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In mammalian cells, two cellular organelles, mitochondria and peroxisomes, share the ability to degrade fatty acid chains. Although each organelle harbors its own fatty acid β-oxidation pathway, a distinct mitochondrial system feeds the oxidative phosphorylation pathway for ATP synthesis. At the same time, the peroxisomal β-oxidation pathway participates in cellular thermogenesis. A scientific milestone in 1965 helped discover the hepatomegaly effect in rat liver by clofibrate, subsequently identified as a peroxisome proliferator in rodents and an activator of the peroxisomal fatty acid β-oxidation pathway. These peroxisome proliferators were later identified as activating ligands of Peroxisome Proliferator-Activated Receptor α (PPARα), cloned in 1990. The ligand-activated heterodimer PPARα/RXRα recognizes a DNA sequence, called PPRE (Peroxisome Proliferator Response Element), corresponding to two half-consensus hexanucleotide motifs, AGGTCA, separated by one nucleotide. Accordingly, the assembled complex containing PPRE/PPARα/RXRα/ligands/Coregulators controls the expression of the genes involved in liver peroxisomal fatty acid β-oxidation. This review mobilizes a considerable number of findings that discuss miscellaneous axes, covering the detailed expression pattern of PPARα in species and tissues, the lessons from several PPARα KO mouse models and the modulation of PPARα function by dietary micronutrients.

The Mediterranean diet is a central element of a healthy lifestyle, where polyphenols play a key role due to their anti-oxidant properties, and for some of them, as nutripharmacological compounds capable of preventing a number of diseases, including cancer. Due to the high prevalence of intestinal cancer (ranking second in causing morbidity and mortality), this review is focused on the beneficial effects of selected dietary phytophenols, largely present in Mediterranean cooking: apigenin, curcumin, epigallocatechin gallate, quercetin-rutine, and resveratrol. The role of the Mediterranean diet in the prevention of colorectal cancer and future perspectives are discussed in terms of food polyphenol content, the effectiveness, the plasma level, and the importance of other factors, such as the polyphenol metabolites and the influence of the microbiome. Perspectives are discussed in terms of microbiome-dependency of the brain-second brain axis. The emergence of polyphenol formulations may strengthen the efficiency of the Mediterranean diet in the prevention of cancer.

The Mediterranean diet is associated with health benefits due to bioactive compounds such as polyphenols. The biological activities of three polyphenols (quercetin (QCT), resveratrol (RSV), apigenin (API)) were evaluated in mouse neuronal N2a cells in the presence of 7-ketocholesterol (7KC), a major cholesterol oxidation product increased in patients with age-related diseases, including neurodegenerative disorders. In N2a cells, 7KC (50 &micro, M, 48 h) induces cytotoxic effects characterized by an induction of cell death. When associated with RSV, QCT and API (3.125, 6.25 &micro, M), 7KC-induced toxicity was reduced. The ability of QCT, RSV and API to prevent 7KC-induced oxidative stress was characterized by a decrease in reactive oxygen species (ROS) production in whole cells and at the mitochondrial level, by an attenuation of the increase in the level and activity of catalase, by attenuating the decrease in the expression, level and activity of glutathione peroxidase 1 (GPx1), by normalizing the expression, level and activity of superoxide dismutases 1 and 2 (SOD1, SOD2), and by reducing the decrease in the expression of nuclear erythroid 2-like factor 2 (Nrf2) which regulates antioxidant genes. QCT, RSV and API also prevented mitochondrial dysfunction in 7KC-treated cells by counteracting the loss of mitochondrial membrane potential (&Psi, &Delta, m) and attenuating the decreased gene expression and/or protein level of AMP-activated protein kinase &alpha, (AMPK&alpha, ), sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor &gamma, coactivator-1&alpha, (PGC-1&alpha, ) implicated in mitochondrial biogenesis. At the peroxisomal level, QCT, RSV and API prevented the impact of 7KC by counteracting the decrease in ATP binding cassette subfamily D member (ABCD)3 (a peroxisomal mass marker) at the protein and mRNA levels, as well as the decreased expresssion of genes associated with peroxisomal biogenesis (Pex13, Pex14) and peroxisomal &beta, oxidation (Abcd1, Acox1, Mfp2, Thiolase A). The 7KC-induced decrease in ABCD1 and multifunctional enzyme type 2 (MFP2), two proteins involved in peroxisomal &beta, oxidation, was also attenuated by RSV, QCT and API. 7KC-induced cell death, which has characteristics of apoptosis (cells with fragmented and/or condensed nuclei, cleaved caspase-3, Poly(ADP-ribose) polymerase (PARP) fragmentation) and autophagy (cells with monodansyl cadaverine positive vacuoles, activation of microtubule associated protein 1 light chain 3&ndash, I (LC3-I) to LC3-II, was also strongly attenuated by RSV, QCT and API. Thus, in N2a cells, 7KC induces a mode of cell death by oxiapoptophagy, including criteria of OXIdative stress, APOPTOsis and autoPHAGY, associated with mitochondrial and peroxisomal dysfunction, which is counteracted by RSV, QCT, and API reinforcing the interest for these polyphenols in prevention of diseases associated with increased 7KC levels.

Resveratrol is one of the best known polyphenol. While its effect on endothelial blood vessel cells, cancer cells, inflammatory processes and neurodegenerative events is well documented, only little is established on the metabolic implication of this phytophenol, particularly on skeletal muscle cells. Here, we report the effect of resveratrol on mouse skeletal muscle cells (C2C12) by measurement of cell proliferation, expression of metabolic genes and their transcription factor dependency, and modulation of non-coding microRNA expression. Resveratrol slightly decreases cell proliferation, while it up regulates PGC-1α a PPAR transcription factor co-activator involved in the control of metabolic genes. It also modulates microRNAs which are expressed in skeletal muscle cells and are involved in differentiation or contraction-relaxation. Results put forward new regulatory properties of resveratrol on skeletal muscles and highlight new potential applications of this molecule in muscle performances.

The cardioprotective effect of moderate and regular wine consumption in primary prevention has been well documented. The goal of the present investigation..

In addition to the traditional treatments of cancer and cancer prevention, the use of natural compounds, especially those found in food, should be considered. To clarify if resveratrol has the potential for cancer prevention and the possibility of use in therapy, the following must be taken into account: data from epidemiology, clinical protocol (case and control), preclinical studies (lab animals), use of established cell lines as models of cancer cells, test tube assays (enzymes activities), and requirements of nanotechnologies in order to discover new drugs to fight cancer. From this perspective and future expected advances, more information is needed such as improved efficacy, methods of application, and the synergistic sensitization of resveratrol as an adjuvant. In addition, resveratrol nanoformulation is considered to overcome its weak bioavailability.

Several of the peroxisomal neurodegenerative disorders are the consequence of a specific deficiency of an enzyme or a transporter involved in peroxisomal beta-oxidation of very long chain fatty acids [1,2]. One of the hallmarks in these peroxisomal rare neurodegenerative diseases and in other common demyelinating disorders is the accompanying oxidative damage and neuroinflammation [3]. Compelling data indicates that oxidative stress can activate microglia leading to the overproduction of pro-inflammatory molecules [4,5]. Thus, targeting oxidative stress to limit neuroinflammation may open a new pharmacological therapy window for these still incurable devastating peroxisomal diseases. Here, we present different natural (resveratrol) [6] and synthetic (organoselenides) [7] antioxidant compounds for their capacity of scavenging oxidative stress and in the perspective therapeutic use against oxidative damage in peroxisomal disorders.

The health benefits of moderate wine consumption have been extensively studied during the last few decades. Some studies have demonstrated protective associations between moderate drinking and several diseases including oral cavity cancer (OCC). However, due to the various adverse effects related to ethanol content, the recommendation of moderate wine consumption has been controversial. The polyphenolic components of wine contribute to its beneficial effects with different biological pathways, including antioxidant, lipid regulating and anti-inflammatory effects. On the other hand, in the oral cavity, ethanol is oxidized to form acetaldehyde, a metabolite with genotoxic properties. This review is a critical compilation of both the beneficial and the detrimental effects of wine consumption on OCC.

The brain, which is a cholesterol-rich organ, can be subject to oxidative stress in a variety of pathophysiological conditions, age-related diseases and some rare pathologies. This can lead to the formation of 7-ketocholesterol (7KC), a toxic derivative of cholesterol mainly produced by auto-oxidation. So, preventing the neuronal toxicity of 7KC is an important issue to avoid brain damage. As there are numerous data in favor of the prevention of neurodegeneration by the Mediterranean diet, this study aimed to evaluate the potential of a series of polyphenols (resveratrol, RSV, quercetin, QCT, and apigenin, API) as well as &omega, 3 and &omega, 9 unsaturated fatty acids (&alpha, linolenic acid, ALA, eicosapentaenoic acid, EPA, docosahexaenoic acid, DHA, and oleic acid, OA) widely present in this diet, to prevent 7KC (50 &micro, M)-induced dysfunction of N2a neuronal cells. When polyphenols and fatty acids were used at non-toxic concentrations (polyphenols: &le, 6.25 &micro, M, fatty acids: &le, 25 &micro, M) as defined by the fluorescein diacetate assay, they greatly reduce 7KC-induced toxicity. The cytoprotective effects observed with polyphenols and fatty acids were comparable to those of &alpha, tocopherol (400 &micro, M) used as a reference. These polyphenols and fatty acids attenuate the overproduction of reactive oxygen species and the 7KC-induced drop in mitochondrial transmembrane potential (&Delta, &Psi, m) measured by flow cytometry after dihydroethidium and DiOC6(3) staining, respectively. Moreover, the studied polyphenols and fatty acids reduced plasma membrane permeability considered as a criterion for cell death measured by flow cytometry after propidium iodide staining. Our data show that polyphenols (RSV, QCT and API) as well as &omega, 9 unsaturated fatty acids (ALA, EPA, DHA and OA) are potent cytoprotective agents against 7KC-induced neurotoxicity in N2a cells. Their cytoprotective effects could partly explain the benefits of the Mediterranean diet on human health, particularly in the prevention of neurodegenerative diseases.

This review presents recent evidence implicating microRNAs (miRNAs) in the beneficial effects of resveratrol (trihydroxystilbene), a nonflavonoid plant polyphenol, with emphasis on its anti-inflammatory effects. Many diseases and pathologies have been linked, directly or indirectly, to inflammation. These include infections, injuries, atherosclerosis, diabetes mellitus, obesity, cancer, osteoarthritis, age-related macular degeneration, demyelination, and neurodegenerative diseases. Resveratrol can both decrease the secretion of proinflammatory cytokines (e.g., IL-6, IL-8, and TNF-α) and increase the production of anti-inflammatory cytokines; it also decreases the expression of adhesion proteins (e.g., ICAM-1) and leukocyte chemoattractants (e.g., MCP-1). Resveratrol's primary targets appear to be the transcription factors AP-1 and NF-κB, as well as the gene COX2. Although no mechanistic link between any particular miRNA and resveratrol has been identified, resveratrol effects depend at least in part upon the modification of the expression of a variety of miRNAs that can be anti-inflammatory (e.g., miR-663), proinflammatory (e.g., miR-155), tumor suppressing (e.g., miR-663), or oncogenic (e.g., miR-21).

International audience; Resveratrol is a well-known phenolic stilbene because of its presence in several edible plants and its proposed properties that are beneficial to human health [...].

To clarify appropriateness of current claims for health and wellness virtues of argan oil, studies were conducted in inflammatory states. LPS induces inflammation with reduction of PGC1-αsignaling and energy metabolism. Argan oil protected the liver against LPS toxicity and interestingly enough preservation of peroxisomal acyl-CoA oxidase type 1 (ACOX1) activity against depression by LPS. This model of LPS-driven toxicity circumvented by argan oil along with a key anti-inflammatory role attributed to ACOX1 has been here transposed to model aging. This view is consistent with known physiological role of ACOX1 in yielding precursors of specialized proresolving mediators (SPM) and with characteristics of aging and related disorders including reduced PGC1-αfunction and improvement by strategies rising ACOX1 (via hormonal gut FGF19 and nordihydroguaiaretic acid in metabolic syndrome and diabetes conditions) and SPM (neurodegenerative disorders, atherosclerosis, and stroke). Delay of aging to resolve inflammation results from altered production of SPM, SPM improving most aging disorders. The strategic metabolic place of ACOX1, upstream of SPM biosynthesis, along with ability of ACOX1 preservation/induction and SPM to improve aging-related disorders and known association of aging with drop in ACOX1 and SPM, all converge to conclude that ACOX1 represents a previously unsuspected and currently emerging antiaging protein.

Inflammation (or inflammatory reaction) is the response to body aggression by a pathogen agent, an allergen, a toxic compound, a tissue lesion, etc.[...]

Since the first report by Rhodin in 1954, our knowledge on mammalian microbodies/peroxisomes has known several periods. An initial two decades period (1954–1973) has contributed to the biochemical individualisation of peroxisomes as a new class of subcellular organelles (de Duve, 1965). The corresponding research period failed to define a clear role of mammalian peroxisomes in vital functions and intermediary metabolism, explaining why feeling that peroxisomes might be in the human cell oddities has prevailed during several decades. The period standing from 1973 to nowadays has progressively removed this cell oddity view of peroxisomes by highlighting vital function and metabolic role of peroxisomes in health and disease along with genetic and metabolic regulation of peroxisomal protein content, organelle envelope formation and protein signal targeting mechanisms. Research on peroxisomes and their response to various drugs and metabolites, dietary and physiological conditions has also played a key role in the discovery of peroxisome proliferator activated receptors (PPARs) belonging to the nuclear hormone receptor superfamily and for which impact in science and medicine goes now by far beyond that of the peroxisomes.

Grape polyphenols are abundant. They play essential roles in the plant's life, particularly in defence mechanisms. Moreover, the grape, fresh or dried, is a widely consumed fruit by humans, as are its by-products, grape juice and wine. They also contain vast and highly varied quantities of polyphenols. Like other phytophenols, grape and wine resveratrol is considered a protective micronutrient. Resveratrol is a well known antioxidant, for example, a protector of low-density lipoproteins against oxidation. Its applications are therefore highly varied. Research supports the idea that wine consumed regularly, without excess, is a natural biological product possesses preventive properties, and not only well-known properties against vascular diseases (illustrated by the so-called French paradox). At least in experimental models so far, resveratrol prevents infections, inflammation, neurodegenerative diseases, and cancer. This review addresses whether the pro-longevity properties of resveratrol are preserved in the human species. If such is the case, it will be possible to imagine new ways of eating based on natural foods, with or without supplements, based on resveratrol. On the other hand, studies such as ours are investigating the synergies between resveratrol and some of the many polyphenols found in wine. These studies should fill in the gaps between the study of a molecule tested in isolation or in a binary system (e.g., with alcohol) and this same molecule in its biological context.

Besides synthesizing nutritive substances (proteins, fats and carbohydrates) for energy and growth, plants produce numerous non-energetic so-called secondary metabolites (mainly polyphenols) that allow them to protect themselves against infections and other types of hostile environments. Interestingly, these polyphenols often provide cells with valuable bioactive properties for the maintenance of their functions and homeostasis (signaling, gene regulation, protection against acquired or infectious diseases, etc.) both in humans and animals. Namely, from a nutritional point of view, and based on epidemiological data, it is now well accepted that the regular consumption of green vegetables, fruits and fibers has protective effects against the onset of cancer as well as of inflammatory, neurodegenerative, metabolic and cardiovascular diseases, and consequently increases the overall longevity. In particular, grapevine plants produce large amounts of a wide variety of polyphenols. The most prominent of those-resveratrol-has been shown to impair or delay cardiovascular alterations, cancer, inflammation, aging, etc. Until recently, the molecular bases of the pleiotropic effects of resveratrol remained largely unclear despite numerous studies on a variety of signaling pathways and the transcriptional networks that they control. However, it has been recently proposed that the protective properties of resveratrol may arise from its modulation of small non-coding regulatory RNAs, namely microRNAs. The aim of this review is to present up-to-date data on the control of microRNA expression by dietary phytophenols in different types of human cells, and their impact on cell differentiation, cancer development and the regulation of the inflammatory response.

Pseudo-neonatal adrenoleukodystrophy (P-NALD) is a neurodegenerative disorder caused by acyl-CoA oxidase 1 (ACOX1) deficiency with subsequent impairment of peroxisomal fatty acid β-oxidation, accumulation of very long chain fatty acids (VLCFAs) and strong reduction in peroxisome abundance. Increase in peroxisome number has been previously suggested to improve peroxisomal disorders, and in this perspective, the present work was aimed at exploring whether modulation of peroxisomes abundance could be achieved in P-NALD fibroblasts. Here we showed that treatment with the natural Argan oil induced peroxisome proliferation in P-NALD fibroblasts. This induction was independent on activations of both nuclear receptor PPARα and its coactivator PGC-1α. Lipopolysaccharides (LPS) treatment, which caused inflammation, induced also a peroxisome proliferation that, in contrast, was dependent on activations of PPARα and PGC-1α. By its ability to induce peroxisome proliferation, Argan oil is suggested to be of potential therapeutic use in patients with P-NALD.

International audience; State of the art. Osteoarthritis (OA) is a chronic articular disease characterized by cartilage degradation and osteophyte formation. OA physiopathology is multifactorial and involves mechanical and hereditary factors. So far, there is neither preventive medicine to delay cartilage breakdown nor curative treatment. Objectives. To investigate pro-inflammatory paracrine interactions between human primary chondrocytes and macrophages following interleukin-1-β (IL-1β) treatment; to evaluate the molecular mechanism responsible for the inhibitory effect of resveratrol. Results. The activation of NF-κB in chondrocytes by IL-1β induced IL-6 secretion. The latter will then activate STAT3 protein in macrophages. Moreover, STAT3 was able to positively regulate IL-6 secretion, as confirmed by the doubling level of IL-6 in the coculture compared to macrophage monoculture. These experiments confirm the usefulness of the coculture model in the inflammatory arthritis-linked process as a closer biological situation to the synovial joint than separated chondrocytes and macrophages. Il also demonstrated the presence of an inflammatory amplification loop induced by IL-1β. Resveratrol showed a strong inhibitory effect on the pro-inflammatory marker secretion. The decrease of IL-6 secretion is dependent on the NFκB inhibition in the chondrocytes. Such reduction of the IL-6 level can limit STAT3 activation in the macrophages, leading to the interruption of the inflammatory amplification loop. Conclusion. These results increase our understanding of the anti-inflammatory actions of resveratrol and open new potential approaches to prevent and treat osteoarthritis.

International audience; Resveratrol (3,4,5 trihydroxy-trans-stilbene) is one of the best known phytophenols with pleiotropic properties. It is a phytoalexin produced by vine and it leads to the stimulation of natural plant defenses but also exhibits many beneficial effects in animals and humans by acting on a wide range of organs and tissues. These include the prevention of cardiovascular diseases, anti-cancer potential, neuroprotective effects, homeostasia maintenance, aging delay and a decrease in inflammation. Age-related macular degeneration (AMD) is one of the main causes of deterioration of vision in adults in developed countries This review deals with resveratrol and ophthalmology by focusing on the antioxidant, anti-inflammatory, and anti-angiogenic effects of this molecule. The literature reports that resveratrol is able to act on various cell types of the eye by increasing the level of natural antioxidant enzymatic and molecular defenses. Resveratrol anti-inflammatory effects are due to its capacity to limit the expression of pro-inflammatory factors, such as interleukins and prostaglandins, and also to decrease the chemo-attraction and recruitment of immune cells to the inflammatory site. In addition to this, resveratrol was shown to possess anti-VEGF effects and to inhibit the proliferation and migration of vascular endothelial cells. Resveratrol has the potential to be used in a range of human ocular diseases and conditions, based on animal models and in vitro experiments.

Resveratrol (RSV), a plant-derived stilbene, induces cell death in Hodgkin lymphoma (HL)-derived L-428 cells in a dose-dependent manner (IC50 = 27 μM, trypan blue exclusion assay). At a lower range (25 μM), RSV treatment for 48 hr causes arrest in the S-phase of the cell cycle, while at a higher concentration range (50 μM), apoptosis can be detected, with activation of caspase-3. The histone/protein deacetylase SIRT1 has been described as a putative target of RSV action in other model systems, even though its role in cancer cells is still controversial. Here we show that RSV, at both concentration ranges, leads to a marked increase in p53, while a decrease of SIRT1 expression level, as well as enzyme activity, only occurred at the higher concentration range. Concomitantly, however, treatments at both concentration ranges resulted in a marked increase in K373-acetylated p53 and lysine-acetylated FOXO3a. Immunohistochemical stainings of human lymph nodes show a preferential distribution of SIRT1 in the germinal center of the follicles while the mantle zone shows nearly no staining to few positive cells. The classical HL-affected lymph nodes show a strong positivity of the diagnostic Hodgkin Reed-Sternberg cells. Notably, both the HL-derived cell lines and the Hodgkin Reed-Sternberg cells of the affected lymph nodes derive from germinal center-derived B cells. The study of SIRT1 distribution and expression on a larger number of biopsies might disclose a novel role for this histone/protein deacetylase as therapeutic target.

Grapes produce large amounts of polyphenols. Many of them accumulate in the skin, pulp, and seeds and are consequently found in wine. The health benefits of a moderate consumption of wine have been attributed at least in part to grape's polyphenols. Among them, resveratrol (3,5,4'-trihydroxystilbene) is a phytoalexin that stimulates plant cell defenses against infections and also plays protective roles in humans, where it delays cardiovascular alterations and exerts anticancer and anti-inflammatory effects. Despite numerous studies, the molecular mechanisms of resveratrol action are only partially understood. Given its pleiotropic effects, it was previously suggested that resveratrol protective properties may arise from its modulation of the expression of microRNAs. Therefore, this review will focus on the effects of resveratrol on microRNA populations in humans and human cell lines, especially emphasizing the microRNAs that have been implicated in resveratrol effects on inflammation, cancer, metabolism, and muscle differentiation.

Resveratrol is a natural dietary polyphenol found in grape skin, red wine, and various other food products. Resveratrol has proved to be an effective chemopreventive agent for different malignant tumors. It has also been shown to prevent vascular alterations such as atherosclerosis and inflammatory-associated events. In view of these observations, we investigated the anti-proliferative and pro-apoptotic activities of resveratrol on a tumoral cardiac cell line (HL-1 NB) derived from mouse tumoral atrial cardiac myocytes. These effects were compared with those found on normal neonatal mouse cardiomyocytes. HL-1 NB cells and neonatal cardiomyocytes were treated with resveratrol (5, 30, and/or 100 μM) for different times of culture (24, 48, and/or 72 h). Resveratrol effects were determined by various microscopical and flow cytometric methods. After resveratrol treatment, a strong inhibition of tumoral cardiac HL1-NB cell growth associated with a loss of cell adhesion was observed. This cell proliferation arrest was associated with an apoptotic process revealed by an increased percentage of cells with fragmented and/or condensed nuclei (characteristic of apoptotic cells) identified after staining with Hoechst 33342 and by the presence of cells in subG1. At the opposite, on normal cardiomyocytes, no cytotoxic effects of resveratrol were observed, and a protective effect of resveratrol against norepinephrine-induced apoptosis was found on normal cardiomyocytes. Altogether, the present data demonstrate that resveratrol (1) induces apoptosis of tumoral cardiac HL1-NB cells, (2) does not induce cell death on normal cardiomyocytes, and (3) prevents norepinephrine-induced apoptosis on normal cardiomyocytes.

Numerous studies have reported interesting properties of trans-resveratrol, a phytoalexin, as a preventive agent of several important pathologies: vascular diseases, cancers, viral infections, and neurodegenerative processes. These beneficial effects of resveratrol have been supported by observations at the cellular and molecular levels in both cellular and in vivo models, but the cellular fate of resveratrol remains unclear. We suggest here that resveratrol uptake, metabolism, and stability of the parent molecule could influence the biological effects of resveratrol. It appears that resveratrol stability involves redox reactions and biotransformation that influence its antioxidant properties. Resveratrol's pharmacokinetics and metabolism represent other important issues, notably, the putative effects of its metabolites on pathology models. For example, some metabolites, mainly sulfate-conjugated resveratrol, show biological effects in cellular models. The modifications of resveratrol stability, chemical structure, and metabolism could change its cellular and molecular targets and could be crucial for improving or decreasing its chemopreventive properties.

IF 2.861; International audience; Carnitine palmitoyltransferase-2 (CPT2) is a mitochondrial enzyme involved in long-chain fatty acid entry into mitochondria for their β-oxidation and energy production. Two phenotypes are associated with the extremely reduced CPT2 activity in genetically deficient patients: neonatal lethality or, in milder forms, myopathy. Resveratrol (RSV) is a phytophenol produced by grape plant in response to biotic or abiotic stresses that displays anti-oxidant properties, in particular through AP-1, NFκB, STAT-3, and COX pathways. Some beneficiary effects of RSV are due to its modulation of microRNA (miRNA) expression. RSV can enhance residual CPT2 activities in human fibroblasts derived from CPT2-deficient patients and restores normal fatty acid oxidation rates likely through stimulation of mitochondrial biogenesis. Here, we report changes in miRNA expression linked to CPT2-deficiency, and we identify miRNAs whose expression changed following RSV treatment of control or CPT2-deficient fibroblasts isolated from patients. Our findings suggest that RSV consumption might exert beneficiary effects in patients with CPT2-deficiency.

10 pages; International audience; The peroxisomal 3-ketoacyl-CoA thiolase B (Thb) gene was previously identified as a direct target gene of PPARalpha, a nuclear hormone receptor activated by hypolipidemic fibrate drugs. To better understand the role of ThB in hepatic lipid metabolism in mice, Sv129 wild-type and Thb null mice were fed or not the selective PPARalpha agonist Wy14,643 (Wy). Here, it is shown that in contrast to some other mouse models deficient for peroxisomal enzymes, the hepatic PPARalpha signaling cascade in Thb null mice was normal under regular conditions. It is of interest that the hypotriglyceridemic action of Wy was reduced in Thb null mice underlining the conclusion that neither thiolase A nor SCPx/SCP2 thiolase can fully substitute for ThB in vivo. Moreover, a significant increased in the expression of lipogenic genes such as Stearoyl CoA Desaturase-1 (SCD1) was observed in Thb null mice fed Wy. Elevation of Scd1 mRNA and protein levels led to higher SCD1 activity, through a molecular mechanism that is probably SREBP1 independent. In agreement with higher SCD1, enrichment of liver mono-unsaturated fatty acids of the n-7 and n-9 series was found in Thb null mice fed Wy. Overall, we show that the reduced peroxisomal beta-oxidation of fat observed in Thb null mice fed Wy is associated with enhanced hepatic lipogenesis, through the combined elevation of microsomal SCD1 protein and activity. Ultimately, not only the amount but also the quality of the hepatic fatty acid pool is modulated upon the deletion of Thb.

Seasonal obesity and fasting-associated hibernation are the two major metabolic events governing hepatic lipid metabolism in hibernating mammals. In this process, however, the role of the nuclear receptor known as peroxisome proliferator-activated receptor (PPAR)-α has not been elucidated yet. Here we show, as in human, that jerboa (Jaculus orientalis) liver expresses both active wild-type PPARα (PPARα1wt) and truncated PPARα forms and that the PPARα1wt to truncated PPARα2 ratio, which indicates the availability of active PPARα1wt, is differentially regulated during fasting-associated hibernation. Functional activation of hepatic jerboa PPARα, during prehibernating and hibernating states, was demonstrated by the induction of its target genes, which encode peroxisomal proteins such as acyl-CoA oxidase 1, peroxisomal membrane protein 70, and catalase, accompanied by a concomitant induction of PPARα thermogenic coactivator PPARγ coactivator-1α. Interestingly, sustained activation of PPARα by its hypolipidemic ligand, ciprofibrate, abrogates the adaptive fasting response of PPARα during prehibernation and overinduces its target genes, disrupting the prehibernation fattening process. In striking contrast, during fasting-associated hibernation, jerboas exhibit preferential up-regulation of hepatic peroxisomal fatty acid oxidation instead of the mitochondrial pathway, which is down-regulated. Taken together, our results strongly suggest that PPARα is subject to a hibernation-dependent splicing regulation in response to feeding-fasting conditions, which defines the activity of PPARα and the activation of its target genes during hibernation bouts of jerboas.Jerboa PPARα is subject to a hibernation-dependent splicing regulation in response to feeding-fasting conditions, which define activation of PPARα and its target genes.

International audience; 2,4-Dichlorophenoxyacetic acid (2,4D) is one of the widely used herbicide of the phenoxy family with possible startling number of adverse effects on species other than the weeds which is designed to kill. The effects of 2,4D were investigated in jerboa (Jaculus orientalis), a wild animal of subdesert highlands. The jerboas have been daily treated intraperitonally with 2,4D 3 mg/kg body weight for 4 weeks. Plasmatic markers, and antioxidants defences systems were assessed and histological alterations were evaluated. The in vivo and in vitro effects of 2,4D on the mitochondrial D-3-hydroxybutyrate dehydrogenase (BDH) were also determined. Our results showed a strong decrease of triglycerides level and HDL cholesterol and an increase in GOT level and LDL cholesterol. The microscopic evaluation showed that 2,4D induced necrosis of seminiferous tubules cells in testis, hyperplasia of hepatocytes in liver and presence of multinucleated giant cells in brain. The results show also an inhibitory effect on BDH in terms of activity and kinetic parameters. All of these results show that 2,4D induces toxicity which affects energy metabolism, morphological perturbation and oxidative stress.

In patients with sepsis, liver metabolism and its capacity to provide other organs with energetic substrates are impaired. This and many other pathophysiological changes seen in human patients are reproduced in mice injected with purified endotoxin (lipopolysaccharide, LPS). In the present study, down-regulation of genes involved in hepatic fatty acid oxidation (FAOx) and gluconeogenesis in mice exposed to LPS was challenged by nutritional intervention with Argan oil. Mice given a standard chow supplemented or not with either 6% (w/w) Argan oil (AO) or 6% (w/w) olive oil (OO) prior to exposure to LPS were explored for liver gene expressions assessed by mRNA transcript levels and/or enzyme activities. AO (or OO) food supplementation reveals that, in LPS-treated mice, hepatic expression of genes involved in FAOx and gluconeogenesis was preserved. This preventive protection might be related to the recovery of the gene expressions of nuclear receptors peroxisome proliferator-activated receptor α (PPARα) and estrogen related receptor α (ERRα) and their coactivator peroxisome proliferator-activated receptor gamma coactivator-1α, (PGC-1α). These preventive mechanisms conveyed by AO against LPS-induced metabolic dysregulation might add new therapeutic potentialities in the management of human sepsis., Highlights • Argan oil prevents LPS-treated mice from liver dysregulation of FAOx and gluconeogenesis. • Argan oil improves hepatic expression of PPARα and ERRα, and their coactivators PGC-1α and Lipin-1. • New preventive mechanisms conveyed by Argan oil against LPS-induced metabolic dysregulation.

International audience; Resveratrol (3,4',5 tri-hydroxystilbene) is a phytoalexin produced in hudge amount in grapevine skin in response to infection by Bothrytis cinerea. This production of resveratrol blocks the proliferation of the pathogen, thereby acting as a natural antibiotic. Numerous studies have reported interesting properties of trans-resveratrol as a preventive agent against important pathologies i.e. vascular diseases, cancers, viral infection or neurodegenerative processes. Moreover, several epidemiological studies have revealed that resveratrol is probably one of the main microcomponents of wine responsible for its health benefits such as prevention of vaso-coronary diseases and cancer. Resveratrol acts on the process of carcinogenesis by affecting the three phases: tumor initiation, promotion and progression phases and suppresses the final steps of carcinogenesis, i.e. angiogenesis and metastasis. It is also able to activate apoptosis, to arrest the cell cycle or to inhibit kinase pathways. Interestingly, resveratrol does not present any cytotoxicity in animal models. Moreover, concentrations of resveratrol in blood seem to be sufficient for anti-invasive activity. The enterohepatic recirculation may contribute to a delayed elimination of the drug from the body and bring about a prolonged effect. By its binding to plasmatic proteins, resveratrol also exhibits a prolonged effect. Interestingly, low doses of resveratrol can sensitize to low doses of cytotoxic drugs and so provide an innovative strategy to enhance the efficacy of anticancer therapy in various human cancers. By these properties, resveratrol appears to be a good candidate in chemopreventive or chemotherapeutic strategies and is believed to be a novel weapon for new therapeutic strategies.

The peroxisomal beta-oxidation system consists of four steps catalysed by three enzymes: acyl-CoA oxidase, 3-hydroxyacyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase (multifunctional enzyme) and thiolase. In humans, thiolase activity is encoded by one gene, whereas in rodents, three enzymes encoded by three distinct genes (i.e. thiolase A, thiolase B and SCP2/thiolase) catalyse the thiolase activity. So far, acyl-CoA oxidase- and multifunctional enzyme-deficient patients have been identified and knock-out mice for these genes have been produced. Conversely, no isolated thiolase-deficient patient has been found, and no thiolase (A or B)-deficient mice have been generated. Hence, to better understand the cause of isolated human thiolase deficiency, we disrupted the catalytic site of the mouse thiolase B by homologous recombination in order to analyse the phenotype of these thiolase B-deficient mice. Mice, made homozygous for the mutation, lack expression of thiolase B mRNA and are viable, fertile and healthy at birth. They exhibit no detectable phenotype defects and no compensation, rather a slight decrease in other peroxisomal thiolase (thiolase A and SCPx) mRNAs, was found.

Resveratrol produced by several plants, berries and fruits, including grapes, is one of the best known natural food microcomponents with potent chemopreventive properties towards the most severe contemporary human diseases: cardiovascular sickness, cancer and neurodegenerative pathologies. Demonstration of its mechanism of action also implies the elucidation of the steps of bioavailability and bioabsorption in cells and tissues. In order to estimate the relationships between the amounts of resveratrol taken up by food or drink intake, and the several possible benefits illustrated from in vitro/in vivo experiments and from epidemiological studies, it is essential to demonstrate step by step the route of resveratrol from plasma to the cell active site. In plasma, resveratrol was shown to interact with lipoproteins. This commentary also contains previously unpublished results about interactions between resveratrol and albumin and the enhancement of this binding in presence of fatty acids. We have previously described that resveratrol uptake by hepatic cells involves two processes--a passive one and a carrier-mediated one. Thanks to this last process, resveratrol, while tightly bound to blood proteins, could be largely delivered to body tissues. The intracellular proteic targets of resveratrol remain to be identified.

This work reports significant advances on the transport in hepatic cells of resveratrol, a natural polyphenol with potent protective properties. First, we describe a new simple technique to qualitatively follow resveratrol cell uptake and intracellular distribution, based on resveratrol fluorescent properties. Second, the time-course study and the quantification of (3)H-labelled resveratrol uptake have been performed using human hepatic derived cells (HepG2 tumor cells) and hepatocytes. The temperature-dependence of the kinetics of uptake as well as the cis-inhibition experiments agree with the involvement of a carrier-mediated transport in addition to passive diffusion. The decrease of passive uptake resulting from resveratrol binding to serum proteins brings to light a mediated mechanism in physiological situation.

International audience; In this study, we aimed to evaluate the antioxidant and anti-inflammatory properties of Opuntia ficus-indica cactus cladode extracts in microglia BV-2 cells. Inflammation associated with microglia activation in neuronal injury can be achieved by LPS exposure. Using four different structurally and biologically well-characterized LPS serotypes, we revealed a structure-related differential effect of LPS on fatty acid β-oxidation and antioxidant enzymes in peroxisomes: Escherichia coli-LPS decreased ACOX1 activity while Salmonella minnesota-LPS reduced only catalase activity. Different cactus cladode extracts showed an antioxidant effect through microglial catalase activity activation and an anti-inflammatory effect by reducing nitric oxide (NO) LPS-dependent production. These results suggest that cactus extracts may possess a neuroprotective activity through the induction of peroxisomal antioxidant activity and the inhibition of NO production by activated microglial cells.

Les microARN (miARN), decouverts en 1993 dans le laboratoire de V. Ambros [1], ont d'abord ete identifies comme regulateurs du developpement chez Caenorhabditis elegans. Les recherches recentes confirment que ces petits ARN non codants simple-brins sont des elements de signalisation cellulaire fondamentaux dans la regulation de processus tels que le developpement, la differenciation ou la proliferation cellulaire. Ces ARN de 22 nucleotides en moyenne s'apparient de facon specifique a des ARN messagers cibles entrainant le blocage de leur traduction (en cas de complementarite parfaite) ou la degradation des transcrits (en cas de un ou quelques mesappariement[s]). Ils pourraient aussi reguler des genes au niveau transcriptionnel. La mutation de genes codant certains miARN entraine des processus oncogeniques [2]. Cependant, les connaissances sur la regulation des genes codant ces miARN sont encore limitees.

Various epidemiological studies have shown that a regular and moderate consumption of red wine is correlated with a decreased relative risk of developing coronary heart disease and cancer. These health benefits are commonly attributed to high contents of polyphenols, particularly resveratrol, representing important sources of antioxidants. However, resveratrol does not seem to be the only bioactive compound present in the wine which contains numerous other polyphenols. The present study investigates the efficiency of red wine extracts (RWEs), containing different polyphenols, on colon cancer cell proliferation in vitro and on colonic aberrant crypt foci (ACF) in vivo. Proliferation, cell cycle analysis and incidence of ACF were monitored to examine the effects of RWEs. RWEs derived from a long vinification process exhibit superior anti-proliferative activity in colon cancer cells and prevent the appearance of ACF in mice. Interestingly, quercetin and resveratrol, representing two major bio-active polyphenols, exhibit synergistic anti-proliferative effects. These data suggest that the efficacy of RWEs on colon carcinogenesis may depend on the polyphenolic content, synergistic interaction of bio-active polyphenols and modulation of cellular uptake of polyphenols.

Grape polyphenols are abundant. They play essential roles in the vine’s life, particularly in its defense mechanisms. Interestingly, the grape, fresh or dried, is a widely consumed fruit by humans, as are its processed products, grape juice and wine. Moreover, they contain vast and highly varied quantities of polyphenols. Like other phytophenols, grape and wine resveratrol is considered a protective micronutrient like flavonoids, epicatechins in green tea and cocoa, quercetin in apples and onions, curcumin of the turmeric root, and hydroxytyrosol in olive oil. Resveratrol is a powerful natural antioxidant in vine. Interestingly, in humans, it protects low density lipoproteins against oxidation and consequently prevents or delays atherosclerosis. On the other hand, inflammation is the reflect of many dysfunctions or pathologies, where resveratrol has a positive effect against these disorders. This review will summarize resveratrol anti-inflammatory properties and mechanisms toward arthritis and retinopathies.

International audience; Background: Inborn enzyme defects of mitochondrial fatty acid beta-oxidation (FAO) form a large group of genetic disorders associated to variable clinical presentations ranging from life-threatening pediatric manifestations up to milder late onset phenotypes, including myopathy. Very few candidate drugs have been identified in this group of disorders. Resveratrol (RSV) is a natural polyphenol with anti-oxidant and anti-inflammatory effects, recently shown to have beneficial metabolic properties in mice models. Our study explores its possible effects on FAO and mitochondrial energy metabolism in human cells, which are still very little documented.Methods: Using cells from controls and from patients with Carnitine Palmitoyl Transferase 2 (CPT2) or Very Long Chain AcylCoA Dehydrogenase (VLCAD) deficiency we characterized the metabolic effects of RSV, RSV metabolites, and other stilbenes. We also focused on analysis of RSV uptake, and on the effects of low RSV concentrations, considering the limited bioavailability of RSV in vivo.Results: Time course of RSV accumulation in fibroblasts over 48 h of treatment were consistent with the resulting stimulation or correction of FAO capacities. At 48 h, half maximal and maximal FAO stimulations were respectively achieved for 37,5 microM (EC50) and 75 microM RSV, but we found that serum content of culture medium negatively modulated RSV uptake and FAO induction. Indeed, decreasing serum from 12% to 3% led to shift EC50 from 37,5 to 13 microM, and a 2.6-3.6-fold FAO stimulation was reached with 20 microM RSV at 3% serum, that was absent at 12% serum. Two other stilbenes often found associated with RSV, i.e. cis- RSV and piceid, also triggered significant FAO up-regulation. Resveratrol glucuro- or sulfo- conjugates had modest or no effects. In contrast, dihydro-RSV, one of the most abundant circulating RSV metabolites in human significantly stimulated FAO (1.3-2.3-fold).Conclusions: This study provides the first compared data on mitochondrial effects of resveratrol, its metabolites, and other natural compounds of the stilbene family in human cells. The results clearly indicate that several of these compounds can improve mitochondrial FAO capacities in human FAO-deficient cells.

International audience

The first PPAR (peroxisome proliferator-activated receptor) was cloned in 1990 by Issemann and Green (Nature 347:645-650). This nuclear receptor was so named since it is activated by peroxisome proliferators including several drugs of the fibrate family, plasticizers, and herbicides. This receptor belongs to the steroid receptor superfamily. After activation by a specific ligand, it binds to a DNA response element, PPRE (peroxisome proliferator response element), which is a DR-1 direct repeat of the consensus sequence TGACCT x TGACCT. This mechanism leads to the transcriptional activation of target genes (Motojima et al., J Biol Chem 273:16710-16714, 1998). After the first discovery, several isoforms were characterized in most of the vertebrates investigated. PPAR alpha, activated by hypolipidemic agents of the fibrate family or by leukotrienes; regulates lipid metabolism as well as the detoxifying enzyme-encoding genes. PPAR beta/delta, which is not very well known yet, appears to be more specifically activated by fatty acids. PPAR gamma (subisoforms 1, 2, 3) is activated by the prostaglandin PGJ2 or by antidiabetic thiazolidinediones (Vamecq and Latruffe, Lancet 354:411-418, 1999). This latter isoform is involved in adipogenesis. The level of PPAR expression is largely dependent on the tissue type. PPAR alpha is mainly expressed in liver and kidney, while PPAR beta/delta is almost constitutively expressed. In contrast, PPAR gamma is largely expressed in white adipose tissue. PPAR is a transcriptional factor that requires other nuclear proteins in order to function, i.e. RXRalpha (9-cis-retinoic acid receptor alpha) in all cases in addition to other regulatory proteins. Peroxisomes are specific organelles for very long-chain and polyunsaturated fatty acid catabolism. From our results and those of others, the inventory of the role of PPAR alpha in the regulation of peroxisomal fatty acid beta-oxidation is presented. In relation to this, we showed that PPAR alpha activates peroxisomal beta-oxidation-encoding genes such as acyl-CoA oxidase, multifunctional protein, and thiolase (Bardot et al., FEBS Lett 360:183-186, 1995). Moreover, rat liver PPAR alpha regulatory activity is dependent on its phosphorylated state (Passilly et al., Biochem Pharmacol 58:1001-1008, 1999). On the other hand, some signal transduction pathways such as protein kinase C are modified by peroxisome proliferators that increase the phosphorylation level of some specific proteins (Passilly et al. Eur J Biochem 230:316-321, 1995). From all these findings, PPAR alpha and kinases appear to play an important role in lipid homeostasis.

The effect of ciprofibrate on early events of signal transduction was previously studied in Fao cells. Protein kinase C (PKC) assays performed on permeabilized cells showed a more than two-fold increase in PKC activity in cells treated for 24 h with 500 microM ciprofibrate. To show the subsequent effect of this increase on protein phosphorylation, the in vitro phosphorylation on particulate fractions obtained from Fao cells was studied. Among several modifications, the phosphorylation of protein(s) with an apparent molecular mass of 85 kDa was investigated. This modification appeared in the first 24 h of treatment with 500 microM ciprofibrate. It was shown to occur on Ser/Thr residue(s). It was calcium but not calmodulin-dependent. The phosphorylation level of this/these protein(s) was reduced with kinase inhibitors and especially with 300 nM GF-109203X, a specific inhibitor of PKC. All these results suggest that the phosphorylation of the 85 kDa protein(s) is due to a PKC or to another Ser/Thr kinase activated via a PKC pathway. A possible biochemical candidate for 85 kDa protein seems to be the beta isoform of phosphatidylinositol 3-kinase regulatory subunit.

The basic mechanism(s) by which peroxisome proliferators activate peroxisome proliferator-activated receptors (PPARs) is (are) not yet fully understood. Given the diversity of peroxisome proliferators, several hypotheses of activation have been proposed. Among them is the notion that peroxisome proliferators could activate PPARs by changing their phosphorylation status. In fact, it is well known that several members of the nuclear hormone receptor superfamily are regulated by phosphorylation. In this report, we show that the rat Fao hepatic-derived cell line, known to respond to peroxisome proliferators, exhibited a high content of PPARalpha. Alkaline phosphatase treatment of Fao cell lysate as well as immunoprecipitation of PPARalpha from cells prelabeled with [32P] orthophosphate clearly showed that PPARalpha is indeed a phosphoprotein in vivo. Moreover, treatment of rat Fao cells with ciprofibrate, a peroxisome proliferator, increased the phosphorylation level of the PPARalpha. In addition, treatment of Fao cells with phosphatase inhibitors (okadaic acid and sodium orthovanadate) decreased the activity of ciprofibrate-induced peroxisomal acyl-coenzyme A oxidase, an enzyme encoded by a PPARalpha target gene. Our results suggest that the gene expression controlled by peroxisome proliferators could be mediated in part by a modulation of the PPARalpha effect via a modification of the phosphorylation level of this receptor.

The specific activity of carnitine palmitoyltransferase I (CPT-I) was similar in mitochondria isolated from rat Fao and human HepG2 hepatoma cells and from rat hepatocytes, but almost twofold higher in permeabilized hepatoma cells than in permeabilized hepatocytes. Short-term exposure to okadaic acid induced a ca. 80% stimulation of CPT-I in hepatocytes, whereas no significant response of the enzyme from hepatoma cells was evident. Thus, the high CPT-I activity displayed by hepatoma cells may be reached by hepatocytes upon challenge to okadaic acid. Reconstitution experiments with purified mitochondrial and cytoskeletal fractions showed that the cytoskeleton of hepatocytes produced a more remarkable inhibition of CPT-I than the cytoskeleton of Fao cells. The present data may be explained by a disruption of interactions between CPT-I and cytoskeletal components in tumor cells that may be involved in the okadaic acid-induced activation of hepatic CPT-I as previously suggested.

After our previous report on the cloning of two cDNA species in guinea pig, both encoding the same hepatic 79 kDa multifunctional protein 1 (MFP-1) [Caira, Cherkaoui-Malki, Hoefler and Latruffe (1996) FEBS Lett. 378, 57-60], here we report the cloning of a cDNA encoding a second multifunctional peroxisomal protein (MFP-2) in guinea-pig liver. This 2356 nt cDNA encodes a protein of 735 residues (79.7 kDa) whose sequence shows 83% identity with rat MFP-2 [Dieuaide-Noubhani, Novikov, Baumgart, Vanhooren, Fransen, Goethals, Vandekerckhove, Van Veldhoven and Mannaerts (1996) Eur. J. Biochem. 240, 660-666]. In parallel, we studied the effect of ciprofibrate, a hypolipaemic agent also known as peroxisome proliferator in rodent, on the expression of MFP-1 and MFP-2 (2.6 kb) in rats and guinea pigs. By Northern blotting analysis we demonstrated that three MFP-1-related mRNA species are expressed in the guinea-pig liver. The expression of two of them (3.5 and 2.6 kb) is slightly increased by ciprofibrate, whereas the 3.0 kb MFP-1 mRNA is, unlike the rat one, strongly down-regulated in guinea pigs treated with ciprofibrate. In a similar way, the hepatic expression of the guinea-pig 2.6 kb MFP-2 mRNA is also down-regulated in guinea pigs treated with ciprofibrate. These results demonstrate (1) that in contrast with the unique 3.0 kb MFP-1 rat mRNA, at least three hepatic MFP-1-related mRNA species are co-expressed in guinea pig; and (2) that, opposed to the accepted idea of non-responsiveness of the guinea pig to ciprofibrate, this drug affects MFP-1 and MFP-2 gene expression in this species. Also, the mRNA species for acyl-CoA oxidase and thiolase, two other enzymes of the peroxisomal β-oxidation pathway that are induced severalfold in responsive species are down-regulated in guinea pig. This paper is the first, to our knowledge, reporting the down-regulation of the expression of genes encoding enzymes involved in the peroxisomal β-oxidation of fatty acids (MFP-1) and bile acid synthesis (MFP-2) in mammals.

Guinea pig was previously classified as a species nonresponsive to peroxisome proliferators. However, none of the previous reports was based on pharmacokinetic data. Here, after a comparative pharmacokinetic study between guinea pig and rat, we evaluate the guinea pig liver peroxisomal response to ciprofibrate, a hypolipemic agent and a potent peroxisome proliferator in rat. (1) Pharmacokinetic results show that plasmatic concentrations of ciprofibrate are equivalent in guinea pig and rat when guinea pigs are treated with ciprofibrate at 30 mg/kg twice a day and rats are treated at 3 mg/kg once a day. (2) The treatment of guinea pigs at 30 mg/kg twice a day for 2 weeks leads to a significant increase in the liver peroxisomal palmitoyl-CoA oxidase activity (×1.6) and also in the microsomal ω-laurate hydroxylase activity (×1.8). These increases are in accordance with the changes in polypeptide patterns of isolated liver peroxisomes as well as in the immunoblotting of acyl-CoA oxidase. It is deduced that a weak, but significant, peroxisome proliferation can occur in guinea pig liver after a ciprofibrate treatment at dosages corresponding to equivalent plasmatic concentrations of the drug between guinea pig and rat. (3) The hybridization of guinea pig liver RNA with the rat liver-inducible acyl-CoA oxidase cDNA probe shows a decrease in the corresponding heterologuous mRNA content after treatment with ciprofibrate at 30 mg/kg twice a day. This result contrasts with the slight increase observed in immunodetection and in enzymatic assays, suggesting the existence of at least two different acyl-CoA oxidases in guinea pig liver peroxisomes.

Scope Resveratrol (RSV) has been proposed to prevent tumor growth; nevertheless, these preventive effects are controversial since RSV pharmacokinetics studies show a low bioavailability. Recent clinical trials show that patients with colorectal cancer and receiving oral RSV have high levels of RSV conjugates in the colorectum, mainly RSV-3-O-sulfate (R3S), RSV-3-O-glucuronide, and RSV-4′-O-glucuronide. However, their potential biological activity has not yet been established. This study thus investigated in human colorectal cancer cell lines whether RSV main metabolites retain anticarcinogenic properties as their parental molecule. Methods and results Proliferation, apoptosis assays and cell cycle analysis were performed to study the effect of RSV, R3S, RSV-3-O-glucuronide, or RSV-4′-O-glucuronide alone or of a mixture of the three metabolites. R3S inhibits colon cancer cells proliferation and an accumulation of cells in S phase. Interestingly, the mixture induced a synergistic effect. This process was associated with an induction of DNA damages and apoptotic process, which allowed sensitization of colon cancer cells to the anticancer drugs. Conclusion Altogether, our data provide significant new insight into the molecular mechanism of RSV and support the notion that despite low bioavailability in vivo, RSV biological effects could be mediated by its metabolites.

The treatment of rats with ciprofibrate, a potent peroxisome proliferator, led to increased levels of the peroxisomal acyl-CoA oxidase (ACO) mRNA. How ciprofibrate functions to elevate ACO mRNA is not known. To help determine the mechanism of ciprofibrate action, in vitro transcription assays were performed. It was determined that ciprofibrate was responsible for a 3.5-fold stimulation of the rate of ACO transcription within 24 hr of ingestion. It was also observed that the transcription rate stimulation following a 2-week ciprofibrate treatment of Wistar rats was maintained following 4 weeks of ciprofibrate withdrawal. Re-introduction of the drug after the 4-week pause resulted in greater stimulation than was initially observed. The results demonstrate that the effect of ciprofibrate is rapid and persists at least twice as long as the initial treatment period. In Zucker rats, both lean and obese, ACO mRNA levels were examined following 2 weeks of ciprofibrate treatment (1 or 3 mg/kg body weight/day). The presence of increased blood levels of triglycerides did not increase ciprofibrate action on transcription, although basal levels of transcription of peroxisomal enzymes were higher in obese rats. The increase in the ACO mRNA level was greater than the transcription rate stimulation suggesting a post-transcriptional regulation.

Purpose Age-related Macular Degeneration (AMD) is a pathology driven by inflammatory and angiogenic processes. The aim of this work was to study the in vitro anti-inflammatory and anti-angiogenic potential of a new resveratrol-based formula (Resvega, Laboratoires THEA, France) on Human retinal pigment epithelium cell line ARPE-19 after an inflammation induced by the bacterial lipopolysaccharide (LPS). Methods Human ARPE-19 cells were subjected to inflammation by LPS (0128:B12) and co-treated during 24 hours with Resveratrol (50,30,10 or 1µM) or the Resvega formula (50,30,10 or 1 µM expressed in Resveratrol equivalent). Cell media were collected and the levels of 6 cytokines were measured by the multiplex Cytometric Bead Array Kit (BD Bioscience) : IL-8, IL-1 beta, IL-6, IL-10, TNF alpha and IL-12p70. Finally the level of the major angiogenic factor VEGF-A was measured in these media by ELISA (eBioscience) Results The results showed that among the 6 cytokines only IL-6 and IL-8 were over-expressed during the inflammation triggered by the LPS treatment. These two pro-inflammatory cytokines were down-regulated by Resveratrol and Resvega treatments by at least 50-60% in all conditions even at the very low concetrations (1 µM). Concerning VEGF-A levels, Resveratrol and Resvega showed a dose-dependent inhibition. The maximum inhibition was observed for the highest concentration of Resvega (50 µM resveratrol equivalent)with a decrease by 74%. Conclusion In conclusion, we demonstrated that Resvega had an anti-inflammatory and anti-angiogenic effect in vitro, on the human retinal pigment epithelial cells.