Multifaceted Roles of the KEAP1–NRF2 System in Cancer and Inflammatory Disease Milieu

Panda, Harit; Wen, Huaichun; Suzuki, Mikiko; Yamamoto, Masayuki

doi:10.3390/antiox11030538

Cited by 36 publications

(21 citation statements)

References 107 publications

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“…Under normal physiological conditions, Kelch-like ECH-associated protein-1(Keap1) bound to Nrf2 and remained in the cytoplasm ( Wang et al, 2020 ). However, under oxidative conditions, elevated ROS levels promote the dissociation of Nrf2 and Keap1 ( Schafer and Werner, 2015 ; Panda et al, 2022 ). Dissociated Nrf2 is transferred to the nucleus and bound to the ARE, which subsequently regulates the expression of downstream antioxidant genes such as HO-1 and NQO1 to repair UV-induced skin damage ( Xian et al, 2019 ; Alcaraz and Ferrandiz, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Modified Qing’e Formula protects against UV-induced skin oxidative damage via the activation of Nrf2/ARE defensive pathway

et al. 2022

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Exposure to ultraviolet (UV) light triggers the rapid generation and accumulation of reactive oxygen species (ROS) in skin cells, which increases oxidative stress damage and leads to photoaging. Nuclear factor E2-related factor 2 (Nrf2) modulates the antioxidant defense of skin cells against environmental factors, especially ultraviolet radiation. Natural products that target Nrf2-regulated antioxidant reactions are promising candidates for anti-photoaging. The aim of this study was to investigate the protective effect of Modified Qing’e Formula (MQEF) on UV-induced skin oxidative damage and its molecular mechanisms. In this study, the photoaging models of human keratinocytes (HaCaT) and ICR mice were established by UV irradiation. In vitro models showed that MQEF displayed potent antioxidant activity, significantly increased cell viability and reduced apoptosis and excess ROS levels. Meanwhile, the knockdown of Nrf2 reversed the antioxidant and anti-apoptotic effects of MQEF. In vivo experiments indicated that MQEF could protect the skin against UV-exposed injury which manifested by water loss, sensitivity, tanning, wrinkling, and breakage of collagen and elastic fibers. The application of MQEF effectively increased the activity of antioxidant enzymes and reduced the content of malondialdehyde (MDA) in mice. In addition, MQEF was able to activate Nrf2 nuclear translocation in mouse skin tissue. In summary, MQEF may attenuate UV-induced photoaging by upregulating Nrf2 expression and enhancing antioxidant damage capacity. MQEF may be a potential candidate to prevent UV-induced photoaging by restoring redox homeostasis.

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Section: Discussionmentioning

confidence: 99%

Modified Qing’e Formula protects against UV-induced skin oxidative damage via the activation of Nrf2/ARE defensive pathway

et al. 2022

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“…Klotho activated Nrf2 in renal, cardiovascular and neurological preclinical disease models ( Maltese et al, 2017 ; Zhu et al, 2017 ; Xing et al, 2021 ; Xiang et al, 2022 ). Nrf2 is a transcription factor that controls responses to oxidative stress and toxins ( Dinkova-Kostova et al, 2018 ; Qu et al, 2020 ; Panda et al, 2022 ). Its Neh2 domains interact with a negative regulator denoted Kelch-like ECH-associated protein 1 (Keap1) ( Panda et al, 2022 ).…”

Section: Klotho Functions Independent Of Fgf23mentioning

confidence: 99%

“…Nrf2 is a transcription factor that controls responses to oxidative stress and toxins ( Dinkova-Kostova et al, 2018 ; Qu et al, 2020 ; Panda et al, 2022 ). Its Neh2 domains interact with a negative regulator denoted Kelch-like ECH-associated protein 1 (Keap1) ( Panda et al, 2022 ). Keap1 binds to Nrf2, promoting its ubiquitination and proteasomal degradation.…”

Section: Klotho Functions Independent Of Fgf23mentioning

confidence: 99%

Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

Prud’homme

Kurt²,

Wang

2022

Front. Aging

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The α-Klotho protein (henceforth denoted Klotho) has antiaging properties, as first observed in mice homozygous for a hypomorphic Klotho gene (kl/kl). These mice have a shortened lifespan, stunted growth, renal disease, hyperphosphatemia, hypercalcemia, vascular calcification, cardiac hypertrophy, hypertension, pulmonary disease, cognitive impairment, multi-organ atrophy and fibrosis. Overexpression of Klotho has opposite effects, extending lifespan. In humans, Klotho levels decline with age, chronic kidney disease, diabetes, Alzheimer’s disease and other conditions. Low Klotho levels correlate with an increase in the death rate from all causes. Klotho acts either as an obligate coreceptor for fibroblast growth factor 23 (FGF23), or as a soluble pleiotropic endocrine hormone (s-Klotho). It is mainly produced in the kidneys, but also in the brain, pancreas and other tissues. On renal tubular-cell membranes, it associates with FGF receptors to bind FGF23. Produced in bones, FGF23 regulates renal excretion of phosphate (phosphaturic effect) and vitamin D metabolism. Lack of Klotho or FGF23 results in hyperphosphatemia and hypervitaminosis D. With age, human renal function often deteriorates, lowering Klotho levels. This appears to promote age-related pathology. Remarkably, Klotho inhibits four pathways that have been linked to aging in various ways: Transforming growth factor β (TGF-β), insulin-like growth factor 1 (IGF-1), Wnt and NF-κB. These can induce cellular senescence, apoptosis, inflammation, immune dysfunction, fibrosis and neoplasia. Furthermore, Klotho increases cell-protective antioxidant enzymes through Nrf2 and FoxO. In accord, preclinical Klotho therapy ameliorated renal, cardiovascular, diabetes-related and neurodegenerative diseases, as well as cancer. s-Klotho protein injection was effective, but requires further investigation. Several drugs enhance circulating Klotho levels, and some cross the blood-brain barrier to potentially act in the brain. In clinical trials, increased Klotho was noted with renin-angiotensin system inhibitors (losartan, valsartan), a statin (fluvastatin), mTOR inhibitors (rapamycin, everolimus), vitamin D and pentoxifylline. In preclinical work, antidiabetic drugs (metformin, GLP-1-based, GABA, PPAR-γ agonists) also enhanced Klotho. Several traditional medicines and/or nutraceuticals increased Klotho in rodents, including astaxanthin, curcumin, ginseng, ligustilide and resveratrol. Notably, exercise and sport activity increased Klotho. This review addresses molecular, physiological and therapeutic aspects of Klotho.

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“…The Neh1 domain has an important role in regulating binding to the DNA molecule and is involved in nuclear translocation. The Neh2 domain has a fundamental role in binding to the Keap1 protein through the DLG and ETGE degrons [ 19 ]. Keap1, the main regulator of Nrf2, consists of 624 amino acids and is classified as a protein rich in cysteines, since it has 27 residues of this amino acid [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Anthocyanins Found in Pinot Noir Waste Induce Target Genes Related to the Nrf2 Signalling in Endothelial Cells

et al. 2022

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Grape pomace is a source of anthocyanins, which can prevent cardiovascular diseases due to their antioxidant properties. Anthocyanin activity is associated with the ability to regulate oxidative stress through the transcription factor Nrf2. Thus, the present study aimed to evaluate if the anthocyanins found in Pinot noir pomace extract can affect the target genes related to the Nrf2 signalling pathway in endothelial cells. Our results highlight that the predominant anthocyanin in the Pinot noir pomace extract was malvidin-3-glucoside (3.7 ± 2.7 Eq. Malv-3-glu/kg). Molecular docking indicated that cyanidin-3-glucoside (−6.9 kcal/mol), malvidin-3-glucoside (−6.6 kcal/mol) and peonidin-3-glucoside (−6.6 kcal/mol) showed the highest affinities for the binding sites of the BTB domains in Keap1, suggesting that these components may modify the interaction of this protein with Nrf2. In addition, when HUVEC cells were exposed to different concentrations of Pinot noir pomace extract (100 µg/mL, 200 µg/mL, and 400 µg/mL), no changes in Nrf2 gene expression were observed. However, the gene expression of HO-1 and NQO1, which are in the signalling pathway of this transcription factor, increased according the concentrations of the extract (p = 0.0004 and p = 0.0084, respectively). In summary, our results show that anthocyanins play a very important role in Nrf2 activation and release, while at the same time not promoting its transcription. These preliminary results strongly suggest that the Pinot noir pomace extract can serve as a potent bioactive component source that protects cells against oxidative stress.

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Multifaceted Roles of the KEAP1–NRF2 System in Cancer and Inflammatory Disease Milieu

Cited by 36 publications

References 107 publications

Modified Qing’e Formula protects against UV-induced skin oxidative damage via the activation of Nrf2/ARE defensive pathway

Modified Qing’e Formula protects against UV-induced skin oxidative damage via the activation of Nrf2/ARE defensive pathway

Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

Anthocyanins Found in Pinot Noir Waste Induce Target Genes Related to the Nrf2 Signalling in Endothelial Cells

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