A Pivotal Role of Nrf2 in Neurodegenerative Disorders: A New Way for Therapeutic Strategies

Süzen, Síbel; Tucci, Paolo; Profumo, Elisabetta; Buttari, Brigitta; Saso, Luciano

doi:10.3390/ph15060692

Cited by 19 publications

(12 citation statements)

References 197 publications

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“…Nrf2 activation counteracts OS, inhibits inflammation, and promote AP; thus, the Nrf2-HO-1 system is critical for preventing the onset of DM and its entailed vascular, cardiac, and kidney complications [133][134][135][136]. Furthermore, neurodegenerative diseases including AD and PD have also been reported to be alleviated by Nrf2-HO-1 upregulation, especially with the ability of Nrf2 to activate AP and UPS systems, which help to eliminate misfolded proteins (β-amyloid and α-synuclein) and attenuate the neuroinflammation caused by OS [137][138][139][140]. For cancer, the role of Nrf2 is paradoxical: in normal cells, Nrf2 expression is moderate to protect DNA and other molecules from damage by OS and carcinogens and prevent the cells from becoming cancerous.…”

Section: Prevention and Attenuation Of Aadsmentioning

confidence: 99%

Oxidative stress, inflammation, dysfunctional redox homeostasis and autophagy cause age-associated diseases

Sobhon

Savedvanich²,

Weerakiet

2023

Exploration of Medicine

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Aging and age-associated diseases (AADs) are growing risk factors in societies worldwide. During aging, there is an accumulation of excessive oxygen free radicals [reactive oxygen species (ROS)] and nitrogen free radicals [reactive nitrogen species (RNS)] due to dysfunctional mitochondria, dysregulated catalytic activities of cytochrome P450 (CYP), nicotinamide adenine dinucleotide (NAD) phosphate [NADP(H)] oxidase (NOX), cyclooxygenases, and nitric oxide synthases (NOS) over the threshold of physiological levels, creating oxidative stress (OS). Excessive ROS and RNS oxidize, break, denature, and sometimes cause aggregations of key cellular components including DNA, proteins, and lipids. Normally, these denatured molecules and their aggregates are eliminated by autophagy (AP) and ubiquitin-proteosome system (UPS). However, these two proteostatic mechanisms are impaired as age progresses. As a result, these abnormal molecules turn into damage-associated molecular patterns (DAMPs), recognized as non-self by immune cells, leading to systemic chronic inflammation (SCI), which together with OS are the major causes of aging and AADs. Therefore, instead of trying to prevent and cure AADs individually, the logical approach should be the restoration of redox homeostasis by the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway which can prevent the damaging effect of OS and the upregulation of AP and UPS to eliminate DAMPs, and together they attenuate SCI to lessen the effect of inflammation. The central regulators, adenosine monophosphate-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and Sestrins, synergistically control the restoration of the redox homeostasis by activating Nrf2, the upregulation of AP-UPS, and the inhibition of SCI. The activation of these central regulators can be achieved by exercise, caloric restriction (CR), and intakes of certain CR mimetic natural compounds. Consequently, the activations of these regulators may lead to the prevention and/or attenuation of the AADs.

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Section: Prevention and Attenuation Of Aadsmentioning

confidence: 99%

Oxidative stress, inflammation, dysfunctional redox homeostasis and autophagy cause age-associated diseases

Sobhon

Savedvanich²,

Weerakiet

2023

Exploration of Medicine

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“…By contrast, only recently have there been studies on the effects of the upregulation of Nrf2-HO-1 in extending longevity [175], while its roles in alleviating and preventing AAD have been long investigated and well recognized, including its ameliorating effects against inflammatory and autoimmune diseases, such as multiple sclerosis (MS), inflammatory bowel diseases (IBDs), systemic lupus erythematosus (SLE), rheumatoid athritis [176], obesity, and metabolic diseases, including NAFLD, hypertension, arthrosclerosis, and CVD [177][178][179][180]. Furthermore, neurodegenerative diseases including AD and PD have also been reported to be alleviated by Nrf2-HO-1 upregulation, especially with the ability of Nrf2 to activate AP and UPS systems, which help to eliminate misfolded proteins (beta amyloid and alpha synuclein),and attenuate the neuroinflammation caused by OS [181][182][183][184].…”

Section: Extension Of Longevity and Attenuation Of Aadsmentioning

confidence: 99%

Oxidative stress and inflammation: the root causes of aging

Sobhon

Gavin²,

Weerakiet

2023

Exploration of Medicine

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Oxygen free radicals [reactive oxygen species (ROS)] and nitrogen free radicals [reactive nitrogen species (RNS)] are generated by mitochondria during adenosine triphosphate synthesis, and catalytic activities of cytochrome P450, nicotinamide adenine dinucleotide phosphate oxidases (NOXs), cyclooxygenases, and nitric oxide synthases during drug catabolism, phagocytosis, and acute inflammation. Under normal circumstances, low levels of ROS and RNS provide redox signalings that control many essential physiological processes. As age progresses ROS and RNS increase excessively due to dysfunctional mitochondria, dysregulated NOX, and other free-radical generating sources, leading to oxidative stress, which causes oxidation and denaturation of key cellular components including DNA, proteins, and lipids, which become abnormal, constituting damage-associated molecular pattern (DAMP), recognized as ‘non-self’ by immune cells, leading to inflammation which is mediated by nuclear factor kappa B-inflammasome, p38-c-Jun N-terminal kinase and Janus kinase-signal transducer and activator of transcription pathways. DAMPs are continuously released from damaged and senescent cells, causing an otherwise normally transient inflammation turning into systemic chronic inflammation, the root cause of aging and age-associated diseases (AADs). Cells restore redox balance by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway that induces the synthesis and release of antioxidation molecules and enzymes including haem oxygenase-1, which also inhibits the three inflammatory pathways. Furthermore, upregulation of autophagy (AP) can get rid of abnormal molecules, prevent the generation of DAMPs, and attenuate inflammation. Both AP and Nrf2 signalings decrease with age. The upregulations of Nrf2, AP, and downregulation of inflammation are controlled by sensors of energy and stress levels, i.e., adenosine monophosphate-activated protein kinase, silent information regulator 1, and Sestrins, as well as the extracellular matrix, while mammalian targets for rapamycin complex 1, a nutrient sensor, act in the opposite direction. If the balance of these sensor systems becomes dysregulated, aging process accelerates, and the risk of AADs increases.

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“…NRF2 acts as a transcription factor that regulates the expression of antioxidant and detoxification genes, thereby helping to mitigate oxidative stress and inflammation [1, [11][12][13]. Beyond its role in oxidative stress resistance, NRF2 has been increasingly recognized for its involvement in age-related diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) [14][15][16]. Thus, understanding the mechanisms through which NRF2 and other oxidative stress resistance pathways modulate brain aging, is paramount in advancing our knowledge of neurodegenerative disorders and promoting healthy aging.…”

Section: Introductionmentioning

confidence: 99%

WDR23 mediates NRF2 proteostasis and cytoprotective capacity in the hippocampus

Liu,

Duangjan,

Irwin

et al. 2023

Preprint

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Pathogenic brain aging and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease are characterized by chronic neuroinflammation and the accumulation of dysfunctional or misfolded proteins that lead to progressive neuronal cell death. Here we demonstrate that a murine model with global loss of the CUL4-DDB1 substrate receptor WDR23 (Wdr23KO) results in changes in multiple age-related hippocampal-dependent behaviors. The behavioral differences observed in Wdr23KO animals accompany the stabilization of the NRF2/NFE2L2 protein, an increase in RNA transcripts regulated by this cytoprotective transcription factor, and an increase in the steady state level of antioxidant defense proteins. Taken together, these findings reveal a role for WDR23-proteostasis in mediating cytoprotective capacity in the hippocampus and reveal the potential for targeting WDR23-NRF2 signaling interactions for development of therapies for neurodegenerative disorders.

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A Pivotal Role of Nrf2 in Neurodegenerative Disorders: A New Way for Therapeutic Strategies

Cited by 19 publications

References 197 publications

Oxidative stress, inflammation, dysfunctional redox homeostasis and autophagy cause age-associated diseases

Oxidative stress, inflammation, dysfunctional redox homeostasis and autophagy cause age-associated diseases

Oxidative stress and inflammation: the root causes of aging

WDR23 mediates NRF2 proteostasis and cytoprotective capacity in the hippocampus

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