Role of 4-hydroxynonenal and its metabolites in signaling

Dwivedi, Shashi Prakash; Sharma, Abha; Patrick, Brad; Sharma, Rajendra; Awasthi, Yogesh C.

doi:10.1179/135100007x162211

Cited by 87 publications

(108 citation statements)

References 45 publications

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“…This is a product of lipid oxidation that has been shown to modulates ligand-independent signaling by membrane receptors and interacts with a variety of kinases [53]. Recently it was found that mice mutant for the glutathione transferase mGSTA4-4, an enzyme implicated in the detoxification of 4-hydroxynonenal (4-HNE) have an extended lifespan despite higher levels of this product of lipid oxidation [54].…”

Section: Ros Signaling Affects Aging and Lifespanmentioning

confidence: 99%

Taking a “good” look at free radicals in the aging process

Hekimi

Lapointe

Yang

2011

Trends in Cell Biology

522

373

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The mitochondrial free radical theory of aging (MFRTA) proposes that aging is caused by damage to macromolecules from mitochondrial reactive oxygen species (ROS). This is based on the observed association of the rate of aging and the aged phenotype with the generation of ROS and with oxidative damage. The theory has led to the strong conviction in the general public that the consumption of antioxidants is crucial to health and beneficial to lifespan. However, a variety of recent findings convincingly demonstrate that ROS generation and oxidative damage cannot be the cause of aging. Here we propose that ROS play a role in mediating a stress response to agedependent damage, which could generate the observed correlation between aging and ROS without implying that ROS cause aging. Redefining our understanding of the relationship between ROS and agingMitochondria are a major source of reactive oxygen species (ROS), a type of molecule that includes free radicals such as superoxide. ROS spontaneously oxidize and damage macromolecules such as proteins, lipids and nucleic acids. Cells and organisms are said to be sustaining oxidative stress when an imbalance between ROS generation and detoxification or repair leads to an increase in the level of ROS-dependent damage. The mitochondrial free radical theory of aging (MFRTA) has provided an attractive framework that integrates numerous observations about the generation, the toxicity and the detoxification of ROS, as well as about how these parameters change with the physiological state of cells and organisms and with chronological age. The theory proposes that aging is actually caused by the toxicity of ROS through a vicious cycle in which ROS damage to the constituents of mitochondria leads to the generation of more ROS. The theory is based on numerous observations, including (1) that there is a strong correlation between chronological age and the level of ROS generation and oxidative damage, (2) that mitochondrial function is gradually lost during aging, (3) that inhibition of mitochondrial function can enhance ROS production, and (4) that several age-dependent diseases are associated with severe increases in oxidative stress.The strength of the MFRTA is that it provides a framework for many observations while also stating a plausible causal theory of aging. Furthermore, it provided a clear research program by proposing a theory to be tested as well as by suggesting that decreasing the generation of ROS will result in health benefits. In fact the MFRTA is often taught in textbooks and in *

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Section: Ros Signaling Affects Aging and Lifespanmentioning

confidence: 99%

Taking a “good” look at free radicals in the aging process

Hekimi

Lapointe

Yang

2011

Trends in Cell Biology

522

373

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“…The chemical basis of action of the aldehydes that results in apoptosis is unknown, but recent research indicates that HNE is a signaling molecule at subtoxic concentrations (70,(72)(73)(74), modulating MAP kinases, PKC isoforms, cell cycle regulators, receptor tyrosine kinases, and caspases and activating the JNK-c-Jun/ AP-1 pathway (75). Subtoxic concentrations of HNE were also observed to induce expression of various antioxidant/detoxification enzymes (76).…”

Section: Oxidative Stress and Neurodegenerative Disease--general Consmentioning

confidence: 99%

Oxidative Stress and Neurotoxicity

Sayre

Perry

Smith

2007

Chem. Res. Toxicol.

754

494

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There is increasing awareness of the ubiquitous role of oxidative stress in neurodegenerative disease states. A continuing challenge is to be able to distinguish between oxidative changes that occur early in the disease from those that are secondary manifestations of neuronal degeneration. This perspective highlights the role of oxidative stress in Alzheimer's, Parkinson's, and Huntington's diseases, amyotrophic lateral sclerosis, and multiple sclerosis, neurodegenerative and neuroinflammatory disorders where there is evidence for a primary contribution of oxidative stress in neuronal death, as opposed to other diseases where oxidative stress more likely plays a secondary or by-stander role. We begin with a brief review of the biochemistry of oxidative stress as it relates to mechanisms that lead to cell death, and why the central nervous system is particularly susceptible to such mechanisms. Following a review of oxidative stress involvement in individual disease states, some conclusions are provided as to what further research should hope to accomplish in the field.

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“…A number of recent reviews covering studies on the role of HNE in the modulation of signaling processes are also available [2][3][4][17][18][19][20][21][22][23][24]. Most of these reviews have focused on the role of HNE in inducing apoptosis, regulation of the expression of genes, and its interactions with target proteins including the components of various signaling cascades.…”

Section: Introductionmentioning

confidence: 99%

Self-regulatory role of 4-hydroxynonenal in signaling for stress-induced programmed cell death

Awasthi

Sharma

et al. 2008

Free Radical Biology and Medicine

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Within the last two decades, 4-hydroxynonenal has emerged as an important second messenger involved in the regulation of various cellular processes. Our recent studies suggest that HNE can induce apoptosis in various cells through the death receptor Fas (CD95)-mediated extrinsic pathway as well as through the p53-dependent intrinsic pathway. Interestingly, through its interaction with the nuclear protein Daxx, HNE can self-limit its apoptotic role by translocating Daxx to cytoplasm where it binds to Fas and inhibits Fas-mediated apoptosis. In this paper, after briefly describing recent studies on various biological activities of HNE, based on its interactions with Fas, Daxx, and p53, we speculate on possible mechanisms through which HNE may affect a multitude of cellular processes and draw a parallel between signaling roles of H 2 O 2 and HNE.

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Role of 4-hydroxynonenal and its metabolites in signaling

Cited by 87 publications

References 45 publications

Taking a “good” look at free radicals in the aging process

Taking a “good” look at free radicals in the aging process

Oxidative Stress and Neurotoxicity

Self-regulatory role of 4-hydroxynonenal in signaling for stress-induced programmed cell death

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