Aryl hydrocarbon receptor (AhR)-mediated immune responses to degeneration of the retinal pigment epithelium.

Injuries to the retinal pigment epithelium (RPE) trigger immune responses, orchestrating interactions within the innate and adaptive immune systems in the outer retina and choroid. We previously reported that interleukin 17 (IL-17) is a pivotal signaling molecule originating from choroidal γδ T cells, exerting protective effects by mediating functional connections between the RPE and subretinal microglia. In this current study, we generated mice with aryl hydrocarbon receptor (AhR) knockout specifically in IL-17-producing cells. These animals had deficiency in IL-17 production from γδ T cells, and exhibited increased sensitivity to both acute and chronic insults targeting the RPE. These findings imply that IL-17 plays a crucial role as a signaling cytokine in preserving the homeostasis of the outer retina and choroid.

Oxidative and carbonyl stress induced AMD and Codonopsis lanceolata ameliorates AMD via controlling oxidative and carbonyl stress.

Age-related macular degeneration (AMD) is one of the leading causes of blindness. AMD is currently incurable; the best solution is to prevent its occurrence. To develop drugs for AMD, it is crucial to have a model system that mimics the symptoms and mechanisms in patients. It is most important to develop safer and more effective anti-AMD drug. In this study, the dose of A2E and the intensity of blue light were evaluated to establish an appropriate atrophic in vitro model of AMD and anti-AMD effect and therapeutic mechanism of Codonopsis lanceolata. The experimental groups included a control group an AMD group treated with A2E and blue light, a lutein group treated with 25 µM lutein after AMD induction, and three groups treated with different doses of C. lanceolata (10, 20, and 50 µg/mL) after AMD induction. Intrinsic apoptotic pathway (Bcl-2 family), anti-oxidative system (Keap1/Nrf2/HO-1 antioxidant response element), and anti-carbonyl effect (4-hydroxynonenal [4-HNE]) were evaluated using immunofluorescence, MTT, TUNEL, FACS, and western blotting analyses. A2E accumulation in the cytoplasm of ARPE-19 cells depending on the dose of A2E. Cell viability of ARPE-19 cells according to the dose of A2E and/or blue light intensity. The population of apoptotic or necrotic cells increased based on the A2E dose and blue light intensity. Codonopsis lanceolata dose-dependently prevented cell death which was induced by A2E and blue light. The antiapoptotic effect of that was caused by activating Keap1/Nrf2/HO-1 pathway, suppressing 4-HNE, and modulating Bcl-2 family proteins like increase of antiapoptotic proteins such as Bcl-2 and Bcl-XL and decrease of proapoptotic protein such as Bim. Based on these findings, 30 µM A2E and 20 mW/cm2 blue light on adult retinal pigment epithelium-19 cells was an appropriate condition for AMD model and C. lanceolata shows promise as an anti-AMD agent.

Association between three-dimensional morphological features and functional indicators of neovascular age-related macular degeneration.

PURPOSE: To investigate the correlation between morphological lesions and functional indicators in eyes with neovascular age-related macular degeneration (nAMD). METHODS: This was a prospective observational study of treatment-naïve nAMD eyes. Various morphological lesions and impaired retinal structures were manually measured at baseline and month-3 in three-dimensional optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) images, including the volumes (mm3) of macular neovascularization (MNV), avascular subretinal hyperreflective material (avascular SHRM), subretinal fluid (SRF), intraretinal fluid (IRF), serous pigment epithelial detachment (sPED) and the impaired area (mm2) of ellipsoid zone (EZ), external limiting membrane (ELM) and outer nuclear layer (ONL). RESULTS: Sixty-three eyes were included. The volume of avascular SHRM showed persistent positive associations with the area of EZ damage, both at baseline, month-3, and change values (all P < 0.001). Poor BCVA (month-3) was associated with larger volumes of baseline IRF (ß = 0.377, P < 0.001), avascular SHRM (ß = 0.306, P = 0.032), and ELM impairment area (ß = 0.301, P = 0.036) in multivariate model. EZ and ELM impairment were primarily associated with baseline avascular SHRM (ß = 0.374, p = 0.003; ß = 0.388, P < 0.001, respectively), while ONL impairment primarily associated with MNV (ß = 0.475, P < 0.001). CONCLUSION: The utilization of three-dimensional measurements elucidates the intrinsic connections among various lesions and functional outcomes. In particular, avascular SHRM plays an important role in prognosis of nAMD.

Age-related macular degeneration: suitability of optogenetic therapy for geographic atrophy.

Age-related macular degeneration (AMD) is a growing public health concern given the aging population and it is the leading cause of blindness in developed countries, affecting individuals over the age of 55 years. AMD affects the retinal pigment epithelium (RPE) and Bruch's membrane in the macula, leading to secondary photoreceptor degeneration and eventual loss of central vision. Late AMD is divided into two forms: neovascular AMD and geographic atrophy (GA). GA accounts for around 60% of late AMD and has been the most challenging subtype to treat. Recent advances include approval of new intravitreally administered therapeutics, pegcetacoplan (Syfovre) and avacincaptad pegol (Iveric Bio), which target complement factors C3 and C5, respectively, which slow down the rate of enlargement of the area of atrophy. However, there is currently no treatment to reverse the central vision loss associated with GA. Optogenetics may provide a strategy for rescuing visual function in GA by imparting light-sensitivity to the surviving inner retina (i.e., retinal ganglion cells or bipolar cells). It takes advantage of residual inner retinal architecture to transmit visual stimuli along the visual pathway, while a wide range of photosensitive proteins are available for consideration. Herein, we review the anatomical changes in GA, discuss the suitability of optogenetic therapeutic sensors in different target cells in pre-clinical models, and consider the advantages and disadvantages of different routes of administration of therapeutic vectors.

Long-term results of the treatment of patients with exudative age-related macular degeneration during the Covid-19 pandemic.

PURPOSE: To quantify the long-term impact (24 months) on the visual results and activity of neovascular lesions of COVID-19 confinement in patients with nAMD in our population. METHODS: A retrospective observational study of patients with nAMD who attended consultation or were treated during the 3 months before confinement was carried out. RESULTS: 144 patients (168 eyes) with nAMD were included, 51 of them (35.42%) came during confinement, and at 24 months the final cohort was 118 patients (133 eyes). The previous VA of 57.99 ± 23.68 letters decreased, clinically relevant and statistically significant, by an average of 6.87 (±16.84) and 7.89 (±19.58) at 12- and 24-months follow-up. This change differs significantly from the two-year vision change observed in the national database of pretreated patients. The median number of injections and consultations is lower in our group at 12 months, compared to the pre-pandemic national database, and tends to equalize at 24 months. We did not find differences in vision when we compared patients who attended consultations during confinement or in treatment intervals greater than 8 weeks (Tq8w). CONCLUSIONS: The VA of patients with nAMD decreased significantly after confinement, probably due to the lower number of antiangiogenic injections and consultations during the first year, and did not recover during the second year despite the increase in the number of injections and visits close to those reported before confinement.

The Management of Two Cases with Retinal Arterial Macroaneurysm by Anti-Vascular Endothelial Growth Factor.

Introduction: We report on one case of age-related macular degeneration and one case of diabetic macular edema with concomitant retinal arterial macroaneurysm (RAM) that were treated with anti-vascular endothelial growth factor (VEGF) intravitreal injections. Case Presentation: Case 1 involved a 71-year-old woman with a 30-year history of diabetes who was undergoing dialysis. Pretreatment visual acuity in the right eye was 0.4. Fundus fluorescein angiography (FA) showed that numerous microaneurysms and RAM were located at a distance of two papillary diameters from the macular area. Diabetic macular edema was diagnosed. After 12 anti-VEGF injections, the macular edema resolved, microaneurysms decreased, and the RAM also disappeared. Visual acuity in the right eye improved to 0.7. Case 2 involved an 81-year-old woman receiving treatment for disorders including hypertension and dyslipidemia. Pretreatment visual acuity in the right eye was 0.03. And vitreous hemorrhage was present. After one ranibizumab intravitreal injection, the fundus became clearly visible. Macular subretinal hemorrhage and an RAM in the upper macula area were evident on FA and optical coherence tomography. After four intravitreal injections of ranibizumab, macular hemorrhage resolved, RAM disappeared, and visual acuity improved to 0.2. All cases were treated by intravitreal injection of anti-VEGF. After several injections, the macular hemorrhage or macular edema was resolved. RAM disappeared, and visual acuity improved. Conclusion: Intravitreal injection of anti-VEGF appears effective for age-related macular degeneration or diabetic macular edema with concomitant RAM. Although anti-VEGF intravitreal injections are not covered by health insurance for the treatment of RAM, their effectiveness means that the expansion of indications is desirable.

Unexpected Vision Loss following Six Intravitreal Injections for Neovascular Age-Related Macular Degeneration.

Introduction: We present a case of a patient with preceding vitreomacular traction (VMT) who developed a full-thickness macular hole (FTMH) following his sixth intravitreal aflibercept injection for the treatment of age-related macular degeneration and review the literature on risk factors and pathogenesis of this adverse event. Case Presentation: FTMH can occur after an extended number of repeat intravitreal injections in the setting of worsening vitreomacular adhesion or VMT. This patient's FTMH was successfully treated surgically in a timely manner, and additional injections were resumed safely. Conclusions: Patients with an unexpected decrease in vision after intravitreal injections should be reevaluated with optical coherence tomography to rule out alternative pathology including vitreomacular interface abnormalities. FTMH, if present, should be treated promptly to allow for resumption of therapy as needed and visual optimization.

Positive and Negative Associations of Myopia with Ocular Diseases in Population-Based Studies.

OBJECTIVE: Prevalence of myopia and vision impairment due to myopic macular degeneration and myopia-related optic neuropathies have markedly increased worldwide. We evaluated whether myopia is associated with the prevalence of other ocular disorders in a positive or negative sense. DESIGN: Population-based studies conducted in Russia, China and India. PARTICIPANTS: The Russian Ural Eye and Medical Study (UEMS) and the Beijing Eye Study (BES) included 5899 individuals and 4439 individuals (all aged 40+ years), respectively, and the Central India Eye and Medical Study (CIEMS) consisted of 4711 individuals, aged 30+ years. The studies were conducted in rural and urban regions in Bashkortostan/Russia, Nagpur/India, and Beijing/China. METHODS: The participants underwent a series of ophthalmological and general medical examinations. MAIN OUTCOME MEASURES: Axial length as surrogate for myopia, and prevalence of diabetic retinopathy (DR), age-related macular degeneration (AMD), angle-closure glaucoma (ACG), and open-angle glaucoma (OAG). RESULTS: In the UEMS, DR prevalence (OR:0.73;95%CI:0.56,0.96), AMD prevalence (OR:0.85;95%CI:0.74,0.98) and ACG prevalence (OR:0.72;95%CI:0.55,0.95) decreased, and OAG prevalence (OR:1.65;95%CI:1.45,1.88) increased with longer axial length in multivariable analyses. In the CIEMS, lower AMD prevalence (OR:0.81;95%CI:0.69,0.95) and lower ACG prevalence (OR:0.55;95%CI:0.36,0.83), and higher OAG prevalence (OR:1.45;95%CI:1.15,1.83) were associated with longer axial length. DR prevalence (0.33%;95%CI:0.16,0.50) was too low for statistical analysis in the CIEMS. In the BES, prevalence (OR:0.64;95%CI:0.50,0.81) and 10-year incidence of DR (OR:0.48;95%CI:0.33,0.71) and prevalence (OR:0.83;95%CI:0.77,0.89) and 5-year incidence of AMD (OR:0.996;95%CI:0.993,0.999) decreased, and prevalence (OR:1.35;95% CI:1.17,1.56) and 10-year incidence of OAG (OR:1.40;95%CI:1.22,1.61) increased with longer axial length. In all three studies, the association between higher OAG prevalence and longer axial length was nonlinear with a slight increase for the moderate myopia range, and a steep increase in the highly myopic range. CONCLUSIONS AND RELEVANCE: Myopia is associated with a lower prevalence of DR, AMD and ACG and lower incidence of DR and AMD, while high myopia more than moderate myopia is associated with a higher prevalence and incidence of OAG. Future studies may assess whether in myopia, in particular in moderate myopia, the myopia-related advantages, i.e., lower prevalence of DR, AMD and ACG, may outweigh the increased risks for OAG and other myopia-related disorders.

Genetic and Epigenetic Biomarkers Linking Alzheimer's Disease and Age-Related Macular Degeneration.

Alzheimer's disease (AD) represents a prominent neurodegenerative disorder (NDD), accounting for the majority of dementia cases worldwide. In addition to memory deficits, individuals with AD also experience alterations in the visual system. As the retina is an extension of the central nervous system (CNS), the loss in retinal ganglion cells manifests clinically as decreased visual acuity, narrowed visual field, and reduced contrast sensitivity. Among the extensively studied retinal disorders, age-related macular degeneration (AMD) shares numerous aging processes and risk factors with NDDs such as cognitive impairment that occurs in AD. Histopathological investigations have revealed similarities in pathological deposits found in the retina and brain of patients with AD and AMD. Cellular aging processes demonstrate similar associations with organelles and signaling pathways in retinal and brain tissues. Despite these similarities, there are distinct genetic backgrounds underlying these diseases. This review comprehensively explores the genetic similarities and differences between AMD and AD. The purpose of this review is to discuss the parallels and differences between AMD and AD in terms of pathophysiology, genetics, and epigenetics.

Thyroid Hormone Signaling in Retinal Development and Function: Implications for Diabetic Retinopathy and Age-Related Macular Degeneration.

Thyroid Hormones (THs) play a central role in the development, cell growth, differentiation, and metabolic homeostasis of neurosensory systems, including the retina. The coordinated activity of various components of TH signaling, such as TH receptors (THRs) and the TH processing enzymes deiodinases 2 and 3 (DIO2, DIO3), is required for proper retinal maturation and function of the adult photoreceptors, Müller glial cells, and pigmented epithelial cells. Alterations of TH homeostasis, as observed both in frank or subclinical thyroid disorders, have been associated with sight-threatening diseases leading to irreversible vision loss i.e., diabetic retinopathy (DR), and age-related macular degeneration (AMD). Although observational studies do not allow causal inference, emerging data from preclinical models suggest a possible correlation between TH signaling imbalance and the development of retina disease. In this review, we analyze the most important features of TH signaling relevant to retinal development and function and its possible implication in DR and AMD etiology. A better understanding of TH pathways in these pathological settings might help identify novel targets and therapeutic strategies for the prevention and management of retinal disease.

Real-world efficacy of intravitreal faricimab for neovascular age-related macular degeneration: a systematic review.

BACKGROUND: To systematically review the real-world outcomes of intravitreal faricimab treatment in patients with neovascular age-related macular degeneration (nAMD) to evaluate its efficacy and safety in clinical settings. This study was conducted due to the need for real-world evidence to complement the findings from controlled clinical phase-III trials. METHODS: A systematic literature search was conducted on March 17, 2024, across 11 databases, utilizing search terms specifically tailored each database. All studies were reviewed qualitatively with specific focus on the outcomes of interest: the best-corrected visual acuity (BCVA), the central retina thickness (CRT), and the burden of therapy. RESULTS: We identified a total of 22 eligible studies of 1762 eyes from 1618 patients with nAMD. Studies reported that intravitreal faricimab injections maintained BCVA in patients with previously treated eyes and demonstrated statistically significant improvement in patients with treatment-naïve eyes. The CRT was reduced after intravitreal faricimab therapy. Faricimab was well-tolerated, with no significant safety concerns identified, and reduced the overall burden of therapy. CONCLUSION: Real-world studies corroborate the conclusions drawn from phase-III trials regarding faricimab treatment, demonstrating improvement in both visual and anatomical outcomes. Additionally, no significant safety issues were identified, as the treatment was generally well-tolerated and reduced the overall burden of therapy in the real-world settings.

Clinical Characteristics of Unilateral Macular Neovascularization Patients with Pachydrusen in the Fellow Eye.

Background/Objectives: To approach the clinical properties of pachydrusen that differ from conventional drusen, we investigated the incidence of macular neovascularization (MNV) in fellow eyes and the treatment outcomes of intravitreal aflibercept (IVA) in MNV eyes of unilateral MNV patients with pachydrusen in the fellow eye. Methods: We retrospectively studied 261 consecutive patients with treatment-naïve unilateral MNV. Patients were classified into four groups according to the type of drusen in the fellow eye: the pachydrusen group (n = 49), the soft drusen group (n = 63), the subretinal drusenoid deposit (SDD) group (n = 24), and the no drusen group (n = 125). The development of the MNV in the fellow eye was evaluated for five years, and the retreatment proportion after three monthly aflibercept injections was evaluated for one year. Results: The choroidal thickness in the fellow eyes and MNV eyes was the greatest in the pachydrusen group (all p < 0.001). The 5-year incidence of MNV in the pachydrusen group was similar to that in the soft drusen group and no drusen group. The pachydrusen group had a lower retreatment rate than the other groups did (pachydrusen group: 46.4%; soft drusen group: 78.1%; SDDs: 87.5%; no drusen group: 83.3%). Conclusions: Unilateral MNV patients with pachydrusen in the fellow eye had a lower retreatment rate (46.4%/1 year); therefore, aflibercept monotherapy using the PRN regimen is one of the preferred treatment methods for MNV patients with pachydrusen in the fellow eye.

Cataract Surgery in nAMD Patients Receiving Intravitreal Aflibercept Injections.

Background: To evaluate functional and anatomical outcomesof cataract surgery in neovascular age-related macular neovascularization (nAMD) eyes receiving anti-vascular endothelial growth factor (anti-VEGF) intravitreal injections in modified pro re nata (PRN) regimen. Materials and Methods: Sixty eyes of 60 nAMD patients, including 41 women (68.3%) and 19 men (31.7%) in an average age of 77.35 ± 6.41 years, under treatment with intravitreal aflibercept injections in modified PRN regimen with no signs of macular neovascularization (MNV) activity during two consecutive visits were included in this prospective, observational study. Best-corrected visual acuity (BCVA), central retinal thickness (CRT), as well as the number of anti-VEGF injections were monitored six months before and after phacoemulsification with intraocular lens (IOL) implantation. Further, the change of the abovementioned parameters was assessed during the six-month follow-up period for CRT and the number of injections, while the BCVA was monitored for 54 months. Results: BCVA measured on the first day after surgery (0.17 ± 0.19 logMAR) as well as in the six-month post-surgery (0.13 ± 0.16 logMAR) significantly improved compared to preop values (0.42 ± 0.20 logMAR). BCVA remains stable during the observational period. We found that both differences were statistically significant (p < 0.01). The mean CRT and the mean number of injections did not differ between the six-month pre- and post-surgical periods. Conclusions: We showed the beneficial effect of phacoemulsification in nAMD patients treated with anti-VEGF agents on visual outcomes in the short and long term. Cataract surgery in nAMD eyes treated with anti-VEGF injections does not increase the frequency of anti-VEGF injections and does not cause deterioration of the macular status.

Natural History of Visual Acuity and Microperimetry-Based Functional Outcome Measures of the Macula in Patients with Geographic Atrophy: A Retrospective Chart Review Study in Germany.

Background/Objectives: Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD) leading to the progressive and irreversible loss of visual function. Characteristics of GA include atrophic lesions resulting from the loss of photoreceptors, retinal pigment epithelium, and choriocapillaris. During GA progression, atrophic lesions typically advance from the macular periphery to the center, affecting foveal light sensitivity and visual acuity. This study analyzed changes in light sensitivity and visual acuity during the natural course of GA progression using the topographic analysis of structural and functional changes based on Early Treatment Diabetic Retinopathy Study (ETDRS) charts, multimodal imaging, and microperimetry assessment. Methods: Medical chart data of GA patients between 2014 and 2022 from the Internationale Innovative Ophthalmochirurgie GbR (I.I.O.) research center (Düsseldorf, Germany) were retrospectively analyzed. All patient eyes fulfilling the phase 3 OAKS study inclusion criteria were included and followed up for 60 months. The imputation of missing measurements and dropouts was performed by linear mixed models. Results: A total of 20 GA eyes from 13 GA patients were included in the study. At the index, 53.8% of patients had bilateral GA, with 70.0% of the eyes showing multifocal GA and 30.0% subfoveal encroachment (SFE). A total of 35.0% of the eyes had 2-5, and 15.0% over 20, areas of atrophy. Over time, the GA lesion size increased from 6.4 mm2 to 11.8 mm2 (1.08 mm2/year). After an average observation time of 2.9 years, 78.6% of the initially unaffected study eyes developed SFE. The percentage of study eyes without visual impairment decreased from 55.0% to 30.0%, with mean normal-luminance best-corrected visual acuity (NL-BCVA) reducing from 63.7 to 55.7 ETDRS letters. The share of absolute scotoma points in microperimetry assessment increased from 15.7% to 43.5% while overall average macular sensitivity declined from 15.7 dB to 7.4 dB. Conclusions: The substantial deterioration of macular outcomes and visual function was comprehensively detected. The results were a documentation of structural and functional aspects of the natural progression of GA for a 60-month follow-up, providing a typical outline for AMD patients with GA.

Exudative Age-Related Macular Degeneration: Association between Treatment Efficacy and Single-Nucleotide Variants in RAD51B, TRIB1, COL8A1, COL10A1, IL-9, IL-10, and VEGFA Genes.

Age-related macular degeneration (AMD) is a progressive neurodegenerative condition leading to vision loss and eventual blindness, with exudative AMD posing a heightened risk due to choroidal neovascularization and localized edema. Therapies targeting the VEGF pathway aim to address this mechanism for treatment effectiveness. Our study aimed to evaluate associations between specific genetic variants (RAD51B rs8017304, rs2588809; TRIB1 rs6987702, rs4351379; COL8A1 rs13095226; COL10A1 rs1064583; IL-9 rs1859430, rs2069870, rs11741137, rs2069885, rs2069884; IL-10 rs1800871, rs1800872, rs1800896; VEGFA rs1570360, rs699947, rs3025033, rs2146323) and the response to anti-VEGF treatment for exudative AMD. We enrolled 119 patients with exudative AMD categorized as responders or non-responders based on their response to anti-VEGF treatment. Statistical analysis revealed that RAD51B rs8017304 heterozygous and homozygous minor allele carriers had increased CMT before treatment compared to wild-type genotype carriers (p = 0.004). Additionally, TRIB1 rs4351379 heterozygous and homozygous minor allele carriers exhibited a greater decrease in central macular thickness (CMT) after 6 months of treatment than wild-type genotype carriers (p = 0.030). IL-9 rs1859430, rs2069870, and rs2069884 heterozygous and homozygous minor allele carriers had worse BCVA before treatment than wild-type genotype carriers (p = 0.018, p = 0.012, p = 0.041, respectively). Conversely, IL-9 rs2069885 heterozygous and homozygous minor allele carriers showed greater improvement in BCVA after 6 months compared to wild-type genotype carriers (p = 0.032). Furthermore, VEGFA rs699947 heterozygous and homozygous minor allele carriers had better BCVA before treatment and after 3 and 6 months of treatment than wild-type genotype carriers (p = 0.003, p = 0.022, respectively), with these carriers also exhibiting higher CMT after 6 months of anti-VEGF treatment (p = 0.032). Not all results remained statistically significant under this stringent correction for multiple comparisons. The comparisons of the serum concentrations of IL-10, VEGF-A, and VEGF-R2/KDR between non-responders and responders did not yield statistically significant differences. Our study identified significant associations between genetic variants, including RAD51B rs8017304, TRIB1 rs4351379, IL-9 rs1859430, rs2069870, rs2069884, rs2069885, and VEGFA rs699947, and parameters related to the efficacy of exudative AMD treatment, such as BCVA and CMT.

Publication trends of vascular endothelial growth factor (VEGF) and anti-VEGF treatment in neovascular age-related macular degeneration during 2001-2020: a 20-year bibliometric study.

PURPOSE: This study sought to provide an overview of the current research and further analyze publication trends in the field of vascular endothelial growth factor (VEGF) and anti-VEGF treatment for neovascular age-related macular degeneration (NVAMD). METHODS: We downloaded all related publications from 2001 to 2020 from the Web of Science Core Collection and conducted a bibliometric analysis using the bibiometrix package in R programming software. RESULTS: A total of 3717 publications were included in the analysis. The USA contributed the largest number of publications (1443), and achieved the highest number of citations (74,946) and H-index value (28). Johns Hopkins University, USA, was the top institution with the most publications, and Peter A. Campochiaro was the most productive professor at The Wilmer Eye Institute, USA. 9.60% of the total publications were from the Journal of Retinal and Vitreous Diseases. Trend analysis demonstrated that anti-VEGF therapy was introduced in early 2000 after steroids, and the last 2 decades have witnessed the blossom of several anti-VEGF agents. "Treat-and-extend" and "resistance" were two popular trend topics in recent years. CONCLUSIONS: The USA occupies a dominant position in the research field of VEGF and anti-VEGF treatments in NVAMD. Steroid administration, photodynamic therapy, and anti-VEGF therapy have been pivotal advances in the treatment of NVAMD patients over the past 2 decades. Limited acting period and resistance are potential investigation directions in future studies.

Insulin resistance in the retina: possible implications for certain ocular diseases.

Insulin resistance (IR) is becoming a worldwide medical and public health challenge as an increasing prevalence of obesity and metabolic disorders. Accumulated evidence has demonstrated a strong relationship between IR and a higher incidence of several dramatically vision-threatening retinal diseases, including diabetic retinopathy, age-related macular degeneration, and glaucoma. In this review, we provide a schematic overview of the associations between IR and certain ocular diseases and further explore the possible mechanisms. Although the exact causes explaining these associations have not been fully elucidated, underlying mechanisms of oxidative stress, chronic low-grade inflammation, endothelial dysfunction and vasoconstriction, and neurodegenerative impairments may be involved. Given that IR is a modifiable risk factor, it may be important to identify patients at a high IR level with prompt treatment, which may decrease the risk of developing certain ocular diseases. Additionally, improving IR through the activation of insulin signaling pathways could become a potential therapeutic target.

Mingjing granule inhibits the subretinal fibrovascular membrane of two-stage laser-induced neovascular age-related macular degeneration in rats.

Objective: The study aims to investigate the protective effect of Mingjing granule (MG) in a fibrovascular membrane rat model of neovascular age-related macular degeneration (nAMD) and explore the underlying mechanism. Methods: The nAMD fibrovascular membrane model was established by two-stage laser photocoagulation. BN rats were randomly divided into four groups: the model group was gavaged with distilled water, the anti-VEGF group was given an intravitreous injection of ranibizumab, the MG + anti-VEGF group was gavaged with MG combined with an intravitreous injection of ranibizumab, and the normal group not modeled only fed conventionally. Lesions were evaluated by color fundus photograph, optical coherence tomography, fundus fluorescein angiography, and retinal pigment epithelial-choroid-sclera flat mount. The changes in the retinal structure were observed by histopathology. The expression of inflammatory cell markers F4/80, Iba-1, and glial fibrillary acidic protein (GFAP); the fibrosis-related factors collagen-1, fibronectin, α-smooth muscle actin (α-SMA), and transforming growth factor-beta (TGF-ß); and the complement system-related factors C3a and C3aR in the retina were detected by immunofluorescence or qRT-PCR. Results: The current study revealed that MG + anti-VEGF administration more significantly reduced the thickness of fibrovascular lesions, suppressed vascular leakage (exudation area and mean density value), inhibited the area of fibrovascular lesions, and restrained the formation of the fibrovascular membrane than the anti-VEGF agent alone in the two-stage laser-induced rat model. The fluorescence intensities of F4/80, Iba-1, collagen-1, fibronectin, TGF-ß, and C3aR showed more significant inhibition in MG + anti-VEGF-treated rats than the anti-VEGF agent alone. The mRNA expression levels of F4/80, Iba-1, GFAP, collagen-1, fibronectin, α-SMA, TGF-ß, and C3a showed lower levels in rats treated with MG + anti-VEGF than the anti-VEGF agent alone. Conclusion: Combining MG with anti-VEGF treatment inhibits the growth of the fibrovascular membrane more effectively than using anti-VEGF treatment alone. The mechanism underlying this effect may involve limiting inflammatory cell aggregation, controlling complement system activation, and decreasing the expression of the fibrotic protein.

Elevated tumor necrosis factor alpha and vascular endothelial growth factor in intermediate age-related macular degeneration and geographic atrophy.

Introduction: Tumor necrosis factor alpha (TNF-α) is an inflammatory cytokine implicated in pathological changes to the retinal pigment epithelium that are similar to changes in geographic atrophy (GA), an advanced form of age related macular degeneration (AMD). TNF-α also modulates expression of other cytokines including vascular endothelial growth factor (VEGF), leading to choroidal atrophy in models of AMD. The purpose of this study was to investigate systemic TNF-α and VEGF in patients with GA and intermediate AMD (iAMD) compared to controls without AMD. Methods: We examined plasma levels of TNF-α and VEGF in patients with GA, iAMD, and controls without AMD from the University of Colorado AMD registry (2014 to 2021). Cases and controls were characterized by multimodal imaging. TNF-α and VEGF were measured via multiplex immunoassay and data were analyzed using a non-parametric rank based linear regression model fit to plasma biomarkers. Results: There were 97 GA, 199 iAMD patients and 139 controls. TNF-α was significantly increased in GA (Median:9.9pg/ml, IQR:7.3-11.8) compared to iAMD (Median:7.4, IQR:5.3-9.1) and in both GA and iAMD compared to controls (Median:6.4, IQR:5.3-7.8), p<0.01 for all comparisons. VEGF was significantly increased in iAMD (Median:8.9, IQR:4.8-14.3) compared to controls (Median:7.7, IQR:4.6-11.1), p<0.01. There was a significant positive correlation between TNF-α and VEGF in GA (0.46, p<0.01), and iAMD (0.20, p=0.01) with no significant interaction between TNF-α and VEGF in any group. Discussion: These findings suggest TNF-α and VEGF may contribute to systemic inflammatory processes associated with iAMD and GA. TNF-α and VEGF may function as systemic biomarkers for disease development.

Aging of the eye: Lessons from cataracts and age-related macular degeneration.

Aging is the greatest risk factor for chronic human diseases, including many eye diseases. Geroscience aims to understand the effects of the aging process on these diseases, including the genetic, molecular, and cellular mechanisms that underlie the increased risk of disease over the lifetime. Understanding of the aging eye increases general knowledge of the cellular physiology impacted by aging processes at various biological extremes. Two major diseases, age-related cataract and age-related macular degeneration (AMD) are caused by dysfunction of the lens and retina, respectively. Lens transparency and light refraction are mediated by lens fiber cells lacking nuclei and other organelles, which provides a unique opportunity to study a single aging hallmark, i.e., loss of proteostasis, within an environment of limited metabolism. In AMD, local dysfunction of the photoreceptors/retinal pigmented epithelium/Bruch's membrane/choriocapillaris complex in the macula leads to the loss of photoreceptors and eventually loss of central vision, and is driven by nearly all the hallmarks of aging and shares features with Alzheimer's disease, Parkinson's disease, cardiovascular disease, and diabetes. The aging eye can function as a model for studying basic mechanisms of aging and, vice versa, well-defined hallmarks of aging can be used as tools to understand age-related eye disease.