Two New Pentacyclic Triterpenoids, an Alkaloid and a Long-chain Fatty Acid from Albizia Coriaria (Welw ex. Oliver)

Herein, we report the occurrence of four new compounds in ethanolic extract of Albizia coriaria Welw ex. Oliver leaves along with other compounds previously reported in this species. The compounds were isolated and characterized using column chromatography, Fourier Transform Infrared (FTIR) and gas chromatography/mass spectrometry. FTIR spectrum of the extract showed phenolic OH stretching (3362.30 cm-1), C=O (1660.08 cm-1), CO stretching (1369.46 cm-1 and 1319.00 cm-1) and CN stretch (1072.44 cm-1) which confirmed the presence of alcohols, carboxylic acids and nitrogen-containing compounds. Oleanolic acid (1), oleanolic acid acetate (2), pterin-6-carboxylic acid (3), undecanol (4), betulinic acid (5), betulin (6) and benzyl alcohol (7) were tentatively identified in the extract. Compounds 1-4 are being reported for the first time in Albizia coriaria

Cardiac manifestations of inherited metabolic disease linked to cellular metabolism of vitamin B12 : study in two murine models of invalidation of Mtr and MMACHC genes

L'insuffisance cardiaque est l'une des causes les plus courantes de morbidité et de mortalité dans les pays occidentaux et son incidence augmente dans les pays en développement. Une carence en folates et en vitamine B12 (cobalamine) au cours de la gestation et de l'allaitement entraîne un effet de programmation fœtale avec une cardiomyopathie métabolique liée à une diminution de la synthèse de méthionine et à une altération de la réméthylation de l'homocystéine. Les défauts génétiques du métabolisme de la cobalamine, y compris la CblG causée par des mutations du gène MTR, qui code pour la méthionine synthase (qui catalyse la reméthylation de l'homocystéine dépendante de la vitamine B12 en méthionine), et CblC causée par des mutations du gène MMACHC provoquent une décompensation cardiométabolique chez les nourrissons. Cependant, les conséquences cardiaques et les mécanismes sous-jacents à ce processus chez l'adulte sont inconnus. Le but de ce projet de doctorat consistait à étudier les conséquences fonctionnelles, métaboliques et moléculaires cardiaques de l'inhibition de la synthèse de la méthionine dans un modèle murin transgénique d'invalidation constitutive du gène Mtr par spécificité cardiaque et invalidation systémique du gène MMACHC. Nous avons constaté que l'invalidation sélective de Mtr dans le cœur produisait une cardiomyopathie avec insuffisance cardiaque, une hypertrophie du myocarde et un dysfonctionnement systolique chez les jeunes souris adultes. Au niveau tissulaire et moléculaire, la cardiomyopathie observée était liée à une altération du métabolisme énergétique avec perturbation de l'oxydation des acides gras et de la phosphorylation oxydative, au stress cellulaire et au remodelage cardiaque avec fibrose. Un métabolisme énergétique altéré, il était lié à une diminution de l'expression de Sirt3. La mauvaise localisation et la séquestration nucléaire de hnRNPA1 pourraient expliquer une partie des modifications de l'expression des gènes et des protéines. Ces résultats suggèrent un mécanisme de cardiomyopathie chez jeunes adultes CblG.Heart failure is one of the most common causes of morbidity and mortality in Western countries and its incidence is increasing in developing countries. Deficiency in folates and vitamin B12 (cobalamin) during gestation and lactation causes a fetal programming effect with metabolic cardiomyopathy related to decreased synthesis of methionine and impaired remethylation (RM) of homocysteine. Inborn errors of cobalamin metabolism, including CblG caused by mutations of MTR gene, which encodes methionine synthase (that catalyzes vitamin B12 dependent remethylation of homocysteine to methionine), and CblC caused by mutations of MMACHC gene cause cardiometabolic decompensation in infants. However, cardiac consequences and mechanisms underlying this process in adults are unknown. The aim of this Ph.D. project was to investigate the cardiac functional, metabolic and molecular consequences of the inhibition of methionine synthesis in transgenic mouse model of constitutive cardiac specific invalidation of Mtr gene and systemic invalidation of MMACHC gene. We found that the selective Mtr invalidation in the heart produces cardiomyopathy with heart failure, myocardium hypertrophy and systolic dysfunction in young adult mice. At the tissue and molecular levels, the observed cardiomyopathy was related to impaired energy metabolism with disruption of fatty acid oxidation and oxidative phosphorylation, cellular stress and cardiac remodeling with fibrosis. Impaired energy metabolism was linked to decreased expression of Sirt3. The mislocalization and nuclear sequestration of hnRNPA1 could explain part of the expression changes of genes and proteins. These findings suggest a further need to evaluate whether CblG could be a new genetic cause of primary heart failure in adult patients

Manifestations cardiaques des maladies héréditaires du métabolisme cellulaire de la vitamine B12 : étude sur deux modéles murins d’invalidation des génes Mtr et MMACHC

Heart failure is one of the most common causes of morbidity and mortality in Western countries and its incidence is increasing in developing countries. Deficiency in folates and vitamin B12 (cobalamin) during gestation and lactation causes a fetal programming effect with metabolic cardiomyopathy related to decreased synthesis of methionine and impaired remethylation (RM) of homocysteine. Inborn errors of cobalamin metabolism, including CblG caused by mutations of MTR gene, which encodes methionine synthase (that catalyzes vitamin B12 dependent remethylation of homocysteine to methionine), and CblC caused by mutations of MMACHC gene cause cardiometabolic decompensation in infants. However, cardiac consequences and mechanisms underlying this process in adults are unknown. The aim of this Ph.D. project was to investigate the cardiac functional, metabolic and molecular consequences of the inhibition of methionine synthesis in transgenic mouse model of constitutive cardiac specific invalidation of Mtr gene and systemic invalidation of MMACHC gene. We found that the selective Mtr invalidation in the heart produces cardiomyopathy with heart failure, myocardium hypertrophy and systolic dysfunction in young adult mice. At the tissue and molecular levels, the observed cardiomyopathy was related to impaired energy metabolism with disruption of fatty acid oxidation and oxidative phosphorylation, cellular stress and cardiac remodeling with fibrosis. Impaired energy metabolism was linked to decreased expression of Sirt3. The mislocalization and nuclear sequestration of hnRNPA1 could explain part of the expression changes of genes and proteins. These findings suggest a further need to evaluate whether CblG could be a new genetic cause of primary heart failure in adult patients.L'insuffisance cardiaque est l'une des causes les plus courantes de morbidité et de mortalité dans les pays occidentaux et son incidence augmente dans les pays en développement. Une carence en folates et en vitamine B12 (cobalamine) au cours de la gestation et de l'allaitement entraîne un effet de programmation fœtale avec une cardiomyopathie métabolique liée à une diminution de la synthèse de méthionine et à une altération de la réméthylation de l'homocystéine. Les défauts génétiques du métabolisme de la cobalamine, y compris la CblG causée par des mutations du gène MTR, qui code pour la méthionine synthase (qui catalyse la reméthylation de l'homocystéine dépendante de la vitamine B12 en méthionine), et CblC causée par des mutations du gène MMACHC provoquent une décompensation cardiométabolique chez les nourrissons. Cependant, les conséquences cardiaques et les mécanismes sous-jacents à ce processus chez l'adulte sont inconnus. Le but de ce projet de doctorat consistait à étudier les conséquences fonctionnelles, métaboliques et moléculaires cardiaques de l'inhibition de la synthèse de la méthionine dans un modèle murin transgénique d'invalidation constitutive du gène Mtr par spécificité cardiaque et invalidation systémique du gène MMACHC. Nous avons constaté que l'invalidation sélective de Mtr dans le cœur produisait une cardiomyopathie avec insuffisance cardiaque, une hypertrophie du myocarde et un dysfonctionnement systolique chez les jeunes souris adultes. Au niveau tissulaire et moléculaire, la cardiomyopathie observée était liée à une altération du métabolisme énergétique avec perturbation de l'oxydation des acides gras et de la phosphorylation oxydative, au stress cellulaire et au remodelage cardiaque avec fibrose. Un métabolisme énergétique altéré, il était lié à une diminution de l'expression de Sirt3. La mauvaise localisation et la séquestration nucléaire de hnRNPA1 pourraient expliquer une partie des modifications de l'expression des gènes et des protéines. Ces résultats suggèrent un mécanisme de cardiomyopathie chez jeunes adultes CblG

Sirt1-PPARS Cross-Talk in Complex Metabolic Diseases and Inherited Disorders of the One Carbon Metabolism

International audienceSirtuin1 (Sirt1) has a NAD (+) binding domain and modulates the acetylation status of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) and Fork Head Box O1 transcription factor (Foxo1) according to the nutritional status. Sirt1 is decreased in obese patients and increased in weight loss. Its decreased expression explains part of the pathomechanisms of the metabolic syndrome, diabetes mellitus type 2 (DT2), cardiovascular diseases and nonalcoholic liver disease. Sirt1 plays an important role in the differentiation of adipocytes and in insulin signaling regulated by Foxo1 and phosphatidylinositol 3'-kinase (PI3K) signaling. Its overexpression attenuates inflammation and macrophage infiltration induced by a high fat diet. Its decreased expression plays a prominent role in the heart, liver and brain of rat as manifestations of fetal programming produced by deficit in vitamin B12 and folate during pregnancy and lactation through imbalanced methylation/acetylation of PGC1α and altered expression and methylation of nuclear receptors. The decreased expression of Sirt1 produced by impaired cellular availability of vitamin B12 results from endoplasmic reticulum stress through subcellular mislocalization of ELAVL1/HuR protein that shuttles Sirt1 mRNA between the nucleus and cytoplasm. Preclinical and clinical studies of Sirt1 agonists have produced contrasted results in the treatment of the metabolic syndrome. A preclinical study has produced promising results in the treatment of inherited disorders of vitamin B12 metabolism

Mechanisms of homocysteine-induced damage to the endothelial, medial and adventitial layers of the arterial wall

International audienceHomocysteine (Hcy) is a non-protein forming amino acid which is the direct metabolic precursor of methionine. Increased concentration of serum Hcy is considered a risk factor for cardiovascular disease and is specifically linked to various diseases of the vasculature. Serum Hcy is associated with atherosclerosis, hypertension and aneurysms of the aorta in humans, though the precise mechanisms by which Hcy contributes to these conditions remain elusive. Results from clinical trials that successfully lowered serum Hcy without reducing features of vascular disease in cardiovascular patients have cast doubt on whether or not Hcy directly impacts the vasculature. However, studies in animals and in cell culture suggest that Hcy has a vast array of toxic effects on the vasculature, with demonstrated roles in endothelial dysfunction, medial remodeling and adventitial inflammation. It is hypothesized that rather than serum Hcy, tissue-bound Hcy and the incorporation of Hcy into proteins could underlie the toxic effects of Hcy on the vasculature. In this review, we present evidence for Hcy-associated vascular disease in humans, and we critically examine the possible mechanisms by which Hcy specifically impacts the endothelial, medial and adventitial layers of the arterial wall. Deciphering the mechanisms by which Hcy interacts with proteins in the arterial wall will allow for a better understanding of the pathomechanisms of hyperhomocysteinemia and will help to define a better means of prevention at the appropriate window of life

Biophysical characterization of human mitochondrial binary complexes formed between ETHE1 and different sulfurtransferases.

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