Publications (160) View all
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Article: Disruption of nongenomic testosterone signaling in a model of spinal and bulbar muscular atrophy.
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ABSTRACT: As one of the nine hereditary neurodegenerative polyQ disorders, spinal and bulbar muscular atrophy (SBMA) results from a polyQ tract expansion in androgen receptor (AR). Although protein aggregates are the pathological hallmark of many neurodegenerative diseases, their direct role in the neurodegeneration is more and more questioned. To determine the early molecular mechanisms causing motor neuron degeneration in SBMA, we established an in vitro system based on the tetracycline-inducible expression of normal (AR20Q), the mutated, 51 glutamine-extended (AR51Q), or polyQ-deleted (AR0Q) AR in NSC34, a motor neuron-like cell line lacking endogenous AR. Although no intracellular aggregates were formed, the expression of the AR51Q leads to a loss of function characterized by reduced neurite outgrowth and to a toxic gain of function resulting in decreased cell viability. In this study, we show that both AR20Q and AR51Q are recruited to lipid rafts in response to testosterone stimulation. However, whereas testosterone induces the activation of the c-jun N-terminal kinase/c-jun pathway via membrane-associated AR20Q, it does not so in NSC34 expressing AR51Q. Phosphorylation of c-jun N-terminal kinase plays a crucial role in AR20Q-dependent survival and differentiation of NSC34. Moreover, c-jun protein levels decrease more slowly in AR20Q- than in AR51Q-expressing NSC34 cells. This is due to a rapid and transient inhibition of glycogen synthase kinase 3α occurring in a phosphatidylinositol 3-kinase-independent manner. Our results demonstrate that the deregulation of nongenomic AR signaling may be involved in SBMA establishment, opening new therapeutic perspectives.Molecular Endocrinology 05/2012; 26(7):1102-16. · 4.54 Impact Factor -
Article: Aromatase et infertilité masculine
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ABSTRACT: Chez la plupart des mammifères étudiés jusqu’à ce jour, l’aromatase est présente dans les cellules somatiques et les cellules germinales du testicule. Ainsi chez le rat adulte nous avons démontré l’existence d’une aromatase fonctionnelle, notamment dans les spermatocytes pachytènes et les spermatides rondes, qui assure une production d’estrogènes équivalente à celle des cellules de Leydig. Chez l’homme, outre les cellules de Leydig nous avons mis en évidence l’aromatase dans les cellules sexuelles immatures et dans les spermatozoïdes éjaculés. Plus précisément, l’expression de l’aromatase diminue de 30% dans la fraction de spermatozoïdes immobiles comparée à celle contenant les spermatozoïdes mobiles d’un même prélèvement. Sur des échantillons issus de patients asthénospermiques, tératospermiques, et asthénotératospermiques, les taux de transcrits de l’aromatase sont respectivement diminués de 44, 52, et 67% par rapport à celui des patients normospermiques. De plus, ces taux de transcrits sont fortement corrélés (r = -0,64) aux pourcentage d’anomalies morphologiques du spermatozoïde et notamment à celles touchant la tête et l’acrosome en particulier. Des techniques immunocytochimiques associées à la microscopie confocale indiquent une forte localisation de l’aromatase au niveau du flagelle et de la pièce intermédiaire. Les altérations de la fertilité chez l’homme déficient en aromatase et nos résultats suggèrent une participation probable des estrogènes dans la mobilité et la survie des spermatozoïdes. De plus, la corrélation du taux de transcrit au degré de tératospermie ainsi qu’une localisation partielle de l’aromatase au niveau de la tête du spermatozoïde semblent confirmer l’implication de l’aromatase au cours de la réaction acrosomique. Il est donc envisageable d’utiliser l’aromatase comme marqueur du bon déroulement de la spermatogenèse et comme paramètre pour estimer la fécondance. En somme, dans le contrôle des fonctions de reproduction chez le mâle, outre les gonadotrophines et la testostérone, les estrogènes ont un rôle certainement plus complexe que cela avait été suggéré, compte tenu de l’expression particulière de l’aromatase et de la présence de récepteurs aux estrogènes dans les cellules testiculaires et les spermatozoïdes en particulier. L’infertilité est un problème de société qui concerne tous les pays et donc les études menées sur les empreintes nucléaires doivent permettre de mieux comprendre certains aspects de la Physiopathologie de la reproduction masculine. The mammalian testis is a complex organ which produces spermatozoa and synthesizes steroids. The transformation of androgens into estrogens is catalyzed by aromatase, an enzymatic complex encoded by a single copy-gene (cyp19) which contains 18 exons, 9 of which are translated. In man, in addition to Leydig cells, we have demonstrated the existence of a biologically active aromatase in immature germ cells and in ejaculated spermatozoa. The presence of estrogen receptors (ERa and ERβ) in immature germ cells and spermatozoa has also been reported. A 30% decrease in the amount of aromatase mRNA is observed in immotile sperm compared to the motile sperm fraction from the same sample. Aromatase and GAPDH transcript levels have also been determined by real-time PCR following RNA extraction in sperm samples from individual ejaculates of normozoospermic, and infertile patients. The aromatase protein and markers of either acrosome (CD 46), or tail (tubulin) or mid-piece (Mitotracker Green) or nucleus (DAPI) were immunolocalized by confocal microscopy. In asthenoteratozoospermic, teratozoospermic and asthenozoospermic patients, aromatase gene expression is decreased by 67%, 52% and 44%, respectively, compared to normospermic controls. Statistical analysis between sperm morphology and aromatase/GAPDH ratio revealed a high degree of correlation (r=-0.64) between this ratio and the percentage of abnormal spermatozoa (especially microcephaly). Using confocal microscopy, we have observed for the first time the existence of two sites for aromatase: the first site co-localized with tubulin is the tail with intensive staining in the mid-piece and the second site corresponds to the equatorial region of the head. Decreased sperm count and motility have been reported in genetically aromatase-deficient men. In addition to gonadotrophins and testosterone, estrogens therefore also probably play a relevant role in spermatogenesis and human male gamete maturation. Our data suggest that aromatase transcripts could be a marker of male gamete quality and the existence of two sites of aromatase could be related to the role of estrogens in motility and acrosome reaction. Male infertility is a worldwide social problem and consequently, comparative studies of mRNA fingerprints in ejaculates between fertile and infertile men may contribute to elucidate some aspects of male reproductive pathology.Andrologie 04/2012; 18(4):258-263. -
Article: Etude de l’effet androgénique de l’extrait au méthanol deBasella alba L. (Basellaceae) sur la fonction de reproduction du rat mâle
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ABSTRACT: Basellaalba est une plante utilisée par les tradipraticiens de la province de l’Ouest Cameroun pour lutter contre l’asthénie sexuelle et l’infertilité chez l’homme. Les travaux antérieursin vitro ont prouvé l’activité androgénique de son extrait au méthanol. Le présent travail porte sur la confirmationin vivo de son effet androgénique chez le rat mâle adulte. Cet extrait est quotidiennement administré (par gavage) pendant 30 jours aux doses de 0, 0,1, 1, 10 et 100 mg/kg respectivement à 5 groupes de 6 rats mâles. Les animaux sont pesés tous les deux jours et au terme de 30 jours de traitement sont sacrifiés. Le sang est recueilli; le foie et les organes de reproduction (testicules, épididymes, vésicules séminales, prostate) prélevés et pesés. Le sang est utilisé pour le dosage de la testostérone du sérum par125I-RIA et de quelques marqueurs de toxicité du foie et des reins. D’autres indicateurs de l’intégrité cellulaire sont également estimés dans le foie. Les résultats montrent que l’extrait au méthanol deB. alba n’a pas d’effet sur le poids corporel des animaux ainsi que sur celui des organes de reproduction. Après 30 jours de traitement, l’effet de l’extrait au méthanol deB. alba sur la production de testostérone est significativement élevé (p<0,0005) à la dose 1 mg/kg, alors qu’à partir de 10 mg/kg d’extrait, ce niveau de testostérone baisse, mais reste élevé par rapport au témoin. Toujours au niveau du sérum, le taux de créatinine et l’activité de l’alanine aminotransférase ne montrent pas de variation significative entre les animaux témoins et ceux traités aux différentes doses d’extrait. Cette observation est identique quant aux paramètres mésurés dans le foie: aniline hydroxylase, taux de protéines, de glutathion, d’aldéhyde malonique. Ces résultats suggèrent que l’extrait au méthanol deB. alba a une activité androgéniquein vivo qui est maximale à la dose 1 mg/kg de poids corporel. Basella alba is a plant used by some herbalists of the West province of Cameroon to enhance male virility and fertility. Previousin vitro studies have shown the androgenic activity of its methanol extract. This study therefore focused on confirmation of the androgenic activity of the methanol extract ofB. alba in vivo in male rats. A suspension of this extract in corn starch was administered daily to 5 groups of rats at doses of 0,0.1, 1, 10 and 100 mg/kg respectively for 30 days. The animals were weighed every second day during this period. On the 31st day of the experiment, the animals were sacrificed and blood was collected for serum assays. The liver and reproductive organs (testes, epididymides, seminal vesicles and prostates) were also collected and weighed. Serum testosterone level was determined by radio-immunoassay (125I-RIA) techniques, and various markers of liver and kidney toxicity (alanine aminotransferase and creatinine) were also assayed. Liver post-mitochondrial supernatant was used to estimate other markers of cell integrity, such as malondialdehyde, glutathione, and aniline hydroxylase activity. The results showed that the methanol extract ofB. alba has no effect on the weight of the animal and reproductive organs compared to the control. After 30 days of treatment, serum testosterone levels were significantly increased (p<0.0005) up to the dose of 1 mg/kg, but decreased at higher dosages of the extract, although remained higher than that of controls. Aniline hydroxylase and aminotransferase activities, malondialdehyde, protein, glutathione and creatinine levels were not significantly altered by administration of the methanol extract ofB. alba. These results suggest that the methanol extract ofB. alba has anin vivo androgenic activity with a maximum effect at the dose of 1 mg/kg body weight.Andrologie 04/2012; 17(2):129-133. -
Article: Inhibitory action of purified hydroxytyrosol from stored olive mill waste on intestinal disaccharidases and lipase activities and pancreatic toxicity in diabetic rats
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ABSTRACT: This study was established that after 3 months storage, olive mill waste (OMW) was enriched with hydroxytyrosol (HT) (2,652 mg/L) and contained only phenolic monomers. It also showed that HT supplementation to surviving diabetic rats decreases considerably intestinal maltase, lactase, sucrose, and lipase activities by 49, 31, 42, and 40%, respectively. In addition, HT enhanced the superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) activities by 330, 170, and 301%, respectively and reduced gluthation (GSH) level by 79% in pancreas compared to diabetic rats. Moreover, a significant decrease in the thiobarbituric acid reactive substances (TBARs) level and lactate dehydrogenase (LDH) activity in diabetic rats pancreas by 34 and 49% respectively after administration of HT. In addition, HT improved plasma triglyceride and cholesterol levels in diabetic rats by lowering low density lipoprotein (LDL)-cholesterol and triglycerides (TG) by 27 and 53%, respectively and increasing high density lipoprotein (HDL)-cholesterol content by 72%. These properties of HT are interesting regarding its use as therapeutic agent in biotechnological applications, especially in developing anti-diabetic and hypocholesterolemic drugs. Keywordshydroxytyrosol-olive mill waste-disaccharidase-lipase-intestinal-diabetesFood science and biotechnology 04/2012; 19(2):439-447. · 0.49 Impact Factor -
Article: Modulatory effect of fenugreek saponins on the activities of intestinal and hepatic disaccharidase and glycogen and liver function of diabetic rats
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ABSTRACT: Diabetes mellitus is a serious health concern throughout the world and is often associated with a variety of bodily disorders such as liver toxicity and dysfunction. This study elucidates the effect of fenugreek saponin administration on disaccharidase and glycogen activities in the intestine and liver of surviving diabetic rats. It also evaluates the effect of saponin feeding using a number of liver toxicity indices, namely stress oxidant, liver dysfunction markers and metabolism. Our findings indicate that the fenugreek saponin fraction significantly modulated the disaccharidase and glycogen enzyme activities in the intestine and liver of rats, increased the hepatic glycogen content, suppressed the increase of blood glucose level and improved results in the oral glucose tolerance test (OGTT). The fenugreek saponin extract also efficiently protected the hepatic function, which was evidenced by the significant increases of superoxide dismutase (SOD), catalase (CAT), gluthation peroxidase (GPX), aspartate transaminase (AST), alanine transaminase (ALT) and lactate deshydrogenase (LDH) enzyme activities. Fenugreek saponin also induced a notable delay in the absorption of LDL-cholesterol and triglycerides and a remarkable increase in levels of HDL-cholesterol. A histological analysis of the hepatic tissues further established the positive effect of fenugreek saponin. Overall, the findings of the current study indicate that fenugreek saponins exhibit attractive properties and can be considered as promising candidates for future application as therapeutic agents in biotechnological and bioprocess-based technologies, particularly those related to the development of anti-diabetic, hepatoprotective and hypolipidemic drugs. Keywordsdiabetes mellitus-modulatory effect-fenugreek saponins-disaccharidases-drugsBiotechnology and Bioprocess Engineering 04/2012; 15(5):745-753. · 1.28 Impact Factor
