Not All Stressors Are Equal: Mechanism of Stressors on RPE Cell Degeneration

Tong, Yao; Wang, Shusheng

doi:10.3389/fcell.2020.591067

Cited by 41 publications

(37 citation statements)

References 180 publications

(180 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To our knowledge, the iPSC-RPE repository established in this study is a first collection of iPSC-RPE lines in which donors have been selected solely on the basis of their genetic risk profile summarized by a GRS considering riskincreasing as well as protective genetic variants rather than their phenotype. By choosing our donors from the two extreme ends of the genetic AMD risk spectrum, the differences in their genetic risk to develop AMD are comparable with the differences usually seen in monogenic disorders (i.e., the odds ratio between HR and LR can reach values as high as 20) [47] .…”

Section: Discussionmentioning

confidence: 99%

In vitro modeling of the complex retinal condition age-related macular degeneration

Plössl¹,

Webster²,

Kiel³

et al. 2022

jtgg

View full text Add to dashboard Cite

Aim: To model a complex retinal disease such as age-related macular degeneration (AMD) in vitro, we aimed to combine genetic and environmental risk factors in a retinal pigment epithelium (RPE) cell culture model generated via induced pluripotent stem cells (iPSCs) from subjects with an extremely high and an extremely low genetic disease risk. As an external stimulus, we chose defined oxidative stress conditions. Methods: Patients were genotyped for known AMD-associated genetic variants and their individual genetic risk score (GRS) was calculated defining individual iPSC-RPE cell lines which reflect the extreme ends of the genetic risk for AMD. Sodium iodate (NaIO3, SI) was used to induce oxidative stress and cellular responses were followed by analyzing nuclear factor erythroid 2-related factor 2 (NRF2) pathway activation by mRNA and protein expression. Results: We present a collection of eight iPSC-RPE cell lines, with four each harboring an extreme low or an extreme high GRS for AMD. RPE identity was verified structurally and functionally. We found that 24 and 72 h of SI treatment induced a significant upregulation of NRF2 response genes HMOX1 and NQO1, without showing cytotoxic effects or negatively influencing RPE cell integrity. High- vs. low-risk cell lines revealed similar first line defenses in oxidative stress response mediated through the NRF2 pathway. Conclusion: Delineating the NRF2-mediated oxidative stress response was sought in iPSC-RPE cell lines with maximally divergent genetic AMD risk profiles. Under the specific stress conditions chosen, our data indicate that genetic predisposition to AMD may not exert a major influence on the NRF2 signaling pathway.

show abstract

Section: Discussionmentioning

confidence: 99%

In vitro modeling of the complex retinal condition age-related macular degeneration

Plössl¹,

Webster²,

Kiel³

et al. 2022

jtgg

View full text Add to dashboard Cite

show abstract

“…Cell death and in ammation are fundamental characteristics in the initiation and development of neurological dysfunction. GSDMD-mediated pyroptosis plays crucial roles in the pathogenesis of multiple neurological diseases and age-related degeneration [33][34][35]. Pyroptosis is a type of lytic programmed cell death, distinguished from apoptosis and necrosis [8,36].…”

Section: The Chemical Composition Of Ea Active Fraction Of Z Bungeanmentioning

confidence: 99%

Ethyl acetate extracts of Bungeanum ameliorates cognitive deficits by suppressing NLRP3 inflammasome-dependent pyroptosis in aging mice

Zhao

Yuan

et al. 2021

Preprint

View full text Add to dashboard Cite

Background: The NLRP3-mediated pyroptosis is a key player in the development of the age-associated neurodegenerative disease. Zanthoxylum bungeanum Maxim (Rutaceae), a homologous of medicine and foodstuff, has previously been demonstrated the potential prevention of cognitive dysfunction in aging mice. However, it is still unknown which fraction is the material basis responsible for their therapeutic effects and whether Z. bungeanum could confer anti-cognitive deficits activity via restraining NLRP3-mediated pyroptosis. Thus, in the current study, we explored the active fraction of Z. bungeanum against cognitive deficits and its underlying mechanism.Methods: In the present study, the D-galactose-induced mouse model of aging was established to explore the effect of cognitive impairment of four fractions of Z. bungeanum, including petroleum ether (PE), methylene chloride (DCM), ethyl acetate (EA), and n-butanol (N-BAI). We next activated the NLRP3 inflammasome in BV-2 microglia cells to investigate the mechanisms for the neuroprotective effect of the active fraction of Z. bungeanum.Results: We demonstrated that the mice treated with EA had significantly alleviated the memory deficit induced by D-galactose. Meanwhile, EA up-regulated the cortex NeuN protein level, improved the survival and morphology of hippocampal neurons. We further found that EA significantly alleviated oxidative damage, inhibited activation of microglia, and suppressed NLRP3 inflammasome activation and subsequent cleaved Caspase-1, IL-1β, IL-18, and GSDMD-N. Correspondingly, in vitro data showed that EA protected BV-2 cells against Lipopolysaccharide (LPS) and adenosine triphosphate (ATP) elicited NLRP3 inflammasome activation and pyroptosis, evidenced by declined the protein levels of NLRP3, cleaved Caspase-1, IL-1β, IL-18, and GSDMD-N. These data indicated that EA inhibited NLRP3-mediated pyroptosis.Conclusions: Our work revealed that the EA active fraction of Z. bungeanum protected neurons from inflammation through inhibition of NLRP3 and subsequent pyroptosis in microglia, and suggested promising clinical use of EA for age-associated neurodegenerative disease.

show abstract

“…Chronic oxidative stress in the RPE plays an important role in RPE loss in dry-AMD [3,8,33,34]. In response to sustained oxidative stress, RPE cells die by necroptosis [35,36]. We hypothesize that sustained expression of EPO-R76E in the RPE using an AAV vector will improve the health and survival of RPE and retinal photoreceptors.…”

Section: Introductionmentioning

confidence: 99%

Erythropoietin Gene Therapy Delays Retinal Degeneration Resulting from Oxidative Stress in the Retinal Pigment Epithelium

et al. 2021

Self Cite

View full text Add to dashboard Cite

Erythropoietin (EPO) plays an important role in erythropoiesis by its action in blocking apoptosis of progenitor cells and protects both photoreceptors and retinal ganglion cells from induced or inherited degeneration. A modified form of EPO, EPO-R76E has attenuated erythropoietic activity but is effective in inhibiting apoptosis, oxidative stress, and inflammation in several models of retinal degeneration. In this study, we used recombinant Adeno Associated Virus (AAV) to provide long-term sustained delivery of EPO-R76E and demonstrated its effects in a mouse model of dry-AMD in which retinal degeneration is induced by oxidative stress in the retinal pigment epithelial (RPE) cells. Experimental vector AAV-EPO-R76E and control vector AAV-GFP were packaged into serotype-1 (AAV1) to enable RPE selective expression. RPE oxidative stress-mediated retinal degeneration was induced by exon specific deletion of the protective enzyme MnSOD (encoded by Sod2) by cre/lox mechanism. Experimental mice received subretinal injection of AAV-EPO-R76E in the right eye and AAV-GFP in the left eye. Western blotting of RPE/choroid protein samples from AAV-EPO-R76E injected eyes showed RPE specific EPO expression. Retinal function was monitored by electroretinography (ERG). EPO-R76E over-expression in RPE delayed the retinal degeneration as measured by light microscopy in RPE specific Sod2 knockout mice. Delivery of EPO-R76E vector can be used as a tool to prevent retinal degeneration induced by RPE oxidative stress, which is implicated as a potential cause of Age-Related Macular Degeneration.

show abstract

Not All Stressors Are Equal: Mechanism of Stressors on RPE Cell Degeneration

Cited by 41 publications

References 180 publications

In vitro modeling of the complex retinal condition age-related macular degeneration

In vitro modeling of the complex retinal condition age-related macular degeneration

Ethyl acetate extracts of Bungeanum ameliorates cognitive deficits by suppressing NLRP3 inflammasome-dependent pyroptosis in aging mice

Erythropoietin Gene Therapy Delays Retinal Degeneration Resulting from Oxidative Stress in the Retinal Pigment Epithelium

Contact Info

Product

Resources

About