Steroids 99 (2015) 117–118

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Editorial

Oxysterols and related sterols: Chemical, biochemical and biological aspects Cholesterol and its congeners phytosterols – which are widely present in animals, plants and/or micro-organisms, are parent compounds of oxygenated forms namely oxysterols and oxyphytosterols that are produced either from auto-oxidation or enzymatically [1,2]. Depending on the concentration, these molecules have potential beneficial or detrimental effects at cellular level. Experiments on various cell types from different species have revealed that oxysterols are cytotoxic at relatively high concentrations. They are important in several diseases, including cardiovascular diseases and neurodegenerative diseases, osteoporosis, and some forms of cancer [3–6]. In these diseases, oxysterols are often found at increased concentrations in the tissues and in various biological fluids of patients [7]. Moreover, whatever the cell type considered, several oxysterols are able to induce oxidative stress, inflammation and/or to trigger different forms of cell death (apoptosis, necrosis, necroptosis, autophagy) [1,8]. However, it is now emerging that low concentrations of oxysterols have specific biological activities [9]. It is expected that a better knowledge on oxysterols effects on cell membranes, cytoplasmic and nuclear receptors capable to modulate gene expression, will contribute to identify new pharmacological targets. Oxyphytosterols, which are mainly C28 and C29 carbon steroid alcohols with a methyl or ethyl chain at C24, are increasingly recognized for their biological activity that could eventually counteract the, putative, beneficial effects of phytosterols given as cholesterol-lowering food supplements [10–14]. This special edition of STEROIDS, on oxysterols and oxyphytosterols, was prepared in conjunction with the 2014 meeting of the European Network for Oxysterol Research (ENOR), which was held in Coimbra, Portugal. ENOR was established in 2010 with the aim of promoting interactions between research groups, to enroll young investigators in the field, and to stimulate novel research on the biological activities of oxysterols and related sterols (http://oxysterols.com/). During the 4th ENOR symposium on ‘‘Translational Research on Oxysterols,’’ held in Coimbra, Portugal, from 18 – 19 September 2014, different aspects of oxysterols, phytosterols and oxyphytosterols were presented and discussed. The meeting was introduced by M. Poirot (INSERM, University Toulouse III, France) who presented a plenary lecture entitled ‘Cholesterol and oxysterol metabolism in cancer: the dark side and the light side’. The special issue is composed of 24 research papers, which were preliminarily presented at the conference, and in the following synopsis we summarize the contributions of the various authors. These contributions span from chemical synthesis to clinical studies, including the diverse actions of oxysterols and http://dx.doi.org/10.1016/j.steroids.2015.05.006 0039-128X/Ó 2015 Published by Elsevier Inc.

oxyphytosterols in biology and medicine, and methodological aspects of analytical procedures. Concerning chemical synthesis, A. Baddredine describes an expeditious synthesis of spinasterol and schottenol, two phytosterols present in argan oil and in cactus pear seed oil. Chemical synthesis is a hot topic for ENOR since most oxysterols and oxyphytosterols are not commercially available. Four papers deal with oxysterol analysis. H. Røberg–Larsen reports on a powerful tool for analyzing limited samples, a nano-LC–ESI– MS method for the analysis of oxysterols without derivatization, and R. Karuna describes the detection of di-hydroxycholesterols in human plasma using HPLC–ESI–MS/MS. This study should allow the analysis of oxysterol levels under disease conditions. The validation of an isotope dilution gas chromatography–mass spectrometry method for combined analysis of oxysterols and oxyphytosterols in serum samples is presented by H.F. Schött, and S. Matysik reports a fast and sensitive method for the determination of steroid hormones in human plasma by GC–MS/MS. The issue of thermal stability and autoxidation of cholesterol and phytosterols connected with food processing is described by two studies. B. Barriuso reports on cholesterol and stigmasterol within a sunflower oil matrix and the related thermal degradation and oxysterols formation. V. Cardenia proposes the use of 2methyl-6-heptanone and 3-methylbutanal as volatile oxidation markers, as a cheap strategy for monitoring cholesterol thermal oxidation in model systems and food samples. Animal studies relying on oxysterol and brain are presented by P.J. Crick on oxysterols and cholestenoic acid profiling in mouse cerebrospinal fluid, an analysis of metabolites with particular interest in neurological diseases; F. Schött describes that 7b-hydroxysitosterol crosses the blood–brain barrier more favourably than its substrate sitosterol in ApoE / mice; and A.A. Saeed shows that a disrupted blood brain barrier facilitates an increased flux of the plant sterols campesterol and sitosterol into the mammalian brain. An ancillary study in the context of potential role of oxysterols in brain function, L. Iuliano describes oxysterol metabolite trafficking across the brain barrier in human. The section of studies at cellular level includes several reports. T. Nury describes the induction of oxiapoptophagy on 158N murine oligodendrocytes treated by 7-ketocholesterol-, 7b-hydroxycholesterol-, and 24(S)-hydroxycholesterol, and the protective effects of a-tocopherol (ViT E) and docosahexaenoic acid. The data produced support the concept of oxiapoptophagy, which can be a particular mode of cell death, elicited by cytotoxic oxysterols. F. Luchetti reports that 7-ketocholesterol and 5,6-secosterol induce human endothelial cell dysfunctions by differential mechanisms and highlights the role of cholesterol autoxidation in cardiovascular disease.

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Editorial / Steroids 99 (2015) 117–118

I. Delton shows that THP-1 macrophages oxidize cholesterol and generate C7-oxidized oxysterols, which are specifically extruded from cells in the presence of HDL. H. Lu describes the requirement of endogenous 25-hydroxycholesterol synthesis for proteasomal elimination of 3-hydroxy-3- methylglutaryl-CoA reductase induced by interferon-c in primary macrophages, ultimately leading to suppress sterol biosynthesis. D.K. Vo describes that in the absence of caspase-8 activity, 24(S)-hydroxycholesterol induces a necroptosis-like cell death which is RIPK1-dependent but MLKL-independent. A. Zarrouk describes the induction of cell death and calcium transients by cholesterol oxides in human SK-N-BE neuronal cells and the protective effects of docosahexaenoic acid. Concerning receptor interaction, H. Kentala reports on sterol liganding of OSBP-related proteins (ORPs) that regulates the subcellular distribution of ORP-VAPA complexes and their impacts on organelle structure, consistent with the notion that this machinery controls lipid homeostasis and signaling in these interfaces; R. Filomenko shows that oxysterols affect plasma membrane rafts microdomains favoring the development of ocular diseases, as retinopathies; and H. de Boussac reports on the Liver X Receptorsmediated regulation of enolase and found it as a new target for LXRs in vivo. Studies on plant sterols and their oxidation products includes a report by A. Luister showing that an increase in plant sterol deposition in vascular tissue characterizes patients with severe aortic stenosis and concomitant coronary artery disease; and a report by S. Baumgartner describes the raise in postprandial plasma concentration of oxyphytosterol in healthy subjects after consumption of a plant sterol or stanol enriched mixed meal. Two human studies close the special issue. M. Trembley-Franco discusses the effect of obesity and metabolic syndrome on plasma oxysterols and fatty acids in humans and the first evidence that these effects are gender specific and associated with changes in circulating fatty acids and oxysterols is reported; and I. Andrade reports on the effect of phytosterols-enriched fermented milk on lipids and markers of cholesterol metabolism in statin-treated elderly patients. The different works presented bring new information on oxysterols, phytosterols and oxyphytosterols. Indeed, they support relevant biological activities for these molecules, which can have major impacts on human health. Furthermore, it is expected that a better knowledge of these compounds will contribute to identify new pharmacological targets and to develop new and efficient treatments for major human diseases.

[3] Björkhem I, Cedazo-Minguez A, Leoni V, Meaney S. Oxysterols and neurodegenerative diseases. Mol Aspects Med 2009 Jun;30(3):171–9. [4] Poli G, Biasi F, Leonarduzzi G. Oxysterols in the pathogenesis of major chronic diseases. Redox Biol 2013 Jan;31(1):125–30. [5] Silvente-Poirot S, Poirot M. Cancer. Cholesterol and cancer, in the balance. Science 2014 Mar 28;343(6178):1445–6. [6] Zarrouk A, Vejux A, Mackrill J, O’Callaghan Y, Hammami M, O’Brien N, Lizard G. Involvement of oxysterols in age-related diseases and ageing processes. Ageing Res Rev 2014 Nov;18:148–62. [7] Leoni V, Caccia C. Oxysterols as biomarkers in neurodegenerative diseases. Chem Phys Lipids 2011 Sep;164(6):515–24. [8] Noguchi N, Saito Y, Urano Y. Diverse functions of 24(S)-hydroxycholesterol in the brain. Biochem Biophys Res Commun 2014 Apr 11;446(3):692–6. [9] Vurusaner B, Gamba P, Testa G, Gargiulo S, Biasi F, Zerbinati C, Iuliano L, Leonarduzzi G, Basaga H, Poli G. Survival signaling elicited by 27hydroxycholesterol through the combined modulation of cellular redox state and ERK/Akt phosphorylation. Free Radic Biol Med 2014 Dec;77:376–85. [10] García-Llatas G, Rodríguez-Estrada MT. Current and new insights on phytosterol oxides in plant sterol-enriched food. Chem Phys Lipids 2011 Sep;164(6):607–24. [11] O’Callaghan Y, McCarthy FO, O’Brien NM. Recent advances in phytosterol oxidation products. Biochem Biophys Res Commun 2014 Apr 11;446(3):786–91. [12] Lizard G. Phytosterols: to be or not to be toxic; that is the question. Br J Nutr 2008 Dec;100(6):1150–1. [13] Hovenkamp E, Demonty I, Plat J, Lütjohann D, Mensink RP, Trautwein EA. Biological effects of oxidized phytosterols: a review of the current knowledge. Prog Lipid Res 2008 Jan;47(1):37–49. [14] Weingärtner O, Baber R, Teupser D. Plant sterols in food: no consensus in guidelines. Biochem Biophys Res Commun 2014 Apr 11;446(3):811–3 .

Maria Luisa Sá e Melo Maria Manuel Cruz Silva Faculty of Pharmacy, University of Coimbra, CNC-Centre for Neuroscience and Cell Biology, Health Sciences Campus, Coimbra, Portugal Luigi Iuliano 1 Sapienza University of Rome, Department of Medico-Surgical Sciences and Biotechnology, Vascular Biology & Mass Spectrometry Lab, Corso della Republica 79, 04100 Latina, Italy E-mail address: [email protected] Gérard Lizard 2 Univ. Bourgogne Franche Comté, Laboratoire BIO-peroxIL (‘Biochimie du Peroxysome, Inflammation et Métabolisme Lipidique’) – EA 7270/INSERM, Faculté des Sciences Gabriel, 6 Bd Gabriel, 21000 Dijon, France E-mail address: [email protected]

References [1] Vejux A, Lizard G. Cytotoxic effects of oxysterols associated with human diseases: induction of cell death (apoptosis and/or oncosis), oxidative and inflammatory activities, and phospholipidosis. Mol Aspects Med 2009 Jun;30(3):153–70. [2] Iuliano L. Pathways of cholesterol oxidation via non-enzymatic mechanisms. Chem Phys Lipids 2011 Sep;164(6):457–68.

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Oxysterols and related sterols: Chemical, biochemical and biological aspects.

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