Oxysterols and mechanisms of apoptotic signaling: implications in the pathology of degenerative diseases☆

Lordan, Sinéad; Mackrill, John J.; O’Brien, Nora M.

doi:10.1016/j.jnutbio.2009.01.001

Cited by 131 publications

(98 citation statements)

References 141 publications

(201 reference statements)

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“…Yellow tetrazolium salt MTT has the property of acting as hydrogen acceptor to be reduced by NADP(H)-dependent oxido-reductase enzymes, such as mitochondrial reductase enzyme, into its purple formazan product [22]. The observed formazan decrease might reflect a mitochondrial dysfunction, in agreement with many studies, which have reported a role of oxysterols in the induction of alteration of mitochondrial integrity, decrease of mitochondrial transmembrane potential and release of cytochrome c [23].…”

Section: Discussionsupporting

confidence: 88%

Evidence of cell damage induced by major components of a diet-compatible mixture of oxysterols in human colon cancer CaCo-2 cell line

et al. 2013

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a b s t r a c tCholesterol oxidation products, termed oxysterols, have been shown to be more reactive than unoxidized cholesterol, possessing marked pro-inflammatory and cytotoxic effects in a number of cells and tissues. Oxysterols, absorbed with the diet as products of cholesterol auto-oxidation, have recently been suggested to potentially interfere with homeostasis of the mucosal intestinal epithelium, by promoting and sustaining irreversible damage.However, the treatment of colon cancer cells with a diet-compatible mixture of oxysterols does not elicit the same responses than individual components added to the cells at the same concentrations at which they are present in the mixture. Sixty mM oxysterol mixture showed a slight pro-apoptotic effect on human colon cancer CaCo-2 cell line, evaluated in terms of caspase-3 and caspase-7 activation; conversely, 7a-hydroxycholesterol, 7b-hydroxycholesterol and 5a,6a-epoxycholesterol were identified to be able to induce a significant pro-apoptotic effect if added to cell culture singly; 7b-hydroxycholesterol had stronger action than other compounds. The enhanced production of reactive oxygen species through up-regulation of the colonic NADPH-oxidase isoform NOX1 appeared to be the key event in oxysterolinduced apoptosis in these colon cancer cells. As regards pro-inflammatory effects of oxysterols, IL-8 and MCP-1 were evaluated for their chemotactic activity. Only MCP-1 production was significantly induced by 7b-hydroxycholesterol, as well as by cholesterol and oxysterol mixture. However, oxysterolinduced inflammation appeared to be NOX1-independent, suggesting a secondary role of this enzyme in inducing inflammation in colon cancer cells.A selective cell death induced by specific oxysterols against colon cancer cells, mainly exploiting their ability to activate NOX1 in generating oxidative reactions, might represent a promising field of investigation in colorectal cancer, and might bring new insights on strategies in anticancer therapy.

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Section: Discussionsupporting

confidence: 88%

Evidence of cell damage induced by major components of a diet-compatible mixture of oxysterols in human colon cancer CaCo-2 cell line

et al. 2013

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“…This does not appear to support a role for oxysterols in the initiation of atherosclerosis. However the oxysterols could exert several biological activities in the arterial cells, including apoptosis, cytotoxicity, and regulation of gene expression (33,170). Several oxysterols appear to upregulate the ROS levels by stimulating the NOX pathway, and to upregulate the synthesis of TGFb (160).…”

Section: Oxysterolsmentioning

confidence: 99%

Oxidized LDL: Diversity, Patterns of Recognition, and Pathophysiology

Levitan

Volkov

Subbaiah

2010

Antioxidants & Redox Signaling

388

328

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Oxidative modification of LDL is known to elicit an array of pro-atherogenic responses, but it is generally underappreciated that oxidized LDL (OxLDL) exists in multiple forms, characterized by different degrees of oxidation and different mixtures of bioactive components. The variable effects of OxLDL reported in the literature can be attributed in large part to the heterogeneous nature of the preparations employed. In this review, we first describe the various subclasses and molecular composition of OxLDL, including the variety of minimally modified LDL preparations. We then describe multiple receptors that recognize various species of OxLDL and discuss the mechanisms responsible for the recognition by specific receptors. Furthermore, we discuss the contentious issues such as the nature of OxLDL in vivo and the physiological oxidizing agents, whether oxidation of LDL is a prerequisite for atherogenesis, whether OxLDL is the major source of lipids in foam cells, whether in some cases it actually induces cholesterol depletion, and finally the Janus-like nature of OxLDL in having both pro-and anti-inflammatory effects. Lastly, we extend our review to discuss the role of LDL oxidation in diseases other than atherosclerosis, including diabetes mellitus, and several autoimmune diseases, such as lupus erythematosus, anti-phospholipid syndrome, and rheumatoid arthritis. Antioxid. Redox Signal. 13, 39-75.

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“…7KCh is an oxidized form of cholesterol commonly found in oxidized LDL (oxLDL) associated with atherosclerotic plaques (1)(2)(3)(4)(5)(6)(7)(23)(24)(25). 7KCh has been shown to have potent proinfl ammatory and cell death properties and has been implicated in foam cell formation in macrophages ( 2,4,7,(23)(24)(25).…”

Section: What Is 7kch?mentioning

confidence: 99%

Cholesterol oxidation in the retina: implications of 7KCh formation in chronic inflammation and age-related macular degeneration

Rodríguez

Larráyoz

2010

Journal of Lipid Research

121

115

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Journal of Lipid Research Volume 51, 20102847 their actions affect the retina and the retinal pigment epithelium (RPE) ( 8-10 ). One particular oxysterol, 7-ketocholesterol (7KCh), has been found more abundantly than other oxysterols in the retina ( 9, 10 ). This oxysterol is known to have potent pharmacological properties that lead to infl ammation and cell death in a variety of cell types ( 1-10 ). This review will focus on what is known about this molecule and the potential implications of its presence in the retina. The retina is a light-capturing tissue that contains at least 5 cell classes and more than 50 different cell types, each performing unique functions that ultimately provide the visual centers in the brain the information to achieve image formation and visual perception. The retina faces a unique photooxidative environment that generates challenges not encountered by other neurological tissues or organs. Phototransduction requires the retina to have a high metabolic rate ( 11 ) and multiple and complex membrane structures ( 12 ). The photoreceptor outer segments are enriched in the highly photosensitive docosahexaenoic acid and other Abstract This review will discuss the formation and potential implications of 7-ketocholesterol (7KCh) in the retina. 7KCh is a proinfl ammatory oxysterol known to be present in high amounts in oxidized LDL deposits associated with atheromatous plaques. 7KCh is generated in situ in these lipoprotein deposits where it can accumulate and reach very high concentrations. In normal primate retina, 7KCh has been found associated with lipoprotein deposits in the choriocapillaris, Bruch's membrane, and the retinal pigment epithelium (RPE). In photodamaged rats, 7KCh has been found in the neural retina in areas of high mitochondrial content, ganglion cells, photoreceptor inner segments and synapses, and the RPE. Intermediates found by LCMS indicate 7KCh is formed via a free radical-mediated mechanism catalyzed by iron. 7KCh seems to activate several kinase signaling pathways that work via nuclear factor B and cause the induction of vascular endothelial growth factor, interleukin (IL)-6, and IL-8. There seems to be little evidence of 7KCh metabolism in the retina, although some form of effl ux mechanism may be active. The chronic mode of formation and the potent infl ammatory properties of 7KCh indicate it may be an "age-related" risk factor in aging diseases such as atherosclerosis, Alzheimer's, and age-related macular degeneration. -Rodríguez, I. R., and I. M. Larrayoz. Cholesterol oxidation in the retina: implications of 7-KCh formation in chronic infl ammation and age-related macular degeneration. J. Lipid Res . 2010. 51: 2847-2862. Supplementary key words 7-ketocholesterol • cytokines • oxysterolsIn the past year, numerous reviews have been published that extensively discuss the multiple functions of oxysterols and their complex relationships to diseases ( 1-7 ). However, the formation and function of oxysterols in the retina has not been well studied. Emerging studies are...

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Oxysterols and mechanisms of apoptotic signaling: implications in the pathology of degenerative diseases☆

Cited by 131 publications

References 141 publications

Evidence of cell damage induced by major components of a diet-compatible mixture of oxysterols in human colon cancer CaCo-2 cell line

Evidence of cell damage induced by major components of a diet-compatible mixture of oxysterols in human colon cancer CaCo-2 cell line

Oxidized LDL: Diversity, Patterns of Recognition, and Pathophysiology

Cholesterol oxidation in the retina: implications of 7KCh formation in chronic inflammation and age-related macular degeneration

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