Search Results (111)

Although oxidative stress plays a critical role in age-related macular degeneration (AMD) progression, natural product–derived single compounds against AMD remain largely unexplored. We investigated the protective effects and underlying mechanism of α-iso-cubebene against AMD-like retinal injury. Alterations in key phenotypes for AMD were analyzed in AMD-mimicking models using ARPE-19 cells co-treated with blue light (BL) and N-retinylidene-N-retinylethanolamine (A2E), as well as BL-exposed BALB/c mice. In BL+A2E-treated ARPE-19 cells, α-iso-cubebene reduced intracellular reactive oxygen species (ROS) and nitric oxide (NO) production and restored superoxide dismutase (SOD) activity and nuclear factor erythroid 2–related factor 2 (Nrf2), suggesting enhancement of the antioxidant defense system. Furthermore, α-iso-cubebene improved cell viability, reduced apoptotic cell populations, and regulated apoptosis-related signaling pathways under oxidative stress conditions. It also attenuated cyclooxygenase-2 (COX-2)-mediated inducible nitric oxide synthase (iNOS) signaling and was associated with reduced inflammasome-related signaling. Importantly, these protective effects were consistently observed regarding the protection of histopathological structure and normalization of inflammatory cytokines in the retina of BL-exposed BALB/c mice. Collectively, our results demonstrate that α-iso-cubebene, as a potential therapeutic candidate, alleviates AMD-like retinal injury and was associated with enhanced antioxidant responses and reduced inflammatory and apoptotic signaling markers. Full article

Photobiomodulation (PBM) is a non-invasive therapeutic strategy that uses red and near-infrared (NIR) light in the 590–950 nm range to modulate the cellular and molecular pathways involved in retinal homeostasis. At the molecular level, PBM acts primarily through photon absorption by cytochrome c oxidase (CcO, complex IV of the mitochondrial electron transport chain), whose four metal centres—two copper (CuA and CuB) and two heme groups (heme a and heme a₃)—absorb light across approximately 600–1000 nm. Photon capture promotes photodissociation of inhibitory nitric oxide (NO) from the binuclear CuB–heme a₃ centre, accelerates electron transfer, restores the proton-motive force and increases ATP synthesis. These primary events trigger a coordinated molecular programme that includes (i) transient mitochondrial reactive oxygen species (ROS) bursts that activate the Nrf2/Keap1/ARE axis and upregulate phase II antioxidant enzymes (HO-1, NQO1, GCLC, SOD2, catalase, GPx); (ii) calcium- and cAMP-dependent secondary signalling that converges on PI3K/Akt, MAPK/ERK, AMPK and mTOR pathways; (iii) suppression of NF-κB-driven cytokine production (TNF-α, IL-1β, IL-6) and of NLRP3 inflammasome activation; (iv) downregulation of the HIF-1α/VEGF axis, particularly at 590 nm; (v) anti-apoptotic remodelling of the Bcl-2/Bax ratio with reduced cytochrome c release and caspase-3/9 activation; and (vi) PGC-1α/TFAM/NRF1-driven mitochondrial biogenesis, alongside restoration of fission/fusion homeostasis (Drp1, Mfn1/2, Opa1) and PINK1/Parkin-mediated mitophagy. Wavelength specificity has a defined molecular basis: 590 nm modulates VEGF signalling and RPE pump activity, 660 nm interacts with the CuB centre and enhances O₂ binding at CcO, and 850 nm is absorbed by CuA and supports electron entry into complex IV. A second molecular axis is the bidirectional crosstalk between PBM and the circadian system: mitochondrial respiration, ATP turnover and CcO activity oscillate over the 24 h cycle under the control of the BMAL1/CLOCK and PER/CRY core machinery, the NAD⁺/SIRT1–SIRT3 axis and REV-ERBα. Preliminary preclinical and human observations suggest that NIR-induced bioenergetic and functional gains may be coupled to this rhythm, with greater benefit reported when light is delivered in the morning window (≈08:00–11:00); this time dependence should be regarded as an emerging hypothesis rather than an established clinical principle. The clinical evidence is unevenly developed across indications. It is most robust for non-exudative age-related macular degeneration, where multiwavelength PBM (590/660/850 nm; Valeda Light Delivery System) has shown disease-modifying potential in randomized controlled trials (LIGHTSITE I–III and the LIGHTSITE IIIB extension), with sustained BCVA gains and reduced incidence of geographic atrophy over 24 months and beyond. Evidence for retinitis pigmentosa, central serous chorioretinopathy and, with red-light monotherapy, childhood myopia is at present limited to small or short-term studies and remains preliminary. This narrative review synthesizes the molecular machinery engaged by PBM, integrates clinical findings across retinal diseases and discusses how chronotherapeutic delivery of light, aligned with the molecular clock, may further optimize therapeutic efficacy. Full article

Oxidative stress is a major contributor to the development of age-related macular degeneration (AMD), and excessive oxidative stress can induce retinal pigment epithelium (RPE) dysfunction, apoptosis, and retinal degeneration. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) is a major enzymatic source of reactive oxygen species (ROS); however, its mechanistic role in sodium iodate (NaIO₃)-induced oxidative injury remains unclear. Tetrahydrocurcumin (THC), the major metabolite of curcumin, exhibits potent antioxidant and cytoprotective activities, but its protective effects against AMD-associated retinal degeneration have not been fully elucidated. In the present study, we investigated whether THC protects against NaIO₃-induced ROS-mediated apoptosis in RPE cells through regulation of NOX2 signaling. In vitro, THC significantly attenuated NaIO₃-induced cytotoxicity and prevented apoptosis by suppressing hydrogen peroxide (H₂O₂) production and intracellular ROS accumulation in ARPE-19 cells. THC also preserved mitochondrial membrane potential by inhibiting the Src/p47^phox/NOX2 signaling pathway and subsequently attenuated mitochondria-mediated apoptotic signaling. Furthermore, THC markedly reduced the expression of apoptotic proteins, including Bax, cleaved caspase-3, and cleaved PARP, concomitantly with suppression of Ras/Raf/MEK/ERK signaling. Mechanistically, treatment with the selective NOX2 inhibitor GSK2795039 significantly attenuated NaIO₃-induced ROS accumulation and mitochondrial depolarization, while co-treatment with THC further enhanced these protective effects. In vivo, THC ameliorated NaIO₃-induced retinal structural abnormalities by preserving the outer nuclear layer (ONL), reducing caspase-3 expression, and improving pupillary light responses in mice. Collectively, these findings demonstrate that THC protects against NaIO₃-induced retinal degeneration through suppressing NOX2-dependent oxidative stress and downstream Ras/Raf/MEK/ERK-mediated apoptotic signaling, highlighting its potential as a therapeutic candidate for AMD and other oxidative stress-related retinal disorders. Full article

Background/Objectives: Cisplatin is a potent chemotherapeutic agent whose clinical utility is limited by severe side effects, including neurotoxicity affecting the ocular system. The pathophysiology involves oxidative stress and mitochondrial dysfunction, to which the retina is particularly vulnerable. Selenium (Se), an essential trace element and component of antioxidant enzymes, has shown potential in mitigating cisplatin toxicity, although its efficacy with respect to retinal structure and the influence of administration routes remain underexplored. This study aimed to evaluate the protective efficacy of selenium against cisplatin-induced retinal toxicity and compare the effects of intraperitoneal and oral selenium administration. Methods: Forty adult male Wistar rats were randomized into four groups (n = 10 each): Group A (Cisplatin Monotherapy, 3.5 mg/kg IP for 5 days; cumulative dose 17.5 mg/kg); Group B (Cisplatin + Intraperitoneal Selenium, 2.73 mg/kg; cumulative dose 60 mg/kg); Group C (Control); and Group D (Cisplatin + Oral Selenium). Selenium prophylaxis, administered as sodium selenite (Na₂SeO₃), began two days prior to cisplatin administration and continued for 15 days post-treatment. Retinal evaluation two weeks after cisplatin cessation included light microscopy, semi-quantitative immunohistochemical (IHC) analysis for inflammatory (IL-6) and fibrotic (TGF-β2) markers, and Transmission Electron Microscopy (TEM) for ultrastructural analysis, which were the primary endpoints. Statistical differences in the IHC scores were analyzed via the Kruskal-Wallis H test with Dunn’s post hoc comparisons. Results: Cisplatin monotherapy (Group A) caused severe disruption of the retinal architecture, including edema, reactive gliosis, and significant upregulation of IL-6 and TGF-β2. Ultrastructural analysis revealed mitochondrial swelling (cristolysis) and photoreceptor disk fragmentation. Intraperitoneal selenium (Group B) was associated with significant structural preservation and intact mitochondria, with TGF-β2 levels comparable to those of the controls, although the IL-6 level remained moderately elevated. Conversely, oral selenium (Group D) suppressed both IL-6 and TGF-β2 expression to near-negative levels but provided less ultrastructural protection, resulting in persistent mitochondrial swelling and focal photoreceptor disruption. Conclusions: Systemic cisplatin induces severe subcellular retinal toxicity characterized by mitochondrial damage and photoreceptor degeneration. Selenium supplementation attenuates these effects; however, outcome patterns differ by administration route. Intraperitoneal selenium was associated with greater morphological and ultrastructural preservation despite persistent IL-6 elevation, whereas oral selenium normalized immunohistochemical marker expression to near-control levels but was associated with more pronounced residual subcellular damage on qualitative TEM assessment. These preliminary morphological and immunohistochemical findings suggest that the route of selenium delivery may influence its neuroprotective profile; however, pharmacokinetic measurements and functional retinal assessments, such as electroretinography, are warranted before its clinical translation. Full article

The zebrafish (Danio rerio) is a widely used model for studying retinal regeneration. In adults, light-induced retinal damage (LIRD) serves as an environmental phototoxic stressor that induces photoreceptor degeneration and regenerative responses, whereas larval models remain comparatively underexplored. In this study, we validate a larval LIRD paradigm as a versatile system for studying acute phototoxic injury and early regeneration-associated transcriptomic responses. Using high-throughput RNA sequencing, we profiled retinal transcriptional changes 48 h post-LIRD and complemented these findings with targeted pharmacological modulation of redox signaling. Larval LIRD induced robust activation of canonical apoptotic and regeneration-associated pathways, recapitulating key features of adult LIRD models while engaging previously underexplored gene-regulatory networks. Among these, pathways related to oxidative stress responses, antioxidant enzymes, and oxygen metabolism were prominently regulated. Functional attenuation of oxidative stress using the N-acetylcysteine reduced phototoxic injury-induced apoptosis and proliferation, while inflammatory markers remained largely unaffected. Conversely, subtoxic intra-retinal hydrogen peroxide exposure was sufficient to induce proliferative markers without eliciting apoptosis response. At the signaling level, modulation of oxidative stress influenced components of growth-associated signaling pathways activated during early injury response. Together, these findings support a role for oxidative stress as a key component of early injury-associated signaling in larval retinal regeneration. This study integrates histological, transcriptomic, and pharmacological analyses to interrogate early regenerative programs and provides a comprehensive transcriptomic resource for exploring redox-associated mechanisms in retinal injury and repair. Full article

Age-related macular degeneration (AMD) is a progressive retinal disorder characterised by oxidative stress and inflammation. Although pyrroloquinoline quinone (PQQ) has been reported to exert neuroprotective effects, its specific efficacy in in vivo models of AMD pathophysiology has not yet been elucidated. In this study, we evaluated the protective effects of PQQ against all-trans-retinal (ATR)-induced cytotoxicity in ARPE-19 cells and light-induced photoreceptor degeneration in rats. Pretreatment of ARPE-19 cells with PQQ dose-dependently mitigated ATR-induced cytotoxicity. In the in vivo model, rats received a single intraperitoneal injection of PQQ (2 or 5 mg/kg) 1 h prior to 1000-lux light exposure. Retinal function and morphology were evaluated by electroretinography and haematoxylin–eosin staining, respectively. The 5 mg/kg PQQ group retained significantly greater retinal function than the vehicle group at 3 days postexposure and demonstrated significant preservation of the outer nuclear layer at 7 days postexposure, indicating the suppression of photoreceptor cell death. Western blot analysis detected the dose-dependent suppression of light-induced c-Fos upregulation following PQQ treatment. These findings suggest that the protective effect of PQQ against phototoxic damage is associated with the suppression of c-Fos signalling, thus lending support to the further investigation of PQQ as a potential therapeutic agent for AMD. Full article

Pathological USH2A mutations cause Usher syndrome type II, characterized by progressive retinitis pigmentosa and hearing and balance impairment. This study aims to investigate the cellular mechanisms underlying USH2A-related retinal degeneration using human induced pluripotent stem cell (hiPSC)-derived retinal organoids. The introduction of a homozygous nonsense mutation in the USH2A hotspot exon-13 resulted in normal photoreceptor development but loss of ciliary localization of usherin long form B and its interacting proteins, ADGRV1 and whirlin. Notably, single-cell RNA sequencing revealed unexpected significant transcriptional changes in Müller glial cells (MGCs), suggestive of disruptions in the translation, innate immune response, and endolysosomal system. These findings suggest that, while photoreceptor cells are mildly affected by the exon-13 USH2A mutation, MGCs exhibit major transcriptional changes, potentially contributing to the disease progression and therefore shedding light on potential alternative therapeutic targets. Full article

Chronic exposure to short-wavelength blue light induces oxidative stress, inflammation, and apoptosis in retinal tissues, contributing to vision loss. This study investigated the protective effects of Lactobacillus reuteri Y7, a human-derived probiotic, against blue light–induced retinal damage in mice. Male C57BL/6 mice were exposed to 400 lux blue light for 35 days and received either low- or high-dose Y7, lutein, or no intervention. Retinal morphology, inflammatory gene expression, gut barrier integrity, and gut microbiota composition were assessed. Low-dose Y7 promoted microbial diversity and enrichment of short-chain fatty acid–producing taxa, while high-dose Y7 favored enrichment of Akkermansia, Parasutterella, and Bacteroides, enhancing mucosal barrier function and metabolic regulation. Both doses attenuated retinal inflammation, preserved retinal layers, and improved gut barrier integrity, with high-dose Y7 matching or exceeding lutein’s protective effects. Mechanistic insights suggest a gut–retina axis whereby microbial metabolites modulate oxidative stress, inflammation, and vascular homeostasis. These findings highlight L. reuteri Y7 as a potential non-invasive strategy for retinal degeneration prevention, with efficacy comparable to dietary antioxidants. Future studies should explore long-term safety, metabolite-mediated mechanisms, and comparative efficacy with other antioxidants. Full article

Thyroid hormone (TH) regulates cell proliferation, differentiation, and metabolism. Increased TH levels in circulation are associated with a higher incidence of age-related macular degeneration. In mice, TH treatment causes photoreceptor degeneration, which is accompanied by an increase in receptor-interacting serine/threonine-protein kinase 3 (RIPK3) in the retina. Here, we investigated the contribution of RIPK3/necroptosis to TH-induced photoreceptor degeneration using mice deficient in RIPK3 and the necroptotic mixed lineage kinase domain-like protein (MLKL). Wild-type (C57BL/6) and mutant mice at postnatal day 30 received triiodothyronine (T3, 20 µg/mL in drinking water) for four weeks, followed by the evaluation of photoreceptor survival/death and retinal function. Deletion of Ripk3 preserved photoreceptor integrity against T3-induced degeneration, evidenced by improved retinal morphology, increased cone density, improved retinal light responses, and reduced cell death. This protection was observed in both global and photoreceptor-specific Ripk3 knockout mice. In contrast, the deletion of Mlkl did not protect photoreceptors. This work supports the view that RIPK3, but not MLKL, contributes to TH-induced photoreceptor degeneration. The lack of protection from Mlkl deletion suggests that RIPK3’s action is likely mediated via a necrosome-independent mechanism. These findings provide significant insight into how TH signaling induces photoreceptor degeneration and implicate RIPK3 as a potential therapeutic target. Full article

Retinal degeneration is associated with dietary factors and environmental light exposure. This study investigated the effects of a high-fructose high-fat (HFHF) diet on susceptibility to blue light (BL)-induced retinal damage. Male ICR mice were randomized into three groups: control, BL alone, and BL plus HFHF diet (BL + HFHF). The BL + HFHF group consumed the HFHF diet for 40 weeks, followed by 8 weeks of low-intensity BL exposure (465 nm, 37.7 lux, 0.8 μW/cm²) for 6 h daily. The BL group underwent the same BL exposure while kept on a standard diet. Histopathological analysis showed that, under BL exposure, the HFHF diet significantly reduced the number of photoreceptor nuclei and the thickness of the outer nuclear layer and inner/outer segments compared to the BL group (p < 0.05). While BL exposure alone caused oxidative DNA damage, rhodopsin loss, and Müller cell activation, the combination with an HFHF diet significantly amplified the oxidative DNA damage and Müller cell activation. Moreover, the HFHF diet increased blood–retinal barrier permeability and triggered apoptosis under BL exposure. Mechanistically, the BL + HFHF group exhibited increased retinal advanced glycated end product (AGE) deposition, accompanied by the activation of the receptor for AGE (RAGE), NFκB, and the NLRP3 inflammasome-dependent IL-1β pathway. In conclusion, this study underscores that unhealthy dietary factors, particularly those high in fructose and fat, may intensify the hazard of BL and adversely impact visual health. Full article

Background: An acute angle-closure attack (AAC) is an ocular emergency that results from a rapid increase in intraocular pressure (IOP). Sustained IOP elevation induces severe degeneration of retinal ganglion cells (RGCs) without treatment. Overactivated microglia, key participants in innate immune responses, have critical roles in the pathogenesis of IOP-induced RGC death, although precise mechanisms remain unclear. In the present study, we used a rat ex vivo acute glaucoma model to investigate the role of microglial signaling in RGC death and examined whether pharmacological depletion of microglia using a CSF-1R inhibitor, PLX5622, exerts neuroprotection against pressure-induced retinal injury. Methods: Ex vivo rat retinas were exposed to hydrostatic pressure (10 mmHg or 75 mmHg) for 24 h. Pressure-dependent changes in retinal microglia and RGCs were detected by immunofluorescence. Morphological changes in the retina and RGC apoptosis were examined using light microscopy and TUNEL staining, respectively. The expression of NLRP3, active caspase-1, pro IL-1β, and IL-1β were examined using Western blotting. Effects of PLX5622, an agent that depletes microglia, were examined in morphology, apoptosis, and protein expression assays, while TAK-242, a TLR4 inhibitor, was examined against protein expression. Results: Pressure loading at 75 mmHg markedly increased activated microglia and apoptotic RGCs in the isolated retinas. Western blotting revealed increases in expression of NLRP3, active caspase-1, pro IL-1β, and IL-1β at 75 mmHg compared to 10 mmHg. Inhibition of pressure-induced increases in NLRP3 by TAK-242 indicates that pressure elevation induces RGC death via activation of the TLR4–NLRP3 inflammasome cascade. PLX5622 depleted microglia at 75 mmHg and significantly decreased expression of NLRP3, active caspase-1, pro IL-1β, and IL-1β at 75 mmHg, resulting in preservation of RGCs. Conclusions: These results indicate that pressure elevation induces proliferation of inflammatory microglia and promotes IL-1β production via activation of the TLR4–NLRP3 inflammasome cascade, resulting in RGC death. Pharmacological depletion of microglia with PLX5622 could be a potential neuroprotective approach to preserve RGCs from inflammatory cytokines in AAC eyes. Full article

The Mediterranean diet, rich in plant-based foods, healthy fats, and herbs, has long been associated with a range of health benefits, including cardiovascular, neuroprotective, and anti-inflammatory effects. Recent studies suggest that certain components of this diet, particularly spices such as bay laurel, thyme, oregano, sage, and rosemary, may play a critical role in protecting the retina from oxidative damage, a key factor in blue-light-induced retinal degeneration. Blue light, emitted by digital screens and artificial lighting, has been implicated in the development of retinal conditions like age-related macular degeneration by inducing oxidative stress and inflammation. This review explores the potential of the herbs and spices commonly present in the Mediterranean diet to mitigate blue-light-induced retinal damage. These herbs are rich in polyphenols, flavonoids, essential oils, and terpenes, which offer antioxidant, anti-inflammatory, and antimicrobial properties, contributing to retinal health and reducing oxidative damage. By focusing on bioactive compounds such as eucalyptol (1,8-cineole), rosmarinic acid, carnosic acid, eugenol, and thymol, this article investigates how these herbs and spices might act as natural protectants against blue-light-induced stress and retinal degeneration. The findings highlight the promising role of these culinary staples in preventing retinal damage and offer insights into future dietary recommendations for eye health in an increasingly digital world. Full article

Myo/Nog cells play a pivotal role in ocular development and demonstrate a rapid response to stress and injury. This study investigates their behavior and distribution in a murine model of retinitis pigmentosa, specifically in C3H/HeJ mice, which exhibit photoreceptor degeneration due to a homozygous mutation in the Pde6brd1 gene. Retinal samples from C3H/HeJ and C57BL/6J mice were analyzed at postnatal weeks 2.5 to 6 using hematoxylin and eosin staining, immunofluorescence for brain-specific angiogenesis inhibitor 1 (BAI1) expressed in Myo/Nog cells, and TUNEL labeling for apoptotic cell detection. The results demonstrated a progressive thinning of the outer nuclear layer (ONL) in C3H mice, accompanied by a significant increase in Myo/Nog cell numbers. In normal retinas, Myo/Nog cells were primarily located in the inner nuclear and outer plexiform layers. However, in C3H/HeJ mice, they accumulated in the ONL near apoptotic photoreceptors and within the choroid. Notably, in these degenerative regions, Myo/Nog cells exhibited features of phagocytosis, suggesting a role in apoptotic cell clearance. Additionally, parallels between Myo/Nog cell responses in retinitis pigmentosa and models of oxygen-induced retinopathy, ocular hypertension, and light damage suggest that these cells may be leveraged for therapeutic purposes. Full article

Retinal degenerations, such as age-related macular degeneration and retinitis pigmentosa, present significant challenges due to genetic heterogeneity, limited therapeutic options, and the progressive loss of photoreceptors in advanced stages. These challenges are compounded by difficulties in precisely targeting residual retinal neurons and ensuring the sustained efficacy of interventions. Optogenetics offers a novel approach to vision restoration by inducing light sensitivity in residual retinal neurons through gene delivery of light-sensitive opsins. This review traces the evolution of opsins in optogenetic therapies, highlighting advancements from early research on channelrhodopsin-2 (ChR2) to engineered variants addressing key limitations. Red-shifted opsins, including ReaChR and ChrimsonR, reduced phototoxicity by enabling activation under longer wavelengths, while Chronos introduced superior temporal kinetics for dynamic visual tracking. Further innovations, such as Multi-Characteristic Opsin 1 (MCO1), optimized opsin performance under ambient light, bridging the gap to real-world applications. Key milestones include the first partial vision restoration in a human patient using ChrimsonR with light-amplifying goggles and ongoing clinical trials exploring the efficacy of opsin-based therapies for advanced retinal degeneration. While significant progress has been made, challenges remain in achieving sufficient light sensitivity for functional vision under normal ambient lighting conditions in a manner that is both effective and safe, eliminating the need for external light-enhancing devices. As research progresses, optogenetic therapies are positioned to redefine the management of retinal degenerative diseases, offering new hope for millions affected by vision loss. Full article

Age-related macular degeneration (AMD) is a leading cause of vision impairment in people over the age of 60. Currently, the FDA-approved drugs for AMD have various side effects, and there is a notable lack of drug development for dry AMD. This study aimed to explore the therapeutic effects of mono-ethyl fumarate (MEF) on AMD. MEF effectively protected ARPE-19 cells from cell death induced by a combination of A2E and blue light exposure. In a C57BL/6J mouse model of retinal degeneration caused by sodium iodate, MEF played a role in preserving retinal thickness and maintaining the layered structure of the retina. It was assessed via fundus imaging, optical coherence tomography, and hematoxylin and eosin staining. Treatment with MEF significantly increased the expression of antioxidant proteins such as HO-1, NQO1, and SOD1 in ARPE-19 cells. Additionally, treatment with MEF significantly increased the levels of the antioxidant proteins SOD1 and GPX4 in the mouse retina. Concurrently, it significantly reduced the levels of apoptosis-related factors, such as the Bax/Bcl-2 ratio and Caspase -3 cleavage. These findings suggest that MEF may represent a promising therapeutic candidate for the management of AMD. Full article