Apo-10'-lycopenoic acid (apo-10-lycac), a metabolite of lycopene, has been shown to possess potent biological activities, notably via the retinoic acid receptors (RAR). In the current study, its impact on adipose tissue and adipocytes was studied. In microarray experiments, the set of genes regulated by apo-10-lycac treatments was compared to the set of genes regulated by all-trans retinoic acid (ATRA), the natural ligand of RAR, in adipocytes. Approximately 27.5% of the genes regulated by apo-10-lycac treatments were also regulated by ATRA, suggesting a common ability in terms of gene expression modulation, possibly via RAR transactivation. The physiological impact of apo-10-lycac on adipose tissue biology was evaluated. If it had no effect on adipogenesis in the 3T3-L1 cell model, this metabolite may have a preventative effect against inflammation, by preventing the increase in the inflammatory markers, interleukin 6 and interleukin 1β in various dedicated models. The ability of apo-10-lycac to transactivate the RAR and to modulate the transcription of RAR target gene was brought in vivo in adipose tissue. While apo-10-lycac was not detected in adipose tissue, a metabolite with a molecular weight with 2Da larger mass was detected, suggesting that a dihydro-apo-10'-lycopenoic acid, may be present in adipose tissue and that this compound could active or may lead to further active RAR-activating apo-10-lycac metabolites. Since apo-10-lycac treatments induce anti-inflammatory effects in adipose tissue but do not inhibit adipogenesis, we propose that apo-10-lycac treatments and its potential active metabolites in WAT may be considered for prevention strategies relevant for obesity-associated pathologies.

Tomato is the main dietary source of lycopene, a carotenoid that is known to have protective effects on health and whose metabolites could also be involved in bioactivity. Herein we present the first organic synthesis of two potentially bioactive lycopene metabolites, namely, 10'-apolycopen-10'-oic acid (6) and 14'-apolycopen-14'-oic acid (13), which were obtained in their (all-E) stereoisomeric forms using Wittig and Horner-Wadsworth-Emmons type coupling reactions. Both molecules are shown to up-regulate the carotenoid asymmetric cleavage enzyme BCO2 while having no effect on BCO1 expression.

Lycopene, the main pigment of tomato, is known to have protective effects on health. Its metabolites could also be involved in these effects. Potentially bioactive lycopene metabolites namely apo-10 0 -lycopenol, apo-10 0 -lycopenal, apo-14 0 -lycopenol, apo-14 0 -lycopenal, and apo-11-lycopenoids with alcohol, carboxylic acid, aldehyde and ethyl ester terminal groups were obtained by organic synthesis as (all-E) stereoisomers using HWE condensation reactions. The ability of (all-E)-lycopene and the synthesized apo-lycopenoids to inhibit lipid peroxidation was tested in a chemical model of postprandial oxidative stress in the gastric compartment. Oxidative stress was generated by metmyoglobin, the main form of dietary iron (from red meat), which is able to catalyse the peroxidation of linoleic acid under mildly acidic conditions. In this model, apo-6 0 -lycopenal and apo-8 0 -lycopenal were better inhibitors of lipid peroxidation than (all-E)-lycopene itself. For the apo-lycopenoids, a long unsaturated chain and a terminal carboxylic acid group both favour the antioxidant activity. The short-chain apo-lycopenoic acid, apo-14 0 -lycopenoic acid, was shown to behave like a hydrophilic antioxidant, i.e. by reducing hypervalent iron forms of metmyoglobin. Thus, besides the polyene chain length, the terminal group of the apo-lycopenoids is expected to deeply influence the lipophilic/hydrophilic balance of the molecule (and consequently its distribution between the aqueous and lipid phases) and its affinity for the heme cavity. It can thus be concluded that the polyene chain length and terminal group are two important parameters modulating the mechanism by which apo-lycopenoids express their antioxidant activity.

The Eph tyrosine kinase receptors and their ephrin ligands play a central role in human cancer as their deregulated expression induces tumorigenesis with aggressive phenotypes. To evaluate their potential contribution to EphA2-ephrinA1 modulation, several colonic catabolites of dietary (poly)phenolics, known to be generated in vivo, were screened using an ELISA-based binding assay. Some of the catabolites inhibited the binding in a dose-dependent manner (IC(50) values from 0.26 to 43 μM). Functional studies on prostate adenocarcinoma cells revealed that pyrogallol and protocatechuic acid specifically antagonized ephrinA1-Fc-induced EphA2 phosphorylation at concentrations that were not cytotoxic. The active concentrations of pyrogallol appear to be close to what can be reached in vivo under physiological conditions. Finally, because of the roles played by the Eph-ephrin system not only in cancer development but also in neurodegeneration and diabetes, pyrogallol and protocatechuic acid are candidates for more detailed functional studies to elucidate their role in these pathophysiological processes.

Lycopene is the red pigment in tomatoes and tomato products and is an important dietary carotenoid found in the human organism. Lycopene-isomers, oxidative lycopene metabolites and apo-lycopenoids are found in the food matrix. Lycopene intake derived from tomato consumption is associated with alteration of lipid metabolism and a lower incidence of cardiovascular diseases (CVD). Lycopene is mainly described as a potent antioxidant but novel studies are shifting towards its metabolites and their capacity to mediate nuclear receptor signalling. Di-/tetra-hydro-derivatives of apo-10´-lycopenoic acid and apo-15´-lycopenoic acids are potential novel endogenous mammalian lycopene metabolites which may act as ligands for nuclear hormone mediated activation and signalling. In this review, we postulate that complex lycopene metabolism results in various lycopene metabolites which have the ability to mediate transactivation of various nuclear hormone receptors like RARs, RXRs and PPARs. A new mechanistic explanation of how tomato consumption could positively modulate inflammation and lipid metabolism is discussed.