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Journal ArticleDOI: 10.1016/J.PHRS.2021.105526

The hormetic dose-response mechanism: Nrf2 activation

02 Mar 2021-Pharmacological Research (Academic Press)-Vol. 167, pp 105526-105526
Abstract: A generalized mechanism for hormetic dose responses is proposed that is based on the redox-activated transcription factor (TF), Nrf2, and its upregulation of an integrative system of endogenous anti-oxidant and anti-inflammatory adaptive responses. Nrf2 can be activated by numerous oxidative stressors (e.g., exercise, caloric restriction/intermittent fasting) and by exposures to synthetic, naturally occurring and endogenous chemicals, to non-ionizing (e.g., low-level light) and ionizing radiation, and to low-to-moderate stress from aging processes, among others. Nrf2 conducts crosstalk with other TFs to further integrate and enhance the effectiveness of adaptive metabolic strategies that produce acquired resilience. This adaptive mechanism of Nrf2 accounts for the generality and ubiquity of hormetic dose responses and supports the fundamental hormetic characteristic of protecting biological systems. At the same time, Nrf2 is highly evolutionarily conserved and quantitatively constrained in response (i.e., modest stimulatory response), further conserving biological resources and enhancing metabolic efficiencies. The notion that Nrf2 may serve as an hormetic mediator not only provides a regulatory-based evolutionary understanding of temporal acquired resilience and adaptive homeostasis but also causally integrates toxicological and pharmacological detoxification processes that are central to ecological and human risk assessments as well as to the development of drugs and therapeutics. These findings can also account for considerable inter-individual variation in susceptibility to toxic substances, the differential effectiveness of numerous therapeutic agents, and the variation in onset and severity of numerous age-related illnesses, such as type II diabetes.

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Topics: Mechanism (biology) (52%)
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23 results found


Journal ArticleDOI: 10.1016/J.ENVRES.2021.111025
Edward J. Calabrese1Institutions (1)
Abstract: This paper evaluates the scientific basis for the adoption of the linear non-threshold (LNT) dose response model for radiation-induced leukemia. This LNT risk assessment application for leukemia is significant because it: (1) was generalized for all tumor types induced by ionizing radiation and chemical carcinogens at relatively high doses and; (2) it was based on the mechanistic assumption of low dose linearity for somatic cell mutations as determined from responses in mature spermatozoa of fruit flies. A serious problem with the latter assumption is that those spermatozoa lack DNA repair. The acceptance of the LNT dose response model for cancer risk assessment was based on the convergence of recommendations of the BEAR I Genetics Panel (1956a) for reproductive cell gene mutations and those of Lewis (1957a) for somatic cell mutation and its capacity to explain apparent and/or predicted linear dose responses of ionizing radiation-induced leukemia in multiple and diverse epidemiological investigations. Use of that model and related dose response beliefs achieved rapid, widespread and enduring acceptance in the scientific and regulatory communities. They provide the key historical foundation for the sustained LNT-based policy for cancer risk assessment to the present. While previous papers in this series have challenged key scientific assessments and ethical foundations of the BEAR I Genetics Panel, the present paper provides evidence that Lewis: 1) incorrectly interpreted the fundamental scientific studies used to support the LNT conclusion even though such studies show consistent hormetic-J-shaped dose response relationships for leukemia in Hiroshima and Nagasaki survivors; and, 2) demonstrated widespread bias in support of an LNT conclusion and related policies, which kept him from making an objective and fair assessment. The LNT recommendation appears to have been uncritically accepted and integrated into scientific and regulatory practice in large part because it inappropriately appealed to existing authority and it garnered the support of those who were willing to risk greatly exaggerating the public's fears of environmentally-induced disease, such as enhanced risk of leukemia, with the goal of stopping the atmospheric testing of atomic bombs. Adoption of the LNT recommendation demonstrated extensive penetration of ideological influence affecting governmental, scientific and regulatory evaluation at the highest levels in the United States. This paper demonstrates that the scientific foundations for cancer risk assessment were inappropriately and inaccurately assessed, unethically adopted and require significant historical, scientific and regulatory remediation.

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Topics: Gene mutation (51%)

5 Citations


Journal ArticleDOI: 10.1016/J.ARR.2021.101364
Maryam Mahjoob1, Ursula Stochaj1Institutions (1)
Abstract: Aging increases the susceptibility to a diverse set of diseases and disorders, including neurodegeneration, cancer, diabetes, and arthritis. Natural compounds are currently being explored as alternative or complementary agents to treat or prevent aging-related malfunctions. Curcumin, a phytochemical isolated from the spice turmeric, has garnered great interest in recent years. With anti-oxidant, anti-inflammatory, anti-microbial, and other physiological activities, curcumin has great potential for health applications. However, the benefits of curcumin are restricted by its low bioavailability and stability in biological systems. Curcumin nanoformulations, or nano-curcumin, may overcome these limitations. This review discusses different forms of nano-curcumin that have been evaluated in vitro and in vivo to treat or prevent aging-associated health impairments. We describe current barriers for the routine use of curcumin nanoformulations in the clinic. Our review highlights outstanding questions and future work that is needed to ensure nano-curcumin is efficient and safe to lessen the burden of aging-related health problems.

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4 Citations


Journal ArticleDOI: 10.1016/J.MAD.2021.111544
Abstract: The present paper provides the first systematic assessment of the capacity of ferulic acid to induce hormetic dose responses in biological systems. Ferulic acid induced hormetic effects in a broad range of animal models, affecting numerous biological endpoints, with particular focus on neuroprotective effects. Emerging evidence in multiple biomedical systems indicates that the hormetic effects of ferulic acid depend upon the activation of the transcription factor Nrf2. Ferulic acid was also shown to have an important role in ecological settings, being routinely released into the environment by numerous plant species, acting as an allelopathic agent affecting the growth of neighboring species via hormetic dose responses. These findings demonstrate the potential ecological and biomedical importance of ferulic acid effects and that these effects are commonly expressed via the hormetic dose response, suggesting complex multisystem evolutionary regulatory strategies.

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Topics: Ferulic acid (54%)

3 Citations


Journal ArticleDOI: 10.1016/J.CBI.2021.109464
Abstract: Current regulatory cancer risk assessment principles and practices assume a linear dose-response relationship-the linear no-threshold (LNT) model-that theoretically estimates cancer risks occurring following low doses of carcinogens by linearly extrapolating downward from experimentally determined risks at high doses. The two-year rodent bioassays serve as experimental vehicles to determine the high-dose cancer risks in animals and then to predict, by extrapolation, the number of carcinogen-induced tumors (tumor incidence) that will arise during the lifespans of humans who are exposed to environmental carcinogens at doses typically orders of magnitude below those applied in the rodent assays. An integrated toxicological analysis is conducted herein to reconsider an alternative and once-promising approach, tumor latency, for estimating carcinogen-induced cancer risks at low doses. Tumor latency measures time-to-tumor following exposure to a carcinogen, instead of tumor incidence. Evidence for and against the concept of carcinogen-induced tumor latency is presented, discussed, and then examined with respect to its relationship to dose, dose rates, and the dose-related concepts of initiation, tumor promotion, tumor regression, tumor incidence, and hormesis. Considerable experimental evidence indicates: (1) tumor latency (time-to-tumor) is inversely related to the dose of carcinogens and (2) lower doses of carcinogens display quantifiably discrete latency thresholds below which the promotion and, consequently, the progression and growth of tumors are delayed or prevented during a normal lifespan. Besides reconciling well with the concept of tumor promotion, such latency thresholds also reconcile favorably with the existence of thresholds for tumor incidence, the stochastic processes of tumor initiation, and the compensatory repair mechanisms of hormesis. Most importantly, this analysis and the arguments presented herein provide sound theoretical, experimental, and mechanistic rationales for rethinking the foundational premises of low-dose linearity and updating the current practices of cancer risk assessment to include the concept of carcinogen thresholds.

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Topics: Tumor initiation (55%), Tumor promotion (52%)

3 Citations


Journal ArticleDOI: 10.1002/IUB.2529
23 Jul 2021-Iubmb Life
Abstract: This article tells the story of hormesis from its conceptual and experimental origins, its dismissal by the scientific and medical communities in the first half of the 20th century, and its rediscovery over the past several decades to be a fundamental evolutionary adaptive strategy. The upregulation of hormetic adaptive mechanisms has the capacity to decelerate the onset and reduce the severity of a broad spectrum of common age-related health, behavioral, and performance decrements and debilitating diseases, thereby significantly enhancing the human health span. Incorporation of hormetic-based lifestyle options within the human population would have profoundly positive impacts on the public health, significantly reducing health care costs.

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Topics: Population (52%)

2 Citations


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120 results found


Journal ArticleDOI: 10.1016/J.MOLMED.2004.09.003
Hozumi Motohashi1, Masayuki Yamamoto1Institutions (1)
Abstract: The transcription factor Nrf2 regulates the basal and inducible expression of numerous detoxifying and antioxidant genes. The cytoplasmic protein Keap1 interacts with Nrf2 and represses its function. Analysis of keap1 -knockout mice provides solid evidence that Keap1 acts as a negative regulator of Nrf2 and as a sensor of xenobiotic and oxidative stresses. The simultaneous ablation of the keap1 and nrf2 genes reversed all apparent phenotypes of the Keap1-deficient mice, suggesting that Nrf2 is a primary target of Keap1. The Nrf2–Keap1 system is now recognized as one of the major cellular defence mechanisms against oxidative and xenobiotic stresses. Furthermore, extensive studies have suggested that the Nrf2–Keap1 system contributes to protection against various pathologies, including carcinogenesis, liver toxicity, respiratory distress and inflammation.

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Topics: KEAP1 (53%), Transcription factor (51%)

1,369 Citations


Open accessJournal ArticleDOI: 10.1016/J.BBADIS.2016.11.005
Abstract: Inflammation is the most common feature of many chronic diseases and complications, while playing critical roles in carcinogenesis. Several studies have demonstrated that Nrf2 contributes to the anti-inflammatory process by orchestrating the recruitment of inflammatory cells and regulating gene expression through the antioxidant response element (ARE). The Keap1 (Kelch-like ECH-associated protein)/Nrf2 (NF-E2 p45-related factor 2)/ARE signaling pathway mainly regulates anti-inflammatory gene expression and inhibits the progression of inflammation. Therefore, the identification of new Nrf2-dependent anti-inflammatory phytochemicals has become a key point in drug discovery. In this review, we discuss the members of the Keap1/Nrf2/ARE signal pathway and its downstream genes, the effects of this pathway on animal models of inflammatory diseases, and crosstalk with the NF-κB pathway. In addition we also discuss about the regulation of NLRP3 inflammasome by Nrf2. Besides this, we summarize the current scenario of the development of anti-inflammatory phytochemicals and others that mediate the Nrf2/ARE signaling pathway.

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683 Citations


Open accessJournal ArticleDOI: 10.1097/NEN.0B013E31802D6DA9
Abstract: In response to oxidative stress, the nuclear factor E2-related factor 2 (Nrf2) transcription factor translocates from the cytoplasm into the nucleus and transactivates expression of genes with antioxidant activity. Despite this cellular mechanism, oxidative damage is abundant in Alzheimer and Parkinson disease (AD and PD). To investigate mechanisms by which Nrf2 activity may be aberrant or insufficient in neurodegenerative conditions, we assessed Nrf2 localization in affected brain regions of AD, Lewy body variant of AD (LBVAD), and PD. By immunohistochemistry, Nrf2 is expressed in both the nucleus and the cytoplasm of neurons in normal hippocampi with predominant expression in the nucleus. In AD and LBVAD, Nrf2 was predominantly cytoplasmic in hippocampal neurons and was not a major component of beta amyloid plaques or neurofibrillary tangles. By immunoblotting, we observed a significant decrease in nuclear Nrf2 levels in AD cases. In contrast, Nrf2 was strongly nuclear in PD nigral neurons but cytoplasmic in substantia nigra of normal, AD, and LBVAD cases. These findings suggest that Nrf2-mediated transcription is not induced in neurons in AD despite the presence of oxidative stress. In PD, nuclear localization of Nrf2 is strongly induced, but this response may be insufficient to protect neurons from degeneration.

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Topics: Neurodegeneration (58%), Substantia nigra (54%), Neuron (53%) ... read more

501 Citations


Open accessJournal ArticleDOI: 10.1073/PNAS.0813361106
Abstract: Oxidative stress has been implicated in the etiology of Parkinson's disease (PD) and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model of PD. It is known that under conditions of oxidative stress, the transcription factor NF-E2-related factor (Nrf2) binds to antioxidant response element (ARE) to induce antioxidant and phase II detoxification enzymes. To investigate the role of Nrf2 in the process of MPTP-induced toxicity, mice expressing the human placental alkaline phosphatase (hPAP) gene driven by a promoter containing a core ARE sequence (ARE-hPAP) were used. ARE-hPAP mice were injected (30 mg/kg) once per day for 5 days and killed 7 days after the last MPTP injection. In response to this design, ARE-dependent gene expression was decreased in striatum whereas it was increased in substantia nigra. The same MPTP protocol was applied in Nrf2(+/+) and Nrf2(-/-) mice; Nrf2 deficiency increases MPTP sensitivity. Furthermore, we evaluated the potential for astrocytic Nrf2 overexpression to protect from MPTP toxicity. Transgenic mice with Nrf2 under control of the astrocyte-specific promoter for the glial fribillary acidic protein (GFAP-Nrf2) on both a Nrf2(+/+) and Nrf2(-/-) background were administered MPTP. In the latter case, only the astrocytes expressed Nrf2. Independent of background, MPTP-mediated toxicity was abolished in GFAP-Nrf2 mice. These striking results indicate that Nrf2 expression restricted to astrocytes is sufficient to protect against MPTP and astrocytic modulation of the Nrf2-ARE pathway is a promising target for therapeutics aimed at reducing or preventing neuronal death in PD.

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Topics: MPTP (63%), Substantia nigra (54%), Neuroprotection (53%) ... read more

485 Citations


Open accessJournal ArticleDOI: 10.1089/ARS.2010.3216
Abstract: Activation of the KEAP1-NRF2 signaling pathway is an adaptive response to environmental and endogenous stresses and serves to render animals resistant to chemical carcinogenesis and other forms of toxicity, whereas disruption of the pathway exacerbates these outcomes. This pathway, which can be activated by sulfhydryl-reactive, small-molecule pharmacologic agents, regulates the inducible expression of an extended battery of cytoprotective genes, often by direct binding of the transcription factor to antioxidant response elements in the promoter regions of target genes. However, it is becoming evident that some of the protective effects may be mediated indirectly through cross talk with additional pathways affecting cell survival and other aspects of cell fate. These interactions provide a multi-tiered, integrated response to chemical stresses. This review highlights recent observations on the molecular interactions and their functional consequences between NRF2 and the arylhydrocarbon receptor (A...

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482 Citations