. Meanwhile, Rg1 upregulated the expression of GAP43, Rac1 and PAX6, which are closely related to the growth of neurons. Meantime, H89, an antagonist of PKA, could block this effect of Rg1. In addition, we preliminarily explored the effect of Rg1 on enhancing the glycolysis of RGCs, which could be one of the mechanisms for its neuroprotective effects. Conclusion Rg1 promoted neurite growth of RGCs through cAMP/PKA/CREB pathways. This study may lay a foundation for its clinical use of optic nerve diseases in the future.
研究领域:
神经科学
·
药理学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2024
·
IF 4.4
Huan Yu,Dan Zhou,Wei Wang,Qingxia Wang,Min Li,Xiaoyun Ma
Background and Purpose: The damage or apoptosis of retinal ganglion cells (RGCs) is one of the leading causes of various blinding eye diseases, such as glaucoma, diabetic retinopathy, optic neuritis, and ischemic optic neuropathy. Oxidative stress is involved in RGCs death. Baicalin, a flavonoid compound extracted from Scutellaria baicalensis, has various beneficial effects, including anti-inflammatory, anti-apoptotic, and antioxidant properties. However, the effects of baicalin on RGCs and the underlying mechanisms require further investigation.Methods: In this study, a glutamate-induced oxidative stress damage model of R28 cells and a rat retinal injury model were established to investigate the effects of baicalin on oxidative stress damage to RGCs and try to elucidate the underlying mechanism.Results: In vitro experiments demonstrated that the survival rate of R28 cells after glutamate treatment dropped to 33.4%, while 10 μM baicalin significantly inhibited glutamate-induced damage in RGCs (P < 0.001) and enhanced cell viability through decreasing ROS levels, increasing antioxidant enzyme activity, and suppressing the expression of inflammatory factors iNOS, TNF-α, IL-6, and IL-1β (P < 0.001). In vivo, baicalin effectively mitigated structural damage to retinal tissue and RGCs morphology induced by glutamate, increasing the thickness of the retinal ganglion cell layer, improving RGCs density, and reducing overall retinal thinning in rats (P < 0.001) in a time- and dose-dependent effects. Mechanistic studies revealed that glutamate evaluated the phosphorylation levels of JAK/STAT, while baicalin effectively inhibited the activation of the JAK/STAT signaling pathway.Conclusion: This study confirmed that baicalin protects against glutamate-induced oxidative stress damage in RGCs. It effectively alleviates oxidative stress and inflammatory responses, reduces cell apoptosis, and improves the pathological changes in the retina of rat models of RGCs damage, thereby decreasing RGCs death. Further exploration of its mechanism revealed that baicalin effectively inhibits the JAK/STAT signaling pathway, protecting RGCs from oxidative stress damage. This provides an experimental basis for the application of baicalin in the treatment of RGCs damage.
研究领域:
眼科学
·
药理学
·
细胞生物学
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神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Neural Regeneration Research
·
2018
·
IF 2.234
Lei Wang,Huai-Cheng Chen,Xi Yang,Jian-Jian Tao,Guang Liang,Jian-Zhang Wu,Wen-Can Wu,Yi Wang,Zong-Ming Song,Xin Zhang
Chalcone is a plant metabolite widely found in fruits, vegetables, spices and tea, and has anti-tumor, anti-inflammation, immunomodulation, antibacterial and anti-oxidation activities, as well as many other pharmacological and biological effects. Our team has shown that its analogs have antioxidant activity, and oxidative stress is a pathological hallmark of retinal ischemia/reperfusion injury that can lead to retinal damage and visual loss. This investigation aims to identify a chalcone that protects retinal ganglion cells in vitro from the effects of oxidative stress and examine its mechanism. Rat retinal ganglion cell-5 cells were pretreated with chalcones and then exposed to tert-butyl hydroperoxide that causes oxidative damage. Controls received dimethyl sulfoxide only or tert-butyl hydroperoxide in dimethyl sulfoxide. Only (E)-3,4-dihydroxy-2′-methylether ketone (L2H17), of the five chalcone analogs, markedly increased the survival rate of oxidatively injured RGC-5 cells. Thus, subsequent experiments only analyzed the results of the L2H17 intervention. Cell viability and apoptosis were measured. Intracellular superoxide dismutase and reactive oxygen species levels were used to assess induced oxidative stress. The mechanism of action by L2H17 was explored by measuring the ER stress/UPR pathway and the expression and localization of Nrf2. All results demonstrated that L2H17 could reduce the apoptosis of oxidatively injured cells, inhibit caspase-3 activity, increase Bcl-2 expression, decrease Bad expression, increase the activity of superoxide dismutase, inhibit the production of reactive oxygen species, increase Nrf2 immunoreactivity, and reduce the activating transcription factor 4, phospho-eukaryotic initiation factor 2 and CHOP expression. L2H17 protects retinal ganglion cells induced by oxidative stress by regulating Nrf2, which indicates that it has the potential to become a drug for retinal ischemia/reperfusion.
研究领域:
药理学
·
眼科学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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