bims-mideyd 2025-12-14 papers

J Ophthalmol. 2025 ;2025 6670966

A Bibliometric Analysis of Research Progress on Age-Related Macular Degeneration and Autophagy From 2010 to 2024.

Nana Meng, Leizhou Xia, Yiqing Gong, Chunhe Shi, Peirong Lu.

Background: Autophagy regulates intracellular metabolism and is crucial in the development of age-related macular degeneration (AMD). Despite the growing number of studies on AMD and autophagy in recent years, bibliometric analyses in this field remain scarce. Therefore, a bibliometric analysis was applied to explore the research trends and hot spots of this field in this study.
Methods: We collected publications on autophagy in AMD from the MEDLINE database, covering the period from January 2010 to October 2024. The "bibliometrix" R package (Version R 4.2.3) was utilized for bibliometric analysis, and WPS Excel, PowerPoint, and Word (12.1.0.18276) were used to manage data and create related tables.
Results: A total of 349 articles were included. The amount of literature was on the rise from 2010 to 2024. China leads in article quantity, whereas the United States holds the most influence. Although Finland ranks the third position in publication volume, followed by China and the United States, Finland led research in this field, with the University of Eastern Finland being the most active and prolific institution and Kaarniranta Kai as the most productive and influential author. International Journal of Molecular Sciences and Autophagy is the journal with the most volume. The three most referenced studies primarily examine the interplay between inflammation, oxidative stress, and autophagy in retinal pigment epithelial cells. The analysis for keywords found that mitophagy has also received increasing attention in this field.
Conclusions: This bibliometric analysis identifies current research hotspots in autophagy related to AMD and informs future research directions. Future trends in this field may involve identifying and developing novel autophagy-targeted therapies for the prevention and treatment of AMD.

Keywords: age-related macular degeneration (AMD); autophagy; bibliometric analysis; mitophagy; oxidative stress

DOI: https://doi.org/10.1155/joph/6670966

Invest Ophthalmol Vis Sci. 2025 Dec 01. 66(15): 25

KLF10-IN-1 Attenuates RPE Cell Apoptosis and Experimental Diabetic Retinopathy Via the KLF10/PERK/eIF2α/ATF4/CHOP Pathway.

Weiwen Hu, Heng Yang, Qiqi Zhu, Guanghao Zheng, Jian Tan, Yeting Lin, Yicang Wang, Yahan Tu, Qiong Zhou.

Purpose: To investigate the roles of Krüppel-like factor 10 (KLF10) and its inhibitor KLF10-IN-1 in regulating high-glucose/hypoxia-induced RPE cell apoptosis and their involvement in diabetic retinopathy (DR).
Methods: A DR mouse model was established using a high-fat, high-glucose diet and streptozotocin. An RPE cell model of high-glucose/hypoxia injury was constructed by culturing cells under high-glucose (30 mM) conditions in the presence of cobalt chloride (200 µM). KLF10 expression, apoptosis, and endoplasmic reticulum (ER) stress levels were assessed. KLF10 expression was modulated with small interfering RNA and overexpression plasmids. Dual luciferase reporter assays were used to evaluated the regulatory effect of KLF10 on PERK. The PERK pathway was activated by CCT020312 and inhibited by GSK2606414 for rescue experiments. The protective effects of KLF10-IN-1 were validated in vitro and in vivo.
Results: KLF10 was highly expressed in RPE cells in DR model mice. After 48 hours of high-glucose/hypoxia exposure, hypoxia, inflammation, ER stress, and apoptosis were significantly exacerbated, accompanied by KLF10 upregulation. KLF10 knockdown suppressed apoptosis and ER stress, whereas KLF10 overexpression had the opposite effect. Western blotting confirmed KLF10 regulated PERK phosphorylation, and dual luciferase assays revealed that KLF10 transcriptionally activates PERK. KLF10 mediated apoptosis through the PERK/eIF2α/ATF4/CHOP pathway. Inhibiting this pathway with KLF10-IN-1 reduced high-glucose/hypoxia-induced damage to RPE cells and ameliorated retinal damage in diabetic mice.
Conclusions: KLF10 is upregulated in DR model mice and high-glucose/hypoxia-exposed RPE cells and modulates apoptosis and ER stress through the PERK/eIF2α/ATF4/CHOP pathway. KLF10-IN-1 has protective effects, suggesting its potential for early DR treatment.

DOI: https://doi.org/10.1167/iovs.66.15.25

STAR Protoc. 2025 Dec 08. pii: S2666-1667(25)00669-0. [Epub ahead of print]6(4): 104263

Protocol for the differentiation of induced pluripotent stem cells into retinal pigment epithelial cells.

Mark Zorin, Rike Ewerling-Hähnel, Kerstin Nagel-Wolfrum.

Induced pluripotent stem cells (iPSCs) are emerging as a valuable system for modeling tissues and organs. Here, we describe a highly scalable protocol for the differentiation of iPSCs into retinal pigment epithelium (RPE), including a new step that makes it easier for researchers to obtain a high-purity culture. We also describe a cryopreservation technique for RPE progenitor cells to enable their storage. The use of cryopreserved cells allows a subsequent reduction in differentiation time compared to the full protocol.

Keywords: Cell culture; Cell differentiation; Developmental biology

DOI: https://doi.org/10.1016/j.xpro.2025.104263

Nat Commun. 2025 Dec 09.

Chemical reprogramming of fibroblasts into retinal pigment epithelium cells for vision restoration.

Shasha Li, Hui Liu, Shao-Hui Pan, Zhengbiao Zhu, Shun Zhang, Jiahang Li, Yinghao Yao, Xinyu Wang, Na Gao, Xiaoyu Liu, Ming Chen, Huijuan Hu, Wenmin Pan, Qunyan Zhu, Yaoyao Cai, Jia Qu, Shaorong Gao, Jianzhong Su.

Restoring retinal pigment epithelium (RPE) cells is crucial for treating retinal degenerative (RD) diseases, with chemical reprogramming offering a transformative, scalable solution. However, identifying key chemical compounds for generating functional RPE cells from somatic cells remains challenging. Here, we present a two-step chemical reprogramming strategy to convert fibroblasts into functional chemical induced RPE (ciRPE) cells. Leveraging the Single-Cell Reprogramming Compound Finder (scRCF), which integrates transcriptomics-guided predictions with advanced screening, we identified chemical cocktails that precisely reprogram fibroblasts through an intermediate state into ciRPE cells. These ciRPE cells closely mimic the structure and function of native RPE cells, and upon transplantation into RD rats, they seamlessly integrate into host tissue, protect photoreceptors, and restore visual function. Omics and mechanistic analyses revealed that the identified compounds synergistically activate core transcription factors, including Ascl1 and Olig2, orchestrating the reprogramming process. This study provides a scalable, non-integrative approach for generating functional RPE cells, offering a promising strategy for cell replacement therapies targeting RD diseases.

DOI: https://doi.org/10.1038/s41467-025-67104-w

Ophthalmol Sci. 2026 Jan;6(1): 100980

CTx001 for Geographic Atrophy: A Gene Therapy Expressing Soluble, Truncated Complement Receptor 1 (Mini-CR1).

Sonika Rathi, Athanasios Didangelos, Sofiya Pisarenka, Rachel Green, Stamatia Zafeiri, Peter Emery-Billcliff, Nakul Patel, Pamela Whalley, Parisa Zamiri, Viranga Tilakaratna, Ewa Szula, Rafiq Hasan, Mustafa M Munye, Richard D Unwin, Paul N Bishop, Dennis Keefe, Simon J Clark.

Purpose: Preclinical evaluation of a novel gene therapy called CTx001 for treating geographic atrophy (GA). CTx001 encodes a protein called mini-CR1, which is a soluble fragment of complement receptor 1.
Design: CTx001 was used in vitro and in vivo to analyze expression and complement-modulating activity. Mini-CR1 was used in vitro to analyze complement-modulating activity, and its ability to cross human Bruch's membrane was evaluated ex vivo.
Participants: CTx001, which is a self-complementary rAAV2 gene therapy vector expressing mini-CR1. Recombinant mini-CR1 protein, retinal pigment epithelium (RPE) cell lines, serum, human donor Bruch's membrane, and a rat model.
Methods: Recombinant mini-CR1 protein was produced in mammalian cells and purified. C3b and C4b breakdown assays were performed. Wieslab assays measured complement regulatory activity in serum. Mini-CR1 binding to C3b was measured using biolayer interferometry. The diffusion of mini-CR1 across human Bruch's membrane was assessed using an Ussing chamber. Retinal pigment epithelium cell lines were transduced with CTx001 to assess expression, including directionality and complement modulatory activity. In vivo efficacy of CTx001 was tested using a rat laser-induced choroidal neovascularization (CNV) model.
Main Outcome Measures: C3b/iC3b/C4b degradation, inhibition of membrane attack complex (MAC) formation in human serum, mini-CR1 binding to C3b, vector transduction efficiency, protein secretion and localization, and complement inhibition in vivo.
Results: Mini-CR1 demonstrated potent cofactor activity for factor I-mediated cleavage of C3b, iC3b, and C4b; therefore, it inhibits both the alternative and classical complement pathways. It inhibited complement activation with an IC50 of 125 nM in human serum. Mini-CR1 demonstrated high-affinity binding to C3b. The mini-CR1 protein diffused across human Bruch's membrane and retained activity postdiffusion. CTx001-transduced RPE cells secreted mini-CR1 apically and basolaterally, leading to reduced C3 activation and MAC deposition. In rats, subretinal administration of CTx001 resulted in a 75.4% reduction in MAC deposition in CNV lesions (P < 0.01).
Conclusions: CTx001 is a potent inhibitor of complement. It efficiently transduces RPE cells, resulting in apical and basolateral secretion and crosses Bruch's membrane, so it is expected to deliver mini-CR1 to the retina and choroid. These findings support its further development as a 1-time gene therapy for addressing complement overactivation in GA.
Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Keywords: AAV; AMD; Complement; Gene therapy; Macular degeneration

DOI: https://doi.org/10.1016/j.xops.2025.100980

Int J Mol Sci. 2025 Nov 24. pii: 11327. [Epub ahead of print]26(23):

Retinal Organoid-Derived Exosomes Reduce CNV Lesion and Restore RPE Integrity in Mouse Laser-Induced Choroidal Neovascularization (CNV) Model.

Jin Young Yang, Yeji Kim, Sumin An, Jung Woo Han, Jun-Sub Choi, Tae Kwann Park.

To address the shortcomings of existing anti-VEGF monotherapy in neovascular age-related macular degeneration (nAMD), we investigated the therapeutic capabilities of exosomes obtained from human induced pluripotent stem cell (hiPSC)-derived retinal organoids in a mouse model of laser-induced choroidal neovascularization (CNV). To evaluate Retinal Organoid-derived exosome (RO-Exo) distribution after intravitreal (IVT) injection, calcein-labeled RO-Exo was observed using confocal microscopy. CNV was induced in C57BL/6 J mice by laser photocoagulation. RO-Exo was isolated from retinal organoids (differentiation days 55-65) and injected 5 days post-laser. Therapeutic efficacy was evaluated on day 12. Vascular leakage and CNV size were assessed by angiography and CD31 immunostaining. We also examined HIF-1α/VEGF-A expression (Western blotting), Retinal Pigment Epithelium (RPE) integrity markers (immunofluorescence staining for α-SMA, fibronectin, and ZO-1), and the activation of the Mitogen-Activated Protein Kinase (MAPK) pathway (phospho-ERK, -p38, -JNK) in CNV lesions. After IVT injection, RO-Exo migrated to the RPE layer, showing high retinotropic distribution. In the CNV model, RO-Exo significantly reduced vascular leakage and CNV size, with greater suppression of HIF-1α and VEGFA expression than aflibercept, the standard-of-care anti-VEGF drug. CD31-positive vasculature was decreased, accompanied by downregulation of fibronectin (a fibrotic marker) and restoration of RPE hexagonality and integrity. Furthermore, RO-Exo inhibited the activation of ERK, P38, and JNK in CNV lesions. Our study results demonstrate that RO-Exo exhibits multi-target therapeutic effects-including anti-angiogenic, anti-fibrotic, and neuroprotective actions-offering a promising alternative to conventional anti-VEGF therapy for nAMD.

Keywords: choroidal neovascularization; exosome; human induced pluripotent stem cell; mitogen-activated protein kinase; neovascular age-related macular degeneration; retinal organoids

DOI: https://doi.org/10.3390/ijms262311327

Int J Mol Sci. 2025 Dec 01. pii: 11641. [Epub ahead of print]26(23):

Liproxstatin-1 Protects SH-SY5Y Cells by Inhibiting H2O2-Induced Excessive Mitophagy and Apoptosis.

Tingting Yan, Feng Ding, Zhongyuan Fang, Yan Zhao.

Oxidative stress is a critical factor in the pathogenesis of various neuronal disorders, causing cellular damage and mitochondrial dysfunction. This study aimed to explore the protective effects of liproxstatin-1 against H2O2-induced neural oxidative damage and elucidate the underlying mechanisms. Our findings demonstrated that 500 μmol/L H2O2 treatment induced mitochondrial dysfunction and apoptosis in SH-SY5Y cells, while 1 μmol/L liproxstatin-1 effectively mitigated these cytotoxic effects by restoring mitochondrial integrity and enhancing cell viability. Furthermore, 500 μmol/L H2O2 exposure significantly suppressed the activation of the protein kinase B/ mammalian target of rapamycin signaling pathway and triggered excessive mitophagy. Pretreatment with 1 μmol/L liproxstatin-1 attenuated the damage by H2O2, suggesting its protective role. Collectively, our results indicated that 500 μmol/L H2O2 induces cytotoxicity through oxidative damage, protein kinase B/ mammalian target of rapamycin pathway inhibition, and aberrant mitophagy, ultimately leading to apoptosis; meanwhile, 1 μmol/L liproxstatin-1 counteracted these effects by preserving mitochondrial function, suppressing excessive mitophagy, and inhibiting apoptotic pathways, thereby protecting SH-SY5Y cells from H2O2-induced cytotoxicity.

Keywords: AKT/mTOR; H2O2; apoptosis; liproxstatin-1; mitophagy

DOI: https://doi.org/10.3390/ijms262311641

bioRxiv. 2025 Dec 01. pii: 2025.11.27.690007. [Epub ahead of print]

Disrupted tRNA modification leads to intestinal mitochondrial dysfunction and microbial dysbiosis.

Di Ran, Yongguo Zhang, Yueqing An, Ying Hu, Yinglin Xia, Jun Sun.

Background and aims: Transfer RNA (tRNA) modifications determine translation fidelity and efficiency. It occurs through the action of specific enzymes that modify the nucleotides within the tRNA molecule. Our previous study demonstrated tRNA modopathies and altered queuine-related metabolites in inflammatory bowel diseases. Queuine tRNA-ribosyltransferase catalytic subunit 1 (QTRT1) and QTRT 2 co-localize in mitochondria and form a heterodimeric TGT participating in tRNA Queuosine (tRNA-Q) modification. Human body acquires Queuine/Vitamin Q from intestinal microbiota or from diet. However, the roles of tRNA-Q modifications in the maintenance of intestinal mitochondrial homeostasis and microbiome are still unclear.
Methods: We used publicly available human IBD datasets, QTRT1 knockout (KO) mice, QTRT1 intestinal epithelial conditional KO (QTRT1 ΔIEC ) mice, cultured cell lines with QTRT1-specific siRNA, and organoids from patients with IBD to investigate the mechanism of tRNA-Q modifications in intestinal mitochondrial homeostasis and therapeutic potential in anti-inflammation.
Results: In single cell RNA sequencing datasets of human IBD, we identified significant reduced intestinal epithelial QTRT1 expression in the patients with Crohn's Disease. Using publicly available datasets, we identified significantly changes of Vitamin Q-associated bacteria in human IBD, compared to the healthy control. Qtrt1 -/- mice had significant reduction of Q-associated bacteria, e.g., Bacteroides . Alcian Blue and Mucin-2 staining revealed mucosal barrier damage and disrupted homeostasis, with reduced colonic cell proliferation. Intestinal tight junction integrity was impaired in QTRT1-KO mice, as evidenced by reduced ZO-1 and increased Claudin-10 expression. QTRT1 ΔIEC mice also showed dysbiosis and disrupted TJs. ATP synthesis was significantly decreased in the colon of QTRT1-KO mice, accompanied by severe mitochondrial dysfunction: reduced mitochondrial quality, Cytochrome-C release, and mitochondrial DNA (mtDNA) leakage. Mitochondrial dysfunction contributed to colonic cell death, as shown by elevated expressions of Cleaved Caspase-3 and Cleaved Caspase-1, increased BAX/Bcl-2 ratio, and positive TUNEL signals. Elevated CDC42, CD14, and CD4 levels in QTRT1-KO colon suggested mucosal immune activation and tissue repair responses. QTRT1-deficient CaCO2-BBE cells showed mitochondrial dysfunction. Cytochrome-C and mito-DNA release leading to cell death characterized by elevated expressions of Cleaved Caspase-3 and Caspase-1, increased BAX/Bcl-2 ratio, and higher apoptosis rate. Organoids isolated from patients with IBD showed reduced levels of QTRT1 and dysfunctional mitochondria. Restoring mitochondrial function leads to enhanced QTRT1.
Conclusions: These findings underscore the critical role of QTRT1/Q-tRNA modification in maintaining intestinal and microbial homeostasis. Mechanistically, QTRT1 loss impacts mitochondrial integrity and mucosal homeostasis. Our study highlights the novel roles of tRNA-Q modification in maintaining mucosal barriers and innate immunity in intestinal health.
What is already known about this subject?: Eukaryotes acquire queuine (q), also known as Vitamin Q, as a micronutrient factor from intestinal microbiota or from diet.Vitamin Q is needed for queuosine (Q) modification of tRNAs for the protein translation rate and fidelity.Queuine tRNA-ribosyltransferase catalytic subunit 1 (QTRT1) is reduced in human IBD.However, health consequences of disturbed availability of queuine and altered Q-tRNA modification in digestive diseases remain to be investigated.
What are the new findings?: QTRT1 deficiency leads to altered microbiome and reduced Vitamin Q-associated bacteria in human IBD and a QTRT1 KO animal model.QTRT1 protects the host against losing intestinal integrity during inflammation.QTRT1 localizes in mitochondria and plays novel functions by maintaining intestinal mitochondrial function. QTRT1 loss impacts tRNA modification in the intestine, linking to mitochondrial integrity and mucosal homeostasis.Human IBD showed reduced levels of QTRT1 and dysfunctional mitochondria. Restoring mitochondrial function leads to enhanced QTRT1.
How might it impact on clinical practice in the foreseeable future?: Targeting tRNA-Q modification in enhancing mitochondrial function will be a novel method to maintain intestinal health.

DOI: https://doi.org/10.1101/2025.11.27.690007

Cells. 2025 Nov 26. pii: 1861. [Epub ahead of print]14(23):

β-Cell Mitochondrial Dysfunction: Underlying Mechanisms and Potential Therapeutic Strategies.

Radwan Darwish, Yasmine Alcibahy, Ghena Abu-Sharia, Alexandra E Butler.

Mitochondria are essential for β-cell function, coupling glucose metabolism to ATP production and insulin secretion. In diabetes, β-cell mitochondrial dysfunction arises from oxidative stress, impaired quality control and disrupted dynamics, leading to reduced oxidative phosphorylation, defective insulin release and progressive cell loss. Key transcriptional regulators link genetic susceptibility to mitochondrial dysfunction in both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). These disruptions impair mitophagy, mitochondrial translation and redox homeostasis. Therapeutic strategies that restore mitochondrial function, including mitophagy enhancers, mitochondrial antioxidants, and transcriptional regulators, have shown potential in preserving β-cell integrity. As mitochondrial failure precedes β-cell loss, targeting mitochondrial pathways may represent a critical approach to modifying diabetes progression.

Keywords: diabetes; mitochondria; mitochondrial dysfunction; mitophagy; β-cell

DOI: https://doi.org/10.3390/cells14231861