Side effects of oxysterols: cytotoxicity, oxidation, inflammation, and phospholipidosis

Véjux, Anne; Malvitte, L.; Lizard, Gérard

doi:10.1590/s0100-879x2008000700001

Cited by 149 publications

(147 citation statements)

References 58 publications

(89 reference statements)

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“…Auto-oxidation of dietary cholesterol generally produces a mixture of oxysterols (mainly 7α-OH, 7β-OH, 7K, α-epoxy and β-epoxy) that has been found in food in concentrations ranging from 10 to 100 μM. 23,24 Generally, when oxysterols reach the intracellular compartment they behave as potent molecular regulators. Intracellular oxysterols could act as secondary messengers in cell signal transduction pathways, of which ERK1/2, p38 MAPK, and JNK play important roles in coordinating a variety of cellular processes, including cell proliferation, differentiation, and death.…”

Section: Discussionmentioning

confidence: 99%

The role of p38 MAPK in the induction of intestinal inflammation by dietary oxysterols: modulation by wine phenolics

et al. 2015

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Dietary oxysterols are cholesterol auto-oxidation products widely present in cholesterol-rich foods.They are thought to affect the intestinal barrier function, playing a role in gut inflammation. This study has characterized specific cell signals that are up-regulated in differentiated CaCo-2 colonic epithelial cells by a mixture of oxysterols representative of a hyper-cholesterolemic diet. p38 MAPK activation plays a major role, while other signal branches, i.e. the JNK and ERK pathways, make minor contributions to the intestinal inflammation induced by dietary oxysterols. p38 transduction might be the missing link connecting the known NADPH oxidase activation, and the induction of NF-κB-dependent inflammatory events related to oxysterols' action in the intestine. A NOX1/p38 MAPK/NF-κB signaling axis was demonstrated by the quenched inflammation observed on blocking individual branches of this signal with specific chemical inhibitors. Further, all these signaling sites were prevented when CaCo-2 cell were pre-incubated with phenolic compounds extracted from selected wines made of typical Sardinian grape varieties: red Cannonau and white Vermentino. Notably, Cannonau was more effective than Vermentino. The effect of Sardinian wine extracts on intestinal inflammation induced by dietary oxysterols might mainly be due to their phenolic content, more abundant in Cannonau than in Vermentino. Furthermore, among different phenolic components of both wines, epicatechin and caffeic acid exerted the strongest effects. These findings show a major role of the NOX1/p38 MAPK/NF-κB signaling axis in the activation of oxysteroldependent intestinal inflammation, and confirm the concept that phenolics act as modulators at different sites of pro-oxidant and pro-inflammatory cell signals.

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Section: Discussionmentioning

confidence: 99%

The role of p38 MAPK in the induction of intestinal inflammation by dietary oxysterols: modulation by wine phenolics

et al. 2015

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“…Sterol oxidation products (SOPs) have been extensively reported to be involved in a variety of pathologies and diseases [1][2][3][4]. Their formation occurs endogenously both by enzymatic or non-enzymatic pathways, from sterols present in plasma and tissues [5].…”

Section: Introductionmentioning

confidence: 99%

Cholesterol and stigmasterol within a sunflower oil matrix: Thermal degradation and oxysterols formation

et al. 2015

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The characteristics of the lipid matrix surrounding sterols exert a great influence in their thermal oxidation process. The objective of this work was to assess the oxidation susceptibility of equal amounts of cholesterol and stigmasterol within a sunflower oil lipid matrix (ratio 1:1:200) during heating (180 ºC, 0 to 180 min). Remaining percentage of sterols was determined and seven sterol oxidation products (SOPs) were analyzed for each type of sterol along the heating treatment. Evolution of the fatty acid profile and vitamin E content of the oil was also studied. Overall oxidation status of the model system was assessed by means of Peroxide Value (PV) and TBARS. PV remained constant from 30 min onwards and TBARS continued increasing along the whole heating treatment.Degradation of both cholesterol and stigmasterol fitted a first order curve (R 2 = 0.937 and 0.883, respectively), with very similar degradation constants (0.004 min -1 and 0.005 min -1 , respectively). However, higher concentrations of oxidation products were found from cholesterol (79 µg/mg) than from stigmasterol (53 µg/mg) at the end of the heating treatment. Profile of individual oxidation products was similar for both sterols, except for the fact that no 25-hydroxystigmasterol was detected. 7α-hydroxy and 7-ketoderivatives were the most abundant SOPs at the end of the treatment. PUFA and vitamin E suffered a significant degradation along the process, which was correlated to sterols oxidation.

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“…Oxysterols are now thought to be involved in the initiation and progression of major chronic diseases, including List of abbreviations: Ac-DEVD-AMC, Acetyl-Asp-Glu-Val-Asp-7-amino-4-methylcoumarin; AMC, 7-amino-4-methylcoumarin; chol, cholesterol; DCF, 2 0 ,7 0 -dichlorofluorescein; DCFH-DA, 2 0 ,7 0 -dichlorofluorescin-diacetate; DHE, dyhydroethidium; DMEM, Dulbecco's modified Eagle's medium; DPI, diphenylene iodonium; ECL, enhanced chemiluminescence; EDTA, ethylenediaminetetraacetic acid; FBS, foetal bovine serum; FITC, fluorescein isothiocyanate; HEPES, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; HRP, horseradish peroxidase; IBD, inflammatory bowel disease; LDH, lactate dehydrogenase, MCP-1 monocyte chemotactic protein; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide; NADPH, nicotinamide adenine dinucleotide phosphate reduced; NOX, NADPH oxidase; Noxa1, Nox activator 1; Noxo1, Nox organizer 1; oxy, oxysterol mixture; PBS, phosphate buffered saline; ROS, reactive oxygen species; 7K, 7-ketocholesterol; a-epox, 5a,6a-epoxycholesterol; b-epox, 5b,6b-epoxycholesterol; 7a-OH, 7a-hydroxycholesterol; 7b-OH, 7b-hydroxycholesterol.atherosclerosis, neurodegenerative processes, diabetes, and ethanol intoxication [3]. Oxysterols are more polar and more readily diffusible through cell membranes, and have consistently been shown to be more reactive than unoxidized cholesterol, possessing marked pro-inflammatory and cytotoxic effects in a number of cells and tissues [4,5].…”

Section: Introductionmentioning

confidence: 99%

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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Side effects of oxysterols: cytotoxicity, oxidation, inflammation, and phospholipidosis

Cited by 149 publications

References 58 publications

The role of p38 MAPK in the induction of intestinal inflammation by dietary oxysterols: modulation by wine phenolics

The role of p38 MAPK in the induction of intestinal inflammation by dietary oxysterols: modulation by wine phenolics

Cholesterol and stigmasterol within a sunflower oil matrix: Thermal degradation and oxysterols formation

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

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