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.

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.

β-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 β-carotene, inter-individual differences regarding β-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 β-carotene in the human body, with a special emphasis on β-carotene oxygenase 1. The hypothesis that higher dietary β-carotene intake and serum level results in higher β-carotene-mediated signalling is partly questioned. Alternative autoregulatory mechanisms in β-carotene / retinoid-mediated signalling are highlighted to better predict and optimise nutritional strategies involving β-carotene-related health beneficial mediated effects.

The retinoid X receptors (RXRs) are ligand-activated transcription factors which heterodimerize with a number of nuclear hormone receptors, thereby controlling a variety of (patho)-physiological processes. Although synthetic RXR ligands are developed for the treatment of various diseases, endogenous ligand(s) for these receptors have not been conclusively identified. We show here that mice lacking cellular retinol binding protein (Rbp1-/-) display memory deficits reflecting compromised RXR signaling. Using HPLC-MS and chemical synthesis we identified in Rbp1-/- mice reduced levels of 9-cis-13,14-dihydroretinoic acid (9CDHRA), which acts as an RXR ligand since it binds and transactivates RXR in various assays. 9CDHRA rescues the Rbp1-/- phenotype similarly to a synthetic RXR ligand and displays similar transcriptional activity in cultured human dendritic cells. High endogenous levels of 9CDHRA in mice indicate physiological relevance of these data and that 9CDHRA acts as an endogenous RXR ligand. Daily nutrition, in addition to being a source of energy, contains micronutrients, a class of nutrients including vitamins which are essential for life and which act by orchestrating a vast number of developmental and physiological processes. During metabolism, micronutrients are frequently transformed into their bioactive forms. Nuclear hormone receptors are a family of proteins functioning as ligand-regulated transcription factors which can sense such bioactive molecules and translate those signals into transcriptional, adaptive responses. Retinoid X receptors occupy a central place in this signaling as they directly interact, and thereby control, activities of several nuclear hormone receptors. We report here the identification of a novel bioactive form of vitamin A, which is the first endogenous form of this vitamin capable to bind and activate retinoid X receptors. Accordingly, we show that this single molecule displays biological activity similar to synthetic agonists of retinoid X receptors and coordinates transcriptional activities of several nuclear receptor signaling pathways. Those findings may have immediate biomedical implications, as retinoid X receptors are implicated in the control of a number of physiological functions and their pathology.

Aggressive periodontitis (AgP) is a rapidly progressing type of periodontal disease in otherwise healthy individuals which causes destruction of the supporting tissues of the teeth. The disease is initiated by pathogenic bacteria in the dental biofilm, and the severity of inflammation and attachment loss varies with the host response. Recently, there has been an increased interest in determining the role of lipid mediators in inflammatory events and the concept of pro-inflammatory and pro-resolution lipid mediators has been brought into focus also in periodontal disease. The present study aimed to determine the profile of omega-3 or n3- as well as omega-6 or n6- polyunsaturated fatty acids (PUFAs) and PUFA-metabolites of linoleic acid, arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in gingival crevicular fluid (GCF), saliva and serum in AgP patients and healthy controls. In total, 60 selected n3- and n6-PUFAs and various PUFA metabolites were measured using high performance liquid chromatography-tandem electrospray ionisation mass spectrometry (HPLC-ESI-MS-MS). Of these, 51 could be quantified in this study. The concentrations of the majority were low in saliva samples compared with serum and GCF, but were mainly higher in AgP patients compared with healthy controls in all three kinds of sample. Ratios of n3- to n6-PUFAs (DHA + EPA)/AA were significantly lower in the GCF of AgP patients than in the healthy controls. Furthermore, various ratios of the direct precursors of the pro-resolution lipid mediators (precursors of resolvins and protectins) were calculated against the precursors of mainly pro-inflammatory lipid mediators. These ratios were mainly lower in GCF and saliva of AgP patients, compared with healthy controls, but only reached significance in GCF (P<0.05). To conclude, the ratios of precursors of pro-resolution/pro-inflammatory lipid mediators seem to be more relevant for describing the disease status of AgP than the concentration of specific lipid mediators.

Carotenoids and retinoids are groups of nutritionally-relevant compounds present in many foods of plant origin (carotenoids) and animal origin (mainly retinoids). Their levels in human subjects vary depending on the diversity and amount of the individual's nutrient intake. Some carotenoids and retinoids have been investigated for their effects on the immune system bothin vitroandin vivo. It has been shown that retinoids have the potential to mediate or induce proliferative and differentiating effects on several immune-competent cells, and various carotenoids are known to be inducers of immune function. The immune-modulating effects of retinoids have been well documented, while the effects of carotenoids on the immune system have not been investigated as extensively, because little is known about their molecular mechanism of action. The present review will mainly focus on the molecular mechanism of action of retinoids and particularly carotenoids, their nutritional origin and intake, their transfer from the maternal diet to the child and their effects or potential effects on the developing immune system.