Olivier Loréal

Unité Inserm U1077, Caen, Lower Normandy, France

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Publications (201)810.02 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Tumor cell growth requires large iron quantities and the deprivation of this metal induced by synthetic metal chelators is therefore an attractive method for limiting the cancer cell proliferation. The antiproliferative effect of the Quilamine HQ1-44, a new iron chelator vectorized toward tumor cells by a polyamine chain, is related to its high selectivity for the Polyamine Transport System (PTS), allowing its preferential uptake by tumoral cells. The difference in PTS activation between healthy cells and tumor cells enables tumor cells to be targeted, whereas the strong dependence of these cells on iron ensures a secondary targeting. Here, we demonstrated in vitro that HQ1-44 inhibits DNA synthesis and cell proliferation of HCT116 cells by modulating the intracellular metabolism of both iron and polyamines. Moreover, in vivo, in xenografted athymic nude mice, we found that HQ1-44 was as effective as cis-platin in reducing HCT116 tumor growth, without its side effects. Furthermore, as suggested by in vitro data, the depletion in exogenous or endogenous polyamines, known to activate the PTS, dramatically enhanced the antitumor efficiency of HQ1-44. These data support the need for further studies to assess the value of HQ1-44 as an adjuvant treatment in cancer. Copyright © 2015. Published by Elsevier Inc.
    Biochemical pharmacology 06/2015; DOI:10.1016/j.bcp.2015.06.001 · 4.65 Impact Factor
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    ABSTRACT: Iron 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 metabolism.
    Biology of Metals 06/2015; 28(4). DOI:10.1007/s10534-015-9862-8 · 2.69 Impact Factor
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    ABSTRACT: As our understanding of iron metabolism improves through the more accurate description of iron metabolism actors, new causes of iron overload are identified. We, here, report 16 cases of hereditary hypotransferrinemia related to 4 previously undescribed TF (transferrin) mutations (p.Val221Gly, p.Arg609Trp, p.Glu370Lys, p.Tyr533X and p.Cys421Arg). We show that, besides increasing serum transferrin saturation without iron overload, hypotransferrinemia, when associated to mutations in HFE or HAMP or to acquired factors, can lead to clinically relevant iron burden. These cases emphasize the usefulness of serum transferrin determination in the diagnostic evaluation of iron overload and the importance for clinicians to be aware of this syndrome. Copyright © 2014 Elsevier Inc. All rights reserved.
    Blood Cells Molecules and Diseases 11/2014; 54(2). DOI:10.1016/j.bcmd.2014.11.020 · 2.33 Impact Factor
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    ABSTRACT: Chalcogenide glass fibers are promising photonic tools to develop Fiber Evanescent Wave Spectroscopy (FEWS) optical sensors working in the mid-infrared region. Numerous pioneering works have already been carried out showing their efficiency, especially for bio-medical applications. Nevertheless, this technology remains confined to academic studies at the laboratory scale because chalcogenide glass fibers are difficult to shape to produce reliable, sensitive and compact sensors. In this paper, a new method for designing and fabricating a compact and robust sensing head with a selenide glass fiber is described. Compact looped sensing heads with diameter equal to 2 mm were thus shaped. This represents an outstanding achievement considering the brittleness of such uncoated fibers. FEWS experiments were implemented using alcoholic solutions as target samples showing that the sensitivity is higher than with the routinely used classical fiber. It is also shown that the best compromise in term of sensitivity is to fabricate a sensing head including two full loops. From a mechanical point of view, the breaking loads of the loop shaped head are also much higher than with classical fiber. Finally, this achievement paves the way for the use of mid-infrared technology during in situ and even in vivo medical operations. Indeed, is is now possible to slide a chalcogenide glass fiber in the operating channel of a standard 2.8 mm diameter catheter.
    Sensors 10/2014; 14(10):17905-17914. DOI:10.3390/s141017905 · 2.05 Impact Factor
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    ABSTRACT: Identification of new players in iron metabolism, such as hepcidin, which regulates ferroportin and divalent metal transporter 1 expression, has improved our knowledge of iron metabolism and iron-related diseases. However, from both experimental data and clinical findings, "iron-related proteins" appear to also be involved in the metabolism of other metals, especially divalent cations. Reports have demonstrated that some metals may affect, directly or indirectly, the expression of proteins involved in iron metabolism. Throughout their lives, individuals are exposed to various metals during personal and/or occupational activities. Therefore, better knowledge of the connections between iron and other metals could improve our understanding of iron-related diseases, especially the variability in phenotypic expression, as well as a variety of diseases in which iron metabolism is secondarily affected. Controlling the metabolism of other metals could represent a promising innovative therapeutic approach.
    Frontiers in Pharmacology 06/2014; 5:128. DOI:10.3389/fphar.2014.00128 · 3.80 Impact Factor
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    ABSTRACT: Background: Defects in human hemochromatosis protein (HFE) cause iron overload due to reduced hepatic hepcidin secretion. Liver transplantation (LT) is a key treatment for potential complications from HFE- related hereditary hemochromatosis (HH). This study evaluated hepcidin secretion and iron burden after LT to elucidate HH pathophysiology. Methods: Patients (n=18) homozygous for the p.Cys282Tyr mutation in the HFE gene underwent LT between 1999 and 2008. Serum iron, serum hepcidin, and hepatic iron concentrations were determined before LT and at the end of follow-up (median 57 months). Mortality and causes of death were determined. Survival was compared to that of the overall patient population that received LT. Results: Before LT, serum hepcidin levels were low (0.54 ± 2.5 nmol/L; normal range: 4-30 nmol/L). After LT, 11 patients had iron evaluations; none received iron depletion therapy; all had normal transferrin saturation. The mean serum ferritin was 185 (±99) µg/L. Magnetic resonance imaging showed that iron overload was absent in 9 patients, mild in one patient with metabolic syndrome, and high (180 µmol/g) in one patient with hereditary spherocytosis unmasked after liver transplantation. At the end of follow-up, serum hepcidin was normal in 10 patients (11.12 ± 7.6 nmol/L; p<0.05) and low in one patient with iron deficiency anemia. Survival was 83% and 67% at one and 5 years, respectively. Survival was similar for patients with HH and patients that received LT for other causes. Conclusion: This study demonstrated that, in HH, LT normalized hepcidin secretion and prevented recurrence of hepatic iron overload. Survival was similar to that of patients that received LTs for other liver diseases. (HEPATOLOGY 2013.).
    Hepatology 03/2014; 59(3). DOI:10.1002/hep.26570 · 11.19 Impact Factor
  • Diabetes & Metabolism 03/2014; 40:A80. DOI:10.1016/S1262-3636(14)72510-8 · 2.85 Impact Factor
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    ABSTRACT: Gender-related disparities in the regulation of iron metabolism may contribute to the differences exhibited by men and women in the progression of chronic liver diseases associated with reduced hepcidin expression, e.g. chronic hepatitis C, alcoholic liver disease, or hereditary hemochromatosis. However their mechanisms remain poorly understood. In this study, we took advantage of the major differences in hepcidin expression and tissue iron loading observed between Bmp6-deficient male and female mice to investigate the mechanisms underlying this sexual dimorphism. We showed that testosterone robustly represses hepcidin transcription by enhancing Egfr signaling in the liver and that selective Egfr inhibition by gefitinib (Iressa®) in males markedly increases hepcidin expression. In males where the suppressive effects of testosterone and Bmp6-deficiency on hepcidin expression are combined, hepcidin is more strongly repressed than in females and iron accumulates massively not only in the liver but also in the pancreas, heart and kidneys. Conclusion: These data indicate that testosterone-induced repression of hepcidin expression becomes functionally important during homeostatic stress from disorders that result in iron loading and/or reduced capacity for hepcidin synthesis. They suggest that novel therapeutic strategies targeting the testosterone/EGF/EGFR axis may be useful for inducing hepcidin expression in patients with iron overload and/or chronic liver diseases. (Hepatology 2013;).
    Hepatology 02/2014; 59(2). DOI:10.1002/hep.26648 · 11.19 Impact Factor
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    ABSTRACT: Chalcogenide glasses are a matchless material as far as mid-infrared (IR) applications are concerned. They transmit light typically from 2 to 12 μm and even as far as 20 μm depending on their composition, and numerous glass compositions can be designed for optical fibers. One of the most promising applications of these fibers consists in implementing fiber evanescent wave spectroscopy, which enables detection of the mid-IR signature of most biomolecules. The principles of fiber evanescent wave spectroscopy are recalled together with the benefit of using selenide glass to carry out this spectroscopy. Then, two large-scale studies in recent years in medicine and food safety are exposed. To conclude, the future strategy is presented. It focuses on the development of rare earth-doped fibers used as mid-IR sources on one hand and tellurium-based glasses to shift the limit of detection toward longer wavelength on the other hand. © The Authors. Published by SPIE under a Creative Commons Attribution 3.
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    ABSTRACT: Fiber Evanescent Wave Spectroscopy (FEWS) is an efficient way to collect optical spectra in situ, in real time and even, hopefully, in vivo. Thanks to selenide glass fibers, it is possible to get such spectra over the whole mid-infrared range from 2 to 12 μm. This working window gives access to the fundamental vibration band of most of biological molecules. Moreover selenide glasses are stable and easy to handle, and it is possible to shape the fiber and create a tapered sensing head to drastically increase the sensitivity. Within the past decades, numerous multi-disciplinary studies have been conducted in collaboration with the City Hospital of Rennes. Clinical trials have provided very promising results in biology and medicine which have led to the creation in 2011 of the DIAFIR Company dedicated to the commercialization of fiber-based infrared biosensors. In addition, new glasses based on tellurium only have been recently developed, initially in the framework of the Darwin mission led by the European Space Agency (ESA). These glasses transmit light further into the far-infrared and could also be very useful for medical applications in the near future. Indeed, they permit to reach the vibrational bands of biomolecules laying from 12 to 16 μm where selenide glasses do not transmit light anymore. However, while Se is a very good glass former, telluride glasses tend to crystallize easily due to the metallic nature of Te bonds. Hence, further work is under way to stabilize the glass composition for fibers drawing and to lower the optical losses for improving their sensitivity as bio-sensors.
    Proceedings of SPIE - The International Society for Optical Engineering 01/2014; DOI:10.1117/12.2036734 · 0.20 Impact Factor
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    ABSTRACT: To selectively target tumor cells expressing an overactive Polyamine Transport System (PTS), we designed, synthesized and evaluated the biological activity of a new generation of iron chelators, derived from the lead compound HQ1-44, which we named Quilamines II. The structures of four new antiproliferative agents were developed. They differ in the size of the linker (HQ0-44 and HQ2-44) or in the nature of the linker (HQCO-44 and HQCS-44) between a hydroxyquinoline moiety (HQ) and a homospermidine (44) chain, the best polyamine vector. The Quilamines II were obtained after 6 to 9 steps by Michael addition, peptide linkage and reductive amination or by using the Willgerodt-Kindler reaction. The biological evaluation of these second-generation Quilamines showed that modifying the size of the linker increased the selectivity of these compounds for the PTS. In addition, measurement of the toxicity of Quilamines HQ0-44 and HQ2-44 highlighted their marked antiproliferative nature on several cancerous cell lines as well as a differential activity on non-transformed cells (fibroblasts). In contrast, Quilamines HQCO-44 and HQCS-44 presented low selectivity for the PTS, probably due to a loss of electrostatic interaction. We also demonstrated that the HCT116 cell line, originating from a human colon adenocarcinoma, was the most responsive to the various Quilamines. As deduced from the calcein and HVA assays, the higher iron chelating capacity of HQ1-44 could explain its higher antiproliferative efficiency.
    Bioconjugate Chemistry 01/2014; 25(2). DOI:10.1021/bc4004734 · 4.82 Impact Factor
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    ABSTRACT: Rare genetic iron overload diseases are an evolving field due to major advances in genetics and molecular biology. Genetic iron overload has long been confined to the classical type 1 hemochromatosis related to the HFE C282Y mutation. Breakthroughs in the understanding of iron metabolism biology and molecular mechanisms led to the discovery of new genes and subsequently, new types of hemochromatosis. To date, four types of hemochromatosis have been identified: HFE-related or type1 hemochromatosis, the most frequent form in Caucasians, and four rare types, named type 2 (A and B) hemochromatosis (juvenile hemochromatosis due to hemojuvelin and hepcidin mutation), type 3 hemochromatosis (related to transferrin receptor 2 mutation), and type 4 (A and B) hemochromatosis (ferroportin disease). The diagnosis relies on the comprehension of the involved physiological defect that can now be explored by biological and imaging tools, which allow non-invasive assessment of iron metabolism. A multidisciplinary approach is essential to support the physicians in the diagnosis and management of those rare diseases.
    Gastroentérologie Clinique et Biologique 12/2013; 38(2). DOI:10.1016/j.clinre.2013.11.003 · 1.98 Impact Factor
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    ABSTRACT: Ferroportin mediates iron export from cells and this function is modulated by serum hepcidin. Mutations in the ferroportin gene (SLC40A1) lead to autosomal dominant iron overload diseases related either to loss or to gain of function, and usually characterized by normal or low transferrin saturation versus elevated transferrin saturation respectively. However, for identical mutation, the phenotypic expression may vary from one patient to another. Using in vitro overexpression of wild-type or mutant ferroportin proteins, we characterized the functional impact of five recently identified ferroportin gene mutations regarding ferroportin localization, cell iron status, and hepcidin sensitivity. Our aim was to integrate functional results and biological findings in probands and relatives. We show that whereas the p.Arg371Gln (R371Q) mutation had no impact on studied parameters, the p.Trp158Leu (W158L), p.Arg88Gly (R88G), and p.Asn185Asp (N185D) mutations caused an iron export defect and were classified as loss-of-function mutations. The p.Gly204Ser (G204S) mutation induced a gain of ferroportin function. Functional studies are useful to determine whether or not a ferroportin gene mutation found in iron overloaded patient is deleterious and to characterize its biological impact, especially when family studies are not fully informative and/or additional confounding factors may affect bio-clinical expression. This article is protected by copyright. All rights reserved.
    Human Mutation 11/2013; 34(11). DOI:10.1002/humu.22396 · 5.05 Impact Factor
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    ABSTRACT: The development of alcoholic liver diseases depends on the ability of hepatocyte to proliferate and differentiate in the case of alcohol-induced injury. Our previous work showed an inhibitory effect of alcohol on hepatocyte proliferation. However, the effect of alcohol on hepatocyte differentiation has not yet been precisely characterized. In the present study, we evaluated the effect of alcohol on hepatocyte differentiation in relationship with changes of iron metabolism in HepaRG cells. This unique bipotent human cell line can differentiate into hepatocytes and biliary epithelial cells, paralleling liver development. Results showed that alcohol reduced cell viability, total protein level and enhanced hepatic enzymes leakage in differentiated HepaRG cells. Moreover, it caused cell enlargement, decreased number of hepatocyte and expression of C/EBPα as well as bile canaliculi F-actin. Alcohol increased expression of hepatic cell-specific markers and alcohol-metabolizing enzymes (ADH2, CYP2E1). This was associated with a lipid peroxidation and an iron excess expressed by an increase in total iron content, ferritin level, iron uptake as well as an overexpression of genes involved in iron transport and storage. Alcohol-induced hepatoxicity was amplified by exogenous iron via exceeding iron overload. Taken together, our data demonstrate that in differentiated hepatocytes, alcohol reduces proliferation while increasing expression of hepatic cell-specific markers. Moreover, iron overload could be one of the underlying mechanisms of effect of alcohol on the whole differentiation process of hepatocytes.
    Chemico-biological interactions 09/2013; 206(2). DOI:10.1016/j.cbi.2013.08.016 · 2.98 Impact Factor
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    ABSTRACT: Las enfermedades por sobrecarga de hierro en los niños abarcan un amplio abanico de enfermedades genéticas y adquiridas. La identificación de las causas genéticas ha sido relativamente reciente, a raíz del descubrimiento del gen HFE. Se ha observado que, además de la hemocromatosis de tipo 1 (vinculada al gen HFE), que se manifiesta en la edad adulta, varias formas de sobrecarga de hierro que afectaban a pacientes jóvenes se debían a mutaciones de genes no relacionados con HFE. Se trata de enfermedades poco comunes pero que, a diferencia de la hemocromatosis vinculada al gen HFE, no afectan únicamente a pacientes caucásicos. El exceso de hierro está relacionado, como en la hemocromatosis de tipo 1, con una hipohepcidinemia que aumenta la absorción digestiva de hierro. Entre las causas adquiridas, predominan las sobrecargas de hierro que se desarrollan en el contexto de diversos trastornos hematológicos y están relacionadas no sólo con la transfusión de hierro, sino también con un exceso de absorción digestiva de éste, debido a hipohepcidinemia por diseritropoyesis. Desde el punto de vista diagnóstico, estas diversas enfermedades se han beneficiado en gran medida de la resonancia magnética (RM), para cuantificar de forma no invasiva la carga de hierro visceral, así como de los avances de la genética molecular, para identificar las mutaciones implicadas. Desde el punto de vista terapéutico, la depleción mediante sangrías es el tratamiento de primera línea de las sobrecargas genéticas. La quelación oral se ha convertido en el tratamiento de elección para las sobrecargas transfusionales. Con la condición de que se instauren de forma precoz, estos enfoques terapéuticos permiten no sólo transformar el pronóstico vital, sino mejorar sensiblemente la calidad de vida de estos jóvenes pacientes.
    06/2013; 48(2):1–9. DOI:10.1016/S1245-1789(13)64496-0
  • American Journal of Hematology 05/2013; 88(5):E178-E178. · 3.48 Impact Factor
  • American Journal of Hematology 05/2013; 88(5):E215-E215. · 3.48 Impact Factor
  • American Journal of Hematology 05/2013; 88(5):E9-E10. · 3.48 Impact Factor
  • American Journal of Hematology 05/2013; 88(5):E175-E176. · 3.48 Impact Factor

Publication Stats

5k Citations
810.02 Total Impact Points

Institutions

  • 1988–2015
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2014
    • National Hospital of Niamey
      Niamey, Niamey, Niger
  • 1998–2014
    • Université de Rennes 1
      • Faculty of Medicine
      Roazhon, Brittany, France
  • 1993–2012
    • French Institute of Health and Medical Research
      • Unit of Liver, Metabolisms and Cancer
      Lutetia Parisorum, Île-de-France, France
  • 1988–2012
    • Centre Hospitalier Universitaire de Rennes
      Roazhon, Brittany, France
  • 2010
    • Université de Bretagne Sud
      Lorient, Brittany, France
  • 2006
    • Université de Rennes 2
      Roazhon, Brittany, France
  • 2002
    • Laboratoire d'Informatique de Grenoble
      Grenoble, Rhône-Alpes, France
    • Washington University in St. Louis
      • Department of Pathology and Immunology
      San Luis, Missouri, United States