25 research outputs found
Recurrent attacks of acute hepatic porphyria: major role of the chronic inflammatory response in the liver
[Background] Acute intermittent porphyria (AIP) is an inherited disorder of haem metabolism characterized by lifeâthreatening acute neurovisceral attacks due to the induction of hepatic δâaminolevulinic acid synthase 1 (ALAS1) associated with hydroxymethylbilane synthase (HMBS) deficiency. So far, the treatment of choice is hemin which represses ALAS1. The main issue in the medical care of AIP patients is the occurrence of debilitating recurrent attacks.
[Objective] The aim of this study was to determine whether chronic hemin administration contributes to the recurrence of acute attacks.
[Methods] A followâup study was conducted between 1974 and 2015 and included 602 French AIP patients, of whom 46 had recurrent AIP. Moreover, we studied the hepatic transcriptome, serum proteome, liver macrophage polarization and oxidative and inflammatory profiles of Hmbsâ/â mice chronically treated by hemin and extended the investigations to five explanted livers from recurrent AIP patients.
[Results] The introduction of hemin into the pharmacopeia has coincided with a 4.4âfold increase in the prevalence of chronic patients. Moreover, we showed that both in animal model and in human liver, frequent hemin infusions generate a chronic inflammatory hepatic disease which induces HO1 remotely to hemin treatment and maintains a high ALAS1 level responsible for recurrence.
[Conclusion] Altogether, this study has important impacts on AIP care underlying that hemin needs to be restricted to severe neurovisceral crisis and suggests that alternative treatment targeting the liver such as ALAS1 and HO1 inhibitors, and antiâinflammatory therapies should be considered in patients with recurrent AIP.LG, JCD, PH, ES and AKA were funded for attending meeting related to ongoing clinical trial by Alnylam Pharmaceuticals.Peer reviewe
Recommended from our members
Accuracy of citrulline, I-FABP and d-lactate in the diagnosis of acute mesenteric ischemia
Data availability:
Research data are not shared.Supplementary Information oi available online at: https://www.nature.com/articles/s41598-021-98012-w#Sec14 .Early diagnosis of acute mesenteric ischemia (AMI) remains a clinical challenge, and no biomarker has been consistently validated. We aimed to assess the accuracy of three promising circulating biomarkers for diagnosing AMIâcitrulline, intestinal fatty acid-binding protein (I-FABP), and D-lactate. A cross-sectional diagnostic study enrolled AMI patients admitted to the intestinal stroke center and controls with acute abdominal pain of another origin. We included 129 patientsâ50 AMI and 79 controls. Plasma citrulline concentrations were significantly lower in AMI patients compared to the controls [15.3 Îźmol/L (12.0â26.0) vs. 23.3 Îźmol/L (18.3â29.8), pâ=â0.001]. However, the area under the receiver operating curves (AUROC) for the diagnosis of AMI by Citrulline was low: 0.68 (95% confidence intervalâ=â0.58â0.78). No statistical difference was found in plasma I-FABP and plasma D-lactate concentrations between the AMI and control groups, with an AUROC of 0.44, and 0.40, respectively. In this large cross-sectional study, citrulline, I-FABP, and D-lactate failed to differentiate patients with AMI from patients with acute abdominal pain of another origin. Further research should focus on the discovery of new biomarkers.Grants from MSD-Avenir and APHP funded the SURVIBIO study; Alexandre Nuzzo received Ph.D. Grants from âFondation de l'Avenirâ and the French Gastroenterology Society (SNFGE)
Utilisation du coefficient de saturation de la transferrine comme critère diagnostique de la carence martiale (CM) : revue systÊmatique
Analytical evaluation of the CA 19-9 assay: Comparison of three different assays on patients samples
Spatio-Developmental Distribution of the Prion-Like Protein Doppel in Mammalian Testis: A Comparative Analysis Focusing on Its Presence in the Acrosome of Spermatids1
Dimercaptosuccinic acid in combination with carbapenems against isogenic strains of Escherichia coli producing or not producing a metallo-β-lactamase in vitro and in murine peritonitis
Background: Carbapenemase-producing Enterobacterales represent a major therapeutic challenge. MBLs, requiring zinc at their catalytic site, could be inhibited by meso-dimercaptosuccinic acid (DMSA), a heavy metal chelator already widely used for treating lead intoxication.Objectives: To evaluate the activity of carbapenems alone or combined with DMSA against MBL-producing Escherichia coli in a severe murine peritonitis model.Methods: Isogenic strains of wild-type E. coli CFT073 producing the MBLs NDM-1, VIM-2 and IMP-1, and the control serine carbapenemases OXA-48 and KPC-3 were constructed. MIC determinations and timeâkill assays were performed for imipenem, meropenem and ertapenem alone or in combination with DMSA. Infected mice were treated intraperitoneally for 24âh with imipenem, DMSA or their combination. Bacterial counts in peritoneal fluid and spleen were assessed at 24â h.Results: DMSA in combination with each carbapenem caused a significant decrease in the MICs for all MBL-producing strains, in a concentration-dependent manner, but did not provide benefit against non-MBL strains. In mice infected with the NDM-1- producing strain, the combination of imipenem and DMSA significantly reduced bacterial counts in peritoneal fluid (Pâ=â0.0006) and spleen (Pâ<â0.0001), as compared with imipenem alone, with no benefit against the KPC-3-producing and CFT073 strains. DMSA concentrations in plasma of mice were comparable to those obtained in humans with a standard oral dose.Conclusions: DMSA restores the activity of carbapenems against MBL-producing strains, and its combination with carbapenems appears to be a promising strategy for the treatment of NDM-producing E. coli infections
Prion-like protein Doppel expression is not modified in scrapie-infected cells and in the brains of patients with CreutzfeldtâJakob disease
AbstractDoppel protein has been discovered in prnp knock-out mouse lines, with overproduction of this protein in the brain causing ataxia and neurodegeneration. We investigated whether Doppel expression (i) affected or was affected by the course of prion propagation in neuroblastoma cells, or (ii) modulated CreutzfeldtâJakob disease pathogenesis. No change in Doppel production was detected in N2a cells, before or after infection. Transient murine Doppel gene expression had no effect on N2a viability or PrPSc production. A sensitive immunometric assay revealed low levels of Doppel in human brain, reflecting weak transcription of the corresponding gene. No difference in brain Doppel levels was observed between CreutzfeldtâJakob disease patients and controls, adding further evidence that Doppel is unlikely to be involved in prion disease pathogenesis
Serotonin regulates hepcidin expression via a gut-liver axis
Abstract Liver hepcidin, is well recognized as the central hormone of systemic iron regulation. Although serotonin is most recognized as a brain neurotransmitter, prodigious quantities are synthesized in gut enterochromaffin cells and several lines of evidence, also identified the gut as an essential sensor and regulator of iron homeostasis. Using a mouse model deficient for peripheral serotonin (Tph1 KO), we identified gut-derived serotonin as a key physiological factor in hepcidin regulation. Serotonin represses hepcidinâs through a 5HT2B receptor-dependent pathway, independently of any other known hepcidin regulators, including bone marrow signals. This regulation is conserved in humans and shows physiological significance as a negative correlation between serotonin and hepcidin levels was observed in a cohort of healthy individuals. Moreover, in pathological situation such as acute heart failure, where iron deficiency has a negative prognostic impact, we provide evidence that an increase in serotonin level seems necessary to repress hepcidin level, to increase iron availability