Semi-pilot scale-up of a continuous packed-bed bioreactor system developed for the lipase-catalyzed production of pseudo-ceramides

Ceramides are sphingolipid compounds that are very attractive as active components in both the pharmaceutical and the cosmetic industries. In this study, the synthesis of 1-O,3-N-diacyl 3-amino-1,2-propanediol-type pseudo-ceramides was developed at the semi-pilot scale, starting from a two-step continuous enzymatic process with immobilized Candida antarctica lipase B (Novozym® 435) in a packed-bed bioreactor, previously optimized at the laboratory scale. This process involved the selective N-acylation of 3-amino-1,2-propanediol (step 1), followed by the selective O-acylation of the N-acyl 3-amino-1,2-propanediol synthesized in the first step, with various fatty acids as acyl donors, to produce N,O-diacyl 3-amino-1,2-propanediol-type pseudo-ceramides (step 2). Under partially optimized operating conditions, high synthesis yields and production rates were obtained, within the ranges 76–92% and 3.7–4.6 g h−1 (step 1), or 23–36% and 1–1.4 g h−1 (step 2), respectively, depending on the fatty acids used as acyl donors. The overall synthesis yields varied from 20 to 33%: the best yield was obtained using palmitic acid and lauric acid as first and second acyl donors, respectively. Together with the high production rates also obtained with these acyl donors, this confirms that this two-step process has great potential for the production of differently functionalized 1-O,3-N-diacyl 3-amino-1,2-propanediol-type pseudo-ceramides on an industrial scale

L’île de La Réunion dans la Seconde Guerre mondiale

Le 1er septembre 1939, pour la métropole, comme pour l’île de La Réunion et les autres colonies françaises, est marqué par la mobilisation générale. Au moment de l’armistice, le gouverneur Aubert, comme la plupart de ses collègues de l’outre-mer, choisit de rester fidèle au gouvernement du maréchal Pétain. Le régime de Vichy est alors reproduit dans la colonie et, aux lois répressives, s’ajoutent tous les problèmes de la colonie : ravitaillement, tissus, rationnement, marché noir, etc. En novembre 1942, l’arrivée de la France libre change la donne : c’est le retour progressif de la démocratie, même si les problèmes récurrents liés aux privations subsistent. Les Réunionnais, qui ont pleinement participé à l’effort de guerre auprès de la France libre, fêtent alors, en 1945, la fin de la guerre avec les espoirs qui y sont liés.The island of Réunion in the war, 1939-1945  September 1, 1939, for the city, as well as for the island of Réunion and other French colonies, was marked by general mobilization. At the time of the armistice, the governor, Aubert, like most of his colleagues overseas, chose to remain loyal to the government of Marshal Pétain. The Vichy regime was then introduced into the colony and, along with repressive laws, added to all the problems of the colony: feeding, work patterns, rationing, black market, etc. In November 1942, the arrival of Free France changed that: it brought the gradual return of democracy, even if the recurring problems associated with deprivation remained. The people of Réunion, who were fully involved in the war effort to free France, celebrated then, in 1945, the end of the war and their hopes which were interconnected

L’île de La Réunion dans la Seconde Guerre mondiale

Le 1er septembre 1939, pour la métropole, comme pour l’île de La Réunion et les autres colonies françaises, est marqué par la mobilisation générale. Au moment de l’armistice, le gouverneur Aubert, comme la plupart de ses collègues de l’outre-mer, choisit de rester fidèle au gouvernement du maréchal Pétain. Le régime de Vichy est alors reproduit dans la colonie et, aux lois répressives, s’ajoutent tous les problèmes de la colonie : ravitaillement, tissus, rationnement, marché noir, etc. En novembre 1942, l’arrivée de la France libre change la donne : c’est le retour progressif de la démocratie, même si les problèmes récurrents liés aux privations subsistent. Les Réunionnais, qui ont pleinement participé à l’effort de guerre auprès de la France libre, fêtent alors, en 1945, la fin de la guerre avec les espoirs qui y sont liés.The island of Réunion in the war, 1939-1945  September 1, 1939, for the city, as well as for the island of Réunion and other French colonies, was marked by general mobilization. At the time of the armistice, the governor, Aubert, like most of his colleagues overseas, chose to remain loyal to the government of Marshal Pétain. The Vichy regime was then introduced into the colony and, along with repressive laws, added to all the problems of the colony: feeding, work patterns, rationing, black market, etc. In November 1942, the arrival of Free France changed that: it brought the gradual return of democracy, even if the recurring problems associated with deprivation remained. The people of Réunion, who were fully involved in the war effort to free France, celebrated then, in 1945, the end of the war and their hopes which were interconnected

Is there a dark decay of neutrons in 6^6He ?

Motivated by the four standard deviations discrepancy between the mean values for the neutron lifetime obtained from beam and bottle experiments, we have searched for a hypothetical neutron dark decay in $^6$He nuclei through the channel $^6{\rm He} \rightarrow ^4{\rm He}+n+\chi$. The experiment used a 25~keV high intensity $^6$He$^+$ beam with a high efficiency neutron detector. The search for a signal correlated with the $^6$He activity in the neutron detection rate resulted in a branching ratio ${\rm Br}_\chi \leq 4.0\times10^{-10}$ with a 95\% C.L. over the mass window $937.993 < m_\chi < m_n-0.975$ MeV. This result is five orders of magnitude smaller than required to solve the neutron lifetime discrepancy

A polyphenol-rich plant extract prevents hypercholesterolemia and modulates gut microbiota in western diet-fed mice

IntroductionTotum-070 is a combination of five plant extracts enriched in polyphenols to target hypercholesterolemia, one of the main risk factors for cardiovascular diseases. The aim of this study was to investigate the effects of Totum-070 on cholesterol levels in an animal model of diet-induced hypercholesterolemia.MethodsC57BL/6JOlaHsd male mice were fed a Western diet and received Totum-070, or not, by daily gavage (1g/kg and 3g/kg body weight) for 6 weeks.ResultsThe Western diet induced obesity, fat accumulation, hepatic steatosis and increased plasma cholesterol compared with the control group. All these metabolic perturbations were alleviated by Totum-070 supplementation in a dose-dependent manner. Lipid excretion in feces was higher in mice supplemented with Totum-070, suggesting inhibition of intestinal lipid absorption. Totum-070 also increased the fecal concentration of short chain fatty acids, demonstrating a direct effect on intestinal microbiota.DiscussionThe characterization of fecal microbiota by 16S amplicon sequencing showed that Totum-070 supplementation modulated the dysbiosis associated with metabolic disorders. Specifically, Totum-070 increased the relative abundance of Muribaculum (a beneficial bacterium) and reduced that of Lactococcus (a genus positively correlated with increased plasma cholesterol level). Together, these findings indicate that the cholesterol-lowering effect of Totum-070 bioactive molecules could be mediated through multiple actions on the intestine and gut microbiota

Study of the selective enzymatic acylation of multifunctional compounds : Application to pseudo-ceramide synthesis

Les céramides sont des lipides de la classe des sphingolipides issus de la N-acylation d’une base sphingoide par un acide gras. Ces lipides et leurs analogues suscitent un grand intérêt comme composants actifs dans les industries pharmaceutique et cosmétique. Parmi les biocatalyseurs capables de réaliser la synthèse de ce type de lipide, la lipase B de Candida antarctica semble être l’enzyme la plus adaptée à la production de « pseudo-céramides » à partir d’amino-polyols. Dans ce contexte, nous avons abordé l’étude de l’acylation de composés de type « amino-alcool »catalysée par la lipase B de Candida antarctica, en gardant à l'esprit une approche fondamentale afin d’élargir les connaissances actuelles sur ce sujet. La première partie de notre travail a ainsi traité de l’étude cinétique de l’acylation de composés monofonctionnels afin de déterminer les mécanismes réactionnels et l’énantio sélectivité de la lipase B de Candida antarctica pour les réactions de N-acylation et de O-acylation. Les parties suivantes de notre travail ont porté sur une étude structure-réactivité du substrat accepteur d’acyle et sur l’étude de l’influence du solvant utilisé (solvant organique ou liquide ionique) afin de déterminer les facteurs clés influençant la chimio sélectivité et la régio sélectivité de la lipase B de Candida antarctica lors de l’acylation de composés multifonctionnels de type « amino-alcool ». Finalement, à partir des connaissances acquises dans les différentes parties, nous avons développé et optimisé un procédé de synthèse enzymatique de « pseudo-céramides » (O,N-diacyl aminopropanediols) mis en oeuvre en réacteur continu à « lit fixe ».Ceramides are lipids from the sphingolipide class derived from the N-acylation of a sphingoid base from a fatty acid. These lipids and their analogs are compounds of interest used as active components in pharmaceutical and cosmetic industries. Among biocatalysts able to synthesize this type of lipids, Candida antarctica lipase B appears to be the most appropriate enzyme for the production of "pseudo-ceramides" derived from amino-polyols. In this context, we have studied the acylation of amino-alcohol-like compounds catalyzed by Candida antarctica lipase B, keeping inmind a fundamental approach to expand the current knowledge on this subject. The first part of our work aimed to determine the reaction mechanisms and the enantio selectivity exhibited by Candida antarctica lipase B during O-acylation and N-acylation reactions, by conducting a kinetic study of mono functional compound acylation. In the following parts of our work, we performed a structurere activity study of the acyl acceptor substrate and evaluated the effect of the solvent used (organic solvent or ionic liquid) to determine the key factors influencing the chemo selectivity and the regio selectivity of the Candida antarctica lipase B-catalyzed acylation of polyfunctional amino alcohol compounds. Finally, starting from the knowledge acquired in the previous parts, we have developed and optimized an enzymatic process of “pseudo-ceramide” (O,N-diacylaminopropanediol) synthesis performed in a continuous packed-bed reactor

Etude de l'acylation sélective de composés multifonctionnels par voie enzymatique : Application à la synthèse de pseudo-céramides

Ceramides are lipids from the sphingolipide class derived from the N-acylation of a sphingoid base from a fatty acid. These lipids and their analogs are compounds of interest used as active components in pharmaceutical and cosmetic industries. Among biocatalysts able to synthesize this type of lipids, Candida antarctica lipase B appears to be the most appropriate enzyme for the production of "pseudo-ceramides" derived from amino-polyols. In this context, we have studied the acylation of amino-alcohol-like compounds catalyzed by Candida antarctica lipase B, keeping inmind a fundamental approach to expand the current knowledge on this subject. The first part of our work aimed to determine the reaction mechanisms and the enantio selectivity exhibited by Candida antarctica lipase B during O-acylation and N-acylation reactions, by conducting a kinetic study of mono functional compound acylation. In the following parts of our work, we performed a structurere activity study of the acyl acceptor substrate and evaluated the effect of the solvent used (organic solvent or ionic liquid) to determine the key factors influencing the chemo selectivity and the regio selectivity of the Candida antarctica lipase B-catalyzed acylation of polyfunctional amino alcohol compounds. Finally, starting from the knowledge acquired in the previous parts, we have developed and optimized an enzymatic process of “pseudo-ceramide” (O,N-diacylaminopropanediol) synthesis performed in a continuous packed-bed reactor.Les céramides sont des lipides de la classe des sphingolipides issus de la N-acylation d’une base sphingoide par un acide gras. Ces lipides et leurs analogues suscitent un grand intérêt comme composants actifs dans les industries pharmaceutique et cosmétique. Parmi les biocatalyseurs capables de réaliser la synthèse de ce type de lipide, la lipase B de Candida antarctica semble être l’enzyme la plus adaptée à la production de « pseudo-céramides » à partir d’amino-polyols. Dans ce contexte, nous avons abordé l’étude de l’acylation de composés de type « amino-alcool »catalysée par la lipase B de Candida antarctica, en gardant à l'esprit une approche fondamentale afin d’élargir les connaissances actuelles sur ce sujet. La première partie de notre travail a ainsi traité de l’étude cinétique de l’acylation de composés monofonctionnels afin de déterminer les mécanismes réactionnels et l’énantio sélectivité de la lipase B de Candida antarctica pour les réactions de N-acylation et de O-acylation. Les parties suivantes de notre travail ont porté sur une étude structure-réactivité du substrat accepteur d’acyle et sur l’étude de l’influence du solvant utilisé (solvant organique ou liquide ionique) afin de déterminer les facteurs clés influençant la chimio sélectivité et la régio sélectivité de la lipase B de Candida antarctica lors de l’acylation de composés multifonctionnels de type « amino-alcool ». Finalement, à partir des connaissances acquises dans les différentes parties, nous avons développé et optimisé un procédé de synthèse enzymatique de « pseudo-céramides » (O,N-diacyl aminopropanediols) mis en oeuvre en réacteur continu à « lit fixe »

Evaluation du programme de "Consultations Anti Vitamines K" au centre hospitalier de Lens

LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF