Risques rénaux des compléments alimentaires: une cause ignorée [Renal risks of dietary complements: a forgotten cause].

The use of dietary complements like vitamins, minerals, trace elements, proteins, aminoacids and plant-derived agents is prevalent in the general population, in order to promote health and treat diseases. Dietary complements are considered as safe natural products and are easily available without prescription. However, these can lead to severe renal toxicity, especially in cases of unknown pre-existing chronic kidney disease (CKD). In particular, Chinese herbs including aristolochic acid, high doses of vitamine C, creatine and protein complements may lead to acute and chronic renal failure, sometimes irreversible. Dietary complement toxicity should be suspected in any case of unexplained renal impairement. In the case of pre-existing CKD, the use of potentially nephrotoxic dietary complements should be screened for.

Authentication of vegetable oils by bulk and molecular carbon isotope analyses with emphasis on olive oil and pumpkin seed oil

The authenticity of vegetable oils consumed in Slovenia and Croatia was investigated by carbon isotope analysis of the individual fatty acids by the use of gas chromatography-combustion-isotope ratio mass spectrometry (GC/C/IRMS), and through carbon isotope analysis of the bulk oil. The fatty acids from samples of olive, pumpkin, sunflower, maize, rape, soybean, and sesame oils were separated by alkaline hydrolysis and derivatized to methyl esters for chemical characterization by capillary gas chromatography/mass spectrometry (GC/MS) prior to isotopic analysis. Enrichment in heavy carbon isotope (C-13) of th, bulk oil and of the individual fatty acids are related to (1) a thermally induced degradation during processing (deodorization, steam washing, or bleaching), (2) hydrolytic rancidity (lipolysis) and oxidative rancidity of the vegetable oils during storage, and (3) the potential blend with refined oil or other vegetable oils. The impurity or admixture of different oils may be assessed from the delta C-13(16:0) VS. delta C-13(18:1) covariations. The fatty acid compositions of Slovenian and Croatian olive oils are compared with those from the most important Mediterranean producer countries (Spain, Italy, Greece, and France).

Characterization of the phosphorylation sites involved in G protein-coupled receptor kinase- and protein kinase C-mediated desensitization of the alpha1B-adrenergic receptor.

Catecholamines as well as phorbol esters can induce the phosphorylation and desensitization of the alpha1B-adrenergic receptor (alpha1BAR). In this study, phosphoamino acid analysis of the phosphorylated alpha1BAR revealed that both epinephrine- and phorbol ester-induced phosphorylation predominantly occurs at serine residues of the receptor. The findings obtained with receptor mutants in which portions of the C-tail were truncated or deleted indicated that a region of 21 amino acids (393-413) of the carboxyl terminus including seven serines contains the main phosphorylation sites involved in agonist- as well as phorbol ester-induced phosphorylation and desensitization of the alpha1BAR. To identify the serines invoved in agonist- versus phorbol ester-dependent regulation of the receptor, two different strategies were adopted, the seven serines were either substituted with alanine or reintroduced into a mutant lacking all of them. Our findings indicate that Ser394 and Ser400 were phosphorylated following phorbol ester-induced activation of protein kinase C, whereas Ser404, Ser408, and Ser410 were phosphorylated upon stimulation of the alpha1BAR with epinephrine. The observation that overexpression of G protein-coupled kinase 2 (GRK2) could increase agonist-induced phosphorylation of Ser404, Ser408, and Ser410, strongly suggests that these serines are the phosphorylation sites of the alpha1BAR for kinases of the GRK family. Phorbol ester-induced phosphorylation of the Ser394 and Ser400 as well as GRK2-mediated phosphorylation of the Ser404, Ser408, and Ser410, resulted in the desensitization of alpha1BAR-mediated inositol phosphate response. This study provides generalities about the biochemical mechanisms underlying homologous and heterologous desensitization of G protein-coupled receptors linked to the activation of phospholipase C.

Novel Bioconjugates of Aminolevulinic Acid with Nucleosides

Esters and amino acid derivatives of 5-aminolevulinic acid (ALA) are efficient prodrugs for the production of protoporphyrin IX (PpIX), which has been used in photodynamic cancer therapy (PDT). The synthesis of novel bioconjugates combining ALA with adenosine and thymidine is reported. The novel bioconjugates have been made using a robust methodology. The new class of prodrugs contains one, two, or three ALA per molecule. Preliminary cell tests in human cancer cell lines indicate that the thymidine conjugate of ALA is an efficient prodrug for PDT.

Exploring the space of histidine containing dipeptides in search of novel efficient RCS sequestering agents.

The study reports a set of forty proteinogenic histidine-containing dipeptides as potential carbonyl quenchers. The peptides were chosen to cover as exhaustively as possible the accessible chemical space, and their quenching activities toward 4-hydroxy-2-nonenal (HNE) and pyridoxal were evaluated by HPLC analyses. The peptides were capped at the C-terminus as methyl esters or amides to favor their resistance to proteolysis and diastereoisomeric pairs were considered to reveal the influence of configuration on quenching. On average, the examined dipeptides are less active than the parent compound carnosine (βAla + His) thus emphasizing the unfavorable effect of the shortening of the βAla residue as confirmed by the control dipeptide Gly-His. Nevertheless, some peptides show promising activities toward HNE combined with a remarkable selectivity. The results emphasize the beneficial role of aromatic and positively charged residues, while negatively charged and H-bonding side chains show a detrimental effect on quenching. As a trend, ester derivatives are slightly more active than amides while heterochiral peptides are more active than their homochiral diastereoisomer. Overall, the results reveal that quenching activity strongly depends on conformational effects and vicinal residues (as evidenced by the reported QSAR analysis), offering insightful clues for the design of improved carbonyl quenchers and to rationalize the specific reactivity of histidine residues within proteins.

The lipid composition of rat brain aggregating cell cultures during development.

The lipid and fatty acid composition of rat brain was studied during its development both in vivo and in an aggregating cell culture system. Although the amount of lipid present in the cultures was very low, the increase in glycolipid content corresponded closely to the period of intense myelin formation. Very long chain fatty acids (hydroxylated and unsubstituted) were present in 41-day cultures. In comparison to the in vivo situation, myelination was delayed in vitro and, after 40 days in culture, cholesterol esters were 5-fold higher than in vivo, indicating that demyelination was occurring.

Phytochemical investigation of plants used in African traditional medicine: "Dioscorea sylvatica" (Dioscoreaceae), "Urginea altissima" (Liliaceae), "Jamesbrittenia fodina" and "Jamesbrittenia elegantissima" (Scrophulariaceae)

Les plantes médicinales représentent la seule source de médicaments pour près de 90 % de la population de certains pays d?Afrique. Le savoir-faire des guérisseurs traditionnels, d?une valeur inestimable, représente un point de départ pour l?investigation pharmacologique et phytochimique de ces médicaments naturels. Dans le cadre de ce travail, nous nous sommes dans un premier temps intéressés à valider l?utilisation en médecine traditionnelle de deux plantes, Diuscorea sylvatica (Dioscoreaceae) et Urginea altissima (Liliaceae), qui produisent, lorsqu?elles sont frottées sur la peau, une inflammation et des démangeaisons. Ces réactions cutanées ont pu être expliquées, au moins en partie, par la présence d?aiguilles acérées d?oxalate de calcium dans les organes souterrains. Ces microtraumatismes répétés de l?épiderme risquent de provoquer, lors d?une utilisation prolongée, des lésions granulomateuses. L?histamine n?a pas été détectée, mais d?autres substances pourraient être impliquées dans le processus inflammatoire. La seconde partie de ce travail a consisté en la détection, l?isolement et la caractérisation de nouveaux composés naturels présentant un intérêt thérapeutique potentiel. 70 extraits provenant de 28 plantes supérieures du Zimbabwe ont été soumis à un criblage chimique et biologique. Les extraits méthanoliques des parties aériennes de Jamesbrittenia fodina et J. elegantissima (Scrophulariaceae) ont été sélectionnés sur la base de leurs nombreuses activités. Le fractionnement guidé par l?activité de J. fudina a permis l?isolement des saponines A et B, responsables des activités antifongique, antibactérienne et molluscicide de l?extrait. De plus, les deux saponines ont montré une activité équivalente en tant qu?inhibiteurs de l?acétylcholinestérase, propriété encore non décrite pour cette classe de composés. Une analyse LC/uv/MS de l?extrait a permis d?attribuer l?activité antiradicalaire au verbascoside, un dérivé du phenylpropane; cette analyse a de plus montré la présence d?une série de dérivés de l?acide cinnamique, dont l?isolement a été entrepris. Deux problèmes d?instabilité sont apparus, empêchant l?isolement des composés par des méthodes chromatographiques de pointe, en dépit de très bonnes conditions de séparations. Des analyses LC/?H-NMR combinées à des analyses RMN classiques des mélanges ont permis d?attribuer ces instabilités d?une part à une isomérisation cis/trans induite par la lumière, et d?autre part à une transacylation du groupe cinnamoyl sur une unité de sucre. Ceci a permis l?identification de 12 esters cinnamiques d?iridoïdes, dont 8 nouveaux produits naturels. Ces dérivés présentent un intérêt thérapeutique, car des composés similaires ont montré des propriétés anti-inflammatoires significatives dans différents modèles in vivo. Deux flavanones ont aussi été isolées de l?extrait. Cette classe de composés n?a jamais été rapportée chez un membre des Scrophulariaceae. Une analyse LC/UV/MS comparative des extraits polaires des deux espèces, J. fodina et J. elegantissima, a été effectuée pour détecter la présence éventuelle de compos.és communs. Les saponines A et B et le verbascoside ont été identifiés dans l?extrait de J. elegantissima. Trois flavonoïdes ont de plus été isolés de ce dernier par CPC et HPLC semi-préparative.<br/><br/>In certain African countries, medicinal plants represent the unique source of to 90% of the population. The knowledge of traditional healers represents a basis for the pharmacological and phytochemical investigation of these natural medicines. This work first focused on the validation of use of two plants frequently employed in traditional medicine, Dioscorea sylvatica (Dioscoreaceae) and Urginea altissimu (Liliaceae), which produce mild inflammation and itching when rubbed on the skin. These cutaneous reactions were shown to be due, at least in part, to the presence of sharp needles of calcium oxalate, implying the risk of granulomatous lesions following a long term use. Histamine was not detected, but other compounds could be involved in the inflammatory process. The second part of this work consisted of the detection, isolation and characterisation of new natural compounds of potential therapeutic interest from African plants. Seventy extracts obtained from 28 higher plants of Zimbabwe were submitted to a chemical and biological screening. The methanol extracts of the whole plants of Jamesbrittenia fodina and J. elegantissima (Scrophulariaceae) were selected for their various activities. An activity-guided fractionation of J. fodina led to the isolation of the saponins A and B, responsible for the antifungal, antibacterial and molluscicidal properties. Both saponins were equally active as inhibitors of acetylcholinesterase, a property that has, to our knowledge, never been described for this class of compounds. A LC/UV/MS analysis of the extract allowed the identification of verbascoside as the product with radical scavenging activity, and indicated the presence of a series of potentially interesting cinnamic acid derivatives. Two types of instability problems occurred in the course of their isolation, as some compounds could not be separated despite very good chromatographic conditions. LC/'H-NMR analyses combined with in-mixture NMR analyses enabled the attribution of the cause of the instability in one case to a cidtrans light-induced isomerisation, and in the other case to a transacylation of the cinnamoyl moiety on a sugar residue. These problems of instability have not been the object of previous studies. 12 cinnamic iridoid esters could be characterised, 8 of these being new natural compounds. Several similar substances have displayed significant anti-inflammatory properties in different in vivo models, suggesting a therapeutic interest for these new derivatives. Two flavanones were isolated from the same extract. This class of compound has not been previously reported from species of the Scrophulariaceae family. A comparative LCAJVNS study of the polar extracts of the two species J. elegantissima and J. fodina was performed in order to detect possible common compounds. Saponins A and B and verbascoside were thus identified in .J. elegantissima. Moreover, three supplementary flavonoids were isolated from J. elegantissima..