Keap1–Nrf2 regulated redox signaling in utero: Priming of disease susceptibility in offspring

Chapple, Sarah J.; Puszyk, William; Mann, Giovanni E.

doi:10.1016/j.freeradbiomed.2015.08.001

Cited by 27 publications

(22 citation statements)

References 155 publications

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“…Nrf2 activation is tightly controlled by its inhibitor protein, Keap1 (Kelch-like ECH-associated protein 1) [ 13 , 17 , 18 ]. Nrf2's binding to Keap1 in the cytoplasm will dictate it to Cullin-3-dependent ubiquitination and proteasomal degradation.…”

Section: Introductionmentioning

confidence: 99%

MIND4-17 protects retinal pigment epithelium cells and retinal ganglion cells from UV

Yan

Wang

et al. 2017

Oncotarget

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Nrf2 activation would efficiently protect retinal cells from UV radiation (UVR). Recent studies have developed a Nrf2-targeting thiazole-containing compound MIND4-17, which activates Nrf2 through blocking its association with Keap1. In the current study, we demonstrated that pretreatment with MIND4-17 efficiently protected retinal pigment epithelium (RPE) cells (RPEs) and retinal ganglion cells (RGCs) from UVR. UVR-induced apoptosis in the retinal cells was also largely attenuated by MIND4-17 pretreatment. MIND4-17 presumably separated Nrf2 from Keap1, allowing its stabilization and accumulation in retinal cells, which then translocated to cell nuclei and promoted transcription of ARE-dependent anti-oxidant genes, including HO1, NQO1 and GCLM. Significantly, shRNA-mediated knockdown of Nrf2 almost completely abolished MIND4-17-induced cytoprotection against UVR. Further studies showed that MIND4-17 largely ameliorated UVR-induced ROS production, lipid peroxidation and DNA damages in RPEs and RGCs. Together, MIND4-17 protects retinal cells from UVR by activating Nrf2 signaling.

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Section: Introductionmentioning

confidence: 99%

MIND4-17 protects retinal pigment epithelium cells and retinal ganglion cells from UV

Yan

Wang

et al. 2017

Oncotarget

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“…The activation of the MAP kinase cascade plays an important role in the heart chamber formation of the fetus [ 8 ]. Data from human studies suggest that environmental stress factors such as hypoxia, increased level of reactive oxygen species or antiviral therapy adversely influence this process [ 9 , 10 ]. It is reasonable to suggest that ionizing radiation may have similar adverse effects on the fetal heart development.…”

Section: Introductionmentioning

confidence: 99%

In-Utero Low-Dose Irradiation Leads to Persistent Alterations in the Mouse Heart Proteome

et al. 2016

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Prenatal exposure to stress such as increased level of reactive oxygen species or antiviral therapy are known factors leading to adult heart defects. The risks following a radiation exposure during fetal period are unknown, as are the mechanisms of any potential cardiac damage. The aim of this study was to gather evidence for possible damage by investigating long-term changes in the mouse heart proteome after prenatal exposure to low and moderate radiation doses. Pregnant C57Bl/6J mice received on embryonic day 11 (E11) a single total body dose of ionizing radiation that ranged from 0.02 Gy to 1.0 Gy. The offspring were sacrificed at the age of 6 months or 2 years. Quantitative proteomic analysis of heart tissue was performed using Isotope Coded Protein Label technology and tandem mass spectrometry. The proteomics data were analyzed by bioinformatics and key changes were validated by immunoblotting. Persistent changes were observed in the expression of proteins representing mitochondrial respiratory complexes, redox and heat shock response, and the cytoskeleton, even at the low dose of 0.1 Gy. The level of total and active form of the kinase MAP4K4 that is essential for the embryonic development of mouse heart was persistently decreased at the radiation dose of 1.0 Gy. This study provides the first insight into the molecular mechanisms of cardiac impairment induced by ionizing radiation exposure during the prenatal period.

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“…Mammalian embryos develop in a low [O 2 ] environment— ≈3% O 2 in utero—which may protect embryos from oxidative stress owing to weak endogenous antioxidant defense and permit beneficial developmental redox signaling . Weak endogenous antioxidant defense to permit developmental redox signaling renders embryos particularly susceptible to oxidative stress .…”

Section: How Ret Mediated Mitochondrial Ros Production Could Lead To mentioning

confidence: 99%

“…Put differently, they are positioned closer to the pruning threshold and are, therefore, unlikely to prevail because their capacity to suppress pruning when inactive is negligible (see Figure 2). A compensatory ploy of making more mitochondria to meet ATP demands will likely fail because it will clonally expand inefficient mitochondria [93] [90,91,94] Weak endogenous antioxidant defense to permit developmental redox signaling renders embryos particularly susceptible to oxidative stress. [91] The pregnancy disorder pre-eclampsia is a paradigmatic example.…”

Section: /H 2 O 2 Defined Synapse Pruningmentioning

confidence: 99%

Synapse Pruning: Mitochondrial ROS with Their Hands on the Shears

Cobley

2018

BioEssays

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No overarching hypotheses tie the basic mechanisms of mitochondrial reactive oxygen species (ROS) production to activity dependent synapse pruning-a fundamental biological process in health and disease. Neuronal activity divergently regulates mitochondrial ROS: activity decreases whereas inactivity increases their production, respectively. Placing mitochondrial ROS as innate synaptic activity sentinels informs the novel hypothesis that: (1) at an inactive synapse, increased mitochondrial ROS production initiates intrinsic apoptosis dependent pruning; and (2) at an active synapse, decreased mitochondrial ROS production masks intrinsic apoptosis dependent pruning. Immature antioxidant defense may enable the developing brain to harness mitochondrial ROS to prune weak synapses. Beyond development, endogenous antioxidant defense constrains mitochondrial (ROS) to mask pruning. Unwanted age-related synapse loss may arise when mitochondrial ROS aberrantly recapitulate developmental pruning. Placing mitochondrial ROS with their hands on the shears is beneficial in early but deleterious in later life.

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Keap1–Nrf2 regulated redox signaling in utero: Priming of disease susceptibility in offspring

Cited by 27 publications

References 155 publications

MIND4-17 protects retinal pigment epithelium cells and retinal ganglion cells from UV

MIND4-17 protects retinal pigment epithelium cells and retinal ganglion cells from UV

In-Utero Low-Dose Irradiation Leads to Persistent Alterations in the Mouse Heart Proteome

Synapse Pruning: Mitochondrial ROS with Their Hands on the Shears

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