In the shadow of resveratrol: biological activities of epsilon-viniferin.

Stilbenes are secondary metabolites belonging to the polyphenol family. Those compounds are derived from the glycosylation, prenylation, methoxylation, hydroxylation, or also oligomerization of the well-known trans-resveratrol. One of them, trans-epsilon-viniferin (ε-viniferin), is a trans-resveratrol dimer that arouses the interest of researchers in the field of human health. The biosynthesis of this molecule in various plant species, particularly high in the Vitaceae family, explains its presence in some red wines, which represent the main source of ε-viniferin in the human diet. Although bioavailability studies have shown poor absorption and high metabolism of this stilbene, multiple studies demonstrated its biological properties. The ε-viniferin exhibits strong activities against inflammatory and oxidative stress. Moreover, various studies have reported great activity of this compound not only in a wide range of disorders and diseases, such as cancer, obesity, and its associated disorders, but also in vascular diseases and neurodegeneration, for which the pathophysiology is closely related to the state of oxidation and inflammation. This review provides a state of art of the main activities of ε-viniferin demonstrated in vitro and in vivo, highlighting that this resveratrol dimer could be a promising candidate for future functional foods or supplement foods used for the management of many chronic diseases of concern in terms of public health.

Trans-ε-Viniferin Encapsulation in Multi-Lamellar Liposomes: Consequences on Pharmacokinetic Parameters, Biodistribution and Glucuronide Formation in Rats.

Trans-ε-viniferin (εVin) is a resveratrol dimer exhibiting promising biological activities for human health. Its bioavailability being low, the development of encapsulation methods would be used to overcome this issue. The aim of this study was to measure the consequences of the encapsulation of εVin in multilamellar liposomes on its pharmacokinetic parameters, metabolism and tissue distribution in rats. After oral administration of εVin (20 mg/kg body weight), either as free or encapsulated forms, plasmas were sequentially collected (from 0 to 4 h) as well as liver, kidneys and adipose tissues (4 h after administration) and analyzed by LC-HRMS. The glucuronide metabolites (εVG) were also produced by hemisynthesis for their quantification in plasma and tissues. The encapsulation process did not significantly modify the pharmacokinetic parameters of εVin itself. However, a significant increase of the T1/2 was noticed for εVG after administration of the encapsulated form as compared to the free form. An accumulation of εVin and εVG in adipose tissues was noticed, and interestingly a significant increase of the latter in the mesenteric one after administration of the encapsulated form was highlighted. Since adipose tissues could represent storage depots, and encapsulation allows for prolonging the exposure time of glucuronide metabolites in the organism, this could be of interest to promote their potential biological activities.

Encapsulation of ε-viniferin in onion-type multi-lamellar liposomes increases its solubility and its photo-stability and decreases its cytotoxicity on Caco-2 intestinal cells.

ε-Viniferin, a resveratrol dimer, is a naturally occurring stilbene that has been studied so far for its potential beneficial effects on human health. Its low water solubility, its photo-sensitivity and its low bioavailability make its applications in the food industry complicated. To overcome these limitations, ε-viniferin was encapsulated in phospholipid-based multi-lamellar liposomes (MLLs) called spherulites or onions. In the best case, an encapsulation efficiency of 58 ± 3% and a bioactive loading of 4.2 ± 0.5% were reached. Encapsulation of ε-viniferin drastically increased its water solubility by more than 5 orders to reach 17.4 g L-1 and provided protection against its UV-induced isomerization. While ε-viniferin was shown to be significantly toxic to Caco-2 intestinal-like cells for concentrations higher than 25 µM, once encapsulated in MLLs, those cells did not experience any mortality even for the highest tested stilbene concentration (100 µM) as revealed by red neutral assay.

Tissular Distribution and Metabolism of trans-ε-Viniferin after Intraperitoneal Injection in Rat.

BACKGROUND: Recent studies showed that trans-ε-viniferin (ε-viniferin), a trans-resveratrol dehydrodimer, has anti-inflammatory and anti-obesity effects in rodents. The main purpose of this work was to assess the tissue distribution study of ε-viniferin and its metabolites after intraperitoneal (IP) administration in rat. METHODS: After IP injection of 50 mg/kg, ε-viniferin and its metabolites were identified and quantified in plasma, liver, kidneys, adipose tissues, urine, and faeces by Liquid Chromatography-High Resolution Mass Spectrometry (LC-HRMS). RESULTS: ε-Viniferin underwent a rapid hepatic metabolism mostly to glucuronides but also to a lesser extent to sulphate derivatives. The highest glucuronide concentrations were found in liver followed by plasma and kidneys whereas only traces amounts were found in adipose tissues. In contrast the highest ε-viniferin areas under concentration (AUC) and mean residence times (MRT) values were found in white adipose tissues. Finally, much lower levels of ε-viniferin or its metabolites were found in urine than in faeces, suggesting that biliary excretion is the main elimination pathway. CONCLUSION: A rapid and large metabolism of ε-viniferin and a high bioaccumulation in white adipose tissues were observed. Thus, these tissues could be a reservoir of the native form of ε-viniferin that could allow its slow release and a sustained presence within the organism.

Oral administration of lipid oil-in-water emulsions performed with synthetic or protein-type emulsifiers differentially affects post-prandial triacylglycerolemia in rats.

In this study, we compared the impact of administration of size-calibrated lipid emulsions prepared with either synthetic or natural emulsifiers on the post-absorptive plasma triacylglycerol responses in rats. We did this using four types of size-calibrated (10 µm diameter) and metastable (3 days) emulsions with 20% of an oleic acid-rich sunflower oil and 1% of either synthetic emulsifiers (Tween 80 or sodium 2-stearoyl-lactylate) or two proteins (ß-lactoglobulin or sodium caseinate). An oral fat tolerance test was performed in fasted rats by oral administration of each of these formulations in continuous or emulsified forms. Kinetic parameters (AUC0-inf., AUC0-6h, Cmax, Tmax, and T1/2) for the description of the plasma triacylglycerol responses were calculated. AUC0-6h and AUC0-inf. calculated for the protein groups were significantly lower than those of the control and the synthetic groups. These lower values were associated with significant decreases in the Cmax, exacerbated by the emulsion form and with marked decreases in the Tmax as compared to the control group. T1/2 values were differentially affected by the lipid administration forms and by the nature of the emulsifiers. As compared with the control group, T1/2 was largely increased in the sodium stearoyl-2-lactylate group, but on the contrary, largely lowered in the casein group. We concluded that the use of proteins as natural emulsifiers in lipid emulsions decreased the magnitude of post-prandial triacylglycerolemia for the same amount of ingested lipids, when the emulsion size is controlled for. Proteins could be a promising alternative to the widespread use of synthetic emulsifiers in the food industry.

Oleic Acid Uptake Reveals the Rescued Enterocyte Phenotype of Colon Cancer Caco-2 by HT29-MTX Cells in Co-Culture Mode.

Gastrointestinal epithelium is the unique route for nutrients and for many pharmaceuticals to enter the body. The present study aimed to analyze precisely whether co-culture of two colon cancer cell lines, mucus-producing cells HT29-MTX and enterocyte-like Caco-2 cells, ameliorate differentiation into an in vitro intestinal barrier model and the signaling pathways involved. Differentiated Caco-2 cells gene datasets were compared first to intestinal or cancer phenotypes and second to signaling pathway gene datasets. Experimental validations were performed in real-time experiments, immunochemistry, and gene expression analyses on Caco-2 versus co-cultures of Caco-2 and HT29-MTX (10%) cells. Partial maintenance of cancer-cell phenotype in differentiated Caco-2 cells was confirmed and fatty acids merged as potential regulators of cancer signaling pathways. HT29-MTX cells induced morphological changes in Caco-2 cells, slightly increased their proliferation rate and profoundly modified gene transcription of phenotype markers, fatty acid receptors, intracellular transporters, and lipid droplet components as well as functional responses to oleic acid. In vitro, enterocyte phenotype was rescued partially by co-culture of cancer cells with goblet cells and completed through oleic acid interaction with signaling pathways dysregulated in cancer cells.

Overexpression of caveolin-3-enhanced protein synthesis rather than proteolysis inhibition in C2C12 myoblasts: relationship with myostatin activity.

Caveolin-3 (cav-3), which is involved in the regulation of signal transduction and vesicular trafficking, could interact with activin receptor IIB to inhibit myostatin (MSTN) activity and may therefore play a role in muscle development and hypertrophy. MSTN is a member of the transforming growth factor-ß family, identified as a negative regulator of skeletal muscle mass. The expression of MSTN is fiber-type specific and the greatest amount of MSTN is present in fiber, which is composed of myosin heavy chain (MHC) type IIb. MSTN acts through the activin receptor IIB to activate smad2/3 which leads to an increase in gene transcription involved in muscle atrophy. Muscle hypertrophy is a consequence of two mechanisms: (1) the inhibition of proteolysis such as the calcium-dependent proteolytic system calpains and calpastatin and (2) an increase in protein synthesis through the Akt/mTOR/p70s6K pathway. In order to determine which of the two processes predominates in inhibition of MSTN activity in a cav-3 context, we transfected a C2C12 cell line with plasmids containing mstn or cav-3 wild genes. The results reported in this study demonstrate that inhibition of MSTN activity by overexpression of cav-3 induces an activation of protein synthesis rather than an inhibition of proteolysis through the calcium proteolytic system. The inhibition of phosphorylation of smad-3 due to overexpression of cav-3 causes an increase in the phosphorylation of the ribosomal protein S6, promoting the synthesis of MHC type II, probably through activation of Akt/mTOR/p70s6K. These data highlight the role of protein synthesis as the predominant mechanism in muscle hypertrophy observed when the expression of MSTN is altered and confirm the value of studying the physiological role of MSTN in the growing processes of skeletal muscle.

Vitamin A supply to mothers and children: challenges and opportunities.

PURPOSE OF REVIEW: Although we are close to the centennial of the discovery of vitamin A, our understanding of the functions of this major micronutrient is still evolving. Given its major role in fetal development, growth, vision, immunity and survival, a subtle balance is required between adequate intake to avoid deficiency and excessive intake to avoid toxicity, both in low income and industrialized countries. RECENT FINDINGS: This review highlights the potential impact of vitamin A supplementation (VAS) in mothers and children suffering from vitamin A deficiency (VAD) on mortality and morbidities, and warns against the increasingly frequent use of bariatric surgery especially to treat severely obese childbearing women, which is known to alter vitamin A status. SUMMARY: Despite massive vitamin A supplementation public health policies in developing countries, the burden of VAD is still common and efforts should be maintained to better target populations at risk, and to develop alternative strategies for supplementation based on sustainable and integrated approaches. In industrialized countries, VAD due to insufficient intake is scarce, but it may surprisingly occur due to the decreased absorption of lipids following antiobesity treatments. Specific approaches should be developed to better monitor and supplement obese childbearing women who have undergone bariatric surgery.

Vitamin A and lipid metabolism: relationship between hepatic stellate cells (HSCs) and adipocytes.

Vitamin A or retinol plays a major role in the regulation of cellular homeostasis. Retinyl palmitate remains the main chemical form of vitamin A storage and is mainly located in hepatic stellate cells (HSCs) in lipid droplets resembling those found in adipose cells. White adipose tissue (WAT), is essentially involved in the regulation of lipid metabolism, through its role in lipid storage, and might also be considered as a vitamin A storage and metabolism site. WAT contains all the intracellular equipment for vitamin A metabolism and signaling pathways which allows retinol to be metabolized into retinoic acid, known to control genomic expression in WAT. The description of molecular mechanisms involved in the activation of HSCs and the differentiation of preadipocytes reveal similar cellular and molecular mechanisms. Indeed HSCs and adipocytes share a common expression of key transcription factors like PPAR-γ and RXR known to influence perilipin expression, which play fundamental roles in lipid droplet metabolism. Both cells are also sources of important endocrine signaling secretions influencing the expression of these transcription factors. The morphological and functional characteristics of HSCs and adipocytes, including the metabolism of vitamin A and other lipids and their related signaling pathways, are summarized and compared in this review. We highlight the complexity of the interrelationship between lipids and vitamin A metabolism and the role of the complex communication existing between HSCs and WAT in diseases such as non-alcoholic fatty liver disease which is the hepatic manifestation of the metabolic syndrome.

Synergic effect of vitamin A and high-fat diet in adipose tissue development and nuclear receptor expression in young rats.

In order to study the effects of dietary lipids and vitamin A on the development of adipose tissues, young rats were submitted for 8 d to a control or to two cafeteria diets with normal (Caf) or higher (Caf + ) vitamin A levels. Retinoid (retinoic acid receptor (RAR) a, RARg, retinoid X receptor(RXR) alpha) and fatty acid (PPARgamma) receptor mRNA was measured in the subcutaneous white adipose tissue (Swat) and in isolated mature adipocytes by RT-PCR. The stroma vascular fraction was cultured in vitro to test the capacities of the adipocyte precursors to proliferate and differentiate.The Caf diet enriched in vitamin A resulted in an increased adiposity, due to increased adipocyte hypertrophy. This was concomitant with a lower expression of RARa and RARg mRNA (234.6 and 238.6 %) and a higher expression of PPARgamma (+59 %) in the Swat and, to a less extent,in isolated adipocytes. Positive correlations were obtained between PPARgamma mRNA and Swat weights and between PPARgamma and RXRalpha mRNA. By contrast, RARgamma mRNA and Swat masses were negatively correlated. The adipocyte precursors from Caf + Swat proliferated more,in vitro, at the beginning of the culture. This difference progressively disappeared and was totally absent after 8 d of culture, but with a higher percentage of differentiated preadipocytes (+80.3 %) in the Caf + group. In conclusion, lipids and vitamin A act synergistically on the normal growth of the adipose tissue in young rats, concomitant with an imbalance in the pattern of the nuclear receptors. These changes influence the early normal development of the endogenous adipocyte precursors.