Somatostatin and opioid receptors do not regulate proliferation or apoptosis of the human multiple myeloma U266 cells

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Mouse genetic background impacts both on iron and non-iron metals parameters and on their relationships

International audienceIron is reported to interact with other metals. In addition, it has been shown that genetic background may impact iron metabolism. Our objective was to characterize, in mice of three genetic backgrounds, the links between iron and several non-iron metals. Thirty normal mice (C57BL/6, Balb/c and DBA/2; n = 10 for each group), fed with the same diet, were studied. Quantification of iron, zinc, cobalt, copper, manganese, magnesium and rubidium was performed by ICP/MS in plasma, erythrocytes, liver and spleen. Transferrin saturation was determined. Hepatic hepcidin1 mRNA level was evaluated by quantitative RT-PCR. As previously reported, iron parameters were modulated by genetic background with significantly higher values for plasma iron parameters and liver iron concentration in DBA/2 and Balb/c strains. Hepatic hepcidin1 mRNA level was lower in DBA/2 mice. No iron parameter was correlated with hepcidin1 mRNA levels. Principal component analysis of the data obtained for non-iron metals indicated that metals parameters stratified the mice according to their genetic background. Plasma and tissue metals parameters that are dependent or independent of genetic background were identified. Moreover, relationships were found between plasma and tissue content of iron and some other metals parameters. Our data: (i) confirms the impact of the genetic background on iron parameters, (ii) shows that genetic background may also play a role in the metabolism of non-iron metals, (iii) identifies links between iron and other metals parameters which may have implications in the understanding and, potentially, the modulation of iron metabolis

α-Catenin stabilises Cadherin–Catenin complexes and modulates actomyosin dynamics to allow pulsatile apical contraction

We have investigated how cell contractility and adhesion are functionally integrated during epithelial morphogenesis. To this end, we have analysed the role of α-Catenin, a key molecule linking E-Cadherin-based adhesion and the actomyosin cytoskeleton, during Drosophila embryonic dorsal closure, by studying a newly developed allelic series. We find that α-Catenin regulates pulsatile apical contraction in the amnioserosa, the main force-generating tissue driving closure of the embryonic epidermis. α-Catenin controls actomyosin dynamics by stabilising and promoting the formation of actomyosin foci, and also stabilises DE-Cadherin (Drosophila E-Cadherin, also known as Shotgun) at the cell membrane, suggesting that medioapical actomyosin contractility regulates junction stability. Furthermore, we uncover a genetic interaction between α-Catenin and Vinculin, and a tension-dependent recruitment of Vinculin to amniosersoa apical cell membranes, suggesting the existence of a mechano-sensitive module operating in this tissue

Iron and other metals : metabolic interrelations and hepcidin role

Les pathologies du métabolisme du fer, dont les surcharges en fer, se caractérisent par une grande variabilité de leur expression phénotypique pour des étiologies similaires. Les mécanismes de cette variabilité ne sont pas pleinement identifiés. L’existence d’interrelations entre le fer et d’autres métaux pourrait y contribuer. L’objectif de ce travail, réalisé chez la souris, a été de préciser les interactions entre le métabolisme du fer et ceux d’autres métaux. Nous avons : i) montré que le fond génétique des souris module le métabolisme d’autres métaux, en sus du fer ; et ii) identifié des liens entre les paramètres de ces métaux en situation physiologique. Nous avons également mis en évidence, dans des modèles de souris surchargées en fer par supplémentation exogène ou bien du fait d’une déficience en hepcidine (le régulateur du métabolisme systémique du fer), un lien fort entre le métabolisme du fer et ceux du molybdène et du manganèse particulièrement au niveau splénique. Ces résultats suggèrent que des mécanismes de régulation, pouvant impliquer de façon directe ou indirecte l’axe hepcidine / ferroportine, pourraient être partagés entre le fer, le molybdène et le manganèse. Le rôle de l’hepcidine devra être précisé. Les explorations dynamiques in vivo avec les isotopes stables constituant une approche possible pour mieux comprendre les mécanismes du métabolisme du fer, nous avons caractérisé la répartition des isotopes stables du fer (par le ratio isotopique 56Fe/54Fe) dans les tissus liés à son métabolisme. Ceci nous a permis de confirmer la variation du ratio isotopique 56Fe/54Fe entre les organes, et de mettre en évidence un fractionnement isotopique du fer différent selon les fonds génétiques de souris au niveau hépatique. Ces résultats montrent ainsi l’importance de prendre en compte cette caractéristique essentielle dans les études métaboliques visant à mieux comprendre le métabolisme du fer et ses liens avec celui d’autres métaux, dans un contexte physiologique ou pathologique.Iron metabolism disorders, including iron overloads, are characterized by important phenotypic expression variabilities for similar etiologies. The mechanisms involved are not fully identified. Interrelations between iron and other metals may contribute to this variability. The aim of this work, performed in mouse, was to investigate interactions between iron and other metals metabolisms. We have: i) shown that mice genetic background modulates other metals metabolism, besides iron; and ii) identified links between parameters of these metals in physiological condition. We have also highlighted, in mice models of iron overload, related either to exogenous iron exposure, or to deficiency in hepcidin (the systemic iron metabolism regulator), a strong link between iron metabolism and molybdenum and manganese metabolisms, particularly in spleen. These results suggest that regulatory mechanisms, possibly involving directly or indirectly the hepcidin / ferroportin axis, may be shared by iron, molybdenum and manganese. The clarification of hepcidin role needs further investigations. In vivo dynamic explorations with stable isotopes being a possible approach to better understand mechanisms of iron metabolism control, we have characterized the distribution of iron stable isotopes (using 56Fe/54Fe isotope ratio) in tissues involved in its metabolism. We have confirmed the variation of 56Fe/54Fe isotope ratio between organs, and highlighted a different iron isotope fractionation in liver according to mice genetic backgrounds. These results show the importance to take into account this essential feature for metabolic studies aspiring to better understand iron metabolism and its links with other metals metabolism, in physiological or pathological conditions

Relation entre l'expression de l'hepcidine, les paramètres du métabolisme du fer et des concentrations en éléments traces chez la souris

Des observations cliniques et des résultats expérimentaux suggèrent des relations entre le métabolisme du fer et celui d'autres éléments traces. Ces relations pourraient participer à la modulation de l'expression de certaines pathologies du métabolisme du fer. Notre objectif a été, en prenant appui sur l'existence de variations du métabolisme du fer entre des souris de fonds génétiques différents (AKR, Balb/c, C57BL/6 et DBA/2), de caractériser les relations entre métabolisme du fer, expression de l'hepcidine qui régule le métabolisme du fer et certains éléments traces. La caractérisation des paramètres du fer et des éléments suivants cuivre, zinc, cobalt, nickel, manganèse, magnésium, sélénium, rubidium et molybdène a été réalisée par ICP-MS dans 4 matrices différentes (plasma, foie, rate et érythrocytes). Les niveaux d'ARNm hépatique et la concentration plasmatique d'hepcidine ont été quantifiés respectivement par RT-PCR quantitative et immuno-dosage. Les résultats mettent en évidence une influence du fond génétique sur les paramètres des métabolismes du fer et de différent éléments traces. Ils montrent également l'existence de relations privilégiées entre les niveaux d'hepcidine, les paramètres du métabolisme du fer et de certains éléments traces (molybdène, cobalt, rubidium et manganèse). Ces relations devront être précisée notamment par l'analyse de modèles animaux présentant une modulation du métabolisme du fer et/ou de l'expression de l'hepcidine d'origine génétique ou expérimentalement induite.RENNES1-BU Santé (352382103) / SudocSudocFranceF

Hemochromatosis: a model of metal-related human toxicosis

International audienceMany environmental agents, such as excessive alcohol intake, xenobiotics, and virus, are able to damage the human body, targeting especially the liver. Metal excess may also assault the liver. Thus, chronic iron overload may cause, especially when associated with cofactors, diffuse organ damage that is a source of significant morbidity and mortality. Iron excess can be either of acquired (mostly transfusional) or of genetic origin. Hemochromatosis is the archetype of genetic iron overload diseases and represents a serious health problem. A better understanding of iron metabolism has deeply modified the hemochromatosis field which today benefits from much more efficient diagnostic and therapeutic approaches

Hfe Gene Knock-Out in a Mouse Model of Hereditary Hemochromatosis Affects Bodily Iron Isotope Compositions

International audienceHereditary hemochromatosis is a genetic iron overload disease related to a mutation within the HFE gene that controls the expression of hepcidin, the master regulator of systemic iron metabolism. The natural stable iron isotope composition in whole blood of control subjects is different from that of hemochromatosis patients and is sensitive to the amount of total iron removed by the phlebotomy treatment. The use of stable isotopes to unravel the pathological mechanisms of iron overload diseases is promising but hampered by the lack of data in organs involved in the iron metabolism. Here, we use Hfe (-/-) mice, a model of hereditary hemochromatosis, to study the impact of the knock-out on iron isotope compositions of erythrocytes, spleen and liver. Iron concentration increases in liver and red blood cells of Hfe (-/-) mice compared to controls. The iron stable isotope composition also increases in liver and erythrocytes, consistent with a preferential accumulation of iron heavy isotopes in Hfe (-/-) mice. In contrast, no difference in the iron concentration nor isotope composition is observed in spleen of Hfe (-/-) and control mice. Our results in mice suggest that the observed increase of whole blood isotope composition in hemochromatosis human patients does not originate from, but is aggravated by, bloodletting. The subsequent rapid increase of whole blood iron isotope composition of treated hemochromatosis patients is rather due to the release of hepatic heavy isotope-enriched iron than augmented iron dietary absorption. Further research is required to uncover the iron light isotope component that needs to balance the accumulation of hepatic iron heavy isotope, and to better understand the iron isotope fractionation associated to metabolism dysregulation during hereditary hemochromatosis

Iron as a Therapeutic Target in <i>HFE</i>-Related Hemochromatosis: Usual and Novel Aspects

Genetic hemochromatosis is an iron overload disease that is mainly related to the C282Y mutation in the HFE gene. This gene controls the expression of hepcidin, a peptide secreted in plasma by the liver and regulates systemic iron distribution. Homozygous C282Y mutation induces hepcidin deficiency, leading to increased circulating transferrin saturation, and ultimately, iron accumulation in organs such as the liver, pancreas, heart, and bone. Iron in excess may induce or favor the development of complications such as cirrhosis, liver cancer, diabetes, heart failure, hypogonadism, but also complaints such as asthenia and disabling arthritis. Iron depletive treatment mainly consists of venesections that permit the removal of iron contained in red blood cells and the subsequent mobilization of stored iron in order to synthesize hemoglobin for new erythrocytes. It is highly efficient in removing excess iron and preventing most of the complications associated with excess iron in the body. However, this treatment does not target the biological mechanisms involved in the iron metabolism disturbance. New treatments based on the increase of hepcidin levels, by using hepcidin mimetics or inducers, or inhibitors of the iron export activity of ferroportin protein that is the target of hepcidin, if devoid of significant secondary effects, should be useful to better control iron parameters and symptoms, such as arthritis

Valproic Acid Induces Hepcidin Expression

International audienceMeeting Abstract: 14