Aug 2026· Biomolecules· Vol 16, pp. 1227· 0 citations· 63 references
TL;DR
Cynarin protects against oxidative stress-induced retinal degeneration by suppressing MAPK and NF-κB inflammatory signaling, representing a promising therapeutic candidate for preventing or delaying NaIO3-induced dry AMD-like retinal injury.
Abstract
Background: Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss and is strongly driven by oxidative stress and inflammation. This study investigated the protective effects of cynarin against sodium iodate (NaIO3)-induced retinal pigment epithelium (RPE) injury, focusing on the MAPK and NF-κB signaling pathways. Materials and Methods: Human ARPE-19 cells were exposed to NaIO3, and cell viability was assessed by the MTT assay. Protein expression of MAPK components (p38, JNK, ERK) and the NF-κB pathway was analyzed by Western blotting, and pro-inflammatory cytokine (IL-1β, IL-6, TNF-α) mRNA expression was measured by RT-qPCR. In vivo, NaIO3-induced retinal degeneration in C57BL/6 mice was treated with cynarin (3 or 10 mg/kg) for seven days, and retinal changes were evaluated by fundus photography, fluorescein angiography, and OCT. Results: Cynarin preserved ARPE-19 cell viability without cytotoxicity. It significantly attenuated NaIO3-induced p38 and JNK phosphorylation, IκB degradation, and NF-κB activation while downregulating IL-1β, IL-6, and TNF-α expression. In vivo, cynarin reduced drusen-like lesions, hyperfluorescent abnormalities, and retinal thinning, and dose-dependently suppressed ocular pro-inflammatory cytokines. Conclusions: Cynarin protects against oxidative stress-induced retinal degeneration by suppressing MAPK and NF-κB inflammatory signaling, representing a promising therapeutic candidate for preventing or delaying NaIO3-induced dry AMD-like retinal injury.
BACKGROUND
Dry age-related macular degeneration (AMD) is driven largely by retinal pigment epithelium (RPE) cell injury. Kinsenoside (KN) exhibits protective activity on RPE cells, but the direct effect on dry AMD and underlying molecular mechanisms remain unclear.
OBJECTIVE
This study aimed to investigate the protective effects of KN against RPE cell injury and dysfunction in dry AMD and to elucidate its regulatory mechanisms.
METHODS
An A2E- and blue light-induced ARPE-19 cell injury model and a blue light-induced AMD-like retinal injury mouse model were established. RPE cytotoxicity, apoptosis, senescence, inflammation, and melanogenesis-associated marker expression were evaluated. MAPK signaling was analyzed by Western blotting, and mechanistic analyses were performed using a JNK inhibitor, molecular docking analysis, an in vitro JNK enzymatic activity assay, exosome characterization, and exosome functional assays.
RESULTS
KN treatment significantly attenuated cytotoxicity, apoptosis, cellular senescence, inflammatory responses, and melanogenesis-associated marker alterations in AMD-like ARPE-19 cells. In vivo, KN reduced drusen-like deposition, improved retinal structural integrity, and partially restored outer nuclear layer thickness while suppressing senescence and inflammation. Mechanistically, KN preferentially attenuated pathological JNK activation under the examined conditions and reduced JNK enzymatic activity in vitro. Pharmacological JNK inhibition phenocopied the protective effects of KN with no additive benefit, indicating pathway convergence. Exosome inhibition, transfer, and depletion experiments supported the contribution of exosome-associated signaling to KN-mediated cytoprotection.
CONCLUSION
These findings suggest that KN alleviates RPE cell injury under AMD-like stress, at least partly through exosome-associated modulation of JNK/MAPK signaling.
Yue Bai, Maosong Xie, Yihua Yao et al.· International Immunopharmaco...· 0 citations
Retinal degeneration (RD) is a group of retinopathies characterized by progressive photoreceptor death and chronic neuroinflammation. Quercetin (QUE) is a natural flavonol with potent anti-inflammatory and free-radical scavenging properties. However, its protective effects against RD remain poorly characterized. This study aims to investigate the therapeutic potential of QUE on RD.In vitro and in vivo models of sodium iodate (NaIO3)-induced oxidative damage were used to evaluate the effects of QUE in RD. NaIO3 was used to induce oxidative damage in 661W cells. QUE was added to the cell cultures, and cell viability and oxidative markers were assessed. In vivo, QUE was delivered into the vitreous cavity of NaIO3-induced RD mice, followed by morphological analysis, visual function evaluation, behavioral testing, and Western blot detection.QUE protected 661W cells from NaIO3-induced oxidative damage by reducing intracellular reactive oxygen species, restoring mitochondrial membrane potential, and alleviating mitochondrial membrane pore disruption. In vivo, intravitreal QUE injection preserved retinal structure, reduced lesion area, elevated electroretinogram P-wave amplitude, and improved behavioral performance. QUE administration was accompanied by alleviated oxidative stress, inhibited glial activation, reduced pro-inflammatory cytokines, and elevated p-PI3K and p-AKT expression in RD. Neuroinflammation and oxidative stress are involved in RD pathology. These findings provide preliminary evidence that QUE exerts protective effects on photoreceptors in NaIO₃-induced RD. No causal relationship between PI3K/AKT activation and the retinal protection of QUE was established in this study.
Background: Diabetic retinopathy (DR) is a leading cause of vision loss, with oxidative stress and inflammation serving as critical drivers of its onset and progression. Curcumin, a natural polyphenol, is known for its potent anti-inflammatory and antioxidant properties. Glial fibrillary acidic protein (GFAP) is commonly used as an indicator of retinal macroglial reactivity, whereas the NLRP3 inflammasome is an important mediator of inflammatory signaling in DR. We evaluated retinal vascular abnormalities and retinal GFAP immunoreactivity and examined whether these findings were accompanied by changes in retinal NLRP3 and IL-1β protein abundance and in the levels of cleaved caspase-1 and cleaved GSDMD. Methods: Diabetes was induced in 7-week-old rats via a single intraperitoneal injection of streptozotocin. Following the confirmation of hyperglycemia, curcumin was administered orally. To evaluate the effects, we performed trypsin digestion, haematoxylin and eosin (H&E) staining, fluorescein isothiocyanate (FITC)–dextran permeability assays, immunofluorescence staining, and Western blotting on the harvested retinas. Results: The DM group showed increased acellular capillary formation, vascular leakage, retinal GFAP immunoreactivity, NLRP3 and IL-1β protein abundance, and levels of cleaved caspase-1 and cleaved GSDMD. Compared with the untreated DM group, the DM + curcumin group showed lower values for all of these outcomes. Conclusions: In diabetic rats, oral administration of a curcumin-containing formulation was associated with fewer retinal vascular abnormalities and lower GFAP immunoreactivity, accompanied by parallel differences in inflammasome-related proteins. These findings support the potential of this formulation as an adjunctive therapeutic approach for early diabetic retinopathy.
Hyoseon Yu, J. Kang, Seo Hyun Kim et al.· Life· 0 citations
BACKGROUND
Dry age-related macular degeneration (dAMD) is a major cause of irreversible vision loss, in which oxidative stress-induced retinal pigment epithelial injury plays a key role. Astragaloside IV (ASIV) has antioxidant potential but is limited by poor aqueous solubility and ocular bioavailability.
PURPOSE
To evaluate the retinal protective effects of an ASIV-loaded antioxidant hydrogel eye drop (ALG) in experimental dAMD.
METHODS
A NaIO₃-induced mouse model of dAMD was established. Retinal protection was evaluated using hematoxylin and eosin (H&E) staining, immunofluorescence, ophthalmic imaging, and functional examinations. Cytocompatibility and cellular uptake were assessed in ARPE-19 cells.
RESULTS
ALG underwent a sol-gel transition at 35 °C and displayed a markedly sustained release profile compared with free ASIV. In vivo, ALG reduced retinal ROS accumulation and increased retinal sirtuin 1 (SIRT1) and nuclear factor erythroid 2-related factor 2 (Nrf2) expression. In addition, ALG exhibited favorable cytocompatibility. Compared with liposomes and eye drops, the liposome gel also showed greater uptake by ARPE-19 cells.
CONCLUSION
ALG attenuated oxidative stress-related retinal injury, and meanwhile retinal SIRT1 and Nrf2 expression increased. Therefore, ALG may exert therapeutic effects against dAMD in association with SIRT1/Nrf2 upregulation.
Yan Xie, Peng He, Jufang Lv et al.· Phytomedicine· 0 citations
Lipopolysaccharide (LPS), a component of Gram-negative bacteria, is a potent activator of the innate immune system and has been implicated in the pathogenesis of eye diseases, including age-related macular degeneration (AMD), primary open-angle glaucoma (POAG), and diabetic retinopathy (DR). LPS enters systemic circulation through bacterial lysis or active secretion, leading to endotoxemia—either acute or chronic. Chronic endotoxemia, often resulting from gut dysbiosis, may link microbial imbalances to eye diseases. Indeed, chronic LPS exposure may contribute to both systemic and local inflammation. Within the retina, it activates resident immune and structural cells triggering pro-inflammatory cytokine production, oxidative stress, complement cascade activation, and inflammasome activation. These immune cascades compromise blood-retinal barrier integrity, increase vascular leakage, and impair neuronal viability. LPS exposure can stimulate the secretion of pro-angiogenic factors, promoting the development of neovascularization within the retina. Furthermore, the aging retina may be particularly vulnerable to LPS-mediated damage due to an increased exposure to LPS (linked to microbial dysbiosis and alterations of both intestinal and blood-retinal barriers) as well as a reduced capacity for repair. Although direct human evidence remains limited, emerging experimental data support a mechanistic role for LPS in AMD, glaucoma, and DR. This review emphasizes that addressing the impact of chronic endotoxemia represents a promising avenue for both understanding and treating eye diseases. Continued investigation into the multifaceted roles of LPS may yield innovative biomarkers and therapeutic targets to slow or prevent neurodegenerative, vascular, and inflammatory processes underlying conditions such as AMD, glaucoma, and DR.
P. Larsen, Morgane Linard, C. Schweitzer et al.· Investigative Ophthalmology...· 0 citations
Qi Huang Granules (QHG), a traditional Chinese medicine (TCM) formulation, have been applied clinically for over two decades to treat dry age-related macular degeneration (AMD) and associated fundus lesions. Although its retinoprotective effects have been documented, the associated underlying mechanisms are largely unexplored. The present work focused on investigating the therapeutic efficacy of QHG in sodium iodate (NaIO₃)-induced retinal damage, with a particular focus on how the formula regulated the interaction between inflammatory responses and imbalances in mitochondrial dynamics. UPLC-HRMS, network pharmacology, and molecular docking analyses were integrated for identifying mitochondria-associated bioactive constituents and potential targets of QHG. In the experimental model, retinal injury was induced in rats through tail vein injection of NaIO3. Retinal morphological and ultrastructural changes were assessed by HE staining and transmission electron microscopy. To assess mitochondrial function, mitochondrial membrane potential, mtROS levels, and mtDNA integrity were measured. Additionally, ELISA was performed to quantify IL-1β and IL-18 levels. Key marker levels, including p-DRP1, DRP1, OPA1, MFN2, and NLRP3, were determined by Western blotting, IHC, and qRT-PCR. DNM1L (encoding DRP1) and MFN2 were identified as the primary targets of QHG through UPLC-HRMS and computational analyses. In vivo experimental results showed that treatment with QHG alleviated morphological alterations and ultrastructural damage to the retina and mitochondria in model rats. Furthermore, QHG treatment increased mitochondrial membrane potential, reduced mtROS levels, mitigated mtDNA damage, and reduced IL-1β and IL-18 contents. Mechanistically, QHG downregulated p-DRP1, DRP1, and NLRP3, while upregulating MFN2 and OPA1. Collectively, these findings demonstrate that QHG can ameliorate retinal morphology and ultrastructural damage in mitochondria, such as cellular mitochondria, improve mitochondrial function, and attenuate retinal inflammation, thereby exerting a protective effect against NaIO₃-induced retinal injury. The underlying mechanism may involve the mitochondrial dynamics-NLRP3 pathway.
Ji-fang Wang, Zhiqiang Wu, Lulu Fang et al.· International Journal of Bio...· 0 citations
