Analysis of the current vitamin A terminology and dietary regulations from vitamin A1 to vitamin A5.

Dietary recommendations on vitamin intake for human food fortification concerning vitamin A in various countries, larger economic zones and international organizations are mainly based on the Food and Agriculture Organization of the United Nations (FAO)/World Health Organization (WHO) "Codex Alimentarius standards". The general vitamin A terminology is based on regulations of the International Union of Pure and Applied Chemistry (IUPAC) that are used to describe the involved derivatives. These regulations and terminology were set up in the middle of the last century. Starting with the decade of the 80ies in the 20th century a large improvement of molecular biological methodologies, background physiological mechanisms as well as analytical techniques contributed to a large diversification of this simply claimed vitamin A terminology. Unfortunately, the following terminology and governmental regulations for food fortification are imprecise and non-harmonized. In this article we tried to unravel this terminology for updating terminology, nutritional suggestions and governmental regulations for vitamin A, which are currently based on various uncertainties. According to the current regulations, the newly found vitamin A5/X can be included in the current vitamin A terminology as "vitamin A5" or alternatively or even in parallel as a new vitamin A-independent terminology as "vitamin X". Based on the detailed knowledge of research from the early beginning of general vitamin A pathway identification towards detailed research of the last decades the commonly used and simplified term vitamin A with relevance for governmental recommendations on vitamin intake and food fortification advice was now more correctly sub-categorized to further vitamin A1, and A5 sub-categories with vitamin A1-alcohol as retinol, vitamin A2-alcohol as 3,4-didehydroretinol and vitamin A5-alcohol as 9-cis-13,14-dihydroretinol as their mainly relevant vitamin forms present in the human organism. Here we suggest and advise how the vitamin A terminology and further governmental regulations should be organized depending on a successful unraveling of the organization of the current vitamin A terminology.

Human nutritional relevance and suggested nutritional guidelines for vitamin A5/X and provitamin A5/X.

In the last century, vitamin A was identified that included the nutritional relevant vitamin A1 / provitamin A1, as well as the vitamin A2 pathway concept. Globally, nutritional guidelines have focused on vitamin A1 with simplified recommendations and calculations based solely on vitamin A. The vitamin A / provitamin A terminology described vitamin A with respect to acting as a precursor of 11-cis-retinal, the chromophore of the visual pigment, as well as retinoic acid(s), being ligand(s) of the nuclear hormone receptors retinoic acid receptors (RARs) α, ß and γ. All-trans-retinoic acid was conclusively shown to be the endogenous RAR ligand, while the concept of its isomer 9-cis-retinoic acid, being "the" endogenous ligand of the retinoid-X receptors (RXRs), remained inconclusive. Recently, 9-cis-13,14-dihydroretinoic acid was conclusively reported as an endogenous RXR ligand, and a direct nutritional precursor was postulated in 2018 and further confirmed by Rühl, Krezel and de Lera in 2021. This was further termed vitamin A5/X / provitamin A5/X. In this review, a new vitamin A5/X / provitamin A5/X concept is conceptualized in parallel to the vitamin A(1) / provitamin A(1) concept for daily dietary intake and towards dietary guidelines, with a focus on the existing national and international regulations for the physiological and nutritional relevance of vitamin A5/X. The aim of this review is to summarize available evidence and to emphasize gaps of knowledge regarding vitamin A5/X, based on new and older studies and proposed future directions as well as to stimulate and propose adapted nutritional regulations.

State-of-the-art methodological investigation of carotenoid activity and metabolism - from organic synthesis via metabolism to biological activity - exemplified by a novel retinoid signalling pathway.

Carotenoids are the most abundant lipophilic secondary plant metabolites and their dietary intake has been related to a large number of potential health benefits relevant for humans, including even reduced total mortality. An important feature is their potential to impact oxidative stress and inflammatory pathways, by interacting with transcription factors. For example, they may act as precursors of bioactive derivatives activating nuclear hormone receptor mediated signalling. These bioactive derivatives, originating e.g. from ß-carotene, i.e. retinoids / vitamin A, can activate the nuclear hormone receptors RARs (retinoic acid receptors). Due to new analytical insights, various novel metabolic pathways were recently outlined to be mediated via distinct nuclear hormone receptor activating pathways that were predicted and further confirmed. In this article, we describe old and novel metabolic pathways from various carotenoids towards novel ligands of alternative nuclear hormone receptors. However, to fully elucidate these pathways, a larger array of techniques and tools, starting from organic synthesis, lipidomics, reporter models, classical in vitro and in vivo models and further omics-approaches and their statistical evaluation are needed to comprehensively and conclusively study this topic. Thus, we further describe state-of-the-art techniques from A to Ω elucidating carotenoid biological mediated activities and describe in detail required materials and methods needed - in practical protocol form - for the various steps of carotenoid investigations.

Carotenoid metabolites, their tissue and blood concentrations in humans and further bioactivity via retinoid receptor-mediated signalling.

Many epidemiological studies have emphasised the relation between carotenoid dietary intake and their circulating concentrations and beneficial health effects, such as lower risk of cardiometabolic diseases and cancer. However, there is dispute as to whether the attributed health benefits are due to native carotenoids or whether they are instead induced by their metabolites. Several categories of metabolites have been reported, most notably involving (a) modifications at the cyclohexenyl ring or the polyene chain, such as epoxides and geometric isomers, (b) excentric cleavage metabolites with alcohol-, aldehyde- or carboxylic acid-functional groups or (c) centric cleaved metabolites with additional hydroxyl, aldehyde or carboxyl functionalities, not counting their potential phase-II glucuronidated / sulphated derivatives. Of special interest are the apo-carotenoids, which originate in the intestine and other tissues from carotenoid cleavage by ß-carotene oxygenases 1/2 in a symmetrical / non-symmetrical fashion. These are more water soluble and more electrophilic and, therefore, putative candidates for interactions with transcription factors such as NF-kB and Nrf2, as well as ligands for RAR-RXR nuclear receptor interactions. In this review, we discuss in vivo detected apo-carotenoids, their reported tissue concentrations, and potential associated health effects, focusing exclusively on the human situation and based on quantified / semi-quantified carotenoid metabolites proven to be present in humans.

A transgenic reporter mouse model for in vivo assessment of retinoic acid receptor transcriptional activation.

Background: Vitamin A is essential for a wide range of life processes throughout embryogenesis to adult life. With the aim of developing an in vivo model to monitor retinoic acid receptor (RAR) transactivation real-time in intact animals, we generated transgenic mice carrying a luciferase (luc) reporter gene under the control of retinoic acid response elements (RAREs) consisting of three copies of a direct repeat with five spacing nucleotides (DR5). Methods: Transgenic mice carrying a RARE dependent luciferase reporter flanked with insulator sequence were generated by pronuclear injection. RARE dependent luciferase activity was detected by in vivo imaging or in tissue extracts following manipulations with RAR/retinoid X receptor (RXR) agonists, RAR antagonists or in vitamin A deficient mice. Results: We found a strong induction of luciferase activity in a time and dose dependent manner by retinoic acid as well as RAR agonists, but not by the RXR agonist (using n=4-6 per group; 94 mice). In addition, luciferase activity was strongly reduced in vitamin A-deficient mice (n=6-9; 30 mice). These observations confirm that luciferase activity was controlled by RAR activation in the RARE-luc mouse. Luciferase activity was detectable in various organs, with high activity especially in brain and testis, indicating strong retinoid signalling in these tissues. Conclusion: The RARE-luc transgenic mice, which enabled real-time in vivo assessment of RAR activation, will be useful in understanding the normal physiology of vitamin A, the role of retinoid signalling in pathologies as well as to evaluate pharmacological ligands for RARs.

An immune-shift induced by lycopene; from an eosinophil-dominant type towards an eosinophil/neutrophil-co-dominant type of airway inflammation.

Lycopene as the main carotenoid from tomatoes is known to have beneficial effects on various inflammatory diseases. In mice, lycopene ameliorates asthma symptoms and in human asthmatic patients serum lycopene levels are reduced. To further investigate the immunomodulatory effect of lycopene, first, we used a ragweed pollen extract (RWE)-induced asthma model in mice. In a second approach, we established a RWE-induced asthma model in gerbils, because of a more human-like carotenoid absorption in these animals. In RWE-sensitized/RWE-challenged gerbils (C+) following a basal diet, mainly the number of eosinophils in the broncho-alveolar lavage (BAL) significantly increased, comparable to RWE-sensitized/PBS-challenged gerbils (C-). In RWE-sensitized/PBS-challenged gerbils with lycopene-supplementation (L-), an elevated number of mainly neutrophils, in addition to eosinophils, was detected compared to C-, whereas in RWE-sensitized/RWE-challenged animals with lycopene-supplementation (L+), mainly increased neutrophil numbers in BAL were detected compared to C+. Furthermore, using LC-MS, we determined an array of eicosanoids/docosanoids in the lungs and observed that 5-, 8-lipoxygenase (LOX) and cyclooxygenase (COX) pathways were significantly increased after intranasal RWE-challenge in sensitized mice and just by tendency in gerbils. In PBS- and RWE-challenged animals, lycopene-supplementation significantly raised COX-pathway metabolites. In conclusion, we found that lycopene-supplementation resulted in an increased inflammatory influx of neutrophils in combination with increased COX-pathways metabolites. This pro-inflammatory, pro-neutrophil activity induced by lycopene might be an important shift from allergic asthma towards an inflammatory symptomatic asthma type, though with the potential for resolution.

Plasma Levels of Bioactive Vitamin D and A5 Ligands Positively Correlate with Clinical Atopic Dermatitis Markers.

BACKGROUND: Over the past decade, several controversial studies described a relationship between vitamin D and atopic diseases. Low plasma vitamin D levels or even vitamin D deficiency was associated with an increased incidence of atopic disease, postulating that a higher dietary intake of vitamin D may be a beneficial strategy against atopic diseases such as atopic dermatitis (AD). OBJECTIVE: Our aim was to determine the relationship between plasma 25-hydroxyvitamin D3 (25(OH)D3) levels, the levels of the ligand of the vitamin D receptor (VDR) heterodimerization partner as well as the retinoid X receptor (RXR) and the active vitamin A5 derivative 9-cis-13,14-dihydroretinoic acid (9CDHRA) and AD severity. METHODS/RESULTS: Samples from AD patients (n = 20) and healthy volunteers (n = 20) were assessed. In our study, the frequently measured VDR ligand precursor 25(OH)D3 in addition to the VDR-ligand 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and 9CDHRA displayed no different levels when compared with the plasma of AD patients and healthy volunteers. When performing further correlation studies focusing on AD patients, plasma 25(OH)D3 levels showed a negative correlation with eosinophils in blood (EOS) and SCORing Atopic Dermatitis (SCORAD) values, while 1,25(OH)2D3 and 9CDHRA levels correlated positively with plasma IgE, EOS, and SCORAD values. CONCLUSION: In consequence, the metabolic activation of vitamin D from 25(OH)D3 towards 1,25(OH)2D3 as well as the co-liganding of the RXR by 9CDHRA may be an important signalling mechanism, an important marker for AD development and severity as well as the basis for novel nutritional and pharmaceutical AD treatment options.

Vitamin A5/X controls stress-adaptation and prevents depressive-like behaviors in a mouse model of chronic stress.

9-cis-13,14-dihydroretinoic acid (9CDHRA), acts as an endogenous ligand of the retinoid X receptors (RXRs), and is an active form of a suggested new vitamin, vitamin A5/X. Nutritional-relevance of this pathway as well as its detailed role in vertebrate physiology, remain largely unknown. Since recent GWAS data and experimental studies associated RXR-mediated signaling with depression, we explored here the relevance of RXR and vitamin A5/X-mediated signaling in the control of stress adaptation and depressive-like behaviors in mice. We found that compromised availability of 9CDHRA in Rbp1-/- mice was associated with increased despair in the forced swim and anhedonia in the sucrose preference test. 9CDHRA similarly to synthetic RXR agonist, BMS649, normalized despair behaviors in Rbp1-/- but not Rxrγ-/- mice, supporting involvement of RXR signaling in anti-despair activity of these ligands. Importantly, similarly to BMS649, the 9CDHRA and its nutritional-precursor, 9-cis-13,14-dihydroretinol (vitamin A5/X alcohol), prevented development of depressive-like behaviors in mice exposed to chronic social defeat stress, revealing the beneficial role of RXRs and its endogenous ligand in stress adaptation process. These data point to the need for relevant nutritional, biochemical and pharmacological studies of this signaling pathway in human, both in physiological conditions and in pathologies of stress-related disorders.

Mechanistic aspects of carotenoid health benefits - where are we now?

Dietary intake and tissue levels of carotenoids have been associated with a reduced risk of several chronic diseases, including cardiovascular diseases, type 2 diabetes, obesity, brain-related diseases and some types of cancer. However, intervention trials with isolated carotenoid supplements have mostly failed to confirm the postulated health benefits. It has thereby been speculated that dosing, matrix and synergistic effects, as well as underlying health and the individual nutritional status plus genetic background do play a role. It appears that our knowledge on carotenoid-mediated health benefits may still be incomplete, as the underlying mechanisms of action are poorly understood in relation to human relevance. Antioxidant mechanisms - direct or via transcription factors such as NRF2 and NF-κB - and activation of nuclear hormone receptor pathways such as of RAR, RXR or also PPARs, via carotenoid metabolites, are the basic principles which we try to connect with carotenoid-transmitted health benefits as exemplified with described common diseases including obesity/diabetes and cancer. Depending on the targeted diseases, single or multiple mechanisms of actions may play a role. In this review and position paper, we try to highlight our present knowledge on carotenoid metabolism and mechanisms translatable into health benefits related to several chronic diseases.

Vitamin A5/X, a New Food to Lipid Hormone Concept for a Nutritional Ligand to Control RXR-Mediated Signaling.

Vitamin A is a family of derivatives synthesized from carotenoids acquired from the diet and can be converted in animals to bioactive forms essential for life. Vitamin A1 (all-trans-retinol/ATROL) and provitamin A1 (all-trans-ß,ß-carotene/ATBC) are precursors of all-trans-retinoic acid acting as a ligand for the retinoic acid receptors. The contribution of ATROL and ATBC to formation of 9-cis-13,14-dihydroretinoic acid (9CDHRA), the only endogenous retinoid acting as retinoid X receptor (RXR) ligand, remains unknown. To address this point novel and already known retinoids and carotenoids were stereoselectively synthesized and administered in vitro to oligodendrocyte cell culture and supplemented in vivo (orally) to mice with a following high-performance liquid chromatography-mass spectrometry (HPLC-MS)/UV-Vis based metabolic profiling. In this study, we show that ATROL and ATBC are at best only weak and non-selective precursors of 9CDHRA. Instead, we identify 9-cis-13,14-dihydroretinol (9CDHROL) and 9-cis-13,14-dihydro-ß,ß-carotene (9CDHBC) as novel direct nutritional precursors of 9CDHRA, which are present endogenously in humans and the human food chain matrix. Furthermore, 9CDHROL displayed RXR-dependent promnemonic activity in working memory test similar to that reported for 9CDHRA. We also propose that the endogenous carotenoid 9-cis-ß,ß-carotene (9CBC) can act as weak, indirect precursor of 9CDHRA via hydrogenation to 9CDHBC and further metabolism to 9CDHROL and/or 9CDHRA. In summary, since classical vitamin A1 is not an efficient 9CDHRA precursor, we conclude that this group of molecules constitutes a new class of vitamin or a new independent member of the vitamin A family, named "Vitamin A5/X".

From carotenoid intake to carotenoid blood and tissue concentrations - implications for dietary intake recommendations.

There is uncertainty regarding carotenoid intake recommendations, because positive and negative health effects have been found or are correlated with carotenoid intake and tissue levels (including blood, adipose tissue, and the macula), depending on the type of study (epidemiological vs intervention), the dose (physiological vs supraphysiological) and the matrix (foods vs supplements, isolated or used in combination). All these factors, combined with interindividual response variations (eg, depending on age, sex, disease state, genetic makeup), make the relationship between carotenoid intake and their blood/tissue concentrations often unclear and highly variable. Although blood total carotenoid concentrations <1000 nmol/L have been related to increased chronic disease risk, no dietary reference intakes (DRIs) exist. Although high total plasma/serum carotenoid concentrations of up to 7500 nmol/L are achievable after supplementation, a plateauing effect for higher doses and prolonged intake is apparent. In this review and position paper, the current knowledge on carotenoids in serum/plasma and tissues and their relationship to dietary intake and health status is summarized with the aim of proposing suggestions for a "normal," safe, and desirable range of concentrations that presumably are beneficial for health. Existing recommendations are likewise evaluated and practical dietary suggestions are included.

Topical Vitamin D Receptor Antagonist/Partial-Agonist Treatment Induces Epidermal Hyperproliferation via RARγ Signaling Pathways.

Vitamin D and A derivatives are well-known endogenous substances responsible for skin homeostasis. In this study we topically treated shaved mouse skin with a vitamin D agonist (MC903) or vitamin D antagonist/partial agonist (ZK159222) and compared the changes with acetone (control treatment) treatment for 14 days. Topical treatment with ZK159222 resulted in increased expression of genes involved in retinoic acid synthesis, increased retinoic acid concentrations and increased expression of retinoid target genes. Clustering the altered genes revealed that heparin-binding epidermal growth factor-like growth factor, the main driver of epidermal hyperproliferation, was increased via RARγ-mediated pathways, while other clusters of genes were mainly decreased which were comparable to the changes seen upon activation of the RARα-mediated pathways. In summary, we conclude that epidermal hyperproliferation of mouse skin in response to a topically administered vitamin D receptor antagonist/partial agonist (ZK159222) is induced via increased retinoic acid synthesis, retinoic acid levels and increased RARγ-mediated pathways.

Vitamin D signaling in a mouse allergic sensitization model.

Vitamin D mediated signalling in the skin is discussed controversially for its beneficial or detrimental influence. In this study we examined various factors involved in Vitamin D-mediated signalling in a mouse model for allergic dermatitis with systemic (OVA IP) and systemic plus topical allergic sensitization (OVA IP + EC). We found that the major enzyme responsible for 1,25-Vitamin D3 synthesis, the 1-hydoxylase CYP27B1 (3,6-fold for OVA IP and 2,7-fold for OVA IP + EC), the vitamin D receptor (not altered) and the sensitive Vitamin D-mediated signalling target gene CYP24A1 (65-fold in OVA IP and 726-fold in OVA IP + EC) are upregulated after systemic and systemic plus topical allergic sensitization (OVA IP + EC). In consequence, active Vitamin D-mediated signalling is involved in systemic as well as systemic/topical allergic sensitization in mouse skin.

Saturated and monounsaturated fatty acids in membranes are determined by the gene expression of their metabolizing enzymes SCD1 and ELOVL6 regulated by the intake of dietary fat.

PURPOSE: We investigated the effect of dietary fats on the incorporation of saturated (SAFAs) and monounsaturated dietary fatty acids (MUFAs) into plasma phospholipids and the regulation of the expression of lipid-metabolizing enzymes in the liver. METHODS: Mice were fed different diets containing commonly used dietary fats/oils (coconut fat, margarine, fish oil, sunflower oil, or olive oil) for 4 weeks (n = 6 per diet group). In a second experiment, mice (n = 6 per group) were treated for 7 days with synthetic ligands to activate specific nuclear hormone receptors (NHRs) and the hepatic gene expression of CYP26A1 was investigated. Hepatic gene expression of stearoyl-coenzyme A desaturase 1 (SCD1), elongase 6 (ELOVL6), and CYP26A1 was examined using quantitative real-time PCR (QRT-PCR). Fatty acid composition in mouse plasma phospholipids was analyzed by gas chromatography (GC). RESULTS: We found significantly reduced hepatic gene expression of SCD1 and ELOVL6 after the fish oil diet compared with the other diets. This resulted in reduced enzyme-specific fatty acid ratios, e.g., 18:1n9/18:0 for SCD1 and 18:0/16:0 and 18:1n7/16:1n7 for ELOVL6 in plasma phospholipids. Furthermore, CYP26A1 a retinoic acid receptor-specific target was revealed as a new player mediating the suppressive effect of fish oil-supplemented diet on SCD1 and ELOVL6 hepatic gene expression. CONCLUSION: Plasma levels of MUFAs and SAFAs strongly reflect an altered hepatic fatty acid-metabolizing enzyme expression after supplementation with different dietary fats/oils.

Retinol Saturase Knock-Out Mice are Characterized by Impaired Clearance of Apoptotic Cells and Develop Mild Autoimmunity.

Apoptosis and the proper clearance of apoptotic cells play a central role in maintaining tissue homeostasis. Previous work in our laboratory has shown that when a high number of cells enters apoptosis in a tissue, the macrophages that engulf them produce retinoids to enhance their own phagocytic capacity by upregulating several phagocytic genes. Our data indicated that these retinoids might be dihydroretinoids, which are products of the retinol saturase (RetSat) pathway. In the present study, the efferocytosis of RetSat-null mice was investigated. We show that among the retinoid-sensitive phagocytic genes, only transglutaminase 2 responded in macrophages and in differentiating monocytes to dihydroretinol. Administration of dihydroretinol did not affect the expression of the tested genes differently between differentiating wild type and RetSat-null monocytes, despite the fact that the expression of RetSat was induced. However, in the absence of RetSat, the expression of numerous differentiation-related genes was altered. Among these, impaired production of MFG-E8, a protein that bridges apoptotic cells to the αvß3/ß5 integrin receptors of macrophages, resulted in impaired efferocytosis, very likely causing the development of mild autoimmunity in aged female mice. Our data indicate that RetSat affects monocyte/macrophage differentiation independently of its capability to produce dihydroretinol at this stage.

Apo-14´-Carotenoic Acid Is a Novel Endogenous and Bioactive Apo-Carotenoid.

Carotenoids can be metabolized to various apo-carotenoids and retinoids. Apo-15´-carotenoic acid (retinoic acid, RA) is a potent activator of the retinoic acid receptor (RAR) in its all-trans- (ATRA) and 9-cis- (9CRA) forms. In this study we show firstly, that apo-14´-carotenoic acid (A14CA), besides retinoic acids, is present endogenously and with increased levels in the human organism after carrot juice supplementation rich in ß-carotene. All-trans-A14C (ATA14CA) is just a moderate activator of RAR-transactivation in reporter cell lines but can potently activate retinoic acid response element (RARE)-mediated signalling in DR5/RARE-reporter mice and potently increase retinoid-reporter target gene expression in ATA14CA-supplemented mice and treated MM6 cells. Further metabolism to all-trans-13,14-dihydroretinoic acid (ATDHRA) may be the key for its potent effects on retinoid target gene activation in ATA14CA-treated MM6 cells and in liver of supplemented mice. We conclude that besides RAs, there are alternative ways to activate RAR-response pathways in the mammalian organism. ATA14CA alone and in combination with its metabolite ATDHRA may be an alternative pathway for potent RAR-mediated signalling.

Alternative retinoid X receptor (RXR) ligands.

Retinoid X receptors (RXRs) control a wide variety of functions by virtue of their dimerization with other nuclear hormone receptors (NRs), contributing thereby to activities of different signaling pathways. We review known RXR ligands as transcriptional modulators of specific RXR-dimers and the associated biological processes. We also discuss the physiological relevance of such ligands, which remains frequently a matter of debate and which at present is best met by member(s) of a novel family of retinoids, postulated as Vitamin A5. Through comparison with other natural, but also with synthetic ligands, we discuss high diversity in the modes of ligand binding to RXRs resulting in agonistic or antagonistic profiles and selectivity towards specific subtypes of permissive heterodimers. Despite such diversity, direct ligand binding to the ligand binding pocket resulting in agonistic activity was preferentially preserved in the course of animal evolution pointing to its functional relevance, and potential for existence of other, species-specific endogenous RXR ligands sharing the same mode of function.

ß-Carotene in the human body: metabolic bioactivation pathways - from digestion to tissue distribution and excretion.

ß-Carotene intake and tissue/blood concentrations have been associated with reduced incidence of several chronic diseases. Further bioactive carotenoid-metabolites can modulate the expression of specific genes mainly via the nuclear hormone receptors: retinoic acid receptor- and retinoid X receptor-mediated signalling. To better understand the metabolic conversion of ß-carotene, inter-individual differences regarding ß-carotene bioavailability and bioactivity are key steps that determine its further metabolism and bioactivation and mediated signalling. Major carotenoid metabolites, the retinoids, can be stored as esters or further oxidised and excreted via phase 2 metabolism pathways. In this review, we aim to highlight the major critical control points that determine the fate of ß-carotene in the human body, with a special emphasis on ß-carotene oxygenase 1. The hypothesis that higher dietary ß-carotene intake and serum level results in higher ß-carotene-mediated signalling is partly questioned. Alternative autoregulatory mechanisms in ß-carotene / retinoid-mediated signalling are highlighted to better predict and optimise nutritional strategies involving ß-carotene-related health beneficial mediated effects.

Transcriptomic and lipidomic profiling of eicosanoid/docosanoid signalling in affected and non-affected skin of human atopic dermatitis patients.

Lipoxygenases (LOX) and cyclooxygenase (COX) are the main enzymes for PUFA metabolism to highly bio-active prostaglandins, leukotrienes, thromboxanes, lipoxins, resolvins and protectins. LOX and COX pathways are important for the regulation of pro-inflammatory or pro-resolving metabolite synthesis and metabolism for various inflammatory diseases such as atopic dermatitis (AD). In this study, we determined PUFAs and PUFA metabolites in serum as well as affected and non-affected skin samples from AD patients and the dermal expression of various enzymes, binding proteins and receptors involved in these LOX and COX pathways. Decreased EPA and DHA levels in serum and reduced EPA level in affected and non-affected skin were found; in addition, n3/n6-PUFA ratios were lower in affected and non-affected skin and serum. Mono-hydroxylated PUFA metabolites of AA, EPA, DHA and the sum of AA, EPA and DHA metabolites were increased in affected and non-affected skin. COX1 and ALOX12B expression, COX and 12/15-LOX metabolites as well as various lipids, which are known to induce itch (12-HETE, LTB4, TXB2, PGE2 and PGF2) and the ratio of pro-inflammatory vs pro-resolving lipid mediators in non-affected and affected skin as well as in the serum of AD patients were increased, while n3/n6-PUFAs and metabolite ratios were lower in non-affected and affected AD skin. Expression of COX1 and COX-metabolites was even higher in non-affected AD skin. To conclude, 12/15-LOX and COX pathways were mainly upregulated, while n3/n6-PUFA and metabolite ratios were lower in AD patients skin. All these parameters are a hallmark of a pro-inflammatory and non-resolving environment in affected and partly in non-affected skin of AD patients.