Bibliometric evaluation of global trends and characteristics of RNA methylation during angiogenesis.

Background: RNA methylation is involved in major life processes. Angiogenesis is a normal phenomenon that occurs constantly in the bodies of all mammals, once it is aberrant or something goes wrong, it may lead to pathological changes. The bibliometric analysis could produce a comprehensive overview of RNA methylation during angiogenesis. Methods: The Web of Science Core Collection (WoSCC) database was used to screen publications about RNA methylation during angiogenesis from Jan 1, 2000 to Nov 24, 2022. Bibliometric and visualization analyses were conducted to understand publication trends by CiteSpace and VOSviewer. Results: In total, 382 publications from 2000 to 2022 were included in the bibliometric and visualization analyses. On the whole, the number of publications had exponential growth. China was the country and Sun Yat-Sen University was the university associated with the largest number of publications, although publications from the United Kingdom and Soochow University were currently having the strongest impact. Cancer was the most studied topic in this field, and N6-methyladenosine is the most studied RNA methylation type. Conclusion: There is a continuously increasing trend in publications related to RNA methylation and angiogenesis, which has attracted much attention, particularly since 2011. RNA methylation might be a promising target in the investigation of pathological angiogenesis and related disorders, which deserves further investigation.

N6-methyladenosine methylation in ophthalmic diseases: From mechanisms to potential applications.

N6-methyladenosine (m6A) modification, as the most common modification method in eukaryotes, is widely involved in numerous physiological and pathological processes, such as embryonic development, malignancy, immune regulation, and premature aging. Under pathological conditions of ocular diseases, changes in m6A modification and its metabolism can be detected in aqueous and vitreous humor. At the same time, an increasing number of studies showed that m6A modification is involved in the normal development of eye structures and the occurrence and progress of many ophthalmic diseases, especially ocular neovascular diseases, such as diabetic retinopathy, age-related macular degeneration, and melanoma. In this review, we summarized the latest progress regarding m6A modification in ophthalmic diseases, changes in m6A modification-related enzymes in various pathological states and their upstream and downstream regulatory networks, provided new prospects for m6A modification in ophthalmic diseases and new ideas for clinical diagnosis and treatment.

Progress and prospects of gene therapy in ophthalmology from 2000 to 2022: A bibliometric analysis.

Background: Gene therapy is a treatment approach at the genetic level, which brings great advances in many diseases and develops rapidly in recent years. Currently, its mechanism of action is mainly through the replacement of missing or defective genes, or the reduction of harmful gene products. However, the application of gene therapy in ophthalmology remains limited. Methods: A total of 1143 articles and reviews published in the field of ocular gene therapies were found in the Web of Science Core Collection database and used for the bibliometric analysis. CiteSpace was mainly applied to the network analysis of countries, institutions, keywords, and dual-map overlay of journals. The visual analysis of authors, journals, and references was used by VOSviewer. The geographical distribution of publications was conducted by R language. Results: The annual publications are increasing in general. Currently, the USA and the UK are two main sources of publications in this field. Switzerland, Denmark, and Finland are the top 3 countries that establish the most cooperation and exchanges with other countries or regions. The most cited and co-cited journal in this field is Investigative Ophthalmology & Visual Science. Gene therapy studies for eye diseases are mainly focused on retinal dysfunctions by the analysis of references, keywords, and counting of original research, including Leber's congenital amaurosis and retinitis pigmentosa. Conclusion: This study used bibliometrics to analyze overall characteristics and put forward prospects for the future in the field of gene therapy in ophthalmology. Ocular diseases, especially hereditary retinal diseases, will be the major focus of gene therapy in the future.

Exosomal non-coding RNAs in angiogenesis: Functions, mechanisms and potential clinical applications.

Exosomes are extracellular vesicles that can be produced by most cells. Exosomes act as important intermediaries in intercellular communication, and participate in a variety of biological activities between cells. Non-coding RNAs (ncRNAs) usually refer to RNAs that do not encode proteins. Although ncRNAs have no protein-coding capacity, they are able to regulate gene expression at multiple levels. Angiogenesis is the formation of new blood vessels from pre-existing vessels, which is an important physiological process. However, abnormal angiogenesis could induce many diseases such as atherosclerosis, diabetic retinopathy and cancer. Many studies have shown that ncRNAs can stably exist in exosomes and play a wide range of physiological and pathological roles including regulation of angiogenesis. In brief, some specific ncRNAs can be enriched in exosomes secreted by cells and absorbed by recipient cells through the exosome pathway, thus activating relevant signaling pathways in target cells and playing a role in regulating angiogenesis. In this review, we describe the physiological and pathological functions of exosomal ncRNAs in angiogenesis, summarize their role in angiogenesis-related diseases, and illustrate potential clinical applications like novel drug therapy strategies and diagnostic markers in exosome research as inspiration for future investigations.

Phosphorylated S6K1 and 4E-BP1 play different roles in constitutively active Rheb-mediated retinal ganglion cell survival and axon regeneration after optic nerve injury.

Ras homolog enriched in brain (Rheb) is a small GTPase that activates mammalian target of rapamycin complex 1 (mTORC1). Previous studies have shown that constitutively active Rheb can enhance the regeneration of sensory axons after spinal cord injury by activating downstream effectors of mTOR. S6K1 and 4E-BP1 are important downstream effectors of mTORC1. In this study, we investigated the role of Rheb/mTOR and its downstream effectors S6K1 and 4E-BP1 in the protection of retinal ganglion cells. We transfected an optic nerve crush mouse model with adeno-associated viral 2-mediated constitutively active Rheb and observed the effects on retinal ganglion cell survival and axon regeneration. We found that overexpression of constitutively active Rheb promoted survival of retinal ganglion cells in the acute (14 days) and chronic (21 and 42 days) stages of injury. We also found that either co-expression of the dominant-negative S6K1 mutant or the constitutively active 4E-BP1 mutant together with constitutively active Rheb markedly inhibited axon regeneration of retinal ganglion cells. This suggests that mTORC1-mediated S6K1 activation and 4E-BP1 inhibition were necessary components for constitutively active Rheb-induced axon regeneration. However, only S6K1 activation, but not 4E-BP1 knockdown, induced axon regeneration when applied alone. Furthermore, S6K1 activation promoted the survival of retinal ganglion cells at 14 days post-injury, whereas 4E-BP1 knockdown unexpectedly slightly decreased the survival of retinal ganglion cells at 14 days post-injury. Overexpression of constitutively active 4E-BP1 increased the survival of retinal ganglion cells at 14 days post-injury. Likewise, co-expressing constitutively active Rheb and constitutively active 4E-BP1 markedly increased the survival of retinal ganglion cells compared with overexpression of constitutively active Rheb alone at 14 days post-injury. These findings indicate that functional 4E-BP1 and S6K1 are neuroprotective and that 4E-BP1 may exert protective effects through a pathway at least partially independent of Rheb/mTOR. Together, our results show that constitutively active Rheb promotes the survival of retinal ganglion cells and axon regeneration through modulating S6K1 and 4E-BP1 activity. Phosphorylated S6K1 and 4E-BP1 promote axon regeneration but play an antagonistic role in the survival of retinal ganglion cells.

Attenuation of Microglial Activation and Pyroptosis by Inhibition of P2X7 Pathway Promotes Photoreceptor Survival in Experimental Retinal Detachment.

Purpose: Photoreceptor (PR) death is the ultimate cause of irreversible vision loss in retinal detachment (RD). Although microglial infiltration in the subretinal space (SRS) was observed after RD, the molecular mechanism underlying microglial activation and the outcomes of infiltrating microglia remain unclear. We aimed to uncover the mechanism of initiation of microglial activation to help explore potential therapy to promote PR survival. Methods: An RD model was conducted by injecting sodium hyaluronate into SRS of C57BL/6J wild type mice. Adenosine triphosphate (ATP) was measured by a ATP Microplate Assay Kit. Bioinformatics analysis was used to evaluate the upregulated receptor relating to ATP binding in human datasets and mouse transcriptomes of RD. Expression of P2X7, its downstream signaling pathways, and microglial pyroptosis were confirmed by qPCR, WB, and immunofluorescence in vivo and in vitro. The cell viability of PR was measured by cell counting kit-8. Brilliant Blue G, a P2X7 antagonist, was subretinally or intraperitoneally injected to inhibit microglial activation in vivo and was applied for microglia cell line treatment in vitro. The decrease in microglial activation and pyroptosis was detected by immunofluorescence and WB. The protective effect on PR was measured by hematoxylin and eosin staining, TUNEL assay, and electroretinogram analysis. Results: The results showed that extracellular ATP released in the SRS after RD triggered P2X7 activation and attracted microglia. The downstream cascade of inflammasome activation induced by P2X7 activation contributed to microglial pyroptosis and then to PR death. ATP-activated microglia led to PR death in vitro. P2X7 blockade rescued PR morphologically and functionally by inhibiting microglial activation and pyroptosis. Conclusions: These results elucidate that ATP-induced P2X7-mediated microglial activation leads to microglial pyroptosis, contributing to PR death. Appropriate inhibition of microglial pyroptosis might serve as a pharmacotherapeutic strategy for decreasing PR death in RD.

Artesunate protects against ocular fibrosis by suppressing fibroblast activation and inducing mitochondria-dependent ferroptosis.

Artesunate, a derivative from extracts of Artemisia annua, has recently been reported to alleviate fibrosis recently. Here, in this study, we sought to determine the anti-fibrosis effect of artesunate in rabbit glaucoma filtration surgery (GFS) model and illuminate underlying mechanisms. Our results showed that artesunate subconjunctival injection alleviated bleb fibrosis by inhibiting fibroblast activation and inducing ferroptosis. Further mechanistic investigation in primary human ocular fibroblasts (OFs) showed that artesunate abrogated fibroblast activation by inhibiting TGF-ß1/SMAD2/3 and PI3K/Akt pathways and scavenged OFs by inducing mitochondria-dependent ferroptosis. Mitochondrial dysfunction, mitochondrial fission, and iron-dependent mitochondrial lipid peroxidation were observed in artesunate-treated OFs. Besides, mitochondria-localized antioxidants inhibited artesunate-induced cell death, suggesting a critical role of mitochondria in artesunate-induced ferroptosis. Our study also found that expression of mitochondrial GPX4 but no other forms of GPX4 was decreased after artesunate treatment and that mitochondrial GPX4 overexpression rescued artesunate-induced lipid peroxidation and ferroptosis. Other cellular ferroptosis defense mechanisms, including cellular FSP1 and Nrf2, were also inhibited by artesunate. In conclusion, our study demonstrated that artesunate protects against fibrosis through abrogation of fibroblast activation and induction of mitochondria-dependent ferroptosis in OFs, which may offer a potential treatment for ocular fibrosis.

Melatonin protects against NMDA-induced retinal ganglion cell injury by regulating the microglia-TNFα-RGC p38 MAPK pathway.

Glaucoma, one of the most common ocular neurodegenerative diseases worldwide, is characterized by retinal ganglion cell (RGC) loss. There is a large body of literature that describes the neuroprotective role of melatonin against neurodegenerative diseases by regulating neuroinflammation, although the exact mechanism through which melatonin acts on RGC is still uncertain. This study assessed the protective effects of melatonin using a NMDA-induced RGC injury model, and studied the possible mechanisms involved in this process. Melatonin promoted RGC survival, improved retinal function, and inhibited the apoptosis and necrosis of retinal cells. To understand the mechanism of the neuroprotective effects of melatonin on RGC, microglia and inflammation-related pathways were assessed after melatonin administration and microglia ablation. Melatonin promoted RGC survival by suppressing microglia-derived proinflammatory cytokines, in particular TNFα, which in turn inhibited the activation of p38 MAPK pathway. Inhibiting TNFα or manipulating p38 MAPK pathway protected damaged RGC. Our results suggest that melatonin protects against NMDA-induced RGC injury by inhibiting the microglial TNFα-RGC p38 MAPK pathway. It should be considered a candidate neuroprotective therapy against retinal neurodegenerative diseases.

m6A modifications of circular RNAs in ischemia-induced retinal neovascularization.

Ischemia-induced pathological neovascularization in the retina is a leading cause of blindness in various age groups. The purpose of the current study was to identify the involvement of circular RNAs (circRNAs) methylated by N6-methyladenosine (m6A), and predict their potential roles in oxygen-induced retinopathy (OIR) in mice. Methylation assessment via microarray analysis indicated that 88 circRNAs were differentially modified by m6A methylation, including 56 hyper-methylated circRNAs and 32 hypo-methylated circRNAs. Gene ontology enrichment analysis predicted that the enriched host genes of the hyper-methylated circRNAs were involved in cellular process, cellular anatomical entity, and protein binding. Host genes of the hypo-methylated circRNAs were enriched in the regulation of cellular biosynthetic process, the nucleus, and binding. According to the Kyoto Encyclopedia of Genes and Genomes analysis, those host genes were involved in the pathways of selenocompound metabolism, salivary secretion, and lysine degradation. MeRIP-qPCR verified significant alterations in m6A methylation levels of mmu_circRNA_33363, mmu_circRNA_002816, and mmu_circRNA_009692. In conclusion, the study revealed the m6A modification alterations in OIR retinas, and the findings above shed light on the potential roles of m6A methylation in circRNA regulatory functions in the pathogenesis of ischemia-induced pathological retinal neovascularization.

Potential biomarkers for retinopathy of prematurity identified by circular RNA profiling in peripheral blood mononuclear cells.

Purpose: This study aims to reveal the altered expression profiles of circular RNAs (circRNAs) in the peripheral blood mononuclear cells (PBMCs) of patients with retinopathy of prematurity (ROP), and to identify potential biomarkers for ROP diagnosis. Methods: Differentially expressed circRNAs in PBMCs of five infants with ROP and five controls were identified using microarray analysis. Twelve altered circRNAs were validated using reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR). Bioinformatic analyses were conducted to predict the circRNA/miRNA interactions, competing endogenous RNA (ceRNA) network, related biological functions, and signaling pathways. Four selected circRNAs in PBMCs were verified using RT-qPCR in another cohort, including 24 infants with ROP and 23 premature controls, and receiver operating characteristic (ROC) curves were used to estimate their potential as diagnostic biomarkers of ROP. Results: A total of 54 and 143 circRNAs were significantly up- and down-regulated, respectively, in the PBMCs of patients with ROP compared with controls. Twelve of the significantly altered circRNAs were preliminarily validated by RT-qPCR, which confirmed the reliability of the microarray analysis. The circRNA/miRNA interactions and ceRNA network were displayed according to the altered circRNAs. Three circRNAs (hsa_circRNA_061346, hsa_circRNA_092369, and hsa_circRNA_103554) were identified as potential diagnostic biomarkers for ROP with certain clinical values. Conclusions: CircRNAs were significantly altered in PBMCs of treatment-requiring ROP patients. CircRNAs may be used as potential biomarkers and possible therapeutic targets for ROP.

Interleukin-19 Promotes Retinal Neovascularization in a Mouse Model of Oxygen-Induced Retinopathy.

Purpose: Retinal neovascularization is a major cause of blindness. This study aimed to investigate the effects of IL-19 and the underlying mechanisms in a mouse model of oxygen-induced retinopathy (OIR). Methods: C57BL/6J wild-type mice and IL-19 knockout (KO) mice were used to establish an OIR mouse model. Bone marrow-derived macrophages (BMDMs) with or without recombinant IL-19 (rIL-19) stimulation were injected intravitreally. Reverse transcription-quantitative polymerase chain reaction was used to determine the mRNA expressions. ELISA and western blotting were performed to assess the protein levels. Immunofluorescence staining was applied to assess retinal neovascularization. Human retinal endothelial cells (HRECs) stimulated with rIL-19 were cultured to evaluate the effects on cell proliferation and migration. Results: The level of IL-19 was significantly elevated at postnatal day 17 in OIR retinas. Both the avascular areas and pathological neovascular tufts were significantly increased in rIL-19-treated OIR retinas and suppressed in IL-19 KO retinas. IL-19 KO mice suppressed expression of ARG1, VEGFA, and pSTAT3. Moreover, BMDMs stimulated by rIL-19 enhanced that expression and suppressed the expression of inducible nitric oxide synthase (iNOS). The proliferation and migration of HRECs were significantly augmented by rIL-19. In addition, intravitreal injection of BMDMs stimulated by rIL-19 enhanced retinal neovascularization. Conclusions: These findings suggest that IL-19 enhances pathological neovascularization through a direct effect on microvascular endothelial cells and the promotion of M2 macrophage polarization. The inhibition of IL-19 may be a potential treatment for retinal neovascularization.

N6-methyladenosine modifications of mRNAs and long noncoding RNAs in oxygen-induced retinopathy in mice.

Retinal neovascular diseases are major causes of blindness worldwide. As a common epitranscriptomic modification of eukaryotic RNAs, N6-methyladenosine (m6A) is associated with the pathogenesis of many diseases, including angiogenesis, through the regulation of RNA metabolism and functions. The aim of this study was to identify m6A modifications of mRNAs and long noncoding RNAs (lncRNAs) and determine their potential roles in retinal neovascularization. The transcriptome-wide m6A profiles of mRNAs and lncRNAs in the retinal tissues of mice with oxygen-induced retinopathy (OIR) and controls were identified by microarray analysis of immunoprecipitated methylated RNAs. The m6A methylation levels of mRNAs and lncRNAs identified in the microarray data were validated by MeRIP-qPCR. A total of 1321 mRNAs (151 hypermethylated and 1170 hypomethylated) and 192 lncRNAs (15 hypermethylated and 177 hypomethylated) were differentially methylated with the m6A modification in OIR and control mice. Gene ontology analysis showed that hypermethylated mRNAs were enriched in the regulation of multicellular organismal process, intracellular organelle, and protein binding, while hypomethylated mRNAs were enriched in cellular metabolic process, intracellular process, and binding. Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that hypermethylated mRNAs were involved in dopaminergic synapses, glutamatergic synapse, and PI3K-Akt signaling pathway, while hypomethylated mRNAs were involved in autophagy, ubiquitin-mediated proteolysis, and spliceosome. Moreover, the altered levels of m6A methylation of ANGPT2, GNG12, ROBO4, and ENSMUST00000153785 were validated by MeRIP-qPCR. The results revealed an altered m6A epitranscriptome in OIR retinas. These methylated RNAs may act as novel modulators and targets in retinal neovascularization.

Novel Potential Biomarkers for Retinopathy of Prematurity.

Retinopathy of prematurity (ROP) is the main risk factor for vision-threatening disease in premature infants with low birth weight. An accumulating number of independent studies have focused on ROP pathogenesis and have demonstrated that laser photocoagulation therapy and/or anti-VEGF treatment are effective. However, early diagnosis of ROP is still critical. At present, the main method of ROP screening is based on binocular indirect ophthalmoscopy. However, the judgment of whether ROP occurs and whether treatment is necessary depends largely on ophthalmologists with a great deal of experience. Therefore, it is essential to develop a simple, accurate and effective diagnostic method. This review describes recent findings on novel biomarkers for the prediction, diagnosis and prognosis of ROP patients. The novel biomarkers were separated into the following categories: metabolites, cytokines and growth factors, non-coding RNAs, iconography, gut microbiota, oxidative stress biomarkers, and others. Biomarkers with high sensitivity and specificity are urgently needed for the clinical applications of ROP. In addition, using non-invasive or minimally invasive methods to obtain samples is also important. Our review provides an overview of potential biomarkers of ROP.

The efficacy and safety of intravitreal injection of Ranibizumab as pre-treatment for vitrectomy in proliferative diabetic retinopathy with vitreous hemorrhage.

BACKGROUND: Intravitreal injection of anti-vascular endothelial growth factor (VEGF) has become first line therapy for diabetic macular edema. This study evaluated the efficacy and safety of intravitreal injection of Ranibizumab (IVR) as pre-treatment for pars plana vitrectomy in proliferative diabetic retinopathy (PDR) patients with vitreous hemorrhage. METHODS: This pilot randomized controlled trial included 48 eyes with vitreous hemorrhage resulting from active PDR. Eyes were treated with IVR 1 or 3 days before vitrectomy or a sham subconjunctival injection 3 days before surgery. The occurrence of new tractional retinal detachment (TRD), total operation time, and intraoperative findings were compared. The concentrations of VEGF and connective tissue growth factor (CTGF) in aqueous humor and plasma collected at the time of IVR and vitrectomy were determined by ELISA. RESULTS: None of the patients who received IVR experienced new TRD. Ranibizumab injection improved intraoperative outcomes. The mean concentrations of VEGF in aqueous humor were significantly lower after than before IVR in patients who received IVR 1 and 3 days before surgery (P < 0.001 each). The CTGF/log10 (VEGF) ratio was significantly higher after than before IVR in patients who received IVR 3 days before vitrectomy (P = 0.046). CONCLUSION: Preoperative IVR is an effective and safe strategy for the surgical treatment of severe PDR combined with vitreous hemorrhage. IVR 1 and 3 days before surgery can significantly reduce VEGF content in aqueous humor and effectively improve intraoperative conditions without causing TRD. TRIAL REGISTRATION: This study was registered with the Chinese Clinical Trial Registry. Name of the registry: Exploratory analysis of effect of intravitreal ranibizumab as pre-treatment for pars plana vitrectomy in proliferative diabetic retinopathy. TRIAL REGISTRATION NUMBER: ChiCTR-ONC-16009520. Date of registration: October 20, 2016. URL of trial registry record: http://www.chictr.org.cn/searchprojen.aspx.

Altered Fecal Microbiome and Metabolome in a Mouse Model of Choroidal Neovascularization.

PURPOSE: Choroidal neovascularization (CNV) is the defining feature of neovascular age-related macular degeneration (nAMD). Gut microbiota might be deeply involved in the pathogenesis of nAMD. This study aimed to reveal the roles of the gut microbiome and fecal metabolome in a mouse model of laser-induced CNV. METHODS: The feces of C57BL/6J mice with or without laser-induced CNV were collected. Multi-omics analyses, including 16S rRNA gene sequencing and untargeted metabolomics, were conducted to analyze the changes in the gut microbial composition and the fecal metabolomic profiles in CNV mice. RESULTS: The gut microbiota was significantly altered in CNV mice. The abundance of Candidatus_Saccharimonas was significantly upregulated in the feces of CNV mice, while 16 genera, including Prevotellaceae_NK3B31_group, Candidatus_Soleaferrea, and Truepera, were significantly more abundant in the controls than in the CNV group. Fecal metabolomics identified 73 altered metabolites (including 52 strongly significantly altered metabolites) in CNV mice compared to control mice. Correlation analysis indicated significant correlations between the altered fecal metabolites and gut microbiota genera, such as Lachnospiraceae_UCG-001 and Candidatus_Saccharimonas. Moreover, KEGG analysis revealed six pathways associated with these altered metabolites, such as the ABC transporter, primary bile acid biosynthesis and steroid hormone biosynthesis pathways. CONCLUSION: The study identified an altered fecal microbiome and metabolome in a CNV mouse model. The altered microbes, metabolites and the involved pathways might be associated with the pathogenesis of nAMD.

Metabolomics Analyses of Mouse Retinas in Oxygen-Induced Retinopathy.

Purpose: Retinal neovascularization is a severe pathological process leading to irreversible blindness. This study aims to identify the altered metabolites and their related pathways that are involved in retinal neovascularization. Methods: To reveal the global metabolomic profile change in the retinal neovascularization process, an untargeted metabolomics analysis of oxygen-induced retinopathy (OIR) mice retinas was carried out first, followed by the validation of amino acids and their derivatives through a targeted metabolomics analysis. The involved pathways were predicted by bioinformatic analysis. Results: By untargeted metabolomics, a total of 58 and 49 metabolites altered significantly in OIR retinas under cationic and anionic modes, respectively. By bioinformatics analysis, "ABC transporters," "central carbon metabolism in cancer." and "alanine, aspartate, and glutamate metabolism" were the most enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with the changed metabolites. By targeted metabolomics, no significant change was found in the assessed amino acids and their derivatives at postnatal day (P) 12, whereas significantly altered amino acids and their derivatives were recognized at P13, P17, and P42 in OIR retinas. Conclusions: The metabolomic profile was significantly altered in the neovascularized retinas. In particular, numerous amino acids and their derivatives were significantly changed in OIR retinas. These altered metabolites, together with their associated pathways, might be involved in the pathogenesis of retinal neovascular diseases.

Role of interferons in diabetic retinopathy.

Diabetic retinopathy (DR) is one of the major causes of visual impairment and irreversible blindness in developed regions. Aside from abnormal angiogenesis, inflammation is the most specific and might be the initiating factor of DR. As a key participant in inflammation, interferon-gamma (IFN-γ) can be detected in different parts of the eye and is responsible for the breakdown of the blood-retina barrier and activation of inflammatory cells and other cytokines, which accelerate neovascularization and neuroglial degeneration. In addition, IFN-γ is involved in other vascular complications of diabetes mellitus and angiogenesis-dependent diseases, such as diabetic nephropathy, cerebral microbleeds, and age-related macular degeneration. Traditional treatments, such as anti-vascular endothelial growth factor agents, vitrectomy, and laser photocoagulation therapy, are more effective for angiogenesis and not tolerable for every patient. Many ongoing clinical trials are exploring effective drugs that target inflammation. For instance, IFN-α acts against viruses and angiogenesis and is commonly used to treat malignant tumors. Moreover, IFN-α has been shown to contribute to alleviating the progression of DR and other ocular diseases. In this review, we emphasize the roles that IFNs play in the pathogenesis of DR and discuss potential clinical applications of IFNs in DR, such as diagnosis, prognosis, and therapeutic treatment.

Implementation of flipped classroom combined with case- and team-based learning in residency training.

The core problem of Chinese resident doctor training is that medical educators present content in an attractive teaching mode to make students more motivated to learn and improve their clinical thinking ability, humanistic care, and practical ability. The traditional classroom mode of teaching cannot meet the needs of modern medical education. The purpose of this study is to explore the benefits and challenges of the flipped classroom (FC) combined with case- and team-based learning (FC-CTBL) for residency training. In this study, 60 junior surgical residents of Xiangya Medical College were enrolled. "Diabetic foot" was selected as the content of this study. Residents were divided into an FC-CTBL group and an FC group. FC-CTBL and FC were compared on the basis of residents' feedback questionnaires, residents' learning burden, test scores from a pre-quiz, and objective structured clinical examinations (OSCE). Residents were more satisfied with the FC-CTBL model compared with FC. In the FC-CTBL group, more participants said that the course improved their teamwork skills, analytical skills and their confidence in tackling unfamiliar problems. Residents in the FC-CTBL group also spent significantly less time preparing for class and performed better in the OSCE than those in the FC group. FC-CTBL stimulates residents' learning motivation, decreases their workload, improves their performance in the OSCE and may help to enhance clinical thinking and teamwork skills. The FC-CTBL approach is a good option for residency training.

The Role of Inflammation in Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is a blinding eye disease which incidence gradually increases with age. Inflammation participates in AMD pathogenesis, including choroidal neovascularization and geographic atrophy. It is also a kind of self-protective regulation from injury for the eyes. In this review, we described inflammation in AMD pathogenesis, summarized the roles played by inflammation-related cytokines, including pro-inflammatory and anti-inflammatory cytokines, as well as leukocytes (macrophages, dendritic cells, neutrophils, T lymphocytes and B lymphocytes) in the innate or adaptive immunity in AMD. Possible clinical applications such as potential diagnostic biomarkers and anti-inflammatory therapies were also discussed. This review overviews the inflammation as a target of novel effective therapies in treating AMD.

Increased vitreal levels of interleukin-10 in diabetic retinopathy: a Meta-analysis.

AIM: To conduct a Meta-analysis for the change of interleukin-10 (IL-10) concentration in vitreous samples of patients with diabetic retinopathy (DR). METHODS: Systemic search for literature was conducted from the databases of PubMed, Web of Science and Cochrane Library by August 2019. Statistical analyses including standard mean difference (SMD) and its 95% confidence interval (CI) were performed by using RevMan 5.3 software. RESULTS: Totally 194 studies were screened and finally 11 studies were included in the Meta-analysis. The concentration of IL-10 in the DR group was higher than in the control group (P=0.003, SMD: 0.77, 95%CI: 0.25-1.28). Significant heterogeneity was found among all studies (P<0.00001, I 2=92%). The subgroup analysis showed that the concentration of IL-10 increased in vitreous samples from patients with DR compared to the non-DR controls (P=0.004, SMD: 1.44, 95%CI: 0.46-2.42). Moreover, the concentration of IL-10 in samples of proliferative diabetic retinopathy (PDR) patients was significantly higher than that of non-proliferative diabetic retinopathy (NPDR) patients (P=0.01, SMD: 0.61, 95%CI: 0.13-1.08). CONCLUSION: The vitreal concentration of IL-10 is significantly increased in patients with DR. Further studies are needed to reveal the mechanisms of IL-10 in DR.