Nox4-mediated ROS production is involved, but not essential for TGFβ-induced lens EMT leading to cataract

Das, Shannon; Wishart, Tayler F.L.; Jandeleit-Dahm, Karin; Lovicu, Frank J.

doi:10.1016/j.exer.2020.107918

Cited by 14 publications

(8 citation statements)

References 40 publications

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“…These animals demonstrated a delay in fibrotic plaque formation with TGFβ over-expression compared to wild type. Fibrosis was therefore impaired, but not ablated with upregulation of NOX2 proposed as a compensatory mechanism (Das et al, 2020).…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

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Posterior capsule opacification: What's in the bag?

Wormstone

Smith

et al. 2021

Progress in Retinal and Eye Research

120

102

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Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

“…Inhibition of NOX4 using VAS2870 suppressed TGFβ-induced fibrosis (Das et al, 2016). This was further investigated using NOX4 deficient mice (Das et al, 2020). These animals demonstrated a delay in fibrotic plaque formation with TGFβ over-expression compared to wild type.…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

Posterior capsule opacification: What's in the bag?

Wormstone

Smith

et al. 2021

Progress in Retinal and Eye Research

120

102

View full text Add to dashboard Cite

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“…TGFβ is one of the most potent EMT inducers, and TGFβ-induced EMT is a wellrecognized mechanism in the PCO initiation and progression [15,33]. To test young and aged LECs' response to TGF-mediated EMT signaling, we treated young (passage 14, P14) and aged (passage 45, P45) FHL124 cells with 10 ng/mL TGFβ2 for 24 h. As shown in Figure 5A-C, without TGFβ2 stimulation, the baseline expression of cadherin 11 (CDH11), αSMA, and fibronectin was significantly lower in passage 45 FHL124 cells compared with passage 14.…”

Section: High Passage Lens Epithelial Cells Are Less Sensitive To Tgf...mentioning

confidence: 99%

Aged Lens Epithelial Cells Suppress Proliferation and Epithelial–Mesenchymal Transition-Relevance for Posterior Capsule Opacification

Wei

Gordon

Hao

et al. 2022

Cells

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Posterior capsule opacification (PCO) is a frequent complication after cataract surgery, and advanced PCO requires YAG laser (Nd: YAG) capsulotomy, which often gives rise to more complications. Lens epithelial cell (LEC) proliferation and transformation (i.e., epithelial–mesenchymal transition (EMT)) are two critical elements in PCO initiation and progression pathogenesis. While PCO marginally impacts aged cataract surgery patients, PCO incidences are exceptionally high in infants and children undergoing cataract surgery. The gene expression of lens epithelial cell aging and its role in the discrepancy of PCO prevalence between young and older people have not been fully studied. Here, we conducted a comprehensive differentially expressed gene (DEG) analysis of a cell aging model by comparing the early and late passage FHL124 lens epithelial cells (LECs). In vitro, TGFβ2, cell treatment, and in vivo mouse cataract surgical models were used to validate our findings. We found that aged LECs decelerated rates of cell proliferation accompanied by dysregulation of cellular immune response and cell stress response. Surprisingly, we found that LECs systematically downregulated epithelial–mesenchymal transition (EMT)-promoting genes. The protein expression of several EMT hallmark genes, e.g., fibronectin, αSMA, and cadherin 11, were gradually decreased during LECs aging. We then confirmed these findings in vitro and found that aged LECs markedly alleviated TGFβ2-mediated EMT. Importantly, we explicitly confirmed the in vitro findings from the in vivo mouse cataract surgery studies. We propose that both the high proliferation rate and EMT-enriched young LECs phenotypic characteristics contribute to unusually high PCO incidence in infants and children.

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“…The oxidant stress evoked by hyperglycemia, as amplified by the free fatty acid excess associated with insulin resistance, can adversely alter cellular function via such mechanisms as up-regulation of MAP kinase and NF-kappaB signaling, support of transforming growth factor-β pro-fibrotic activity, uncoupling of endothelial nitric oxide synthase, and induction of DNA damage with PARP activation [ 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 ]. The key sources of oxidant stress in diabetes appear to be structurally damaged mitochondria processing excess substrate, activated NADPH oxidase complexes (particularly NOX2 and NOX4), and uncoupled endothelial nitric oxide synthase (eNOS) [ 1 , 5 ].…”

Section: Sources Of Diabetic Oxidative Stressmentioning

confidence: 99%

Nutraceutical Prevention of Diabetic Complications—Focus on Dicarbonyl and Oxidative Stress

McCarty

DiNicolantonio²,

O’Keefe³

2022

CIMB

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Oxidative and dicarbonyl stress, driven by excess accumulation of glycolytic intermediates in cells that are highly permeable to glucose in the absence of effective insulin activity, appear to be the chief mediators of the complications of diabetes. The most pathogenically significant dicarbonyl stress reflects spontaneous dephosphorylation of glycolytic triose phosphates, giving rise to highly reactive methylglyoxal. This compound can be converted to harmless lactate by the sequential activity of glyoxalase I and II, employing glutathione as a catalyst. The transcription of glyoxalase I, rate-limiting for this process, is promoted by Nrf2, which can be activated by nutraceutical phase 2 inducers such as lipoic acid and sulforaphane. In cells exposed to hyperglycemia, glycine somehow up-regulates Nrf2 activity. Zinc can likewise promote glyoxalase I transcription, via activation of the metal-responsive transcription factor (MTF) that binds to the glyoxalase promoter. Induction of glyoxalase I and metallothionein may explain the protective impact of zinc in rodent models of diabetic complications. With respect to the contribution of oxidative stress to diabetic complications, promoters of mitophagy and mitochondrial biogenesis, UCP2 inducers, inhibitors of NAPDH oxidase, recouplers of eNOS, glutathione precursors, membrane oxidant scavengers, Nrf2 activators, and correction of diabetic thiamine deficiency should help to quell this.

show abstract

Nox4-mediated ROS production is involved, but not essential for TGFβ-induced lens EMT leading to cataract

Cited by 14 publications

References 40 publications

Posterior capsule opacification: What's in the bag?

Posterior capsule opacification: What's in the bag?

Aged Lens Epithelial Cells Suppress Proliferation and Epithelial–Mesenchymal Transition-Relevance for Posterior Capsule Opacification

Nutraceutical Prevention of Diabetic Complications—Focus on Dicarbonyl and Oxidative Stress

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