Nrf2 in health and disease: current and future clinical implications

Al‐Sawaf, Othman; Clarner, Tim; Fragoulis, Athanassios; Kan, Yuet Wai; Streetz, Konrad L.; Wruck, Christoph Jan

doi:10.1042/cs20150436

Cited by 112 publications

(94 citation statements)

References 103 publications

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“…These findings do not rule out the possibility that dh404 may have direct protective effects on the retinal vasculature. Our results highlight the potential therapeutic utility of Nrf2 activators to improve some diseases [44] which may extend to vision-threatening retinal pathologies such as ROP and diabetic retinopathy.…”

Section: Discussionmentioning

confidence: 93%

A potent Nrf2 activator, dh404, bolsters antioxidant capacity in glial cells and attenuates ischaemic retinopathy

et al. 2016

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An imbalance in oxidative stress and antioxidant defense mechanisms contributes to the development of ischaemic retinopathies such as diabetic retinopathy and retinopathy of prematurity (ROP). Currently, the therapeutic utility of targeting key transcription factors to restore this imbalance remains to be determined. We postulated that dh404, an activator of nuclear factor erythroid-2 related factor 2 (Nrf2), the master regulator of oxidative stress responses, would attenuate retinal vasculopathy by mechanisms involving protection against oxidative stress-mediated damage to glia. Oxygen-induced retinopathy (OIR) was induced in neonatal C57BL/6J mice by exposure to hyperoxia (phase I) followed by room air (phase II). dh404 (1 mg/kg/every second day) reduced the vaso-obliteration of phase I OIR and neovascularization, vascular leakage and inflammation of phase II OIR. In phase I, the astrocytic template and vascular endothelial growth factor (VEGF) expression necessary for physiological angiogenesis are compromised resulting in vaso-obliteration. These events were attenuated by dh404 and related to dh404's ability to reduce the hyperoxia-induced increase in reactive oxygen species (ROS) and markers of cell damage as well as boost the Nrf2-responsive antioxidants in cultured astrocytes. In phase II, neovascularization and vascular leakage occurs following gliosis of Müller cells and their subsequent increased production of angiogenic factors. dh404 reduced Müller cell gliosis and vascular leakage in OIR as well as the hypoxia-induced increase in ROS and angiogenic factors with a concomitant increase in Nrf2-responsive antioxidants in cultured Müller cells. In conclusion, agents such as dh404 that reduce oxidative stress and promote antioxidant capacity offer a novel approach to lessen the vascular and glial cell damage that occurs in ischaemic retinopathies.

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Section: Discussionmentioning

confidence: 93%

A potent Nrf2 activator, dh404, bolsters antioxidant capacity in glial cells and attenuates ischaemic retinopathy

et al. 2016

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“…5,6 Therefore, Nrf2 is a potential target for many chronic diseases, such as chronic kidney disease, asthma, neurodegenerative diseases, and cancer. [7][8][9][10][11][12][13] It is known that small molecules Nrf2 activators, such as sulforaphane (SFN), 14 curcumin, 15 and chalcone derivatives, 16 have been identified as cancer chemopreventive agents. Screening for Nrf2 activators would lead to the discovery of new pharmaceuticals for oxidative stress-associated chronic diseases.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, evaluation, and metabolism of novel [6]-shogaol derivatives as potent Nrf2 activators

Zhu

Wang

Zhao

et al. 2016

Free Radical Biology and Medicine

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“…It regulates the transcription of >200 cytoprotective genes through antioxidant/electrophile response elements (ARE) in target gene promoters. 3 The Nrf2 response pathway is an evolutionarily conserved adaptive mechanism to limit oxidative stress and maintain cellular/tissue homeostasis. The pathway may confer unique protection to the lungs because of the exposure of this organ to a variety of pro-oxidant environmental insults, including airborne toxins and infectious agents.…”

mentioning

confidence: 99%

Nuclear Factor–Erythroid-2–Related Factor 2 in Aging and Lung Fibrosis

Swamy

Rajasekaran

Thannickal

2016

The American Journal of Pathology

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Aging and age-related diseases have been associated with elevated oxidative stress, which may be related to increased production of reactive species and/or a deficiency in antioxidant defenses. The nuclear factor-erythroid-2erelated factor 2 (Nrf2)-mediated antioxidant response pathway maintains cellular reduction-oxidation homeostasis by inducing the transcription of an array of cytoprotective genes. However, there is evidence of impaired Nrf2 response in aging contributing to age-related fibrotic diseases. Herein, we review mechanisms for the dysregulation of Nrf2 signaling in aging. This understanding will pave the way for the design of novel therapeutic strategies that restore Nrf2 signaling to reestablish cellular homeostasis in aging and age-related fibrotic diseases.

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Nrf2 in health and disease: current and future clinical implications

Cited by 112 publications

References 103 publications

A potent Nrf2 activator, dh404, bolsters antioxidant capacity in glial cells and attenuates ischaemic retinopathy

A potent Nrf2 activator, dh404, bolsters antioxidant capacity in glial cells and attenuates ischaemic retinopathy

Synthesis, evaluation, and metabolism of novel [6]-shogaol derivatives as potent Nrf2 activators

Nuclear Factor–Erythroid-2–Related Factor 2 in Aging and Lung Fibrosis

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