NRF2 pathway activation by KEAP1 inhibition attenuates the manifestation of aging phenotypes in salivary glands

Wati, Sisca Meida; Matsumaru, Daisuke; Motohashi, Hozumi

doi:10.1016/j.redox.2020.101603

Cited by 31 publications

(19 citation statements)

References 67 publications

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“…The antiaging function of NRF2 in the salivary gland has been demonstrated in Keap1 -KD mice. Aging phenotypes of the salivary gland, such as iron and collagen deposition, immune cell infiltration, increased DNA damage and apoptosis accompanied by elevated oxidative stress, are all markedly attenuated in Keap1 -KD mice [ 105 ]. Intriguingly, anethole trithione, which has been shown to increase salivary flow and is clinically used for the treatment of hyposalivation [ 106 ], induces the expression of NRF2-dependent genes [ 107 ].…”

Section: Tissue Aging and The Keap1-nrf2 Systemmentioning

confidence: 99%

The KEAP1-NRF2 System in Healthy Aging and Longevity

Matsumaru

Motohashi

2021

Antioxidants

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Aging is inevitable, but the inherently and genetically programmed aging process is markedly influenced by environmental factors. All organisms are constantly exposed to various stresses, either exogenous or endogenous, throughout their lives, and the quality and quantity of the stresses generate diverse impacts on the organismal aging process. In the current oxygenic atmosphere on earth, oxidative stress caused by reactive oxygen species is one of the most common and critical environmental factors for life. The Kelch-like ECH-associated protein 1-NFE2-related factor 2 (KEAP1-NRF2) system is a critical defense mechanism of cells and organisms in response to redox perturbations. In the presence of oxidative and electrophilic insults, the thiol moieties of cysteine in KEAP1 are modified, and consequently NRF2 activates its target genes for detoxification and cytoprotection. A number of studies have clarified the contributions of the KEAP1-NRF2 system to the prevention and attenuation of physiological aging and aging-related diseases. Accumulating knowledge to control stress-induced damage may provide a clue for extending healthspan and treating aging-related diseases. In this review, we focus on the relationships between oxidative stress and aging-related alterations in the sensory, glandular, muscular, and central nervous systems and the roles of the KEAP1-NRF2 system in aging processes.

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Section: Tissue Aging and The Keap1-nrf2 Systemmentioning

confidence: 99%

The KEAP1-NRF2 System in Healthy Aging and Longevity

Matsumaru

Motohashi

2021

Antioxidants

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“…Therefore, Nrf2 is a key regulator in the signaling pathway for lifespan extension because of its role in regulating antioxidant expression [ 20 ]. Activation of the Nrf2-related antioxidant defense system prevents cell senescence, while inhibiting Nrf2 activity significantly promotes cell senescence [ 21 ], indicating that Nrf2 has a protective effect on aging. Furthermore, Nrf2 expression and activity decrease during aging [ 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

The Keap1‐Nrf2 System: A Mediator between Oxidative Stress and Aging

Chao

Xiao

2021

Oxidative Medicine and Cellular Longevity

270

136

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Oxidative stress, a term that describes the imbalance between oxidants and antioxidants, leads to the disruption of redox signals and causes molecular damage. Increased oxidative stress from diverse sources has been implicated in most senescence-related diseases and in aging itself. The Kelch-like ECH-associated protein 1- (Keap1-) nuclear factor-erythroid 2-related factor 2 (Nrf2) system can be used to monitor oxidative stress; Keap1-Nrf2 is closely associated with aging and controls the transcription of multiple antioxidant enzymes. Simultaneously, Keap1-Nrf2 signaling is also modulated by a more complex regulatory network, including phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), protein kinase C, and mitogen-activated protein kinase. This review presents more information on aging-related molecular mechanisms involving Keap1-Nrf2. Furthermore, we highlight several major signals involved in Nrf2 unbinding from Keap1, including cysteine modification of Keap1 and phosphorylation of Nrf2, PI3K/Akt/glycogen synthase kinase 3β, sequestosome 1, Bach1, and c-Myc. Additionally, we discuss the direct interaction between Keap1-Nrf2 and the mammalian target of rapamycin pathway. In summary, we focus on recent progress in research on the Keap1-Nrf2 system involving oxidative stress and aging, providing an empirical basis for the development of antiaging drugs.

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“…Thus, Nrf2 provides protection against oxidative stress. In support, Nrf2 knockout mice are highly susceptible to oxidative stress-related chemical toxicity and disease [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ], leading researchers to postulate that targeting Nrf2′s protective role against oxidative stress and mitochondrial dysfunction [ 42 , 43 , 44 , 45 ] may provide a novel target for alleviating neuropathic pain. Here, we discuss pre-clinical evidence across several animal models of neuropathic pain of the therapeutic potential of targeting Nrf2 signaling and Nrf2 inducers (chemical structures are illustrated in Table 1 ).…”

Section: Peripheral Neuropathic Pain and Erythroid 2 (Nfe2)-related F...mentioning

confidence: 99%

The Effects of Nuclear Factor Erythroid 2 (NFE2)-Related Factor 2 (Nrf2) Activation in Preclinical Models of Peripheral Neuropathic Pain

et al. 2022

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Oxidative stress, resulting from an imbalance between the formation of damaging free radicals and availability of protective antioxidants, can contribute to peripheral neuropathic pain conditions. Reactive oxygen and nitrogen species, as well as products of the mitochondrial metabolism such as superoxide anions, hydrogen peroxide, and hydroxyl radicals, are common free radicals. Nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2) is a transcription factor encoded by the NFE2L2 gene and is a member of the cap ‘n’ collar subfamily of basic region leucine zipper transcription factors. Under normal physiological conditions, Nrf2 remains bound to Kelch-like ECH-associated protein 1 in the cytoplasm that ultimately leads to proteasomal degradation. During peripheral neuropathy, Nrf2 can translocate to the nucleus, where it heterodimerizes with muscle aponeurosis fibromatosis proteins and binds to antioxidant response elements (AREs). It is becoming increasingly clear that the Nrf2 interaction with ARE leads to the transcription of several antioxidative enzymes that can ameliorate neuropathy and neuropathic pain in rodent models. Current evidence indicates that the antinociceptive effects of Nrf2 occur via reducing oxidative stress, neuroinflammation, and mitochondrial dysfunction. Here, we will summarize the preclinical evidence supporting the role of Nrf2 signaling pathways and Nrf2 inducers in alleviating peripheral neuropathic pain.

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NRF2 pathway activation by KEAP1 inhibition attenuates the manifestation of aging phenotypes in salivary glands

Cited by 31 publications

References 67 publications

The KEAP1-NRF2 System in Healthy Aging and Longevity

The KEAP1-NRF2 System in Healthy Aging and Longevity

The Keap1‐Nrf2 System: A Mediator between Oxidative Stress and Aging

The Effects of Nuclear Factor Erythroid 2 (NFE2)-Related Factor 2 (Nrf2) Activation in Preclinical Models of Peripheral Neuropathic Pain

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