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Subretinal fibrosis secondary to neovascular age-related macular degeneration:mechanisms and potential therapeutic targets

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Neural Regeneration Research 2025年第2期20卷 378-393页

作者： Jingxiang Zhang Xia Sheng Quanju Ding Yujun Wang Jiwei Zhao Jingfa Zhang Department of ophthalmology People’s Hospital of Huangdao DistrictQingdaoShandong ProvinceChina Department of Urology People’s Hospital of Huangdao DistrictQingdaoShandong ProvinceChina Department of ophthalmology Shanghai General Hospital(Shanghai First People’s Hospital)Shanghai Jiao Tong University School of MedicineShanghaiChina National Clinical Research Center for Eye Diseases Shanghai Key Laboratory of Ocular Fundus DiseasesShanghai Engineering Center for Visual Science and PhotomedicineShanghai Engineering Center for Precise Diagnosis and Treatment of Eye DiseasesShanghaiChina

Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular *** causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central vision loss of patients with neovascular age-related macular *** pathogenesis of subretinal fibrosis is complex,and the underlying mechanisms are largely ***,there are no effective treatment options.A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential *** current article reviews several aspects of subretinal fibrosis,including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis;multimodal imaging techniques for subretinal fibrosis;animal models for studying subretinal fibrosis;cellular and non-cellular constituents of subretinal fibrosis;pathophysiological mechanisms involved in subretinal fibrosis,such as aging,infiltration of macrophages,different sources of mesenchymal transition to myofibroblast,and activation of complement system and immune cells;and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis,such as vascular endothelial growth factor,connective tissue growth factor,fibroblast growth factor 2,platelet-derived growth factor and platelet-derived growth factor receptor-β,transforming growth factor-βsignaling pathway,Wnt signaling pathway,and the axis of heat shock protein 70-Toll-like receptors 2/*** review will improve the understanding of the pathogenesis of subretinal fibrosis,allow the discovery of molecular targets,and explore potential treatments for the management of subretinal fibrosis.

关键词： choroidal neovascularization epithelial-mesenchymal transition mesenchymal transition myofibroblast neovascular age-related macular degeneration submacular fibrosis subretinal fibrosis therapeutic targets transforming growth factor-β vascular endothelial growth factor

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Serum amyloid A and pairing formyl peptide receptor 2 are expressed in corneas and involved in inflammation-mediated neovascularization

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International Journal of ophthalmology(English edition) 2014年第2期7卷 187-193页

作者： Sheng-Wei Ren Xia Qi Chang-Kai Jia Yi-Qiang Wang qingdao university-sei joint ophthalmology program Qingdao University Medical College Shandong Provincial Key Lab of ophthalmology Shandong Eye Institute Shandong Academy of Medical Sciences

AIM:To solidify the involvement of Saa-related pathway in corneal neovascularization(CorNV).The pathogenesis of inflammatory CorNV is not fully understood yet,and our previous study implicated that serum amyloid A(Saa)1(Saa1)and Saa3 were among the genes up-regulated upon CorNV induction in ***:Microarray data obtained during our profiling project on CorNV were analyzed for the genes encoding the four SAA family members(Saa1-4),six reported SAA receptors(formyl peptide receptor 2,Tlr2,Tlr4,Cd36,Scarb1,P2rx7)and seven matrix metallopeptidases(Mmp)1a,1b,2,3,9,10,13reportedly to be expressed upon SAA pathway *** baseline expression or changes of interested genes were further confirmed in animals with CorNV using molecular or histological *** was induced in Balb/c and C57BL/6 mice by placing either three interrupted 10-0 sutures or a 2 mm filter paper soaked with sodium hydroxide in the central area of the *** desired time points,the corneas were harvested for histology examination or for extraction of mRNA and *** mRNA levels of Saa1,Saa3,Fpr2,Mmp2and Mmp3 in corneas were detected using quantitative reverse transcription-PCR,and SAA3 protein in tissues detected using immunohistochemistry or western ***:Microarray data analysis revealed that Saa1,Saa3,Fpr2,Mmp2,Mmp3 messengers were readily detected in normal corneas and significantly upregulated upon CorNV *** changes of these five genes were confirmed with real-time PCR *** contrary,other SAA members(Saa2,Saa4),other SAA receptors(Tlr2,Tlr4,Cd36,P2rx7,etc),or other Mmps(Mmp1a,Mmp1b,Mmp9,Mmp10,Mmp13)did not show consistent *** study and western blotting further confirmed the expression of SAA3 products in normal corneas as well as their upregulation in corneas with ***:SAA-FPR2 pathway composing genes were expressed in normal murine corneas and,upon inflammatory stimuli challenge to the corneas,their expressi

关键词： corneal neovascularization serum amyloid A formyl peptide receptor matrix metallopeptidase inflammation

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Electrode/Electrolyte Optimization‑Induced Double‑Layered Architecture for High‑Performance Aqueous Zinc‑(Dual)Halogen Batteries

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Nano-Micro Letters 2025年第3期17卷 121-137页

作者： Chengwang Zhou Zhezheng Ding Shengzhe Ying Hao Jiang Yan Wang Timing Fang You Zhang Bing Sun Xiao Tang Xiaomin Liu School of Textiles and Clothing School of Chemistry and Chemical EngineeringQingdao UniversityQingdao 266071ShandongPeople’s Republic of China Centre for Clean Energy Technology School of Mathematical and Physical SciencesFaculty of ScienceUniversity of Technology SydneyUltimoNSW 2007Australia School of Chemistry and Chemical Engineering Henan Normal UniversityXinxiang 453007HenanPeople’s Republic of China

Aqueous zinc-halogen batteries are promising candidates for large-scale energy storage due to their abundant resources,intrinsic safety,and high theoretical ***,the uncontrollable zinc dendrite growth and spontaneous shuttle effect of active species have prohibited their practical ***,a double-layered protective film based on zinc-ethylenediamine tetramethylene phosphonic acid(ZEA)artificial film and ZnF2-rich solid electrolyte interphase(sei)layer has been successfully fabricated on the zinc metal anode via electrode/electrolyte synergistic *** ZEA-based artificial film shows strong affinity for the ZnF2-rich sei layer,therefore effectively suppressing the sei breakage and facilitating the construction of double-layered protective film on the zinc metal *** double-layered architecture not only modulates Zn2+flux and suppresses the zinc dendrite growth,but also blocks the direct contact between the metal anode and electrolyte,thus mitigating the corrosion from the active *** employing optimized metal anodes and electrolytes,the as-developed zinc-(dual)halogen batteries present high areal capacity and satisfactory cycling *** work provides a new avenue for developing aqueous zinc-(dual)halogen batteries.

关键词： Zn metal anodes Double-layered protective film Electrode/electrolyte optimization Aqueous zinc-(dual)halogen batteries

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Natamycin in the treatment of fungal keratitis : a systematic review and Meta-analysis

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International Journal of ophthalmology(English edition) 2015年第3期8卷 597-602页

作者： Sheng Qiu Gui-Qiu Zhao Jing Lin Xue Wang Li-Ting Hu Zhao-Dong Du Qian Wang Cheng-Cheng Zhu Department of ophthalmology Medical College Qingdao University Department of ophthalmology the Affiliated Hospital of Qingdao University

AIM: To review published clinical studies examining the effect of natamycin in the treatment of fungal ***: We selected the publications in CENTRAL,MEDLINE, EMBASE, CNKI, and CBM. This study systematically reviewed published randomized controlled trials(RCTs) that compared natamycin to other antifungal agents, and conducted feasible Meta-analysis of efficacy results using Revman 5.2 ***: We included seven trials which were mainly carried out in developing countries of Asia, with five trials conducted in India, one each in China and Bangladesh. A total of 804 participants were randomized to following comparisons: 2% econazole versus 5%natamycin showed little difference in the effects of treatment of fungal keratitis [RR =0.99, 95% confidence interval(CI), 0.8 to 1.21]; chlorhexidine gluconate versus5% natamycin indicated that the results on healing of the ulcer at 21 d was less conclusive(RR=0.77, 95% CI, 0.55 to 1.08; I2=0%); 1% voriconazole versus 5% natamycin suggested that natamycin treatment appeared to be significantly better outcomes than voriconazole(regression coefficient =-0.18 log MAR; 95% CI,-0.30 to-0.05; P =0.006), especially in Fusarium cases(regression coefficient=-0.41 log MAR; 95% CI,-0.61 to-0.20; P <0.001);natamycin versus fluconazole showed a significant difference in cure rate(χ2=5.048, P <0.05) and natamycin group was more effective than fluconazole in average period of therapy(t =7.94, P <0.01).CONCLUSION: Natamycin was a preferable choice in the treatment of fungal keratitis, especially in the early period of Fusarium cases.

关键词： eye infection fungal natamycin Metaanalysis

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Fungus induces the release of IL- 8 in human corneal epithelial cells, via Dectin-1-mediated protein kinase C pathways

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International Journal of ophthalmology(English edition) 2015年第3期8卷 441-447页

作者： Xu-Dong Peng Gui-Qiu Zhao Jing Lin Nan Jiang Qiang Xu Cheng-Cheng Zhu Jian-Qiu Qu Lin Cong Hui Li Department of ophthalmology the Affiliated Hospital of Qingdao University

AIM: To identify whether Aspergillus fumigatus(***) hyphae antigens induced the release of interleukin-8(IL-8) in anti-fungal innate immunity of cultured human corneal epithelial cells(HCECs) and determine the involvement of intracellular signalling pathways. METHODS: HCECs were treated with A. fumigatus hyphae antigens with different concentrations and *** cytoplasmic calcium of HCECs were assessed by fluorescence imaging. Western blot was used to detect the expression of Ca2 +-dependent protein kinase C(PKC). The IL-8 levels were determined by specific human IL-8 enzyme-linked immunosorbent assay(ELISA) and reverse transcriptase polymerase chain reaction(RT-PCR). Using a series of pharmacological inhibitors, we examined the upstream signalling pathway responsible for IL-8 expression in response to *** hyphae antigens. RESULTS: Cells exposed to A. fumigatus hyphae antigens showed higher level of IL-8 m RNA expression and protein production. We demonstrated here that stimulation of HCECs with A. fumigatus hyphae triggers an intracellular Ca2 +flux and results in the activation of Ca2 +-dependent PKC(α, βⅠ and βⅡ) which can be attenuated by pre-treatment of cells with laminarin,suggesting that Dectin-1 signals pathway induced cytoplasmic calcium and influence the activation of PKC in HCECs. Inhibitors of Ca2 +-dependent PKC(Ro-31-8220 and Go6976) significantly abolished hyphae-induced expression of ***: Our findings suggest that A. fumigatushyphae-induced IL-8 expression was regulated by the activation of Dectin-1-mediated Ca2 +-dependent PKC in HCECs.

关键词： Dectin-1 Ca 2+ protein kinase C interleukin-8 corneal epithelium Aspergillus fumigatus

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Dectin-1 agonist curdlan modulates innate immunity to Aspergillus fumigatus in human corneal epithelial cells

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International Journal of ophthalmology(English edition) 2015年第4期8卷 690-696页

作者： Cheng-Cheng Zhu Gui-Qiu Zhao Jing Lin Li-Ting Hu Qiang Xu Xu-Dong Peng Xue Wang Sheng Qiu Department of ophthalmology the Affiliated Hospital of Qingdao University

· AIM: To explore the immunomodulatory effects of curdlan on innate immune responses against Aspergillus fumigatus(A. fumigatus) in cultured human corneal epithelial cells(HCECs), and whether C-type lectin receptor Dectin-1 mediates the immunomodulatory effects of curdlan.·METHODS: The HCECs were stimulated by curdlan in different concentrations(50, 100, 200, 400 μg/m L) for various time. Then HCECs pretreated with or without laminarin(Dectin-1 blocker, 0.3 mg/m L) and curdlan were stimulated by A. fumigatus hyphae. The m RNA and protein production of tumor necrosis factor-α(TNF-α)and interleukin-6(IL-6) were determined by real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The protein level of Dectin-1 was measured by Western blot.· RESULTS: Curdlan stimulated m RNA expression of TNF-α and IL-6 in a dose and time dependent manner in HCECs. Curdlan pretreatment before A. fumigatus hyphae stimulation significantly enhanced the expression of TNF-α and IL-6 at m RNA and protein levels compared with A. fumigatus hyphae stimulation group(P <0.05).Both curdlan and A. fumigatus hyphae up-regulated Dectin-1 protein expression in HCECs, and Dectin-1expression was elevated to 1.5- to 2-fold by curdlan pretreatment followed hyphae stimulation. The Dectin-1blocker laminarin suppressed the m RNA expression and protein production of TNF-α and IL-6 induced by curdlan and hyphae(P <0.05).· CONCLUSION: These findings demonstrated that curdlan pretreatment enhanced the inflammatory response induced by A. fumigatus hyphae in ***-1 is essential for the immunomodulatory effectsof curdlan. Curdlan may have high clinical application values in fungal keratitis treatment.

关键词： curdlan Dectin-1 innate immunity Aspergillus fumigatus corneal epithelium

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Expression of indoleamine 2,3-dioxygenase in a murine model of Aspergillus fumigatus keratitis

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International Journal of ophthalmology(English edition) 2016年第4期9卷 491-496页

作者： Nan Jiang Gui-Qiu Zhao Jing Lin Li-Ting Hu Cheng-Ye Che Cui Li Qian Wang Qiang Xu Jie Zhang Xu-Dong Peng Department of ophthalmology the Affiliated Hospital of Qingdao University

AIM： To observe the presence and expression of indoleamine 2,3-dioxygenase（IDO） during the corneal immunity to Aspergillus fumigatus（A. fumigatus） in the murine models.·METHODS： The murine model of fungal keratitis was established by smearing with colonies of A. fumigatus after scraping central epithelium of cornea and covering with contact lenses in C57BL/6 mice. The mice were randomly divided into control group, sham group and *** keratitis group. The cornea was monitored daily using a slit lamp and recorded disease score after infection. Corneal lesion was detected by immunofluorescence staining. IDO m RNA and protein were also detected by quantitative reverse transcription-polymerase chain reaction（q RT-PCR） and Western blot.· RESULTS： The disease score and slit lamp photography indicated that disease severity was consistent with corneal inflammation in the murine models, and the disease scores in A. fumigatus keratitis group were obviously higher than those in the sham group. By immunofluorescence staining, IDO was mainly localized in corneal epithelium and stroma in the murine corneal tissues with A. fumigatus keratitis. Compared with the sham group, IDO m RNA expression was significantly enhanced in corneal epithelium infected by A. fumigatus. Furthermore, IDO protein expression detected by Western blot was in accord with transcript levels of IDO m RNA measured by q RT-PCR. IDO protein expression was enhanced after A. fumigatus infection compared with the sham group.·CONCLUSION： IDO is detected in corneal epithelium and stroma locally, which indicates IDO takes part in the pathogenesis of A. fumigatus keratitis and plays a key role in immune regulation at the early stage.

关键词： indoleamine 2 3-dioxygenase corneal epithelium fungal keratitis Aspergillus fumigatus innate immune response

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The role of Dectin-1/Raf-1 signal cascade in innate immune of human corneal epithelial cells against Aspergillus fumigatus infection

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International Journal of ophthalmology(English edition) 2016年第10期9卷 1371-1375页

作者： Gui-Qiu Zhao Jing Lin Li-Ting Hu Xiao-Ni Yin Qian Wang Qiang Xu Hui Li Department of ophthalmology the Affiliated Hospital of Qingdao University

AIM： To investigate the expression of the v-raf-1murine leukemia viral oncogene homolog 1（Raf-1） and its role in the innate immune response of human corneal epithelial cells（HCECs） infected by Aspergillus ***： HCECs were cultured in *** were randomly divided into 4 groups,including control group,Aspergillus fumigatus group,GW5074（an inhibitor of Raf-1） group and Laminarin [an inhibitor of Dendriti-cell-associated C-type lectin 1（Dectin-1）] *** protein expression level of total Raf-1 and p-Raf-1 was measured by Western *** expression of IL-6 and IL-8 m RNA in each group was detected by real-time polymerase chain ***： In Aspergillus fumigatus group,total Raf-1 protein levels in HCECs remained unchanged at 5,15,30 and 45min after infection,while p-Raf-1 expression was significantly enhanced at 30 min after infection compared with control ***,the expression of p-Raf-1 was apparently declined after treated with GW5074 or Laminarin compared with Aspergillus fumigatus *** expression levels of IL-6,IL-8 m RNA were significantly increased after stimulation with fumigatus compared with control ***-treated with GW5074 significantly inhibited Aspergillus fumigatus-induced upregulation of IL-8 and ***： Aspergillus fumigatus stimulation can elevate the expression of p-Raf-1 in HCECs in ***-1/Raf-1 signal pathway may play a role on regulating the expression of inflammatory cytokines,including IL-6 and IL-8.

关键词： Dectin-1/Raf-1 signal pathway Aspergillus fumigatus innate immune human corneal epithelial cells

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Early expression of PTX3 in Aspergillus fumigatus infected rat cornea

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International Journal of ophthalmology(English edition) 2018年第7期11卷 1084-1089页

作者： Jie Zhang Gui-Qiu Zhao Jing Qu Jing Lin Cheng-Ye Che Xue-Jiao Yang Department of ophthalmology the Affiliated Hospital of Qingdao University Department of Administrative Office the Affiliated Hospital of Qingdao University

AIM： To investigate the expression of pentraxin 3（PTX3） in rat corneal epithelium at the early stage of Aspergillus fumigatus（A. fumigatus） infection. METHODS： A total of 50 Wistar rats were randomly divided into control group, Sham group and experimental group（fungal keratitis group, FK group）. The right eye was chosen as the experiment one and infected by A. fumigatus. Rats were executed at 8, 16 and 24 h after the experimental models being established. Corneal epithelia were collected to assess the expression of PTX3 by quantitative reverse transcription polymerase chain reaction（q RT-PCR） and Western blot analysis. RESULTS： Corneal inflammation scores increased as infection prolonged（P〈0.05, P〈0.001）. PTX3 m RNA expression was low in normal and Sham group rats＇ corneas. Level of PTX3 m RNA in infected rat cornea was elevated at 8 h and peaked at 16 h. The difference was significant compared with control group（P〈0.001）. Western blot analysis also showed a significant increase of PTX3 protein in experimental group at 8 h and peaked at 16 h（P〈0.001）. The synchronous expression of control group and experimental group were also in significant difference（P〈0.001）. CONCLUSION： PTX3 exists in cornea epithelium and is significantly increased after A. fumigatus infection. PTX3 plays an important role in the early stage of cornea innate immunity against A. fumigatus.

关键词： fungal keratitis AspergiIlus fumigates pentraxin 3 innate immunity

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The role of LOX-1 on innate immunity against Aspergillus keratitis in mice

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International Journal of ophthalmology(English edition) 2016年第9期9卷 1245-1250页

作者： Kun He Li-Hui Yue Gui-Qiu Zhao Cui Li Jing Lin Nan Jiang Qian Wang Qiang Xu Xu-Dong Peng Li-Ting Hu Jie Zhang Department of ophthalmology the Affiliated Hospital of Qingdao University Qingdao 266003 Shandong ProvinceChina

AIM：To explore the effects of lectin-like ox-LDL receptor（LOX-1） on innate immunity against Aspergillus fumigatus（***） in mice ***：The mRNA levels of LOX-1 were tested in normal and *** infected corneas of C57BL/6and BALB/c *** expression of LOX-1,pro-inflammatory cytokines TNF-α,CXCL1 and IL-6,antiinflammatory cytokines IL-10,and matrix metalloproteinase 9（MMP9） were tested with treatment with LOX-1 neutralizing antibody or control IgG in ***/gatus infected corneas of C57BL/*** and neutrophils were extracted from susceptible C57BL/6mice,and pretreated with LOX-1 neutralizing antibody or IgG,then stimulated with ***/*** mRNA levels of LOX-1,TNF-α,CXCL1,IL-6,IL-10 and MMP9 were evaluated by polymerase chain ***：The expression of LOX-1 was significantly increased in C57BL/6 mice corneas after ***/gatus infection compared with BABL/c *** treatment with LOX-1 neutralizing antibody,the expression of LOX-1,TNF-α,CXCL1,IL-6,MMP9 and IL-10 in C57BL/6corneas were significantly decreased compared with treatment with control IgG;the expression of LOX-1,CXCL1,IL-6 and IL-10 were significantly decreased in macrophages,while TNF-α and MMP9 expressions had no change;LOX-1,TNF-α,CXCL1,IL-6,MMP9 and IL-10 expressions were significantly decreased in ***：The expression of LOX-1 can affect the expression of pro-inflammatory and anti-inflammatory cytokines in fungal infected corneas,macrophages and neutrophils of C57BL/***-1 inhibition rebalances the inflammatory response of fungal keratitis in mice.

关键词： lectin-like ox-LDL receptor fungal kemtitis macrophages neutrophils mice

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