Jean-Louis Beaudeux

Resveratrol bioavailability and toxicity in humans.

Numerous data are now available on the beneficial properties of the polyphenolic compound resveratrol including its anti-inflammatory and antitumor effects. However, few studies have been performed with resveratrol in humans, and the results of these studies appear fragmentary and sometimes contradictory due to variations in conditions of administration, protocols and methods of assessment. This review article presents the results of recent studies investigating the pharmacokinetics, bioavailability, and toxicity of resveratrol in humans. Resveratrol is well absorbed, rapidly metabolized, mainly into sulfo and glucuronides conjugates which are eliminated in urine. Resveratrol seems to be well tolerated and no marked toxicity was reported. These data are important in the context of human efficacy studies, and they provide further support for the use of resveratrol as a pharmacological drug in human medicine.

Matrix metalloproteinases, inflammation and atherosclerosis: therapeutic perspectives

Abstract Matrix metalloproteinases (MMPs), also called matrixins, are proteinases that participate in extracellular matrix remodelling and degradation. Under normal physiological conditions, the activities of MMPs are precisely regulated at the level of transcription, of activation of the pro-MMP precursor zymogens and of inhibition by endogenous inhibitors (tissue inhibitors of metalloproteinases; TIMPs). Alteration in the regulation of MMP activity is implicated in diseases such as cancer, fibrosis, arthritis and atherosclerosis. The pathological effects of MMPs and TIMPs in cardiovascular diseases involve vascular remodelling, atherosclerotic plaque instability and left ventricular remodelling after myocardial infarction. Since excessive tissue remodelling and increased matrix metalloproteinase activity have been demonstrated during atherosclerotic lesion progression (including plaque disruption), MMPs represent a potential target for therapeutic intervention aimed at modification of vascular pathology by restoring the physiological balance between MMPs and TIMPs. This review describes the members of the MMP and TIMP families and discusses the structure, function and regulation of MMP activity; finally, pharmacological approaches to MMP inhibition are highlighted.

Simple spectrophotometric assessment of the trans-/cis-resveratrol ratio in aqueous solutions

The solubility and molar absorptivity of trans- and cis-resveratrol isomers in aqueous solvents are poorly described. This study aimed to develop and describe a new simple method for the determination of trans- and cis-resveratrol concentrations in aqueous solutions. Up to 300 microM trans-resveratrol was dissolved in water by sonication for 2h. Cis-resveratrol was obtained by exposing a 100-muM trans-resveratrol aqueous solution to sunlight for 8h, followed by HPLC separation and analysis by mass spectrometry (resveratrol oxidation products were absent). Accurate values for UV absorbance in water were [see text], epsilon(286 nm)=23400 M(-1)cm(-1) for trans-resveratrol and [see text], epsilon(304nm)=9515 M(-1)cm(-1) for cis-resveratrol. These values allowed us to propose formulae to assess the trans-/cis-resveratrol ratio in water, using a simple and reliable UV-vis spectrophotometric method. Statistical analysis revealed no significant difference between our UV method and the commonly used HPLC method. All these data are transferable to 150 mM NaCl and 10 mM phosphate buffer solutions, which could be particularly useful for cell culture, ex vivo and in vivo studies.

High Density Lipoproteins (HDL) and the Oxidative Hypothesis of Atherosclerosis

Abstract The oxidative hypothesis of atherosclerosis classically implies a central role for low density lipoprotein (LDL) oxidation. However, new antiatherogenic properties have been recognized for high density lipoproteins (HDL), apart from their ability to reverse cholesterol transport. Indeed, native HDL could protect LDL from oxidation, thereby minimizing the deleterious consequences of this process. Several mechanisms have been suggested to explain this protective role. Two HDL-associated enzymes, paraoxonase and PAF-acetylhydrolase, detoxify oxidized phospholipids produced by lipid peroxidation. In addition, HDL could reduce hydroperoxides to their corresponding hydroxides. It has also been suggested that HDL could inhibit oxidized LDL-induced transduction signals. However, in vivo HDL oxidation in the subendothelial space would favor the atherosclerotic process. Indeed, atherogenic properties of these oxidized HDL partly result from some loss of their cholesterol effluxing capacity and from an inactivation of the lecithin-cholesterol acyltransferase, which is a HDL-associated enzyme involved in reverse cholesterol transport. Finally, oxidized HDL could induce cholesterol accumulation in macrophages. Further in-depth investigation is needed to assess these antagonistic effects and their consequences for the atherosclerotic process.

Enhanced susceptibility of low-density lipoprotein to in vitro oxidation in type 1 and type 2 diabetic patients

Macrovascular disease represents a major cause of morbidity and mortality in patients with diabetes mellitus. Low-density lipoprotein (LDL) is involved in the pathogenesis of atherosclerotic lesions, through modifying processes such as oxidation. We examined the in vitro susceptibility to oxidation and the oxidizability of LDL isolated from the plasma of Type 1 and Type 2 diabetic patients. Two groups of diabetic patients (20 Type 1, 20 Type 2) were compared with sex- and age-matched non-diabetic control groups. In vitro oxidation of the purified LDL preparations was assessed by determination of the kinetics for the formation of conjugated dienes (lag phase duration, maximal rate and maximal dienes concentration) and by measurement of thiobarbituric acid-reacting substances (TBARS) in the presence of copper ions. LDL from both Type 1 and Type 2 diabetic patients exhibited a shorter lag phase duration for conjugated dienes formation (94 +/- 14 vs. 108 +/- 20 and 97 +/- 26 vs. 112 +/- 18 min for Type 1 and Type 2 diabetic groups vs. respective control groups, P < 0.05). We also observed an increase in maximal rate of conjugated dienes formation (2.21 +/- 0.55 vs. 1.52 +/- 0.31 and 2.02 +/- 0.55 vs. 1.52 +/- 0.31 nmol/mg LDL/min, P < 0.01) and of maximal production of TBARS (77.9 +/- 11.8 vs. 65.5 +/- 10.4 and 76.7 +/- 9.9 vs. 65.3 +/- 9.4 nmol/mg LDL protein, P < 0.05) in diabetic groups. Our results demonstrate both a higher susceptibility to oxidation and a higher oxidizability of LDL from diabetic patients, as much for Type 1 as Type 2 diabetic subjects with or without pre-existent vascular complications. This enhanced propensity of LDL oxidation in patients with diabetes mellitus could at least partly be attributable to quantitative and qualitative alterations in the chemical composition of LDL and to the glycoxidation process occurring on these lipoproteins.

Piceatannol is more effective than resveratrol in restoring endothelial cell dimethylarginine dimethylaminohydrolase expression and activity after high-glucose oxidative stress

Abstract Glucose-induced oxidative stress is involved in endothelial dysfunction. Dimethylarginine dimethylaminohydrolase (DDAH) and arginase are regulators of the endothelial NO synthase (eNOS). This study aimed to compare the effect of two polyphenolic antioxidants, resveratrol and piceatannol, on DDAH and arginase pathways in bovine aortic endothelial cells under 25 mM glucose for 24 h. DDAH activity and expression were decreased in these cells as compared to control cells, whereas arginase activity was unchanged. DDAH inhibition led to intracellular accumulation of asymmetric dimethylarginine (ADMA), a natural inhibitor of eNOS. Under these conditions, cell pre-treatment with resveratrol (0.1–10 μM) restored basal DDAH activity and ADMA level with a dose-dependent effect. Piceatannol acted as resveratrol on DDAH pathway but at 10-fold lower concentrations. Resveratrol and piceatannol restored DDAH activity even in the presence of splitomicin, a specific inhibitor of Sirtuin 1. These results suggest potential therapeutic intervention targeting resveratrol or piceatannol administration to improve endothelial dysfunction.

Resveratrol: a relevant pharmacological approach for the treatment of metabolic syndrome?

Purpose of reviewThe metabolic syndrome is associated with increased risk for development of both cardiovascular disease and type 2 diabetes in humans. Because experimental data and clinical experience have shown that metabolic syndrome and caloric restriction have, at least partly, opposite pathophysiological pathways, the activation of sirtuins may constitute a pharmacological approach to treat metabolic syndrome. Resveratrol is a polyphenol produced by plants that has multiple beneficial activities similar to those associated with caloric restriction. Recent findingsThrough its regulatory action of both AMP kinase and the sirtuin sirtuin-1, resveratrol is a natural sirtuin activator that certainly will be the head of a new pharmacological family of drugs targeted on sirtuin-1 activity exacerbation in order to treat/protect from obesity and diabetes, and thus metabolic syndrome. SummaryThis review discusses the therapeutic use of resveratrol and sirtuin activators in the context of insulin resistance and obesity, the two main features of metabolic syndrome.

Serum tissue inhibitors of metalloproteinases 1 (TIMP-1) and carotid atherosclerosis and aortic arterial stiffness.

Background The results of experimental studies have suggested that matrix metalloproteinases (MMPs) and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), are involved in vascular remodeling. In a population-based study, we report the relationships of serum TIMP-1 with carotid intima–media thickness, carotid plaques and aortic arterial stiffness. Methods Free health examinations were performed on 238 men free of coronary heart diseases (aged 56.5 ± 10.4 years, 57.1% were hypertensive). Carotid–femoral pulse-wave velocity (PWV) was used to assess aortic stiffness. Carotid ultrasound examination included measurements (at sites free of plaques) of intima–media thickness (IMT) at the common carotid arteries (CCA) and assessment of atherosclerotic plaques in the extracranial carotid arteries. Results The percentage of subjects with plaques was lower in subjects with low TIMP-1 values (P for trend = 0.0001). In multivariate analysis adjusted for age, body mass index, smoking habits, total cholesterol, triglycerides, C-reactive protein, heart rate, diabetes and systolic blood pressure, the odds ratio of carotid plaques in subjects with high values of TIMP-1 (tertile 3) compared to those with low values (tertile 1) was 2.89 (95% confidence interval 1.12–7.47, P < 0.01). TIMP-1 was positively associated with CCA-IMT and PWV in univariate analysis. However, the associations disappeared once age and systolic blood pressure were taken into account in the multivariate analysis. Conclusion This study shows that there is a differential association of TIMP-1 with PWV, CCA-IMT and carotid plaques. Our results suggest that TIMP-1 might be involved in plaque formation.

trans-Resveratrol downregulates Txnip overexpression occurring during liver ischemia-reperfusion.

Txnip (thioredoxin-interacting protein) is a protein with multifunctional roles in cellular responses and stress-related diseases. Txnip is involved in intracellular redox regulation and has been recently described as a possible link between redox state and metabolism. trans-Resveratrol (T-res) is a natural phytoalexin with antiproliferative, antiapoptotic and antioxidative effects. However, to date there have been no reports of the implication of Txnip in a model of liver acute stress such as ischemia-reperfusion (I/R) and no work has looked for a T-res effect on Txnip. Here we studied the effects of a post-ischemic treatment of T-res on the liver thioredoxin (Trx)/Txnip system and investigated whether the T-res effects were dependent on *NO production. In this work, liver I/R induced hepatic Txnip expression and T-res inhibited I/R Txnip expression. This decrease in Txnip expression by T-res was associated with an increase in liver Trx redox activity and a decrease in hepatic I/R-induced Trx-1 expression with no effect on Trx-2, on plasma Trx redox activity or on liver and plasma Trx reductase activity, independently of *NO production. In conclusion, these results show that in our model, not only did T-res protect Trx redox activity by diminishing the Txnip protein expression; it also reduced secretion of Trx1. This is the first report of a major implication of the Trx1/Txnip system in hepatic I/R injuries. It also affirms the importance of the antioxidant effect of T-res on the Trx1/Txnip system.

Reference Values for Serum S-100B Protein Depend on the Race of Individuals

S-100B is expressed by cells of neuroectodermal origin, particularly cerebral glial cells (astrocytes), and in several tumor processes, including malignant melanocytic lesions (1). Although S-100B is localized primarily in the intracellular compartment, it is physiologically detectable in biological fluids (cerebrospinal fluid, serum, and urine). Measurement of S-100B has been proposed as a biological marker of brain damage, e.g., head injury, cerebral hypoxia, and stroke (2), and of malignant melanoma(3). Serum S-100B values in healthy individuals range from 0.02 to 0.15 μg/L, as determined by immunoluminometric analytical methods. Although studies are controversial, S-100B concentrations in biological fluids appear to be age- and sex-dependent (4)(5)(6)(7). No information is available regarding potential differences according to the race or ethnicity of individuals. Here we report the results …