bims-mideyd 2022-05-22 papers

Cell Death Dis. 2022 May 18. 13(5): 468

Involvement of FSP1-CoQ10-NADH and GSH-GPx-4 pathways in retinal pigment epithelium ferroptosis.

Ming Yang, Michelle Grace Tsui, Jessica Kwan Wun Tsang, Rajesh Kumar Goit, Kwok-Ming Yao, Kwok-Fai So, Wai-Ching Lam, Amy Cheuk Yin Lo.

Retinal pigment epithelium (RPE) degeneration plays an important role in a group of retinal disorders such as retinal degeneration (RD) and age-related macular degeneration (AMD). The mechanism of RPE cell death is not yet fully elucidated. Ferroptosis, a novel regulated cell death pathway, participates in cancer and several neurodegenerative diseases. Glutathione peroxidase 4 (GPx-4) and ferroptosis suppressor protein 1 (FSP1) have been proposed to be two main regulators of ferroptosis in these diseases; yet, their roles in RPE degeneration remain elusive. Here, we report that both FSP1-CoQ10-NADH and GSH-GPx-4 pathways inhibit retinal ferroptosis in sodium iodate (SIO)-induced retinal degeneration pathologies in human primary RPE cells (HRPEpiC), ARPE-19 cell line, and mice. GSH-GPx-4 signaling was compromised after a toxic injury caused by SIO, which was aggravated by silencing GPx-4, and ferroptosis inhibitors robustly protected RPE cells from the challenge. Interestingly, while inhibition of FSP1 caused RPE cell death, which was aggravated by SIO exposure, overexpression of FSP1 effectively protected RPE cells from SIO-induced injury, accompanied by a significant down-regulation of CoQ10/NADH and lipid peroxidation. Most importantly, in vivo results showed that Ferrostatin-1 not only remarkably alleviated SIO-induced RPE cell loss, photoreceptor death, and retinal dysfunction but also significantly ameliorated the compromised GSH-GPx-4 and FSP1-CoQ10-NADH signaling in RPE cells isolated from SIO-induced RPE degeneration. These data describe a distinct role for ferroptosis in controlling RPE cell death in vitro and in vivo and may provide a new avenue for identifying treatment targets for RPE degeneration.

DOI: https://doi.org/10.1038/s41419-022-04924-4

Ophthalmic Res. 2022 May 18.

Conditioned medium from human uterine cervical stem cells regulates oxidative stress and angiogenesis of retinal pigment epithelial cells.

Noemi Eiro, Juan Sendón-Lago, Sandra Cid, Jorge Saá, Nagore de Pablo, Belen Vega, María A Bermudez, Roman Perez-Fernandez, Francisco J Vizoso.

INTRODUCTION: Retinal homeostasis is essential to avoid retinal pigment epithelium (RPE) damage resulting in photoreceptor death and blindness. Mesenchymal stem cells-based cell therapy could contribute to the maintenance of the retinal homeostasis. We have explored the effect of human uterine cervical stem cells (hUCESCs) conditioned medium (hUCESC-CM) on RPE cells under oxidative stress condition.
METHODS: ARPE-19 cells were treated with hydrogen peroxide (H2O2) in presence or absence of hUCESC-CM. qRT-PCR and Western blot were used to evaluate the expression of oxidative stress (HO-1, GCLC and HSPB1) and vasculogenesis (VEGFA, PDGFA and PDGFB) related factors. Also, we assessed in vitro effects of hUCESC-CM on endothelial cells (HUVEC) tube formation.
RESULTS: mRNA expression of HO-1, GCLC, HSPB1, VEGFA, PDGFA and PDGFB were significantly increased in ARPE-19 cells treated with H2O2 + hUCESC-CM compared to cells treated with H2O2 only. Regarding the tube formation assay, HUVEC treated with supernatant from ARPE-19 cells treated with H2O2 + hUCESC-CM showed a significant increase in average vessel length, number of capillary-like junctions and average of vessels area compared with HUVEC treated with supernatant from ARPE-19 cells treated with H2O2 only.
CONCLUSION: Our results show potential therapeutic effects of hUCESC-CM on RPE, such as protection from damage by oxidative stress, stimulation of detoxifying genes and a better vascularization.

DOI: https://doi.org/10.1159/000524484

Aging (Albany NY). 2022 05 16. 14(undefined):

Effect of Humanin G (HNG) on inflammation in age-related macular degeneration (AMD).

Sonali Nashine, Pinchas Cohen, Junxiang Wan, M. Cristina Kenney.

Inflammation plays a crucial role in the etiology and pathogenesis of AMD (Age-related Macular Degeneration). Humanin G (HNG) is a Mitochondrial Derived Peptide (MDP) that is cytoprotective in AMD and can protect against mitochondrial and cellular stress induced by damaged AMD mitochondria. The goal of this study was to test our hypothesis that inflammation-associated marker protein levels are increased in AMD and treatment with HNG leads to reduction in their protein levels. Humanin protein levels were measured in the plasma of AMD patients and normal subjects using ELISA assay. Humanin G was added to AMD and normal (control) cybrids which had identical nuclei from mitochondria-deficient ARPE-19 cells but differed in mitochondrial DNA (mtDNA) content derived from clinically characterized AMD patients and normal (control) subjects. Cell lysates were extracted from untreated and HNG-treated AMD and normal cybrids, and the Luminex XMAP multiplex assay was used to measure the levels of inflammatory proteins. AMD plasma showed reduced Humanin protein levels, but higher protein levels of inflammation markers compared to control plasma samples. In AMD RPE cybrid cells, Humanin G reduced the CD62E/ E-Selectin, CD62P/ P-Selectin, ICAM-1, TNF-α, MIP-1α, IFN-γ, IL-1β, IL-13, and IL-17A protein levels, thereby suggesting that Humanin G may rescue from mtDNA-mediated inflammation in AMD cybrids. In conclusion, we present novel findings that: A) show reduced Humanin protein levels in AMD plasma vs. normal plasma; B) suggest the role of inflammatory markers in AMD pathogenesis, and C) highlight the positive effects of Humanin G in reducing inflammation in AMD.

Keywords: AMD; HNG; Humanin G; age-related macular degeneration; inflammation

DOI: https://doi.org/10.18632/aging.204074