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      Melatonin attenuates choroidal neovascularization by regulating macrophage/microglia polarization via inhibition of RhoA/ROCK signaling pathway

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          Choroidal neovascularization (CNV) is an important characteristic of advanced wet age-related macular degeneration (AMD) and leads to severe visual impairment among elderly patients. Previous studies have demonstrated that melatonin induces several biological effects related to antioxidation, anti-inflammation, and anti-angiogenesis. However, the role of melatonin in CNV, and its underlying mechanisms, has not been investigated thus far. In this study, we found that melatonin administration significantly reduced the scale and volume of CNV lesions, suppressed vascular leakage, and inhibited the capacity of vascular proliferation in the laser-induced mouse CNV model. Additionally, the results also show that the melatonin-treated retinal microglia in the laser-induced mice exhibited enhanced expression of M1-type markers, such as iNOS, CCL-3, CCL-5, and TNF-α, as well as decreased production of M2-type markers, such as Arg-1, Fizz-1, IL-10, YM-1, and CD206, indicating that melatonin switched the macrophage/microglia polarization from pro-angiogenic M2 phenotype to anti-angiogenic M1 phenotype. Furthermore, the RhoA/ROCK signaling pathway was activated during CNV formation, yet was suppressed after an intraperitoneal injection of melatonin. In conclusion, melatonin attenuated CNV, reduced vascular leakage, and inhibited vascular proliferation by switching the macrophage/microglia polarization from M2 phenotype to M1 phenotype via inhibition of RhoA/ROCK signaling pathway in CNV. This suggests that melatonin could be a novel agent for the treatment of AMD.

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          Resistance to anti-VEGF therapy in neovascular age-related macular degeneration: a comprehensive review

          As a progressive chronic disease, age-related macular degeneration (AMD) is the leading cause of irreversible vision impairment worldwide. Experimental and clinical evidence has demonstrated that vascular endothelial growth factor (VEGF) plays a vital role in the formation of choroidal neovascularization. Intravitreal injections of anti-VEGF agents have been recommended as a first-line treatment for neovascular AMD. However, persistent fluid or recurrent exudation still occurs despite standardized anti-VEGF therapy. Patients suffering from refractory or recurrent neovascular AMD may develop mechanisms of resistance to anti-VEGF therapy, which results in a diminished therapeutic effect. Until now, there has been no consensus on the definitions of refractory neovascular AMD and recurrent neovascular AMD. This article aims at clarifying these concepts to evaluate the efficacy of switching drugs, which contributes to making clinical decision more scientifically. Furthermore, insight into the causes of resistance to anti-VEGF therapy would be helpful for developing possible therapeutic approaches, such as combination therapy and multi-target treatment that can overcome this resistance.
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            Anti-vascular endothelial growth factor for neovascular age-related macular degeneration

            Age‐related macular degeneration (AMD) is the most common cause of uncorrectable severe vision loss in people aged 55 years and older in the developed world. Choroidal neovascularization (CNV) secondary to AMD accounts for most cases of AMD‐related severe vision loss. Intravitreous injection of anti‐vascular endothelial growth factor (anti‐VEGF) agents aims to block the growth of abnormal blood vessels in the eye to prevent vision loss and, in some instances, to improve vision. • To investigate ocular and systemic effects of, and quality of life associated with, intravitreous injection of three anti‐VEGF agents (pegaptanib, ranibizumab, and bevacizumab) versus no anti‐VEGF treatment for patients with neovascular AMD • To compare the relative effects of one of these anti‐VEGF agents versus another when administered in comparable dosages and regimens To identify eligible studies for this review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Eyes and Vision Trials Register (searched January 31, 2018); MEDLINE Ovid (1946 to January 31, 2018); Embase Ovid (1947 to January 31, 2018); the Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to January 31, 2018); the International Standard Randomized Controlled Trials Number (ISRCTN) Registry ( www.isrctn.com/editAdvancedSearch ‐ searched January 31, 2018); ClinicalTrials.gov ( www.clinicaltrials.gov ‐ searched November 28, 2018); and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) ( www.who.int/ictrp/search/en ‐ searched January 31, 2018). We did not impose any date or language restrictions in electronic searches for trials. We included randomized controlled trials (RCTs) that evaluated pegaptanib, ranibizumab, or bevacizumab versus each other or versus a control treatment (e.g. sham treatment, photodynamic therapy), in which participants were followed for at least one year. Two review authors independently screened records, extracted data, and assessed risks of bias. We contacted trial authors for additional data. We compared outcomes using risk ratios (RRs) or mean differences (MDs). We used the standard methodological procedures expected by Cochrane. We included 16 RCTs that had enrolled a total of 6347 participants with neovascular AMD (the number of participants per trial ranged from 23 to 1208) and identified one potentially relevant ongoing trial. Six trials compared anti‐VEGF treatment (pegaptanib, ranibizumab, or bevacizumab) versus control, and 10 trials compared bevacizumab versus ranibizumab. Pharmaceutical companies conducted or sponsored four trials but funded none of the studies that evaluated bevacizumab. Researchers conducted these trials at various centers across five continents (North and South America, Europe, Asia, and Australia). The overall certainty of the evidence was moderate to high, and most trials had an overall low risk of bias. All but one trial had been registered prospectively. When compared with those who received control treatment, more participants who received intravitreous injection of any of the three anti‐VEGF agents had gained 15 letters or more of visual acuity (risk ratio [RR] 4.19, 95% confidence interval [CI] 2.32 to 7.55; moderate‐certainty evidence), had lost fewer than 15 letters of visual acuity (RR 1.40, 95% CI 1.27 to 1.55; high‐certainty evidence), and showed mean improvement in visual acuity (mean difference 6.7 letters, 95% CI 4.4 to 9.0 in one pegaptanib trial; mean difference 17.8 letters, 95% CI 16.0 to 19.7 in three ranibizumab trials; moderate‐certainty evidence) after one year of follow‐up. Participants treated with anti‐VEGF agents showed improvement in morphologic outcomes (e.g. size of CNV, central retinal thickness) compared with participants not treated with anti‐VEGF agents (moderate‐certainty evidence). No trial directly compared pegaptanib versus another anti‐VEGF agent and followed participants for one year; however, when compared with control treatments, ranibizumab and bevacizumab each yielded larger improvements in visual acuity outcomes than pegaptanib. Visual acuity outcomes after bevacizumab and ranibizumab were similar when the same RCTs compared the same regimens with respect to gain of 15 or more letters of visual acuity (RR 0.95, 95% CI 0.81 to 1.12; high‐certainty evidence) and loss of fewer than 15 letters of visual acuity (RR 1.00, 95% CI 0.98 to 1.02; high‐certainty evidence); results showed similar mean improvement in visual acuity (mean difference [MD] ‐0.5 letters, 95% CI ‐1.5 to 0.5; high‐certainty evidence) after one year of follow‐up, despite the substantially lower cost of bevacizumab compared with ranibizumab. Reduction in central retinal thickness was less among bevacizumab‐treated participants than among ranibizumab‐treated participants after one year (MD ‐11.6 μm, 95% CI ‐21.6 to ‐1.7; high‐certainty evidence); however, this difference is within the range of measurement error, and we did not interpret it to be clinically meaningful. Ocular inflammation and increased intraocular pressure (IOP) after intravitreal injection were the most frequently reported serious ocular adverse events. Researchers reported endophthalmitis in less than 1% of anti‐VEGF‐treated participants and in no cases among control groups. The occurrence of serious systemic adverse events was comparable across anti‐VEGF‐treated groups and control groups; however, the numbers of events and trial participants may have been insufficient to show a meaningful difference between groups (evidence of low‐ to moderate‐certainty). Investigators rarely measured and reported data on visual function, quality of life, or economic outcomes. Results of this review show the effectiveness of anti‐VEGF agents (pegaptanib, ranibizumab, and bevacizumab) in terms of maintaining visual acuity; studies show that ranibizumab and bevacizumab improved visual acuity in some eyes that received these agents and were equally effective. Available information on the adverse effects of each medication does not suggest a higher incidence of potentially vision‐threatening complications with intravitreous injection of anti‐VEGF agents compared with control interventions; however, clinical trial sample sizes were not sufficient to estimate differences in rare safety outcomes. Future Cochrane Reviews should incorporate research evaluating variable dosing regimens of anti‐VEGF agents, effects of long‐term use, use of combination therapies (e.g. anti‐VEGF treatment plus photodynamic therapy), and other methods of delivering these agents. Anti‐vascular endothelial growth factor for neovascular age‐related macular degeneration What is the aim of this review? 
 The aim of this Cochrane review was to compare treatment with anti‐vascular endothelial growth factor (anti‐VEGF) agents for neovascular age‐related macular degeneration (wet AMD). This review focuses on two questions: (1) whether using anti‐VEGF agents is better than not using them, and (2) which anti‐VEGF agent works best. Key messages 
 Anti‐VEGF agents were better than no anti‐VEGF agents or other types of treatment for patients with wet AMD. When studies compared anti‐VEGF agents, researchers found that ranibizumab and bevacizumab were similar in terms of vision‐related outcomes and numbers of adverse events among participants followed for at least one year. The major difference was cost, as bevacizumab was cheaper. What was studied in this review? 
 Wet AMD is a common cause of severe vision loss among people 55 years of age and older. The macula, located in the central retina in the back of the eye, is important for vision. Wet AMD occurs when abnormal growth of blood vessels in the back of the eye damages the macula. Wet AMD causes blurriness, darkness, or distortion in the center of the field of vision, thus reducing the individual's ability to read, drive, and see faces. Injection into the eye of medicines like pegaptanib, ranibizumab, and bevacizumab can help block abnormal growth of blood vessels in the back of the eye. These drugs are known as anti‐VEGF agents. We conducted this review to compare benefits and risks of treatment with anti‐VEGF agents versus treatment without anti‐VEGF agents and to compare different types of anti‐VEGF agents. What are the main results of the review? 
 We found 16 studies that enrolled a total of 6347 people with wet AMD. Six studies compared anti‐VEGF agents against no anti‐VEGF agent, and ten studies compared bevacizumab versus ranibizumab. Drug companies conducted or sponsored four of the studies. Investigators conducted the 16 studies at various centers on five continents (North and South America, Europe, Asia, and Australia); they treated people and provided follow‐up for at least one year. After one year, more people treated with any of the three anti‐VEGF agents (pegaptanib, ranibizumab, or bevacizumab) had improved vision, fewer had vision loss, and fewer were legally blind in the study eye when compared with people who did not receive anti‐VEGF agents. People treated with anti‐VEGF agents also showed structural improvements in the eye, which doctors use to monitor the disease and determine the need for more treatment. People who did not receive anti‐VEGF agents did not show the same kind of improvement. Treatment with ranibizumab or bevacizumab yielded larger improvements in vision compared with treatment with pegaptanib in trials comparing anti‐VEGF treatment against treatment not using anti‐VEGF agents. Comparison of bevacizumab versus ranibizumab revealed no major differences with respect to any vision‐related outcomes. The major difference between the two agents was cost; bevacizumab was cheaper. Inflammation and increased pressure in the eye were the most common unwanted effects caused by anti‐VEGF agents. Investigators reported endophthalmitis (infection in the inner part of the eye, which can cause blindness) in less than 1% of anti‐VEGF‐treated eyes and observed no cases among those not treated with anti‐VEGF agents. The occurrence of serious side effects, such as high blood pressure and internal bleeding, was low and was similar between anti‐VEGF‐treated groups and groups that did not receive anti‐VEGFs. The number of total side effects was very small, so it is impossible to tell which drug may have caused the most harmful effects. How up‐to‐date is this review? 
 Cochrane researchers searched for studies that had been published up to January 31, 2018.
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              Diverse roles of macrophages in intraocular neovascular diseases: a review.

              Macrophages are involved in angiogenesis, and might also contribute to the pathogenesis of intraocular neovascular diseases. Recent studies indicated that macrophages exert different functions in the process of intraocular neovascularization, and the polarization of M1 and M2 phenotypes plays extremely essential roles in the diverse functions of macrophages. Moreover, a large number of cytokines released by macrophages not only participate in macrophage polarization, but also associate with retinal and choroidal neovascular diseases. Therefore, macrophage might be considered as a novel therapeutic target to the treatment of pathological neovascularization in the eye. This review mainly summarizes diverse roles of macrophages and discusses the possible mechanisms in retinal and choroidal neovascularization.

                Author and article information

                (View ORCID Profile)
                Journal of Pineal Research
                J Pineal Res
                August 2020
                May 15 2020
                August 2020
                : 69
                : 1
                [1 ]State Key Laboratory of Ophthalmology Zhongshan Ophthalmic CenterSun Yat‐sen University Guangzhou, Guangdong Province China
                © 2020





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