bims-mideyd 2026-09-13 papers

Mol Biol Rep. 2026 Sep 09. pii: 1558. [Epub ahead of print]53(1):

Acteoside alleviates high glucose-induced ROS accumulation and ferroptosis in ARPE-19 cells by activating the NRF2 signaling pathway.

Shuhong Shen, Qianbo Chen, Yan Li, Jia Ma, Yuxin Zhang, Huipeng Luo, Dan Peng, Xiaoting Xi.

OBJECTIVE: The role of Acteoside (ACT) in regulating ferroptosis of retinal pigment epithelial (RPE) cells in diabetic retinopathy (DR) through the NRF2 pathway was investigated.
METHODS: An in vitro DR model was constructed by inducing ARPE-19 cells with 33 mmol/L high glucose (HG), and a C57BL/6 mouse DR model was established via intraperitoneal injection of STZ and treated with different doses of ACT. Ferroptosis was assessed using CCK-8 assay, kits, BODIPY-C11 staining, and Western blot. NRF2 nuclear translocation was examined by immunofluorescence. Retinal damage was evaluated by HE staining.
RESULTS: Compared to the NG group, the HG group showed significantly reduced ARPE-19 cell viability, increased intracellular Fe2+ levels and lipid peroxidation, decreased GSH content, and downregulated expression of GPX4 and SLC7A11. Ferroptosis inhibitors Fer-1 and DFO significantly ameliorated HG-induced reductions in cell viability and increases in lipid peroxidation. Further ACT intervention markedly reversed the HG-induced promotion of ferroptosis. Additionally, ACT significantly promoted NRF2 nuclear translocation, and silencing NRF2 weakened ACT's inhibitory effect on ferroptosis. In animal experiments, mice in ACT intervention groups exhibited significantly alleviated retinal tissue damage, reduced tissue Fe2+, 4-HNE, and MDA levels, increased GSH content, and upregulated expression of NRF2, GPX4, and SLC7A11 proteins, with a dose-dependent trend.
CONCLUSION: ACT alleviated HG-induced ROS accumulation and ferroptosis in ARPE-19 cells by activating the NRF2 pathway, and ACT upregulated NRF2 and inhibited ferroptosis in the retina of DR mice, thereby ameliorating retinal injury.

Keywords: Acteoside; Diabetic retinopathy; Ferroptosis; NRF2; RPE

DOI: https://doi.org/10.1007/s11033-026-12608-x

BMC Pharmacol Toxicol. 2026 Sep 01. pii: 124. [Epub ahead of print]27(1):

Protective role of aldehyde dehydrogenase 2 in retinal pigment epithelium cells with CoCl₂-induced hypoxic injury: an in-vitro study.

Sheng Zhang, Guanyu Chen, Lin Xiao, Jialing Dong, Yin Chao, Yuxin Xia, Pan Long, Weiming Yan.

BACKGROUND: Retinal pigment epithelial (RPE) cells are vulnerable to hypoxia-related and oxidative stress. Cobalt chloride (CoCl₂) is widely used as a chemical hypoxia mimetic; however, an appropriate concentration window for producing measurable RPE injury without the more extensive damage associated with higher concentrations remains incompletely defined. Aldehyde dehydrogenase 2 (ALDH2) contributes to reactive-aldehyde detoxification and cellular stress defense.
METHODS: ARPE-19 cells were exposed to 0, 10, 100, 500, 1000, or 2000 µM CoCl₂. Scratch-wound recovery and representative morphology were evaluated for up to 72 h, and relative CCK-8 metabolic activity was quantified at 24, 48, and 72 h. The 500 µM condition was selected for molecular and pharmacological experiments based on the integrated dose-response profile. Culture-supernatant 4-HNE and VEGF-A were measured by ELISA, whereas HIF-1α, ALDH2, and BAX were assessed by Western blotting. Alda-1 and Daidzin were used as an ALDH2 activator/chemical chaperone and an enzymatic inhibitory comparator, respectively.
RESULTS: CoCl₂ caused concentration- and time-associated impairment of scratch-wound recovery. Wound closure was largely preserved at 0-100 µM, whereas 500-2000 µM produced wound-closure failure. The CCK-8 profile showed that 500 µM retained a nonmaximal metabolic signal compared with the substantially greater late reductions observed at 1000 and 2000 µM. Thus, 500 µM represented the lowest tested concentration producing significant functional injury while avoiding the more extensive injury phenotype observed at higher concentrations. Under 500 µM CoCl₂, HIF-1α increased early, ALDH2 protein abundance decreased, and culture-supernatant 4-HNE and VEGF-A increased at the later time point. Alda-1 improved wound recovery and restored ALDH2 protein abundance, whereas Daidzin aggravated the functional injury phenotype and shifted extracellular stress-marker readouts in an unfavorable direction.
CONCLUSIONS: CoCl₂ produced a concentration-resolved, hypoxia-related and aldehyde-associated RPE injury phenotype. Alda-1 improved wound recovery and increased ALDH2 protein abundance, whereas Daidzin aggravated the functional injury phenotype. These findings support ALDH2-associated aldehyde-detoxifying defense as a modulatory component of CoCl₂-induced RPE stress.

Keywords: ALDH2; Cobalt chloride; Cytoprotection; Hypoxia; Retinal pigment epithelial cells

DOI: https://doi.org/10.1186/s40360-026-01207-y

Int Ophthalmol. 2026 Sep 10. pii: 389. [Epub ahead of print]46(1):

Alpinia Oxyphylla-Shenqi Siwu Decoction protects against high glucose-induced retinal pigment epithelial cell injury involving the PI3K/AKT/mTOR pathway.

Weiling Zhang, Chunying Jing.

BACKGROUND: Diabetic retinopathy (DR) is a leading cause of vision loss in working-age adults, and current treatments (anti-VEGF drugs, steroids, laser photocoagulation) mainly target late-stage microvascular complications while offering little for the neurodegeneration and neurovascular unit dysfunction that characterize early DR. Multi-component, multi-target traditional Chinese medicine compound decoctions are attractive candidates for early intervention. Here we investigated the protective effect and molecular mechanism of Alpinia Oxyphylla-Shenqi Siwu Decoction (AOSWSD) in a high glucose-induced ARPE-19 injury model of early DR.
METHODS: ARPE-19 cells were exposed to 30 mmol/L glucose and treated with drug-containing rat serum obtained from rats gavaged with AOSWSD at low, middle and high doses (4.6, 9.2 and 18.4 g/kg/day of crude drug), with a matched normal-rat-serum control. Cell viability, migration, apoptosis, intracellular ROS, cytokine secretion, VEGFR2 immunofluorescence, p-AKT/AKT and p-mTOR/mTOR ratios, and mRNA levels of VEGFA, VEGFR2, HIF-1α, PIK3CA, AKT1, mTOR, Caspase-3, Bcl-2 and Bax were quantified by CCK-8 assay, scratch assay, flow cytometry, DCFH-DA staining, ELISA, immunofluorescence and RT-qPCR, respectively.
RESULTS: Under high-glucose exposure, AOSWSD-containing serum dose-dependently improved cell viability, restored migration, suppressed apoptosis, reduced intracellular ROS, and lowered the secretion of VEGFA, TNF-α and IL-6. Mechanistically, AOSWSD acted along a coordinated VEGFA/VEGFR2-PI3K/AKT/mTOR axis: it reduced secreted VEGFA and VEGFR2 protein at the upstream end, and lowered PIK3CA, AKT1 and mTOR transcripts together with the p-AKT/AKT and p-mTOR/mTOR ratios at the downstream end. Bcl-2, Bax and Caspase-3 expression and the Bax/Bcl-2 ratio were likewise restored towards control values.
CONCLUSION: AOSWSD protects ARPE-19 cells from high glucose-induced injury through simultaneous, dose-dependent modulation of oxidative stress, inflammation, apoptosis and angiogenic signaling, with the VEGFA/VEGFR2-PI3K/AKT/mTOR cascade acting as a principal molecular substrate. These results support AOSWSD as a candidate multi-target intervention for early-stage DR and provide a basis for further mechanistic, chemical and translational studies.

Keywords: ARPE−19; Alpinia Oxyphylla-Shenqi Siwu Decoction; Diabetic retinopathy; PI3K/AKT/mTOR; Traditional Chinese medicine; VEGFA/VEGFR2

DOI: https://doi.org/10.1007/s10792-026-04272-8

Geroscience. 2026 Sep 08.

LAPTM5 correlates with RPE senescence and subretinal fibrosis through the LAPTM5-WWP2-OPTN mitophagy cascade and cGAS/STING activation in a D-galactose-induced aging model.

Xiaowei Yang, Shenglai Zhang, Yan Wang, Jiarong Shi, Wenlong Li, Xueying Lou, Ying Yu, Jiangao Zhang, Aimin Sang.

Retinal pigment epithelium (RPE) senescence acts as a core driver of subretinal fibrosis, a major irreversible pathological feature that exacerbates age-related macular degeneration (AMD). Mitophagy is essential for maintaining RPE homeostasis during aging. However, the upstream molecular mechanisms underlying mitophagy impairment in senescent RPE remain poorly defined. Here, we show that lysosomal-associated transmembrane protein 5 (LAPTM5) is significantly upregulated in human AMD specimens and D-galactose (D-gal)-induced aging mouse model, with its overexpression correlating with transcriptomic signatures of RPE senescence and fibrogenesis. Gain- and loss-of-function assays validate that LAPTM5 acts as an important regulator of RPE senescence and senescence-associated secretory phenotype (SASP) production. Mechanistically, LAPTM5 physically interacts with and promotes the lysosome-dependent degradation of WW domain-containing E3 ubiquitin protein ligase 2 (WWP2), which in turn diminishes optineurin (OPTN) polyubiquitination and ablates OPTN-mediated mitophagy. The resulting mitophagy deficiency is associated with cytoplasmic mitochondrial DNA leakage and sustained cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) innate immune activation, stimulating robust senescence-associated secretory phenotype (SASP) release that promotes RPE epithelial-mesenchymal transition (EMT) and exacerbates subretinal fibrotic scarring. Notably, AAV-mediated RPE-specific Laptm5 knockdown efficiently alleviates subretinal fibrotic lesions in the aged mouse model, while pharmacological STING inhibition with H-151 markedly attenuates EMT progression. Collectively, our findings identify a previously uncharacterized LAPTM5-WWP2-OPTN mitophagy cascade and reveal a new pathogenic circuit linking impaired mitophagy to RPE senescence and age-related retinal fibrosis, offering translational prospects for treating senescence-associated fibrotic diseases.

Keywords: Age-related macular degeneration; LAPTM5; Mitophagy; Retinal pigment epithelium; Senescence-associated secretory phenotype; Subretinal fibrosis

DOI: https://doi.org/10.1007/s11357-026-02506-2

Exp Eye Res. 2026 Sep 10. pii: S0014-4835(26)00387-8. [Epub ahead of print] 111231

HepG2 cells-derived exosomes exacerbate blue light-induced AMD-like retinal degeneration in A2E-laden ARPE-19 cells and BALB/c mice.

Ayun Seol, Jea Sic Jeong, Ji Eun Kim, Hee Jin Song, Su Jeong Lim, Su Ha Wang, Ye Eun Ryu, Ye Ryeong Kim, Woobin Yun, Beum-Soo An, Dae Youn Hwang.

Exosomes derived from hepatic cells have emerged as important mediators of inter-organ communication and may contribute to retinal degeneration associated with age-related macular degeneration (AMD) through the liver-eye axis. However, their role in AMD pathogenesis remains poorly understood. In this study, we investigated whether HepG2 cell-derived exosomes (HG-EX) exacerbate AMD-like retinal degeneration using in vitro and in vivo AMD-mimicking models. ARPE-19 cells co-treated with N-retinylidene-N-retinylethanolamine (A2E) and blue light (BL), as well as BL-exposed BALB/c mice, were pretreated with HG-EX. In AMD-mimicking ARPE-19 cells, HG-EX pretreatment significantly increased intracellular reactive oxygen species (ROS) and nitric oxide (NO) production while suppressing the expression of superoxide dismutase (SOD) and nuclear factor erythroid 2-related factor 2 (Nrf2). In addition, HG-EX altered inflammatory signaling by suppressing inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression, while enhancing inflammasome-related protein expression. Apoptosis-related proteins and pro-angiogenic factors were also markedly elevated following HG-EX treatment. In AMD-mimicking mice, HG-EX administration significantly increased the retinal expression of COX-2, B-cell lymphoma 2 (Bcl-2)/ Bcl-2-associated X protein (Bax), tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6, accompanied by a reduction in the thickness of the outer segment (OS) and inner nuclear layer (INL). Collectively, these findings demonstrate that HG-EX exacerbate oxidative stress, inflammation, apoptosis, and angiogenesis in both cellular and animal models that recapitulate selected pathological features of AMD. Our results suggest that HG-EX may contribute to AMD-like retinal degeneration and warrant further investigation into their potential role in AMD pathogenesis.

Keywords: Age-related macular degeneration; Blue light; Exosome; Liver; Retina

DOI: https://doi.org/10.1016/j.exer.2026.111231