Activators of Nrf2 to Counteract Neurodegenerative Diseases

Amoroso, Rosa; Maccallini, Cristina; Bellezza, Ilaria

doi:10.3390/antiox12030778

Cited by 13 publications

(9 citation statements)

References 104 publications

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“…6, vii and viii), which is controlled by both: IIS and DR. This theme is in line with the evidence that the activation of NRF2, the mammalian orthologue of SKN-1, can potentially counter neurodegenerative disorders (49).…”

Section: Discussionsupporting

confidence: 81%

Cathepsin B Promotes Aβ Proteotoxicity by Modulating Aging Regulating Mechanisms

Cohen,

Siddiqui,

Merquiol

et al. 2023

Preprint

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While the activities of certain proteases promote proteostasis and prevent neurodegeneration-associated phenotypes, the protease cathepsin B (CTSB) enhances proteotoxicity in Alzheimer’s disease (AD) model mice, and its levels are elevated in brains of AD patients. How CTSB exacerbates the toxicity of the AD-causing Amyloid β (Aβ), is controversial. Using an activity-based probe, aging-altering interventions and the nematode C. elegans we discovered that the CTSB CPR-6 promotes Aβ proteotoxicity but mitigates the toxicity of polyQ stretches. While the knockdown of cpr-6 does not affect lifespan, it alleviates Aβ toxicity by reducing the expression of swsn-3 and elevating the level of the protein SMK-1, both involved in the regulation of aging. These observations unveil a novel mechanism by which CTSB aggravates Aβ–mediated toxicity, indicate that it plays opposing roles in the face of distinct proteotoxic insults and highlight the importance of tailoring specific remedies for distinct neurodegenerative disorders.

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Section: Discussionsupporting

confidence: 81%

Cathepsin B Promotes Aβ Proteotoxicity by Modulating Aging Regulating Mechanisms

Cohen,

Siddiqui,

Merquiol

et al. 2023

Preprint

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“…These enzymes are under the control of oxidative response elements that, once activated, induce their expression. This process is dependent on a nuclear receptor, such as nrf2, and melatonin has been suggested to be able to induce the expression of cellular defenses against oxidative stress (see also discussion in Amoroso et al [ 82 ]). Many years later, this nuclear receptor has still not been found.…”

Section: Some Proposed Mechanisms Behind the Claimed Beneficial Effec...mentioning

confidence: 99%

Melatonin: Facts, Extrapolations and Clinical Trials

2023

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Melatonin is a fascinating molecule that has captured the imagination of many scientists since its discovery in 1958. In recent times, the focus has changed from investigating its natural role as a transducer of biological time for physiological systems to hypothesized roles in virtually all clinical conditions. This goes along with the appearance of extensive literature claiming the (generally) positive benefits of high doses of melatonin in animal models and various clinical situations that would not be receptor-mediated. Based on the assumption that melatonin is safe, high doses have been administered to patients, including the elderly and children, in clinical trials. In this review, we critically review the corresponding literature, including the hypotheses that melatonin acts as a scavenger molecule, in particular in mitochondria, by trying not only to contextualize these interests but also by attempting to separate the wheat from the chaff (or the wishful thinking from the facts). We conclude that most claims remain hypotheses and that the experimental evidence used to promote them is limited and sometimes flawed. Our review will hopefully encourage clinical researchers to reflect on what melatonin can and cannot do and help move the field forward on a solid basis.

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“…Thus, the application of exogenous approaches that are capable of elevating endogenous Nrf2 stimulation can contribute to protecting the brain tissue against oxidative damage [7]. However, exogenous Nrf2 activators themselves are not without drawbacks [8][9][10], necessitating the search for new non-pharmacological approaches to modulate OS. The purpose of this review is to present some relevant preclinical and clinical examples, focusing on certain exogenous and endogenous Nrf2 activators and the therapeutic plasma exchange (TPE) modulation of OS in MS.…”

Section: Introductionmentioning

confidence: 99%

Oxidative Stress and the Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Pathway in Multiple Sclerosis: Focus on Certain Exogenous and Endogenous Nrf2 Activators and Therapeutic Plasma Exchange Modulation

Tonev,

Momchilova

2023

IJMS

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The pathogenesis of multiple sclerosis (MS) suggests that, in genetically susceptible subjects, T lymphocytes undergo activation in the peripheral compartment, pass through the BBB, and cause damage in the CNS. They produce pro-inflammatory cytokines; induce cytotoxic activities in microglia and astrocytes with the accumulation of reactive oxygen species, reactive nitrogen species, and other highly reactive radicals; activate B cells and macrophages and stimulate the complement system. Inflammation and neurodegeneration are involved from the very beginning of the disease. They can both be affected by oxidative stress (OS) with different emphases depending on the time course of MS. Thus, OS initiates and supports inflammatory processes in the active phase, while in the chronic phase it supports neurodegenerative processes. A still unresolved issue in overcoming OS-induced lesions in MS is the insufficient endogenous activation of the Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) pathway, which under normal conditions plays an essential role in mitochondria protection, OS, neuroinflammation, and degeneration. Thus, the search for approaches aiming to elevate endogenous Nrf2 activation is capable of protecting the brain against oxidative damage. However, exogenous Nrf2 activators themselves are not without drawbacks, necessitating the search for new non-pharmacological therapeutic approaches to modulate OS. The purpose of the present review is to provide some relevant preclinical and clinical examples, focusing on certain exogenous and endogenous Nrf2 activators and the modulation of therapeutic plasma exchange (TPE). The increased plasma levels of nerve growth factor (NGF) in response to TPE treatment of MS patients suggest their antioxidant potential for endogenous Nrf2 enhancement via NGF/TrkA/PI3K/Akt and NGF/p75NTR/ceramide-PKCζ/CK2 signaling pathways.

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Activators of Nrf2 to Counteract Neurodegenerative Diseases

Cited by 13 publications

References 104 publications

Cathepsin B Promotes Aβ Proteotoxicity by Modulating Aging Regulating Mechanisms

Cathepsin B Promotes Aβ Proteotoxicity by Modulating Aging Regulating Mechanisms

Melatonin: Facts, Extrapolations and Clinical Trials

Oxidative Stress and the Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Pathway in Multiple Sclerosis: Focus on Certain Exogenous and Endogenous Nrf2 Activators and Therapeutic Plasma Exchange Modulation

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