Transcripts of ceruloplasmin but not hepcidin, both major iron metabolism genes, exhibit a decreasing pattern along portocentral axis of mouse liver

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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

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

GATA-4 transcription factor regulates hepatic hepcidin expression.

International audienceHepcidin, an hormone mainly synthesized by hepatocytes and secreted in plasma, controls iron bioavailability. Thus, by inducing the internalization of the iron exporter ferroportin, it regulates iron release from macrophages, enterocytes and hepatocytes towards plasma. Abnormal levels of hepcidin expression alter plasma iron parameters and lead to iron metabolism disorders. To understand the mechanisms controlling hepcidin gene expression is therefore an important goal. We identified a potential GATA binding site within the human hepcidin promoter. Indeed, in hepatic HepG2 cells, luciferase experiments demonstrated that mutation of this GATA binding site impaired the hepcidin promoter transcriptional activity in basal condition. Gel retardation experiment showed that GATA-4 could bind this site. Cotransfection of GATA-4 expression vector with an hepcidin promoter reporter construct enhanced hepcidin promoter transcriptional activity. Furthermore, modulation of GATA-4 mRNA expression using specific siRNAs downregulated endogenous hepcidin gene expression. Finally, we found that mutation of the GATA binding site impaired the interleukin-6 induction of hepcidin gene expression, but did not prevent the bone morphogenetic protein-6 response. In conclusion, our findings: i) indicate that GATA-4 may participate to the control of hepcidin expression, and ii) suggest that alteration of its expression could contribute to the development of iron-related disorders

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

Valproic Acid Induces Hepcidin Expression

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Decreased Bone Formation Explains Osteoporosis in a Genetic Mouse Model of Hemochromatosiss

International audienceOsteoporosis may complicate iron overload diseases such as genetic hemochromatosis. However, molecular mechanisms involved in the iron-related osteoporosis remains poorly understood. Recent in vitro studies support a role of osteoblast impairment in iron-related osteoporosis. Our aim was to analyse the impact of excess iron in Hfe-/- mice on osteoblast activity and on bone microarchitecture. We studied the bone formation rate, a dynamic parameter reflecting osteoblast activity, and the bone phenotype of Hfe-/- male mice, a mouse model of human hemochromatosis, by using histomorphometry. Hfe-/- animals were sacrificed at 6 months and compared to controls. We found that bone contains excess iron associated with increased hepatic iron concentration in Hfe-/- mice. We have shown that animals with iron overload have decreased bone formation rate, suggesting a direct impact of iron excess on active osteoblasts number. For bone mass parameters, we showed that iron deposition was associated with bone loss by producing microarchitectural impairment with a decreased tendency in bone trabecular volume and trabecular number. A disorganization of trabecular network was found with marrow spaces increased, which was confirmed by enhanced trabecular separation and star volume of marrow spaces. These microarchitectural changes led to a loss of connectivity and complexity in the trabecular network, which was confirmed by decreased interconnectivity index and increased Minkowski's fractal dimension. Our results suggest for the first time in a genetic hemochromatosis mouse model, that iron overload decreases bone formation and leads to alterations in bone mass and microarchitecture. These observations support a negative effect of iron on osteoblast recruitment and/or function, which may contribute to iron-related osteoporosi

Modifications de l’environnement luminal et dysfonction mitochondriale des cellules épithéliales coliques chez la souris obèse

International audienceL’obésité et le surpoids sont associés à une inflammation de bas-grade en lien avec des perturbations de l’homéostasie intestinale. Le maintien de cette homéostasie est permis par l’activité mitochondriale des cellules épithéliales intestinales dont la fonction peut être modulée par des modifications de l’environnement luminal, également décrites dans l’obésité. Le but de cette étude était d’évaluer si la consommation d’un régime obésogène altère la fonction mitochondriale des colonocytes chez la souris. Des souris ont été nourries pendant 22 semaines avec un régime contrôle ou un régime obésogène (WD) puis les colonocytes isolés. Les souris WD ont développé une obésité associée à une endotoxémie. L’analyse du métabolisme énergétique des colonocytes a révélé une nette diminution de la respiration maximale et de la capacité respiratoire de réserve chez les souris WD, signes d’une dysfonction mitochondriale. Pourtant, la consommation d’un WD n’a pas modifié les expressions génique et protéique des complexes de la chaîne de respiration mitochondriale et la dynamique mitochondriale ne semblait pas altérée. En revanche, l’étude du métabolome colique a révélé que la consommation d’un WD induisait une augmentation des concentrations d’acides biliaires chez les souris WD, associée à une augmentation de l’abondance des Desulfovibrionaceae et plus particulièrement des Bilophila, bactérie productrice de H2S. Ces résultats suggèrent que des modifications de l’environnement luminal induites par la consommation d’un WD perturbe la chaine respiratoire mitochondriale, potentiellement par le biais de métabolites tels que le H2S. Cette dysfonction mitochondriale pourrait favoriser la perte d’homéostasie intestinale voire augmenter la susceptibilité à l’inflammation intestinale

Oral dysbiosis induced by Porphyromonas gingivalis is strain-dependent in mice

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Professeurs des écoles en formation initiale au fil des réformes

Tandis que la formation initiale des professeurs des écoles passait en dix ans par trois organisations différentes, que s’est-il produit, du point de vue des personnes en formation initiale dans ces contextes successifs ? Telle est la question à laquelle répond ce véritable « roman » scientifique de la professionnalité des professeurs des écoles et de leur formation. À partir des résultats d’une enquête statistique reconduite en 2007, 2012 et 2015 auprès d’étudiants des deux IUFM, puis ESPE normandes, les chercheurs observent des mutations, en particulier dans la déconstruction progressive du métier représenté et du métier en cours dans les pratiques chez les professeurs débutants. La dimension longitudinale de la recherche et le parti pris de considérer, non l’offre de formation mais l’appropriation qu’en font ces débutants, souligne les à-coups, paradoxes et incertitudes grandissantes d’un modèle de professionnalisation des professeurs du premier degré par leur formation initiale