bims-mideyd 2025-03-02 papers

Int J Mol Sci. 2025 Feb 11. pii: 1496. [Epub ahead of print]26(4):

Combination of Saffron (Crocus sativus), Elderberry (Sambucus nigra L.) and Melilotus officinalis Protects ARPE-19 Cells from Oxidative Stress.

Alessandra Puddu, Massimo Nicolò, Davide C Maggi.

Oxidative stress is considered a common underlying mechanism in many retinal degenerative diseases and is often associated with inflammation. The use of dietary supplements containing Saffron has beneficial effects in ocular diseases, though the molecular mechanisms are still unclear. In this study, we investigated how Saffron can exert protective effects against oxidative damage in retinal pigment epithelial cells (ARPE-19) and whether its combination with Elderberry and Melilotus may have additive beneficial effects. ARPE-19 cells were pretreated with Saffron alone or in a mix containing Saffron, Elderberry and Melilotus, then exposed to hydrogen peroxide (H2O2) for 3 h. Afterwards, we evaluated cell viability, oxidative stress and inflammatory status. Our results showed that H2O2 reduced cell viability and total glutathione levels, while increasing caspase-3, caspase-1 and LDH activity. Moreover, H2O2 triggered ROS production, glutathione oxidation and IL-1β secretion. Pretreatments with Saffron alone or with the mix counteract these damaging effects by improving cell viability, reducing oxidative stress and enhancing SOD2 expression. Pretreatment with the mix activated the NRF2 pathway and was more effective than Saffron alone in preventing caspase-1 activation. These findings suggest that the combination of Saffron, Elderberry and Melilotus could have therapeutic potential in the prevention and treatment of retinal degenerative diseases.

Keywords: Elderberry; Melilotus; Saffron; inflammation; oxidative stress; retinal diseases; retinal pigment epithelium

DOI: https://doi.org/10.3390/ijms26041496

Mol Ther Nucleic Acids. 2025 Mar 11. 36(1): 102460

TMEM97 governs partial epithelial-mesenchymal transition of retinal pigment epithelial cells via the CTNND2-ADAM10 axis.

Jing Li, Yosuke Nagasaka, Hongtao Shen, Xinyu Zhou, Jianjie Ma, Dilza Trevisan-Silva, Nicholas E Sherman, Jayakrishna Ambati, Bradley D Gelfand, Lian-Wang Guo.

Epithelial-mesenchymal transition (EMT) is associated with retinal pigment epithelium (RPE) dysfunction in degenerative retinal diseases. However, the role of partial EMT (pEMT), a hybrid state exhibiting both epithelial and mesenchymal markers, remains poorly understood in this context. Our previous research demonstrated that TMEM97 ablation in mice worsens photoreceptor loss in an oxidant-induced RPE damage model. Here, we link TMEM97 to pEMT in RPE cells and explore the underlying molecular mechanisms. We found that re-expressing TMEM97 in the RPE of TMEM97-knockout mice, via subretinal lentiviral delivery, mitigated oxidant (NaIO3)-induced photoreceptor loss. Interestingly, TMEM97 knockout in ARPE19 cells in vitro led to upregulation of cadherin/adhesion-binding pathways, even without oxidant exposure. Integrated proteomic, transcriptomic, segmentation, and immunoblot analyses revealed that TMEM97 ablation induces pEMT, marked by the concurrent expression of epithelial E-cadherin and mesenchymal N-cadherin, a process reversed upon TMEM97 re-expression. Furthermore, TMEM97 negatively regulated CTNND2 protein (catenin δ-2), but not the known EMT driver β-catenin, and CTNND2 was found to promote ADAM10, which sustains both E- and N-cadherin protein levels. These findings identify TMEM97 as a novel regulator of RPE-cell pEMT through the CTNND2-ADAM10 axis, highlighting potential new targets for therapeutic intervention in RPE-related pathophysiology.

Keywords: AMD; E-cadherin; MT: Oligonucleotides: Therapies and Applications; N-cadherin; RPE; ZO-1; catenin; partial EMT; photoreceptor; retinal degeneration; sigma-2 receptor

DOI: https://doi.org/10.1016/j.omtn.2025.102460

J Microbiol Biotechnol. 2025 Feb 24. 35 e2411037

BlingLife®-Marigold Extract Alleviates Blue Light-Induced Retinal Mitochondria Oxidative Stress and Senescence by Activating NRF2/HO-1 Signaling.

Zixiu Zhou, Sizhen Li, Qingsong Yang, Pengjie Zheng, Kexin Xie.

Blue light poses a risk of retinal damage with excessive exposure. BlingLife®-marigold extract (BLM) is an alcohol extract of magrigold, which contains abundant lutein, zeaxanthin and meso-zeaxanthin. This study aimed to explore the role and potential mechanisms of BLM in blue light-induced retinal damage both in vivo and in vitro. Rats or human retinal pigment epithelial cell line (ARPE-19) were exposed to blue LED light with or without BLM treatment. The retinal morphology changes of rat were evaluated by H&E staining. Mitochondrial morphology was examined by using a transmission electron microscope. Besides, mitochondria oxidative stress was evaluated by detecting mitochondrial membrane potential, ROS, MDA and SOD levels. By measuring γH2AX expression and performing SA-β-galactosidase (gal) staining, cell senescence was assessed. Additionally, cell cycle was detected using flow cytometry. Western blot was employed to examine the expression of NRF2 and HO-1. Results indicated that BLM could protect against blue light-induced damage of rat retinal tissues and ARPE-19 cells, as evidenced by the improved histopathological changes, alleviated mitochondria oxidative stress and attenuated senescence of tissues and cells. More importantly, BLM activated NRF2/HO-1 signaling, and addition of NRF2 inhibitor ML385 significantly blocked the protective effects of BLM on ARPE-19 cells exposed to blue light. In conclusion, BLM can provide an effective protection against blue light-induced retinal damage at least partly by activating NRF2/HO-1 signaling, suggesting that BLM may be useful for the prevention of blue light-induced retinal injury.

Keywords: NRF2/HO-1 signaling; Retinal damage; blue light; meso-zeaxanthin; reactive oxygen species

DOI: https://doi.org/10.4014/jmb.2411.11037

J Diabetes Investig. 2025 Feb 24.

YY2 mediates transcriptional repression of PHGDH and expedites oxidative stress in retinal pigment epithelial cells in diabetic retinopathy.

Xiang Lei, Xiu Wang, Xinai Zhang.

AIMS/INTRODUCTION: Phosphoglycerate dehydrogenase (PHGDH), which controls serine synthesis, has been linked to retinal disease. However, there are no clues about its involvement in the diabetic retinopathy (DR) progression. Therefore, we aimed to investigate the relationship between PHGDH, serine synthesis, and DR and their underlying molecular mechanisms.
METHOD: Differentially expressed genes in DR were screened using bioinformatics tools. DR mice were induced, and retinal histopathology was observed in mice. Overexpression of PHGDH was induced in the DR mice to measure l-serine, ROS, and MDA content in the retinas of DR mice. ARPE-19 cells were transfected with overexpression of PHGDH and exposed to high glucose to induce a DR in vitro model, and cell viability and apoptosis assays, serine content, and oxidative stress factor measurement were conducted. The transcriptional regulation of PHGDH by YY2 was explored by ChIP and dual-luciferase reporter assays. Finally, the combined role of YY2 and PHGDH in regulating serine synthesis, oxidative stress, and ferroptosis was investigated.
RESULTS: PHGDH expression was reduced in DR mice, and overexpression of PHGDH alleviated DR progression by promoting serine synthesis and attenuating oxidative stress. YY2 bound to the promoter of PHGDH and mediated its transcriptional repression. YY2-mediated transcriptional repression of PHGDH caused disturbances in serine synthesis, leading to oxidative stress-triggered ferroptosis.
CONCLUSIONS: Our data prove that YY2 plays a vital role in modulating PHGDH expression, impairing serine synthesis, and expediting oxidative stress and ferroptosis.

Keywords: Diabetic retinopathy; Ferroptosis; Oxidative stress

DOI: https://doi.org/10.1111/jdi.70011