bims-mideyd 2022-07-10 papers

bims-mideyd

Biomed News

on Mitochondrial dysfunction in eye diseases

Issue of 2022–07–10
ten papers selected by
Rajalekshmy “Raji” Shyam, Indiana University Bloomington

Fisetin Attenuated Oxidative Stress-Induced Cellular Damage in ARPE-19 Human Retinal Pigment Epithelial Cells Through Nrf2-Mediated Activation of Heme Oxygenase-1.
Lycium barbarum L. and Salvia miltiorrhiza Bunge protect retinal pigment epithelial cells through endoplasmic reticulum stress.
Dabigatran and Wet AMD, Results From Retinal Pigment Epithelial Cell Monolayers, the Mouse Model of Choroidal Neovascularization, and Patients From the Medicare Data Base.
Oxidative stress and mitochondrial transfer: A new dimension towards ocular diseases.
Collagen Mimetic Peptides Promote Adherence and Migration of ARPE-19 Cells While Reducing Inflammatory and Oxidative Stress.
Inflammasome Activation in Retinal Pigment Epithelium from Human Donors with Age-Related Macular Degeneration.
Explore the molecular mechanism of angle-closure glaucoma in elderly patients induced telomere shortening of retinal ganglion cells through oxidative stress.
Optic nerve injury-induced regeneration in the adult zebrafish is accompanied by spatiotemporal changes in mitochondrial dynamics.
Integrated Stress Response Regulation of Corneal Epithelial Cell Motility and Cytokine Production.
Changes of retinal ganglion cell complex after vitrectomy in rhegmatogenous retinal detachment patients and its correlation with inflammatory blood biomarkers.

Front Pharmacol. 2022 ;13 927898

Fisetin Attenuated Oxidative Stress-Induced Cellular Damage in ARPE-19 Human Retinal Pigment Epithelial Cells Through Nrf2-Mediated Activation of Heme Oxygenase-1.

Cheol Park, Jeong Sook Noh, Youngmi Jung, Sun-Hee Leem, Jin Won Hyun, Young-Chae Chang, Taeg Kyu Kwon, Gi-Young Kim, Hyesook Lee, Yung Hyun Choi.

  Fisetin is a kind of bioactive flavonol, widely present in various fruits such as strawberries and apples, and is known to act as a potent free radical scavenger. However, the mechanism of action related to the antioxidant activity of this compound in human retinal pigment epithelial (RPE) cells is not precisely known. In this study, we aimed to investigate whether fisetin could attenuate oxidative stress-induced cytotoxicity on human RPE ARPE-19 cells. To mimic oxidative stress, ARPE-19 cells were treated with hydrogen peroxide (H2O2), and fisetin significantly inhibited H2O2-induced loss of cell viability and increase of intracellular reactive oxygen species (ROS) production. Fisetin also markedly attenuated DNA damage and apoptosis in H2O2-treated ARPE-19 cells. Moreover, mitochondrial dysfunction in H2O2-treated cells was alleviated in the presence of fisetin as indicated by preservation of mitochondrial membrane potential, increase of Bcl-2/Bax expression ratio, and suppression of cytochrome c release into the cytoplasm. In addition, fisetin enhanced phosphorylation and nuclear translocation of nuclear factor erythroid 2 related factor 2 (Nrf2), which was associated with increased expression and activity of heme oxygenase-1 (HO-1). However, the HO-1 inhibitor, zinc protoporphyrin, significantly reversed the protective effect of fisetin against H2O2-mediated ARPE-19 cell injury. Therefore, our results suggest that Nrf2-mediated activation of antioxidant enzyme HO-1 may play an important role in the ROS scavenging activity of fisetin in RPE cells, contributing to the amelioration of oxidative stress-induced ocular disorders.

Keywords:  DNA damage; Nrf2/HO-1; ROS; apoptosis; fisetin; human retinal pigment epithelial cells

DOI:  https://doi.org/10.3389/fphar.2022.927898
J Ethnopharmacol. 2022 Jul 02. pii: S0378-8741(22)00558-X. [Epub ahead of print]296 115519

Lycium barbarum L. and Salvia miltiorrhiza Bunge protect retinal pigment epithelial cells through endoplasmic reticulum stress.

Chen Ou, Wei Xie, Pengfei Jiang, Ying Wang, Jun Peng, Yasha Zhou, Houpan Song, Qinghua Peng.

   ETHNOPHARMACOLOGICAL RELEVANCE: Lycium barbarum L. and Salvia miltiorrhiza Bunge (Gouqi and Danshen, LS) are traditional herbs for the treatment of retinal degeneration in China. LS have been integrated into pharmacopoeia and health care system of many countries around the world. However, the mechanisms by which LS protect retina are not fully clarified.
AIM OF THE STUDY: We aimed at exploration of the effect of LS on retinal pigment epithelium (RPE) cells apoptosis as well as the endoplasmic reticulum (ER) stress mechanisms.
MATERIAL AND METHODS: ARPE-19 cells were exposed to tunicamycin to induce ER stress, followed by LS treatment for 24 h. The cell morphology was photographed using the Incucyte S3 instrument, and the potential cytotoxic effect and viability were evaluated by CCK-8 assays. The Annexin V-FITC/PI staining and TUNEL assay were conducted to detect cells apoptotic. Western blot and digital PCR were used to detected related protein and gene expression.
RESULTS: The ARPE-19 cells are increased in number and aligned after treating with LS. 1 mg/ml is the LS high dose group dose and treatment with LS increased cell vitality. LS significantly inhibit ARPE-19 cells apoptosis. Moreover, LS were markedly decreased the expression levels of ER stress-related factors in the ARPE-19 cells.
CONCLUSIONS: This study reveals that LS relieve ARPE-19 cells apoptosis by inhibiting ER stress, and here we can speculate that LS have a certain protective effect on retina.

Keywords:  ARPE-19 cells; Endoplasmic reticulum stress; Lycium barbarum L.; Retinal pigment epithelial cells; Salvia miltiorrhiza Bunge

DOI:  https://doi.org/10.1016/j.jep.2022.115519
Front Immunol. 2022 ;13 896274

Dabigatran and Wet AMD, Results From Retinal Pigment Epithelial Cell Monolayers, the Mouse Model of Choroidal Neovascularization, and Patients From the Medicare Data Base.

Tanjina Akter, Balasubramaniam Annamalai, Elisabeth Obert, Kit N Simpson, Bärbel Rohrer.

   Background: Age-related macular degeneration (AMD), the leading cause of irreversible blindness in elderly Caucasian populations, includes destruction of the blood-retina barrier (BRB) generated by the retinal pigment epithelium-Bruch's membrane complex (RPE/BrM), and complement activation. Thrombin is likely to get access to those structures upon BRB integrity loss. Here we investigate the potential role of thrombin in AMD by analyzing effects of the thrombin inhibitor dabigatran.
Material and Methods: MarketScan data for patients aged ≥65 years on Medicare was used to identify association between AMD and dabigatran use. ARPE-19 cells grown as mature monolayers were analyzed for thrombin effects on barrier function (transepithelial resistance; TER) and downstream signaling (complement activation, expression of connective tissue growth factor (CTGF), and secretion of vascular endothelial growth factor (VEGF)). Laser-induced choroidal neovascularization (CNV) in mouse is used to test the identified downstream signaling.
Results: Risk of new wet AMD diagnosis was reduced in dabigatran users. In RPE monolayers, thrombin reduced TER, generated unique complement C3 and C5 cleavage products, led to C3d/MAC deposition on cell surfaces, and increased CTGF expression via PAR1-receptor activation and VEGF secretion. CNV lesion repair was accelerated by dabigatran, and molecular readouts suggest that downstream effects of thrombin include CTGF and VEGF, but not the complement system.
Conclusions: This study provides evidence of association between dabigatran use and reduced exudative AMD diagnosis. Based on the cell- and animal-based studies, we suggest that thrombin modulates wound healing and CTGF and VEGF expression, making dabigatran a potential novel treatment option in AMD.

Keywords:  CTGF; MarketScan; VEGF; complement; dabigatran; mouse CNV; retinal pigment epithelium; thrombin

DOI:  https://doi.org/10.3389/fimmu.2022.896274
Genes Dis. 2022 May;9(3): 610-637

Oxidative stress and mitochondrial transfer: A new dimension towards ocular diseases.

Mohana Devi Subramaniam, Mahalaxmi Iyer, Aswathy P Nair, Dhivya Venkatesan, Sinnakaruppan Mathavan, Nimmisha Eruppakotte, Soumya Kizhakkillach, Manoj Kumar Chandran, Ayan Roy, Abilash Valsala Gopalakrishnan, Balachandar Vellingiri.

  Ocular cells like, retinal pigment epithelium (RPE) is a highly specialized pigmented monolayer of post-mitotic cells, which is located in the posterior segment of the eye between neuro sensory retina and vascular choroid. It functions as a selective barrier and nourishes retinal visual cells. As a result of high-level oxygen consumption of retinal cells, RPE cells are vulnerable to chronic oxidative stress and an increased level of reactive oxygen species (ROS) generated from mitochondria. These oxidative stress and ROS generation in retinal cells lead to RPE degeneration. Various sources including mtDNA damage could be an important factor of oxidative stress in RPE. Gene therapy and mitochondrial transfer studies are emerging fields in ocular disease research. For retinal degenerative diseases stem cell-based transplantation methods are developed from basic research to preclinical and clinical trials. Translational research contributions of gene and cell therapy would be a new strategy to prevent, treat and cure various ocular diseases. This review focuses on the effect of oxidative stress in ocular cell degeneration and recent translational researches on retinal degenerative diseases to cure blindness.

Keywords:  Mitochondrial transfer; Oxidative stress; RPE Degeneration; Retinal pigment epithelium (RPE); Stem cell treatment

DOI:  https://doi.org/10.1016/j.gendis.2020.11.020
Int J Mol Sci. 2022 Jun 23. pii: 7004. [Epub ahead of print]23(13):

Collagen Mimetic Peptides Promote Adherence and Migration of ARPE-19 Cells While Reducing Inflammatory and Oxidative Stress.

Marcio Ribeiro, Silvia Pasini, Robert O Baratta, Brian J Del Buono, Eric Schlumpf, David J Calkins.

  Epithelial cells of multiple types produce and interact with the extracellular matrix to maintain structural integrity and promote healthy function within diverse endogenous tissues. Collagen is a critical component of the matrix, and challenges to collagen's stability in aging, disease, and injury influence survival of adherent epithelial cells. The retinal pigment epithelium (RPE) is important for maintaining proper function of the light-sensitive photoreceptors in the neural retina, in part through synergy with the collagen-rich Bruch's membrane that promotes RPE adherence. Degradation of Bruch's is associated with RPE degeneration, which is implicated early in age-related macular degeneration, a leading cause of irreversible vision loss worldwide. Collagen mimetic peptides (CMPs) effectively repair damage to collagen helices, which are present in all collagens. Our previous work indicates that in doing so, CMPs promote survival and integrity of affected cells and tissues in models of ocular injury and disease, including wounding of corneal epithelial cells. Here, we show that CMPs increase adherence and migration of the ARPE-19 line of human RPE cells challenged by digestion of their collagen substrate. Application of CMPs also reduced both ARPE-19 secretion of pro-inflammatory cytokines (interleukins 6 and 8) and production of reactive oxygen species. Taken together, these results suggest that repairing collagen damaged by aging or other pathogenic processes in the posterior eye could improve RPE adherence and survival and, in doing so, reduce the inflammatory and oxidative stress that perpetuates the cycle of destruction at the root of age-related diseases of the outer retina.

Keywords:  Bruch’s membrane; collagen mimetic peptides; cytokines; extracellular matrix; macular degeneration; ocular collagen; ocular inflammation; oxidative stress; retinal pigment epithelium

DOI:  https://doi.org/10.3390/ijms23137004
Cells. 2022 Jun 30. pii: 2075. [Epub ahead of print]11(13):

Inflammasome Activation in Retinal Pigment Epithelium from Human Donors with Age-Related Macular Degeneration.

Mara C Ebeling, Cody R Fisher, Rebecca J Kapphahn, Madilyn R Stahl, Shichen Shen, Jun Qu, Sandra R Montezuma, Deborah A Ferrington.

  Age-related macular degeneration (AMD), the leading cause of blindness in the elderly, is characterized by the death of retinal pigment epithelium (RPE) and photoreceptors. One of the risk factors associated with developing AMD is the single nucleotide polymorphism (SNP) found within the gene encoding complement factor H (CFH). Part of the innate immune system, CFH inhibits alternative complement pathway activation. Multi-protein complexes called inflammasomes also play a role in the innate immune response. Previous studies reported that inflammasome activation may contribute to AMD pathology. In this study, we used primary human adult RPE cell cultures from multiple donors, with and without AMD, that were genotyped for the Y402H CFH risk allele. We found complement and inflammasome-related genes and proteins at basal levels in RPE tissue and cell cultures. Additionally, treatment with rotenone, bafilomycin A, and ATP led to inflammasome activation. Overall, the response to priming and activation was similar, irrespective of disease state or CFH genotype. While these data show that the inflammasome is present and active in RPE, our results suggest that inflammasome activation may not contribute to early AMD pathology.

Keywords:  age-related macular degeneration; complement factor H; inflammasome; inflammation; retinal pigment epithelium

DOI:  https://doi.org/10.3390/cells11132075
Nucleosides Nucleotides Nucleic Acids. 2022 Jul 08. 1-12

Explore the molecular mechanism of angle-closure glaucoma in elderly patients induced telomere shortening of retinal ganglion cells through oxidative stress.

Jinzi Zhou, Fenghua Chen, Aimin Yan, Xiaobo Xia.

  Senile glaucoma is a common ophthalmological disease in the elderly. It is a disease of visual papillary perfusion caused by elevated intraocular pressure, complicated by visual dysfunction. Glaucoma can cause serious damage to the normal vision of the elderly. Therefore, exploring the related molecular mechanisms of glaucoma is of great significance to the diagnosis and treatment of glaucoma. This is an exploratory study. Establish a mouse model and conduct experimental groupings. After one week of adaptive feeding, the mice were intraperitoneally injected with an anesthetic mixture: ketamine + xylazine. Then the mice were sacrificed by neck dissection, and the eyeball tissues were immediately dissected. HE staining was used to analyze the histopathological characteristics of the retina of each group of mice. MitoSOX fluorescent probe was used to analyze the content of ROS in retinal tissue. The ELISA analysis was used to detect the activation of β-galactosidase for the aging characteristics of retinal ganglion cells in retinal tissues. Immunohistochemistry experiments were used to analyze the expression of telomerase TERT in retinal tissues. Western blot analysis was used to determine the expression of proteins POT1, TERF1, TERF2, and TINF2 in retinal tissues. The HE staining experiment showed that the damage of retinal tissue decreased from group Glaucoma to group Old, group Old to group Young. The experimental results of MitoSOX fluorescent probe show that ROS content is positively correlated with the degree of tissue damage. ELISA analysis results showed that the expression trend of β-galactosidase was the same as the ROS content. The protein expression levels related to telomere protection (TRET, POT1, TREF1, TREF2 and TINF2) all increased from group Glaucoma to group Old, group Old to group Young. The increase in ROS content, the decrease in telomere protection-related protein expression (telomere shortening) induced by ROS, and the increase of the expression of β-galactosidase, are all potential molecular mechanisms for the occurrence of angle-closure glaucoma in elderly patients.

Keywords:  C-nucleosides; Femoral shaft fractdure (FSF); antibacterial nucleosides; autotransfusion; hemodilution; predeposit; salvage

DOI:  https://doi.org/10.1080/15257770.2022.2094947
Neural Regen Res. 2023 Jan;18(1): 219-225

Optic nerve injury-induced regeneration in the adult zebrafish is accompanied by spatiotemporal changes in mitochondrial dynamics.

An Beckers, Luca Masin, Annelies Van Dyck, Steven Bergmans, Sophie Vanhunsel, Anyi Zhang, Tine Verreet, Fabienne E Poulain, Karl Farrow, Lieve Moons.

  Axonal regeneration in the central nervous system is an energy-intensive process. In contrast to mammals, adult zebrafish can functionally recover from neuronal injury. This raises the question of how zebrafish can cope with this high energy demand. We previously showed that in adult zebrafish, subjected to an optic nerve crush, an antagonistic axon-dendrite interplay exists wherein the retraction of retinal ganglion cell dendrites is a prerequisite for effective axonal repair. We postulate a 'dendrites for regeneration' paradigm that might be linked to intraneuronal mitochondrial reshuffling, as ganglion cells likely have insufficient resources to maintain dendrites and restore axons simultaneously. Here, we characterized both mitochondrial distribution and mitochondrial dynamics within the different ganglion cell compartments (dendrites, somas, and axons) during the regenerative process. Optic nerve crush resulted in a reduction of mitochondria in the dendrites during dendritic retraction, whereafter enlarged mitochondria appeared in the optic nerve/tract during axonal regrowth. Upon dendritic regrowth in the retina, mitochondrial density inside the retinal dendrites returned to baseline levels. Moreover, a transient increase in mitochondrial fission and biogenesis was observed in retinal ganglion cell somas after optic nerve damage. Taken together, these findings suggest that during optic nerve injury-induced regeneration, mitochondria shift from the dendrites to the axons and back again and that temporary changes in mitochondrial dynamics support axonal and dendritic regrowth after optic nerve crush.

Keywords:  axonal regeneration; central nervous system; dendrite remodeling; energy metabolism; fission; mitochondria; mitochondrial trafficking; optic nerve crush; retina; zebrafish

DOI:  https://doi.org/10.4103/1673-5374.344837
Invest Ophthalmol Vis Sci. 2022 Jul 08. 63(8): 1

Integrated Stress Response Regulation of Corneal Epithelial Cell Motility and Cytokine Production.

Hsiao-Sang Chu, Cornelia Peterson, Xitiz Chamling, Cynthia Berlinicke, Donald Zack, Albert S Jun, James Foster.

Purpose: To investigate the effect of an active integrated stress response (ISR) on human corneal epithelial cell motility and cytokine production.
Methods: ISR agonists tunicamycin (TUN) and SAL003 (SAL) were used to stimulate the ISR in immortalized corneal epithelial cell lines, primary human limbal epithelial stem cells, and ex vivo human corneas. Reporter lines for ISR-associated transcription factors activating transcription factor 4 (ATF4) and XBP1 activity were generated to visualize pathway activity in response to kinase-specific agonists. Scratch assays and multiplex magnetic bead arrays were used to investigate the effects of an active ISR on scratch wounds and cytokine production. A C/EBP homologous protein (CHOP) knockout cell line was generated to investigate the effects of ISR ablation. Finally, an ISR antagonist was assayed for its ability to rescue negative phenotypic changes associated with an active ISR.
Results: ISR stimulation, mediated through CHOP, inhibited cell motility in both immortalized and primary human limbal epithelial cells. Scratch wounding of ex vivo corneas elicited an increase in the ISR mediators phosphorylated-eIF2α and ATF4. ISR stimulation also increased the production of vascular endothelial growth factor (VEGF) and proinflammatory cytokines. ISR ablation, through CHOP knockout or inhibition with integrated stress response inhibitor (ISRIB) rescued epithelia migration ability and reduced VEGF secretion.
Conclusions: We demonstrate that the ISR has dramatic effects on the ability of corneal epithelial cells to respond to wounding models and increases the production of proinflammatory and angiogenic factors. Inhibition of the ISR may provide a new therapeutic option for corneal diseases in which the ISR is implicated.

DOI: https://doi.org/10.1167/iovs.63.8.1
BMC Ophthalmol. 2022 Jul 02. 22(1): 290

Changes of retinal ganglion cell complex after vitrectomy in rhegmatogenous retinal detachment patients and its correlation with inflammatory blood biomarkers.

Jiayi Song, Ting Chen, Wen Zuo, Wenyu Chen, Min Lei, Ming Ai.

   PURPOSE: To compare retinal ganglion cell complex (GCC) parameters between rhegmatogenous retinal detachment (RRD) eyes and normal contralateral eyes after vitrectomy and to evaluate their correlation with inflammatory blood markers.
METHODS: We investigated 25 eyes that underwent vitrectomy due to RRD. Venous blood samples were collected from all participants before 08:00 a.m. on the second day of admission after a 12-hour fast for blood counts. The differences of retinal structure between RRD and contralateral eyes were compared 1 week postoperatively.
RESULTS: Focal loss volume (FLV) (2.009 ± 1.286)% was significantly increased compared with the contralateral eyes (p < 0.001). Monocyte-to-high-density lipoprotein was significantly positively correlated with GCC thickness parameters, and negatively correlated with FLV and global loss volume (GLV). Postoperative best-corrected visual acuity was negatively correlated with GLV (p = 0.039, R2 = 0.172).
CONCLUSION: Retinal ganglion cells (RGCs) loss might present early postoperatively in RRD eyes, and was associated with systemic inflammation. RGCs loss might affect postoperative vision.

Keywords:  Ganglion cell complex; Inflammatory blood biomarker; Rhegmatogenous retinal detachment; Silicone oil; Vitrectomy

DOI:  https://doi.org/10.1186/s12886-022-02512-w