Targeting the KEAP1-NRF2 System to Prevent Kidney Disease Progression

American Journal of Nephrology, Год журнала: 2017, Номер 45(6), С. 473 - 483

Опубликована: Янв. 1, 2017

<b><i>Background:</i></b> Nuclear factor erythroid 2-related 2 (NRF2) is a critical transcription for the antioxidative stress response and it activates variety of cytoprotective genes related to redox detoxification. NRF2 activity regulated by oxidative-stress sensor molecule Kelch-like ECH-associated protein 1 (KEAP1) that induces proteasomal degradation through ubiquitinating under unstressed conditions. Because oxidative major pathogenic aggravating kidney diseases, KEAP1-NRF2 system has been proposed be therapeutic target renal protection. <b><i>Summary:</i></b> Oxidative-stress molecules, such as reactive oxygen species, accumulate in kidneys animal models acute injury (AKI), which transiently slightly activated. Genetic or pharmacological enhancement tubules significantly ameliorates damage AKI prevents progression chronic disease (CKD) reducing stress. These beneficial effects activation highlight an important treatment. However, phase-3 clinical trial KEAP1 inhibitor patients with stage 4 CKD type-2 diabetes mellitus (T2DM) was terminated due occurrence cardiovascular events. recent basic studies have accumulated positive inhibitors moderate stages CKD, phase-2 trials restarted. The data from ongoing projects demonstrate improves glomerular filtration rate 3 T2DM without safety concerns. <b><i>Key Message:</i></b> one most promising targets disease, could part therapies disease.

Язык: Английский

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Mechanisms of mitophagy in cellular homeostasis, physiology and pathology

Nature Cell Biology, Год журнала: 2018, Номер 20(9), С. 1013 - 1022

Опубликована: Авг. 20, 2018

Язык: Английский

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Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases

Nature Reviews Drug Discovery, Год журнала: 2019, Номер 18(4), С. 295 - 317

Опубликована: Янв. 4, 2019

Язык: Английский

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Regulation of Mitochondrial Biogenesis as a Way for Active Longevity: Interaction Between the Nrf2 and PGC-1α Signaling Pathways

Frontiers in Genetics, Год журнала: 2019, Номер 10

Опубликована: Май 14, 2019

Aging is a general degenerative process related to deterioration of cell functions in the entire organism. Mitochondria, which play key role energy homeostasis and metabolism reactive oxygen species (ROS), require lifetime control constant renewal. This explains recently peaked interest processes mitochondrial biogenesis mitophagy. The principal event regulation DNA (mtDNA) transcription translation, complex coordinated that involves at least two systems factors. It commonly believed its major regulatory protein PGC-1α, acts as factor connecting several regulator cascades involved metabolism. In recent years, number publications on essential Nrf2/ARE signaling has grown exponentially. Nrf2 induced by various xenobiotics antioxidants oxidize some negative regulators. Thus, ROS, particular H2O2, were found be strong activators. At present, there are concepts biogenesis. Some authors suggest direct involvement this process. Others believe regulates expression antioxidant genes, while only PGC-1α. Several studies have demonstrated existence loop involving both PGC-1α Nrf2. review, we summarized data mutual promising targets for drug application other therapies aimed increase active longevity.

Язык: Английский

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Reactive Oxygen Species and Mitochondrial Dynamics: The Yin and Yang of Mitochondrial Dysfunction and Cancer Progression

Antioxidants, Год журнала: 2018, Номер 7(1), С. 13 - 13

Опубликована: Янв. 16, 2018

Mitochondria are organelles with a highly dynamic ultrastructure maintained by delicate equilibrium between its fission and fusion rates. Understanding the factors influencing this balance is important as perturbations to mitochondrial dynamics can result in pathological states. As terminal site of nutrient oxidation for cell, powerhouses harness energy form ATP process driven electron transport chain. Contemporaneously, electrons translocated within chain undergo spontaneous side reactions oxygen, giving rise superoxide variety other downstream reactive oxygen species (ROS). Mitochondrially-derived ROS mediate redox signaling or, excess, cause cell injury even death. Recent evidence suggests that tightly coupled generation depending on physiological status cell. Yet, mechanism which changes shape modulate function homeostasis less clear. Aberrant morphology may lead enhanced formation, which, turn, deteriorate health further exacerbate oxidative stress self-perpetuating vicious cycle. Here, we review latest findings intricate relationship production, focusing mainly role malignant disease.

Язык: Английский

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Regulation of Nrf2 by Mitochondrial Reactive Oxygen Species in Physiology and Pathology

Biomolecules, Год журнала: 2020, Номер 10(2), С. 320 - 320

Опубликована: Фев. 17, 2020

Reactive oxygen species (ROS) are byproducts of aerobic respiration and signaling molecules that control various cellular functions. Nrf2 governs the gene expression endogenous antioxidant synthesis ROS-eliminating enzymes in response to electrophilic compounds inactivate negative regulator Keap1. Accumulating evidence has shown mitochondrial ROS (mtROS) activate Nrf2, often mediated by certain protein kinases, induce genes involved quality/quantity control. Mild physiological stress, such as caloric restriction exercise, elicits beneficial effects through a process known "mitohormesis." Exercise induces NOX4 heart, which activates increases endurance capacity. Mice transiently depleted SOD2 or overexpressing skeletal muscle-specific UCP1 exhibit Nrf2-mediated PGC1α-mediated biogenesis. ATF4 activation may transcriptional program enhances NADPH mitochondria might cooperate with system. In severe oxidative Klf9 expression, represses mtROS-eliminating enhance cell death. is inactivated pathological conditions, diabetes, but Keap1 down-regulation mtROS elimination rescues improves pathology. These reports aid us understanding roles pathophysiological alterations involving mtROS.

Язык: Английский

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Targeting Nrf2 to Suppress Ferroptosis and Mitochondrial Dysfunction in Neurodegeneration

Frontiers in Neuroscience, Год журнала: 2018, Номер 12

Опубликована: Июль 10, 2018

Ferroptosis is a newly described form of regulated cell death, distinct from apoptosis, necroptosis and other forms death. induced by disruption glutathione synthesis or inhibition peroxidase 4, exacerbated iron, prevented radical scavengers such as ferrostatin-1, liproxstatin-1 endogenous vitamin E. terminates with mitochondrial dysfunction toxic lipid peroxidation. Although conclusive identification ferroptosis in vivo challenging, several salient very well established features neurodegenerative diseases are consistent ferroptosis, including peroxidation, iron dysregulation. Accordingly, interest the role neurodegeneration escalating specific evidence rapidly emerging. One aspect that has thus far received little attention antioxidant transcription factor nuclear erythroid 2-related 2 (Nrf2). This regulates hundreds genes, which many either directly indirectly involved modulating metabolism glutathione, lipids, function. potentially positions Nrf2 key deterministic component onset outcomes ferroptotic stress. The minimal direct currently available this indicates may be critical for protection against ferroptosis. In contrast, abundant demonstrates enhancing signaling potently neuroprotective models neurodegeneration, although exact mechanism achieved unclear. Further studies required to determine extent effects activation involve prevention

Язык: Английский

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Antioxidants: Positive or Negative Actors?

Biomolecules, Год журнала: 2018, Номер 8(4), С. 124 - 124

Опубликована: Окт. 25, 2018

The term “antioxidant” is one of the most confusing definitions in biological/medical sciences. In chemistry, simply conceived “a compound that removes reactive species, mainly those oxygen-derived”, while a cell context, conceptual definition an antioxidant poorly understood. Indeed, non-clinically recommended antioxidants are often consumed large amounts by global population, based on belief cancer, inflammation and degenerative diseases triggered high oxygen levels (or species) through blocking species production, organic unbalances/disorders can be prevented and/or even treated. popularity these chemicals arises part from widespread public mistrust allopathic medicine. fact, play dual role dealing with different disorders, since they may contribute to disease onset progression but also key prevention. Further, ability commonly used supplements, such as vitamins C, E, selenium, herbal supplements decrease pathologic not clearly established. Hence, present review aims provide nuanced understanding where current knowledge it should go.

Язык: Английский

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The Role of Mitophagy in Innate Immunity

Frontiers in Immunology, Год журнала: 2018, Номер 9

Опубликована: Июнь 5, 2018

Mitochondria are cellular organelles essential for multiple biological processes, including energy production, metabolites biosynthesis, cell death and immunological responses among others. Recent advances in the field of immunology research reveal pivotal role metabolism innate immune cells fate function. Therefore, maintenance mitochondrial network integrity activity is a prerequisite system homeostasis. Mitochondrial selective autophagy, known as mitophagy, surveils population eliminating superfluous and/or impaired mediating survival viability response to injury/trauma infection. Defective removal damaged mitochondria leads hyperactivation inflammatory signaling pathways subsequently chronic systemic inflammation development diseases. Here, we review molecular mechanisms mitophagy highlight its critical

Язык: Английский

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Effects of curcumin on mitochondria in neurodegenerative diseases

BioFactors, Год журнала: 2019, Номер 46(1), С. 5 - 20

Опубликована: Окт. 3, 2019

Abstract Neurodegenerative diseases (NDs) result from progressive deterioration of selectively susceptible neuron populations in different central nervous system (CNS) regions. NDs are classified accordance with the primary clinical manifestations (e.g., parkinsonism, dementia, or motor disease), anatomic basis neurodegeneration frontotemporal degenerations, extrapyramidal disorders, spinocerebellar degenerations), and fundamental molecular abnormalities mutations, mitochondrial dysfunction, its related alterations). include Alzheimer disease Parkinson disease, among others. There is a growing evidence that dysfunction mutations form oxidative/nitrosative stress neurotoxic compounds play major roles pathogenesis various NDs. Curcumin, polyphenol nontoxic compound, obtained turmeric, has been shown to have therapeutic beneficial effect disorders especially on CNS cells. It curcumin considerable neuro‐ mitochondria‐protective properties against broad‐spectrum diseases/injury‐associating In this article, we reviewed effects

Язык: Английский

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