bims-mideyd 2025-11-02 papers

EMBO Mol Med. 2025 Oct 30.

Defective chaperone-mediated autophagy in the retinal pigment epithelium of age-related macular degeneration patients.

Juan Ignacio Jiménez-Loygorri, Peng Shang, Ibrahim Bayramoglu, Raquel Gómez-Sintes, Adrián Martín-Segura, Helena Ambrosino, Johnson Hoang, Antonio Díaz, Zhaohui Geng, Evripidis Gavathiotis, James R Dutton, Jörn Dengjel, Ana Maria Cuervo, Deborah A Ferrington, Patricia Boya.

Autophagy is one of the main intracellular recycling systems and its impairment is considered a primary hallmark of the aging process. Defective macroautophagy in the retinal pigment epithelium (RPE) has been described in age-related macular degeneration (AMD), a blindness-causing disease that affects roughly 200 million patients worldwide. The relevance of chaperone-mediated autophagy (CMA), a selective type of autophagy for proteins containing a KFERQ-like motif, in RPE cell biology and homeostasis remains to be elucidated. Here we describe decreased CMA activity in the RPE of AMD patients compared to healthy age-matched controls, along with accumulation of substrate proteins, and in donor-derived iPSC-RPE cells, which we used to further characterize AMD-associated alterations of cellular homeostasis derived from proteotoxicity. Treatment with CA77.1 (CMA activator) restores proteostasis and remodels specific subsets of the proteome in cells from healthy and AMD donors. CA77.1-treated AMD iPSC-RPE display reduced oxidative stress and improved mitochondrial function. These findings may explain the specific vulnerability of the RPE during AMD and shed light on CMA as a new druggable target for this as-of-now incurable disease.

Keywords: Age-related Macular degeneration; Chaperone-mediated Autophagy; Oxidative Stress; Proteostasis; RPE

DOI: https://doi.org/10.1038/s44321-025-00329-w

Mar Drugs. 2025 Sep 26. pii: 381. [Epub ahead of print]23(10):

A Sulfated Polysaccharide from Gelidium crinale Suppresses Oxidative Stress and Epithelial-Mesenchymal Transition in Cultured Retinal Pigment Epithelial Cells.

Yurong Fang, Haiyan Zheng, Yizhu Chen, Bomi Ryu, Zhong-Ji Qian.

Age-related macular degeneration (AMD) progresses to vision-threatening dry and wet forms, with no effective dry AMD treatments available. The sulfated polysaccharide (GNP, 25.8 kDa) derived from Gelidium crinale exhibits diverse biological activities and represents a potential source of novel therapeutic agents. This study employed a hydrogen peroxide (H2O2)-induced oxidative stress and epithelial-mesenchymal transition (EMT) model in retinal pigment epithelial (RPE) cells to investigate GNP's protective mechanisms against both oxidative damage and EMT. The results demonstrated that GNP effectively suppressed oxidative stress, with the 600 μg/mL dose significantly inhibiting excessive reactive oxygen species (ROS) generation to levels comparable to untreated controls. Concurrently, at concentrations of 200-600 μg/mL, GNP inhibited NF-κB signaling and increased the Bax/Bcl-2 ratio, effectively counteracting H2O2-induced oxidative damage and cell apoptosis. Furthermore, in H2O2-treated ARPE-19 cells, 600 μg/mL GNP significantly reduced the secretion of N-cadherin (N-cad), Vimentin (Vim), and α-smooth muscle actin (α-SMA), while increasing E-cadherin (E-cad) expression, consequently inhibiting cell migration. Mechanistically, GNP activated the Nrf2/HO-1 pathway, thereby mitigating oxidative stress. These findings suggest that GNP may serve as a potential therapeutic agent for dry AMD.

Keywords: Gelidium crinale; antioxidant; epithelial-mesenchymal transition; sulfated polysaccharide

DOI: https://doi.org/10.3390/md23100381

Antioxidants (Basel). 2025 Oct 18. pii: 1251. [Epub ahead of print]14(10):

Title Oxidative Stress in Age-Related Macular Degeneration: From Molecular Mechanisms to Emerging Therapeutic Targets.

Tatsuya Mimura, Hidetaka Noma.

Age-related macular degeneration (AMD) is a leading cause of irreversible visual impairment in the elderly, and oxidative stress, primarily mediated by reactive oxygen species (ROS), is widely recognized as a central driver of its onset and progression. The retina is highly susceptible to oxidative damage due to its elevated oxygen consumption, abundant polyunsaturated fatty acids, and continuous exposure to light. Recent studies have elucidated molecular mechanisms in which mitochondrial dysfunction, disruption of redox homeostasis, inflammation, and complement activation interact to promote degeneration of retinal pigment epithelium (RPE) and photoreceptor cells. In addition to age-related oxidative stress, environmental factors such as motor vehicle exhaust and volatile organic compounds (VOCs) can accelerate the accumulation of lipofuscin and drusen, thereby fostering a chronic pro-inflammatory milieu. From a therapeutic perspective, beyond conventional antioxidant supplementation, emerging strategies targeting oxidative stress-related pathways have gained attention, including mitochondrial protectants, activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, anti-inflammatory agents, and gene therapy. Importantly, several innovative approaches are under investigation, such as saffron supplementation with neuroprotective properties, drug repositioning of levodopa, and nanotechnology-based delivery systems to enhance retinal bioavailability of antioxidants and gene therapies. This review summarizes the pathophysiological role of oxidative stress in AMD from a molecular mechanistic perspective and discusses recent advances in research and novel therapeutic targets.

Keywords: age-related macular degeneration; antioxidant therapy; mitochondrial dysfunction; oxidative stress; reactive oxygen species (ROS)

DOI: https://doi.org/10.3390/antiox14101251

BMC Res Notes. 2025 Oct 29. 18(1): 459

Combined thermal and mild electrical stimulations modulate heat shock protein and VEGF in retinal pigment epithelial cells under high glucose.

Ryosuke Fujino, Kiyoto Totsuka, Tomoyasu Shiraya, Takashi Ueta, Fumiyuki Araki, Ryo Terao.

OBJECTIVE: Macular laser for diabetic macular edema (DME) is known to increase heat shock protein (HSP) expression in retinal pigment epithelial (RPE) cells, and increased HSP expression may be a mechanism for improving macular edema. Furthermore, the effectiveness of mild electrical stimulation (MES) as a cofactor in further enhancing HSP expression by thermal stimulation has been reported. In the current study, the effect of this combination treatment was examined in an in vitro HG (high glucose) + DFX (deferoxamine mesylate salt) model that simulates DME using a human RPE cell line (ARPE-19).
RESULTS: Combined thermal stimulation and MES significantly increased HSP70 expression in both the control and HG + DFX model groups, while suppressing VEGF and inflammatory cytokine levels in HG + DFX model. The combined treatment also showed a protective effect on the blood-retinal barrier integrity, although transient, as measured by TEER. These findings suggest that combined thermal stimulation and MES represent a promising therapeutic approach for managing DME, by modulating HSP and VEGF expression and potentially reducing inflammation and promoting protective mechanisms in the retina.

Keywords: Diabetic macular edema; Heat shock protein; Mild electrical stimulation; Thermal stimulation

DOI: https://doi.org/10.1186/s13104-025-07539-y

ACS Omega. 2025 Oct 21. 10(41): 48984-48990

Tetrahedral DNA Framework Penetrating Ocular Barrier for Treatment of Retinal Oxidative Stress.

Tianqin Wang, Yuelu Zhang, Wenjuan Xiao, Yangyang Jin, Qiuxue Yi, Qi Chen, Jiayang Xiang, Ruobing Wang, Jin Li, Lin Liu.

Excessive accumulation of reactive oxygen species in the retina is the predominant pathogenic mechanism underlying dry age-related macular degeneration (dAMD). Although antioxidant chemicals have been shown to be effective in reducing ROS levels, their bioavailability and therapeutic efficacy are restricted by ocular barriers. Herein, we developed a tetrahedral framework nucleic acid (tFNA)-based antioxidant drug for the treatment of retinal oxidative stress diseases. By exploiting their penetration capability, these tFNAs penetrated multiple ocular tissues and cellular barriers. These tFNAs protected retinal pigment epithelium cells from glyoxal-induced oxidative stress damage by exerting their intrinsic antioxidant properties through the JNK and AKT pathways upon entering the cells. The subconjunctival administration of tFNAs alleviated structural damage and reduced retinal cell apoptosis in a retinal oxidative stress rat model. These results indicated that tFNAs are a promising therapeutic drug for the treatment of retinal oxidative stress diseases, which sheds light on the development of dAMD therapy.

DOI: https://doi.org/10.1021/acsomega.5c07330

Sci Rep. 2025 Oct 29. 15(1): 37862

Mechanistic analysis of luteolin in mitigating dry age-related macular degeneration through network pharmacology and experimental validation.

Maomei Luo, Min Zhang, Zhen Xing, Wei Yu, Hongbin Lv.

Dry age-related macular degeneration (AMD) ranks among the primary causes of irreversible vision loss in the elderly. Luteolin, with its diverse biological activities, has attracted significant attention as a promising candidate for intervening in dry AMD. Explore the protective effect of luteolin on dry AMD to address the unmet need for current therapeutic agents. Luteolin's target information and dry AMD-related genes were retrieved from public databases. Shared targets of luteolin and dry AMD were used to construct a protein‒protein interaction network, followed by Gene Ontology and pathway enrichment analyses. Finally, molecular docking between the active ingredient and core targets was validated. In vitro, sodium iodate was used to induce ARPE-19 cells, after which cell viability was analyzed via a Cell Counting Kit-8 (CCK-8) assay. Reactive oxygen species (ROS) levels and mitochondrial membrane potential were detected via fluorescent dye staining. In the network pharmacology analysis, a total of 213 potential therapeutic targets associated with luteolin's activity against dry AMD were identified. Among these genes, TP53, TNF, IL6, AKT1, BCL2, STAT3, JUN, and CASP3 were identified as core therapeutic targets. These targets are primarily involved in pathways including lipid and atherosclerosis, cancer-related pathways, and the AGE-RAGE signaling pathway in diabetic complications. Molecular docking analyses revealed strong binding affinities between luteolin and the core targets, validating the molecular mechanisms underlying luteolin's efficacy against dry AMD. Experimental data demonstrated that luteolin not only mitigated sodium iodate-induced reductions in ARPE-19 cell viability but also decreased intracellular ROS levels and restored mitochondrial membrane potential. Luteolin effectively enhances the viability of damaged RPE cells, reduces oxidative stress levels, and protects mitochondrial function. This protective effect is likely mediated through the coordinated action of multiple targets and pathways, highlighting luteolin's promising potential in the prevention and management of dry AMD. However, this study is limited by its sole reliance on in vitro cell validation and inability to fully reflect real in vivo effects and potential side effects.

Keywords: Dry age-related macular degeneration; Luteolin; Molecular docking; Network pharmacology; Oxidative stress

DOI: https://doi.org/10.1038/s41598-025-21730-y