bims-mideyd Biomed News
on Mitochondrial dysfunction in eye diseases
Issue of 2023‒09‒24
eight papers selected by
Rajalekshmy “Raji” Shyam, Indiana University Bloomington
  1. LIN28A attenuates high glucose-induced retinal pigmented epithelium injury through activating SIRT1-dependent autophagy.
  2. Hyperbaric oxygen therapy suppresses hypoxia and reoxygenation injury to retinal pigment epithelial cells through activating peroxisome proliferator activator receptor-alpha signalling.
  3. A Novel Primary Porcine Retinal Pigment Epithelium Cell Model with Preserved Properties.
  4. Aging, Cellular Senescence, and Glaucoma.
  5. Identifying biomarkers of heterogeneity and transplantation efficacy in retinal pigment epithelial cells.
  6. Restored retinal physiology after administration of niacin with citicoline in a mouse model of hypertensive glaucoma.
  7. MG132, Attenuates the Retinal Vascular Injury Through the Upregulation of Nrf2 Expression.
  8. Editorial: Oxidative stress link associated with mitochondrial bioenergetics: relevance in cell aging and age-related pathologies.
  1. Int J Ophthalmol. 2023 ;16(9): 1465-1474
    LIN28A attenuates high glucose-induced retinal pigmented epithelium injury through activating SIRT1-dependent autophagy.
    Dan-Qing Yu, Song-Ping Yu, Jing Wu, Li-Na Lan, Bang-Xun Mao.
      AIM: To evaluate the effects of LIN28A (human) on high glucose-induced retinal pigmented epithelium (RPE) cell injury and its possible mechanism.METHODS: Diabetic retinopathy model was generated following 48h of exposure to 30 mmol/L high glucose (HG) in ARPE-19 cells. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot tested the expression of the corresponding genes and proteins. Cell viability as well as apoptosis was determined through cell counting kit-8 (CCK-8) and flow cytometry assays. Immunofluorescence assay was adopted to evaluate autophagy activity. Caspase 3 activity, oxidative stress markers, and cytokines were appraised adopting their commercial kits, respectively. Finally, ARPE-19 cells were preincubated with EX527, a Sirtuin 1 (SIRT1) inhibitor, prior to HG stimulation to validate the regulatory mechanism.
    RESULTS: LIN28A was downregulated in HG-challenged ARPE-19 cells. LIN28A overexpression greatly inhibited HG-induced ARPE-19 cell viability loss, apoptosis, oxidative damage as well as inflammatory response. Meanwhile, the repressed autophagy and SIRT1 in ARPE-19 cells challenged with HG were elevated after LIN28A overexpression. In addition, treatment of EX527 greatly inhibited the activated autophagy following LIN28A overexpression and partly abolished the protective role of LIN28A against HG-elicited apoptosis, oxidative damage as well as inflammation in ARPE-19 cells.
    CONCLUSION: LIN28A exerts a protective role against HG-elicited RPE oxidative damage, inflammation, as well as apoptosis via regulating SIRT1/autophagy.
    Keywords:  LIN28A; Sirtuin 1; autophagy; high glucose; oxidative stress; retinal pigmented epithelial cells
    DOI:  https://doi.org/10.18240/ijo.2023.09.13
  2. J Cell Mol Med. 2023 Sep 20.
    Hyperbaric oxygen therapy suppresses hypoxia and reoxygenation injury to retinal pigment epithelial cells through activating peroxisome proliferator activator receptor-alpha signalling.
    Tzong-Bor Sun, Kuo-Feng Huang, Ko-Chi Niu, Cheng-Hsien Lin, Wen-Pin Liu, Chao-Hung Yeh, Shu-Chun Kuo, Ching-Ping Chang.
      Retinal ischemia followed by reperfusion (IR) is a common cause of many ocular disorders, such as age-related macular degeneration (AMD), which leads to blindness in the elderly population, and proper therapies remain unavailable. Retinal pigment epithelial (RPE) cell death is a hallmark of AMD. Hyperbaric oxygen (HBO) therapy can improve IR tissue survival by inducing ischemic preconditioning responses. We conducted an in vitro study to examine the effects of HBO preconditioning on oxygen-glucose deprivation (OGD)-induced IR-injured RPE cells. RPE cells were treated with HBO (100% O2 at 3 atmospheres absolute for 90 min) once a day for three consecutive days before retinal IR onset. Compared with normal cells, the IR-injured RPE cells had lower cell viability, lower peroxisome proliferator activator receptor-alpha (PPAR-α) expression, more severe oxidation status, higher blood-retinal barrier disruption and more elevated apoptosis and autophagy rates. HBO preconditioning increased PPAR-α expression, improved cell viability, decreased oxidative stress, blood-retinal barrier disruption and cellular apoptosis and autophagy. A specific PPAR-α antagonist, GW6471, antagonized all the protective effects of HBO preconditioning in IR-injured RPE cells. Combining these observations, HBO therapy can reverse OGD-induced RPE cell injury by activating PPAR-α signalling.
    Keywords:  PPARα; age-related macular degeneration; apoptosis; autophagy; hyperbaric oxygen; oxidative stress; retinal pigment epithelial cell
    DOI:  https://doi.org/10.1111/jcmm.17963
  3. Curr Eye Res. 2023 Sep 19. 1-11
    A Novel Primary Porcine Retinal Pigment Epithelium Cell Model with Preserved Properties.
    Dinna Zhou, Anne Petersen, Julia Adelöf, Malin Hernebring, Madeleine Zetterberg.
      PURPOSE: To establish an ethical, reliable, and expandable retinal pigment epithelial (RPE) cell model with maintained RPE properties compatible with multifarious assays.METHODS: RPE cells from abattoir-obtained porcine eyes were cultured under various conditions. Morphology, RPE cell-specific protein markers (RPE-65, CRALBP), and the tight junction marker ZO-1 were analyzed by phase-contrast microscopy, immunocytochemistry, and western blot, and transepithelial electrical resistance (TEER) was determined to assess barrier function.
    RESULTS: The porcine RPE cells (pRPE) were best established using TrypLE Express, 10% fetal bovine serum (FBS) supplemented high-glucose media, and subculturing at semi-confluency. The pRPE cells maintained epithelioid morphology with ZO-1 positive tight junctions at the cell-to-cell borders, the ability to establish proper barrier function (TEERmax: 346/375 Ω⋅cm2 at passage I/passage VI), and expressed CRALBP and RPE-65 for several passages. The RPE characteristics decreased and disappeared with transdifferentiation.
    CONCLUSIONS: This work describes, for the first time, a pRPE cell model that exhibits preserved RPE properties for several passages on cell culture plastic plates. Though RPE characteristics were maintained for at least 6 passages, the reduced CRALBP and RPE-65 with passaging emphasize that lower passage cells are advantageous to utilize, and that morphology, barrier function, and ZO-1 localization cannot be solely employed as a quality measure of RPE identity. Pigs are phylogenetically similar to humans, including similar physiology, anatomy and immune system. Therefore, porcine RPE cells constitute a relevant model system for studying human eye diseases, such as AMD.
    Keywords:  3R; AMD; RPE cell model; RPE-specific protein markers; transepithelial electrical resistance (TEER)
    DOI:  https://doi.org/10.1080/02713683.2023.2259636
  4. Aging Dis. 2023 Jul 16.
    Aging, Cellular Senescence, and Glaucoma.
    Yumeng Zhang, Shouyue Huang, Bing Xie, Yisheng Zhong.
      Aging is one of the most serious risk factors for glaucoma, and according to age-standardized prevalence, glaucoma is the second leading cause of legal blindness worldwide. Cellular senescence is a hallmark of aging that is defined by a stable exit from the cell cycle in response to cellular damage and stress. The potential mechanisms underlying glaucomatous cellular senescence include oxidative stress, DNA damage, mitochondrial dysfunction, defective autophagy/mitophagy, and epigenetic modifications. These phenotypes interact and generate a sufficiently stable network to maintain the cell senescent state. Senescent trabecular meshwork (TM) cells, retinal ganglion cells (RGCs) and vascular endothelial cells reportedly accumulate with age and stress and may contribute to glaucoma pathologies. Therapies targeting the suppression or elimination of senescent cells have been found to ameliorate RGC death and improve vision in glaucoma models, suggesting the pivotal role of cellular senescence in the pathophysiology of glaucoma. In this review, we explore the biological links between aging and glaucoma, specifically delving into cellular senescence. Moreover, we summarize the current data on cellular senescence in key target cells associated with the development and clinical phenotypes of glaucoma. Finally, we discuss the therapeutic potential of targeting cellular senescence for the management of glaucoma.
    DOI:  https://doi.org/10.14336/AD.2023.0630-1
  5. J Exp Med. 2023 12 04. pii: e20230913. [Epub ahead of print]220(12):
    Identifying biomarkers of heterogeneity and transplantation efficacy in retinal pigment epithelial cells.
    Farhad Farjood, Justine D Manos, Yue Wang, Anne L Williams, Cuiping Zhao, Susan Borden, Nazia Alam, Glen Prusky, Sally Temple, Jeffrey H Stern, Nathan C Boles.
      Transplantation of retinal pigment epithelial (RPE) cells holds great promise for patients with retinal degenerative diseases, such as age-related macular degeneration. In-depth characterization of RPE cell product identity and critical quality attributes are needed to enhance efficacy and safety of replacement therapy strategies. Here, we characterized an adult RPE stem cell-derived (RPESC-RPE) cell product using bulk and single-cell RNA sequencing (scRNA-seq), assessing functional cell integration in vitro into a mature RPE monolayer and in vivo efficacy by vision rescue in the Royal College of Surgeons rats. scRNA-seq revealed several distinct subpopulations in the RPESC-RPE product, some with progenitor markers. We identified RPE clusters expressing genes associated with in vivo efficacy and increased cell integration capability. Gene expression analysis revealed lncRNA (TREX) as a predictive marker of in vivo efficacy. TREX knockdown decreased cell integration while overexpression increased integration in vitro and improved vision rescue in the RCS rats.
    DOI:  https://doi.org/10.1084/jem.20230913
  6. Front Med (Lausanne). 2023 ;10 1230941
    Restored retinal physiology after administration of niacin with citicoline in a mouse model of hypertensive glaucoma.
    Alberto Melecchi, Rosario Amato, Massimo Dal Monte, Dario Rusciano, Paola Bagnoli, Maurizio Cammalleri.
      Introduction: Much interest has been addressed to antioxidant dietary supplements that are known to lower the risk of developing glaucoma or delay its progression. Among them, niacin and citicoline protect retinal ganglion cells (RGCs) from degeneration by targeting mitochondria, though at different levels. A well-established mouse model of RGC degeneration induced by experimental intraocular pressure (IOP) elevation was used to investigate whether a novel combination of niacin/citicoline has better efficacy over each single component in preserving RGC health in response to IOP increase.Methods: Ocular hypertension was induced by an intracameral injection of methylcellulose that clogs the trabecular meshwork. Electroretinography and immunohistochemistry were used to evaluate RGC function and density. Oxidative, inflammatory and apoptotic markers were evaluated by Western blot analysis.
    Results: The present results support an optimal efficacy of niacin with citicoline at their best dosage in preventing RGC loss. In fact, about 50% of RGCs were spared from death leading to improved electroretinographic responses to flash and pattern stimulation. Upregulated levels of oxidative stress and inflammatory markers were also consistently reduced by almost 50% after niacin with citicoline thus providing a significant strength to the validity of their combination.
    Conclusion: Niacin combined with citicoline is highly effective in restoring RGC physiology but its therapeutic potential needs to be further explored. In fact, the translation of the present compound to humans is limited by several factors including the mouse modeling, the higher doses of the supplements that are necessary to demonstrate their efficacy over a short follow up period and the scarce knowledge of their transport to the bloodstream and to the eventual target tissues in the eye.
    Keywords:  apoptotic cascade; electroretinography; inflammation; intraocular pressure; mitochondrial dysfunction; oxidative stress
    DOI:  https://doi.org/10.3389/fmed.2023.1230941
  7. J Ocul Pharmacol Ther. 2023 Sep 20.
    MG132, Attenuates the Retinal Vascular Injury Through the Upregulation of Nrf2 Expression.
    Peipei Wang, Shipei Fan, Xin Hu, Li Luo, Jia Ying, Jun Li.
      Purpose: This study clarifies the beneficial effects of MG132, a proteasomal inhibitor, on retinal vascular injury mediated by diabetes-induced oxidative stress through nuclear factor erythroid 2-related factor 2 (Nrf2). Methods: Diabetic rats and control animals were randomly assigned to receive MG132 or vehicle for 24 weeks, and human retinal endothelial cells (HRECs) were incubated with normal or high glucose with or without MG132. 26S proteasome activity in the rat retinas or cultured HRECs was measured using Suc-LLVY-7-amido-4-methylcoumarin. NADPH-quinone oxidoreduc-tase (NQO1), heme oxygenase (HO)-1, kelch-like ECH-associated protein 1 (Keap1) and Nrf2 were examined by Western blotting and real-time reverse transcription polymerase chain reaction. Cell apoptosis is measured through flow cytometry assay, mitochondrial reactive oxygen species (ROS) production, and retinal vascular leakage were assayed using CM-H2DCFDA fluorescent probes and Evans blue, respectively. Results: MG132 significantly inhibited the activation of 26S proteasome induced by diabetes or elevated glucose, and subsequently increased the expression of Nrf2, NQO1, and HO-1, and further reduced ROS accumulation. These changes were associated with a decrease of diabetes-induced retinal vascular leakage and retinal capillary cell apoptosis. Conclusions: MG132 decreases diabetes-induced 26S proteasome activation and exerts protective effects against retinal microvascular dysfunction in diabetic rats in association with the alleviation of retinal oxidative stress mediated by Nrf2.
    Keywords:  MG132; Nrf2; diabetic retinopathy; oxidative stress
    DOI:  https://doi.org/10.1089/jop.2023.0053
  8. Front Cell Dev Biol. 2023 ;11 1273420
    Editorial: Oxidative stress link associated with mitochondrial bioenergetics: relevance in cell aging and age-related pathologies.
    Rajkumar Singh Kalra, Subodh Kumar, Dhanendra Tomar.
      
    Keywords:  age-related pathologies; aging; bioenergetics; cancer; mitochondria; neurodegenerative disease; oxidative stress
    DOI:  https://doi.org/10.3389/fcell.2023.1273420
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