Getting to the core of fibrosis: targeting redox imbalance in aging

Hecker, Louise; Thannickal, Victor J.

doi:10.21037/atm.2015.12.45

Cited by 9 publications

(12 citation statements)

References 45 publications

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“…3) is an important avenue for further investigation. Likewise, the accumulation of senescent cells in the context of chronic and recurring injury, as well as aging itself, may offer new insights (Sanders et al 2013;Thannickal 2013;Hecker and Thannickal 2016). For example, mice lacking caveolin 1 expression were found to be protected from fibrosis through decreased epithelial senescence after bleomycin-induced injury (Shivshankar et al 2012).…”

Section: Tgf-b1 Signaling and Tissue Fibrosismentioning

confidence: 99%

TGF-β1 Signaling and Tissue Fibrosis

Kim

Sheppard

Chapman

2017

Cold Spring Harb Perspect Biol

499

367

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Activation of TGF-β1 initiates a program of temporary collagen accumulation important to wound repair in many organs. However, the outcome of temporary extracellular matrix strengthening all too frequently morphs into progressive fibrosis, contributing to morbidity and mortality worldwide. To avoid this maladaptive outcome, TGF-β1 signaling is regulated at numerous levels and intimately connected to feedback signals that limit accumulation. Here, we examine the current understanding of the core functions of TGF-β1 in promoting collagen accumulation, parallel pathways that promote physiological repair, and pathological triggers that tip the balance toward progressive fibrosis. Implicit in better understanding of these processes is the identification of therapeutic opportunities that will need to be further advanced to limit or reverse organ fibrosis.

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Section: Tgf-b1 Signaling and Tissue Fibrosismentioning

confidence: 99%

TGF-β1 Signaling and Tissue Fibrosis

Kim

Sheppard

Chapman

2017

Cold Spring Harb Perspect Biol

499

367

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“…These rare CYBA variants may affect all NOX family members that rely on p22 phox as a dimerization partner (NOX1-4). Because the CYBA p.Gly24Arg variant in TMH1 is rather common (http://structure.bmc.lu.se/idbase/CYBAbase) (48), 5 it was introduced into p22-LB2 and co-expressed with SB1-NOX4. H 2 O 2 production and heterodimerization were significantly reduced, and ϳ50% of the SB1-NOX4/p22-LB2 G24R complex was trapped in the ER in epithelial cells (Fig.…”

Section: Integrated Analysis Of Nox4 and Cyba Mutations Identifies Ppmentioning

confidence: 99%

“…To identify the most suitable templates, a BLAST search of PDB was performed with the NOX4(1-305) sequence and cyanobacterium Cylindrospermum stagnale Nox5 (PDB 5O0T), and four cytochrome c oxidoreductase complexes with the highest homology served as initial templates. The NOX4(1-305) sequence was aligned to the templates using Clustal (http://www.ebi.ac.uk/ Tools/msa/clustalo/) 5 (49) and alignment was adjusted manually, taking into account the secondary structure prediction and previously published data (6, 7, 10, 30 -34). Modeling was per-…”

Section: Protein Modeling Docking and Molecular Dynamics Simulationmentioning

confidence: 99%

Quantitative interaction analysis permits molecular insights into functional NOX4 NADPH oxidase heterodimer assembly

O’Neill

Mathis

Kovačič

et al. 2018

Journal of Biological Chemistry

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Protein-protein interactions critically regulate many biological systems, but quantifying functional assembly of multipass membrane complexes in their native context is still challenging. Here, we combined modeling-assisted protein modification and information from human disease variants with a minimal-size fusion tag, split-luciferase-based approach to probe assembly of the NADPH oxidase 4 (NOX4)-p22 enzyme, an integral membrane complex with unresolved structure, which is required for electron transfer and generation of reactive oxygen species (ROS). Integrated analyses of heterodimerization, trafficking, and catalytic activity identified determinants for the NOX4-p22 interaction, such as heme incorporation into NOX4 and hot spot residues in transmembrane domains 1 and 4 in p22 Moreover, their effect on NOX4 maturation and ROS generation was analyzed. We propose that this reversible and quantitative protein-protein interaction technique with its small split-fragment approach will provide a protein engineering and discovery tool not only for NOX research, but also for other intricate membrane protein complexes, and may thereby facilitate new drug discovery strategies for managing NOX-associated diseases.

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“…ROS has been shown to regulate the cellular phenotypes and fates, including differentiation [42] , [43] , apoptosis [44] , migration [45] , [46] , and invasion [47] during tissue repair. There is growing evidence of a pathological role of redox imbalance and oxidative stress in fibrotic repair [39] , [48] . It is plausible that redox imbalance associated with aging alters redox signaling during tissue repair, thus, predisposing to non-resolving fibrosis.…”

Section: Redox Mechanisms In Fibrosismentioning

confidence: 99%

Redox mechanisms in age-related lung fibrosis

Kurundkar

Thannickal

2016

Redox Biology

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Redox signaling and oxidative stress are associated with tissue fibrosis and aging. Aging is recognized as a major risk factor for fibrotic diseases involving multiple organ systems, including that of the lung. A number of oxidant generating enzymes are upregulated while antioxidant defenses are deficient with aging and cellular senescence, leading to redox imbalance and oxidative stress. However, the precise mechanisms by which redox signaling and oxidative stress contribute to the pathogenesis of lung fibrosis are not well understood. Tissue repair is a highly regulated process that involves the interactions of several cell types, including epithelial cells, fibroblasts and inflammatory cells. Fibrosis may develop when these interactions are dysregulated with the acquisition of pro-fibrotic cellular phenotypes. In this review, we explore the roles of redox mechanisms that promote and perpetuate fibrosis in the context of cellular senescence and aging.

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Getting to the core of fibrosis: targeting redox imbalance in aging

Cited by 9 publications

References 45 publications

TGF-β1 Signaling and Tissue Fibrosis

TGF-β1 Signaling and Tissue Fibrosis

Quantitative interaction analysis permits molecular insights into functional NOX4 NADPH oxidase heterodimer assembly

Redox mechanisms in age-related lung fibrosis

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