4‐Hydroxynonenal in the Pathomechanisms of Oxidative Stress

Poli, Giuseppe; Schaur, Jörg

doi:10.1080/713803726

Cited by 127 publications

(66 citation statements)

References 46 publications

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“…Lipid peroxidation products such as MDA and HNE and the hydroxyethyl radical form adducts with proteins which may alter their normal function. These adducts have also been shown to display cytotoxic effects in several cell types [45,46], interfere with intracellular proteolysis [47], and may alter intracellular signaling pathways [31]. In addition, adducted proteins also stimulate the host immune response and result in an autoimmune-like disease.…”

Section: Discussionmentioning

confidence: 99%

Effects of N-acetylcysteine on ethanol-induced hepatotoxicity in rats fed via total enteral nutrition

Ronis

Butura

Sampey

et al. 2005

Free Radical Biology and Medicine

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The effects of the dietary antioxidant N-acetylcysteine (NAC) on alcoholic liver damage were examined in a total enteral nutrition (TEN) model of ethanol toxicity in which liver pathology occurs in the absence of endotoxemia. Ethanol treatment resulted in steatosis, inflammatory infiltrates, occasional foci of necrosis, and elevated ALT in the absence of increased expression of the endotoxin receptor CD14, a marker of Kupffer cell activation by LPS. In addition, ethanol treatment induced CYP2E1 and increased TNFα and TGFβ mRNA expression accompanied by suppressed hepatic IL-4 mRNA expression. Ethanol treatment also resulted in the hepatic accumulation of malondialdehyde (MDA) and hydroxynonenal (HNE) protein adducts, decreased antioxidant capacity, and increased antibody titers toward serum hydroxyethyl radical (HER), MDA, and HNE adducts. NAC treatment increased cytosolic antioxidant capacity, abolished ethanol-induced lipid peroxidation, and inhibited the formation of antibodies toward HNE and HER adducts without interfering with CYP2E1 induction. NAC also decreased ethanol-induced ALT release and inflammation and prevented significant loss of hepatic GSH content. However, the improvement in necrosis score and reduction of TNFα mRNA elevation did not reach statistical significance. Although a direct correlation was observed among hepatic MDA and HNE adduct content and TNFα mRNA expression, inflammation, and necrosis scores, no correlation was observed between oxidative stress markers or TNFα and steatosis score. These data suggest that ethanol-induced oxidative stress can contribute to inflammation and liver injury even in the absence of Kupffer cell activation by endotoxemia.

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Section: Discussionmentioning

confidence: 99%

Effects of N-acetylcysteine on ethanol-induced hepatotoxicity in rats fed via total enteral nutrition

Ronis

Butura

Sampey

et al. 2005

Free Radical Biology and Medicine

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“…In this report we show for the first time that HNE induces HO-1 mRNA, protein, and activity in pulmonary epithelial cells. HNE is not only a marker of oxidative stress that is induced by environmental exposure to "pollutants" and in diseases and disorders of the lung with an inflammatory component; it is also a mediator of both injury and adaptive responses [22,24,[52][53][54][55]. The induction of HO-1 by HNE was both rapid and dramatic.…”

Section: Discussionmentioning

confidence: 99%

“…HNE is an α,β-unsaturated aldehyde that is formed from the reaction of oxygen species with arachidonate in cellular membranes during many forms of environmental stress, including exposure to cigarette smoke [9,21,22]. HNE is known to impact the cell in many ways, which include inactivation of enzymes, depletion of intracellular glutathione, and inhibition of DNA and protein synthesis [23][24][25]. Recent data suggest that HNE may also modulate biological responses by triggering intracellular signal transduction pathways [26][27][28].…”

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confidence: 99%

HNE increases HO-1 through activation of the ERK pathway in pulmonary epithelial cells

Iles

Dickinson

Wigley

et al. 2005

Free Radical Biology and Medicine

101

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Heme oxygenase-1 (HO-1) is a key cytoprotective enzyme and an established marker of oxidative stress. Increased HO-1 expression has been found in the resident macrophages in the alveolar spaces of smokers. The lipid peroxidation product 4-hydroxynonenal (HNE) is also increased in the bronchial and alveolar epithelium in response to cigarette smoke. This suggests a link between a chronic environmental stress, HNE formation, and HO-1 induction. HNE is both an agent of oxidative stress in vivo and a potent cell signaling molecule. We hypothesize that HNE acts as an endogenously produced pulmonary signaling molecule that elicits an adaptive response culminating in the induction of HO-1. Here we demonstrate that HNE increases HO-1 mRNA, protein, and activity in pulmonary epithelial cells and identify ERK as a key pathway involved. Treatment with HNE increased ERK phosphorylation, c-Fos protein, JNK phosphorylation, c-Jun phosphorylation, and AP-1 binding. Whereas inhibiting the ERK pathway with the MEK inhibitor PD98059 significantly decreased HNEmediated ERK phosphorylation, c-Fos protein induction, AP-1 binding, and HO-1 protein induction, inhibition of the ERK pathway had no effect on HNE-induced HO-1 mRNA. This suggests that ERK is involved in the increase in HO-1 through regulation of translation rather than transcription. Keywords 4-Hydroxynonenal; Oxidative stress; HO-1; MAPK signaling; Free radicals Heme oxygenase-1 (HO-1) is an important cytoprotective enzyme and widely accepted marker of oxidative stress. HO-1 catalyzes the first and rate-limiting step in the catabolism of heme, which generates equimolar amounts of biliverdin, ferrous iron, and carbon monoxide [1][2][3]. Although heme is the major substrate of HO-1, a variety of non-heme-containing agents are also strong inducers of HO-1. HO-1 has been shown to respond to a number of proinflammatory cytokines, including TNF-α, . HO-1 is also induced by a variety of agents NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript that cause oxidative stress and/or in response to environmental stress [5][6][7][8]. For example, increased HO-1 expression has recently been found in the alveolar spaces in the resident macrophages of smokers [9]. Once induced, HO-1 provides protection against multiple types of tissue injury [10][11][12][13]; specific to the lung, overexpression of HO-1 in pulmonary epithelial cells has been shown to protect against oxygen toxicity [14]. In contrast, HO-1 deficiency in mice (HO-1 −/− ) increases susceptibility to inflammatory lung injury [15], as does HO-1 deficiency in humans [16]. Although the precise mechanisms by which HO-1 exerts its cytoprotective effects are not known, there is mounting evidence that carbon monoxide plays a key role in this process. For thorough reviews of the recent literature see [17,18].Another characteristic of oxidative stress is the formation of the lipid peroxidation product 4-hydroxy-2-nonenal (HNE). HNE has been shown to increase HO-1 in the cell [19,20], but the mechanism(s...

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“…This aldehyde is a relatively stable molecule, which can diffuse to sites distant from its origin, by this way propagating the initially local injury. An increasing bulk of experimental evidence points to HNE as a candidate molecule for a role in the pathogenesis of numerous inflammatory and degenerative processes, including atherosclerosis, Alzheimer's and Parkinson's diseases, liver fibrosis, glomerulosclerosis, gastrointestinal diseases and cancer [26,88]. In addition, various studies have focused on the biological impact of lower concentrations of this aldehyde, which is produced in physiological conditions as a product of the normal renewing process of PUFAs in cell plasma membranes.…”

Section: Dietary Lipidsmentioning

confidence: 99%

“…HNE can control growth and differentiation, cell cycle progression and apoptosis. Indeed, this molecule may be considered as antiproliferative, being able to regulate genes encoding for other molecules such as c-myc, c-myb, cyclins, p21 and TGF-b1 [7,50,54,88,110].…”

Section: Dietary Lipidsmentioning

confidence: 99%

TGFβ1 expression in colonic mucosa: modulation by dietary lipids

2007

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Transforming growth factor beta1 (TGFb1) is fundamental to maintain the intestinal epithelial cell homeostasis through its control action on cell proliferation, differentiation and apoptosis. TGFb1 dysregulation has been observed in several chronic human diseases, including ulcerative colitis, Crohn's disease and colon carcinoma. In the first two conditions, a marked oxidative stress is consistently present, while in the third one, levels of reactive oxygen species tend to be significantly lower than in the surrounding normal tissue. Lipid-derived compounds such as the aldehyde 4-hydroxynonenal (HNE) or cholesterol oxidation products (oxysterols) were shown able to induce expression and synthesis of TGFb1, an event which can be detrimental or beneficial, essentially depending on its actual intensity. Understanding how specific dietary lipids may influence the complex molecular signaling underlying this cytokine expression, may provide new indications for therapeutic and preventive strategies in inflammatory bowel diseases and colon carcinoma.

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4‐Hydroxynonenal in the Pathomechanisms of Oxidative Stress

Cited by 127 publications

References 46 publications

Effects of N-acetylcysteine on ethanol-induced hepatotoxicity in rats fed via total enteral nutrition

Effects of N-acetylcysteine on ethanol-induced hepatotoxicity in rats fed via total enteral nutrition

HNE increases HO-1 through activation of the ERK pathway in pulmonary epithelial cells

TGFβ1 expression in colonic mucosa: modulation by dietary lipids

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