Diabetes mellitus is associated with several clinically significant abnormalities in the oral cavity and salivary glands, the most common being periodontitis, salivary gland enlargement and a sensation of dry mouth. The pre­valence of dental caries in diabetics is mostly reported to be decreased or unaffected. Since there is a shortage of information concerning the influence of metabolic control and duration of diabetes on these abnormalities, the present studies were performed. Three-month-old rats were made alloxan-diabetic and investigated after one and twelve months’ duration of dia­betes for oral lesions and feeding behavior. They had free access to a standard pellet diet and tap water. Strepto­coccus mutans and lactobacilli were naturally occurring. In diabetic rats the proportion of the oral flora which was lactobacilli was positively correlated to the blood glucose level. Untreated long-term alloxan-diabetic rats de­veloped advanced periodontal disease and root surface caries in the molars at sites of interdental impaction of foreign material. The degree of alveolar bone loss was positively correlated to the blood glucose level. Diabetic rats were hyperphagic and had a longer total eating time, including day-time eating, mainly by having longer meals but no significant increase of meal frequency, as compared with non-diabetic animals. The untreated al­loxan-diabetic rats developed reduced salivary gland weight which was of the same degree in short- and long­term diabetic animals. Short- and long-term untreated alloxan-diabetic rats showed a similar degree of morpho- metrically estimated lipid accumulation in the acinar cells of the submandibular glands, and the degree was posi­tively correlated to the blood glucose level. However, lipid inclusion occurred only in rats with a morning non­fasting blood glucose level exceeding 15 mmol/L. The capillaries in the submandibular glands of the untreated long-term alloxan-diabetic rats had a significantly increased thickness of the basement membranes as compared with the observations in short-term diabetic and non-diabetic rats. Untreated alloxan-diabetic rats were also shown to have a decreased salivary flow rate compared with non-diabetic rats, and the decreased flow was negatively correlated to the blood glucose concentration. Salivary flow rate increased with the duration of the disease. The diabetic rats had increased salivary glucose levels, which were positively correlated to blood glucose values when the latter were above 15 mmol/L, suggesting a threshold mechanism for salivary glucose excretion. Insulin therapy reversed salivary flow rate and salivary glucose concentrations toward normal. Salivary investigations were performed in eleven diabetic patients on two occasions with different metabolic con­trol. Salivary flow rate showed marked interindividual differences but was not significantly changed by improv­ed metabolic control although several of the patients initially had severely deranged glucose metabolism. A posi­tive correlation between the glucose concentration in blood and saliva was seen in the parotid saliva during secre­tory stimulation. No significant change in electrolytes, amylase or antimicrobial factors was found. / <p>S. 1-48: sammanfattning, s. 49-90: 5 uppsatser</p> / digitalisering@umu

During marijuana and alcohol consumption as well as during inflammation the reproductive axis is inhibited, mainly through the inhibition of luteinizing hormone-releasing hormone release. In male rats, this inhibitory effect is mediated, at least in part, by the activation of hypothalamic cannabinoid type 1 receptors (CB1). During inflammation, this activation of the endocannabinoid system seems to be mediated by an increase in TNF-α production followed by anandamide augmentations, similarly the effect of intragastric administration of ethanol (3 g/kg) seems to be due to an increase in anandamide. On the other hand, a number of different actions mediated by the endocannabinoid system in various organs and tissues have been described. Both cannabinoid receptors, CB1 and CB2, are localized in the submandibular gland where they mediate the inhibitory effect of intrasubmandibular injections of the endocannabinoid anandamide (6 × 10–5M) on salivary secretion. Lipopolysaccharide (5 mg/kg/3 h) injected intraperitoneally and ethanol (3 g/kg/1 h) injected intragastrically inhibited the salivary secretion induced by the sialogogue metacholine; this inhibitory effect was blocked by CB1 and/or CB2 receptor antagonists. Similar to the hypothalamus, these effects seem to be mediated by increased anandamide. In summary, similar mechanisms mediate the inhibitory actions of endocannabinoids and cannabinoids in both hypothalamus and submandibular gland during drug consumption and inflammation. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

The aim of the present investigation was to study the influence of the sympathetic nervous system and of various adrenoceptor agents on enzyme secretion and morphology in rat parotid and guinea-pig submandibular glands. Biochemical methods were combined with electron microscopical techniques. Two different in vitro systems were employed, batch-incubation and microperifusion, to characterize the sympathetically evoked amylase release and its correlation to cyclic AMP. By using various selective β-adrenoceptor agonists and antagonists a dominance of the β1-adrenoceptor over the β2 - in regulating amylase release - was establ ished. Continuous noradrenaline perifusion caused a rapid initial amylase discharge, closely correlated to tissue levels of cyclic AMP; no correlation between the two was observed during the later phase. Prenalterol (a β1-agonist) failed to elevate glandular cyclic AMP. This was in contrast to its potent secretagogic effect. On the other hand, terbutaline (a β2-agonist) was a weak secretagogue but markedly raised the levels of cyclic AMP. Thus, β-adrenoceptor activation may lead to release of large amounts of amylase despite minimal or no increase in cyclic AMP. Moreover, these effects seemed to be dissociated in salivary glands with regard to the β-adrenoceptor subtypes. This was further substantiated by the findings that repeated injections of prenalterol induced qualitative changes in the granule populations, similar to those caused by the non-selective β-agonist isoprenaline. Terbutaline was without effect. However, acinar cells size was increased following both prenalterol and terbutaline treatment. The data suggest that the 3-adrenergic effects on acinar cell size and granule population may be independently regulated. A decreased sympathetic activity of long duration was induced by neonatal or adult extirpation of the superior cervical ganlion on one side. Acinar cell size, as well as granule and amylase content was reduced 9 weeks after neonatal denervation. Ganglionectomy performed in adult animals was without significant effects. The secretory behaviour of neonatally denervated glands was characterized by an increased postjunctional sensitivity to 3-adrenoceptor agonists. Of special interest was the finding that neonatal denervation seemed to transform terbutaline from a partial to a full secretory agonist, thus changing its effects in the direction of those of prenalterol and noradrenaline. Moreover, increased levels of cyclic AMP as well as an enhanced response to DBcAMP were noted in the denervated glands as were intracellular changes. The denervation supersensitivity after neonatal denervation seems to differ from that observed in adult denervated glands. The results of the studies on denervated glands suggest that the sympathetic nervous system plays a fundamental role in the early maturation of the rat parotid gland as well as for the development of the β-adrenoceptor subtypes. / <p>S. 1-34: sammanfattning, s. 35-128: 6 uppsatser</p> / digitalisering@umu

No description available.

L'amertume fait partie intégrante de notre alimentation. Elle est par exemple fortement représentée dans certaines boissons (ex: café) ou dans certains légumes tels les crucifères. Néanmoins, la perception de l'amertume varie entre les individus et certains aliments considérés comme bénéfiques pour la santé peuvent être rejetés en raison de leur goût amer. Des facteurs génétiques (ex : polymorphisme génétique des récepteurs du goût amer) ou environnementaux (ex : âge, prise de médicaments) expliquent en partie les variations interindividuelles dans la perception de l'amertume. Cependant, d'autres facteurs péri-récepteurs pourraient intervenir, notamment la composition salivaire. Afin d'investiguer dans un premier temps le lien existant entre le protéome salivaire propre à un individu et sa sensibilité à l'amertume, le seuil de détection du goût amer de la caféine a été mesuré sur 29 hommes sains. Leur salive au repos a été étudiée par électrophorèse mono- et bidimensionnelle. L'analyse par électrophorèse bidimensionnelle de la salive au repos des 6 sujets les plus sensibles et 6 les sujets les moins sensibles à la caféine a permis la détection de 255 spots, dont 26 étaient significativement différents entre hyper- et hyposensibles. L'identification de ces 26 spots a révélé la surexpression de fragments d'alpha amylase, de fragments d'albumine sérique, et de sous-unités alpha de l'immunoglobuline A ainsi que la sous-expression de cystatine SN chez les hypersensibles. Ce dernier résultat a été confirmé par Western Blot. Ceci a permis de formuler une hypothèse sur le rôle de la protéolyse en bouche sur la sensibilité à l'amertume. Dans un deuxième temps et afin d'étudier l'effet des molécules amères sur la composition salivaire, une étude in vitro a été menée sur la lignée cellulaire de glandes salivaires humaines HSG différenciées en acini ou non. Après une mise au point des conditions de différenciation (culture dite en 3D), la cystatine SN a été détectée dans les cellules HSG par Western blot après traitement des cellules à la caféine, à la quinine, et à l'urée. Après traitement à la caféine à 5, 50 ou 100µM, une quantification par ELISA a mis en évidence que la cystatine SN était toujours plus abondante dans les cellules HSG différenciées que dans les cellules non-différenciées. Spécifiquement dans les cellules différenciées, l'exposition à la caféine induisait une sur-expression de cystatine SN, la teneur maximale en cystatine SN étant observée avec la caféine à 50 µM. La présence de cystatine SN a également été détectée dans les milieux de culture

Durant la dernière décennie, la problématique de santé liée aux perturbateurs endocriniens (PE) s’est étendue à la toxicité des mélanges. L’objectif de ce travail était de définir les conséquences d’une exposition continue à des cocktails des PE, à des doses faibles et définies comme «non nocives » par les autorités réglementaires. Des mélanges associant la génistéine, la vinclozoline, et le Bisphénol A, ont fait l’objet d’étude intégrative et multi-générationnelle chez le rat qui prend en compte le comportement maternel, le comportement alimentaire et le développement. Nos résultats montrent que ces mélanges peuvent: a) diminuer le comportement maternel, b) modifier les préférences gustatives (sucré, salé), c) affecter le développement dès la période utérine (malformations) jusqu’à l’âge adulte (surpoids), d) perturber le bilan métabolique (femelles) et l’expression par la glande salivaire de gènes codant des protéines impliquées dans la gustation, d’engendrer des effets épigénétiques sur sur la génération F2 non exposée. L’étude in vitro confirme que la Génistéine et/ou la Vinclozoline, introduites durant l’induction de la différenciation adipocytaire affectent le développement des 3T3-L1et leur activité endocrine (leptine; triglycérides), et révèle que la Vinclozoline potentialise l’effet anti-adipogénique de la Génistéine.En conclusion, ce travail montre qu’une exposition à des mélanges de PE peut altérer le comportement et le développement, et prédisposer l’organisme à développer des maladies métaboliques telles que le diabète et l’obésité, mais que les propriétés hormonales de chaque composant ne sont pas prédictives des effets cocktails / During the last decade, the issue of health-related endocrine disruptors (ED) has been extended to the toxicity of mixtures. The objective of this study was to define the effects of lifelong exposure to ED mixtures, at low doses defined as "non-harmful" by the authorities. In this aim, the effects of mixtures combining genistein, vinclozolin and bisphenol A, have been investigated in the rat by using an integrative and multi-generational experimental approach which takes into account maternal behavior, feeding behavior and development. Our results show that these mixtures could: a) reduce maternal behavior, b) change taste preferences (sweet, salty), c) affect the development from the in utero period (birth defects) up to adulthood (body overweight) d) disrupt the metabolic balance (females) and the salivary gland expression of genes encoding proteins involved in gustation, and e) generate epigenetic effects on the unexposed F2 generation.An in vitro study confirms that Genistein and / or Vinclozolin, introduced at the step of the induction of adipocyte differentiation affect the development and endocrine activity (leptin, triglycerides) of 3T3-L1 cells and reveals that Vinclozolin potentiates the anti-adipogenic effect of Genistein. To conclude, this study shows that exposure to PE mixtures could affect behavior and development, and could predispose the body to develop metabolic diseases such as diabetes and obesity, but the own hormonal properties of component could not be used to predict the cocktails toxicity