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1. The endocytic receptor protein LRP-1 modulate P-glycoprotein mediated drug resistance in MCF-7 cells.

Author: Aubery Henry, Marine Mauperin, Jerome Devy, Stephane Dedieu, Lise Chazee, Cathy Hachet, Christine Terryn, Laurent Duca, Laurent Martiny, Emmanuelle Devarenne-Charpentier, and Hassan El Btaouri
Subjects: Medicine, Science
Abstract: Multidrug resistance (MDR) is a major obstacle to successful cancer chemotherapy. A typical form of MDR is due to the overexpression of membrane transport proteins., such as Glycoprotein-P (P-gp), resulting in an increased drug efflux preventing drug cytotoxicity. P-gp is mainly localized on the plasma membrane; however, it can also be endocytosed resulting in the trafficking of P-gp in endoplasmic reticulum, Golgi, endosomes, and lysosomes. The lysosomal P-gp has been found to be capable of transporting and sequestering P-gp substrates (e.g., Doxorubicin (Dox)) into lysosomes to protect cells against cytotoxic drugs. Many translational studies have shown that low-density lipoprotein receptor-related protein-1 (LRP-1) is involved in endocytosis and regulation of signalling pathways. LRP-1 mediates the endocytosis of a diverse set of extracellular ligands that play important roles in tumor progression. Here, we investigated the involvement of LRP-1 in P-gp expression and subcellular redistribution from the cell surface to the lysosomal membrane by endocytosis and its potential implication in P-gp-mediated multidrug resistance in MCF-7 cells. Our results showed that MCF-7 resistant cells (MCF-7R) overexpressed the P-gp, LRP-1 and LAMP-1 and were 11.66-fold resistant to Dox. Our study also revealed that in MCF-7R cells, lysosomes were predominantly high density compared to sensitized cells and P-gp was localized in the plasma membrane and lysosomes. LRP-1 blockade reduced lysosomes density and level of LAMP-1 and P-gp. It also affected the subcellular distribution of P-gp. Under these conditions, we restored Dox nuclear uptake and ERK 1/2 activation thus leading to MCF-7R cell sensitization to Dox. Our data suggest that LRP-1 is able to modulate the P-gp expression and subcellular redistribution by endocytosis and to potentiate the P-gp-acquired Dox resistance.
Published: 2023
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2. Characterization of novel interactions with membrane NEU1 highlights new regulatory functions for the Elastin Receptor Complex in monocyte interaction with endothelial cells

Author: Olivier Bocquet, Dignê Tembely, Damien Rioult, Christine Terryn, Béatrice Romier, Amar Bennasroune, Sébastien Blaise, Hervé Sartelet, Laurent Martiny, Laurent Duca, and Pascal Maurice
Subjects: Elastin remodeling, Elastin peptides, Elastin receptor complex, NEU1, Desialylation, Membrane glycoproteins, Biotechnology, TP248.13-248.65, Biology (General), QH301-705.5, Biochemistry, QD415-436
Abstract: Abstract Background Vascular aging is associated with remodeling of elastin, one of the main extracellular matrix component of the arterial wall, and production of elastin-derived peptides (EDP). These extracellular matrix degradation products have been shown to trigger biological activities through the elastin receptor complex (ERC) and data from the last decade have brought significant insights on the critical role played by its NEU1 subunit in the biological effects mediated by EDP and the ERC in vascular and metabolic diseases. Results Using a proteomic approach, we previously identified new potential interaction partners of membrane NEU1. Here, we validated the interaction between NEU1 and the β2 integrin in human monocytes and show that binding of EDP to the ERC leads to desialylation of β2 integrin through NEU1. A similar action mechanism was identified in human umbilical vein endothelial cells (HUVEC) for intercellular cell adhesion molecule-1 (ICAM-1). Importantly, these effects were associated with a significant increase in monocyte adhesion to endothelial cells and monocyte transendothelial migration. Conclusions These results demonstrate that membrane NEU1 sialidase interacts and modulates the sialylation levels of the β2 integrin and ICAM-1 through the ERC in monocytes and endothelial cells, respectively, and suggest that EDP and the ERC, through this newly identified common mode of action governed by NEU1, may be important regulators of circulating monocyte recruitment to inflamed vascular sites. Moreover, by its ability to interact with and to modulate the sialylation of key membrane glycoproteins through NEU1, new biological functions are anticipated for EDP and the ERC in elastin remodeling-associated disorders.
Published: 2021
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3. Apelin expression deficiency in mice contributes to vascular stiffening by extracellular matrix remodeling of the aortic wall

Author: Beatrice Romier, Cédric Dray, Laetitia Vanalderwiert, Amandine Wahart, Thinhinane Hocine, Alizée Dortignac, Christian Garbar, Corinne Garbar, Camille Boulagnon, Nicole Bouland, Pascal Maurice, Amar Bennasroune, Hervé Sartelet, Laurent Martiny, Laurent Duca, Philippe Valet, and Sébastien Blaise
Subjects: Medicine, Science
Abstract: Abstract Numerous recent studies have shown that in the continuum of cardiovascular diseases, the measurement of arterial stiffness has powerful predictive value in cardiovascular risk and mortality and that this value is independent of other conventional risk factors, such as age, cholesterol levels, diabetes, smoking, or average blood pressure. Vascular stiffening is often the main cause of arterial hypertension (AHT), which is common in the presence of obesity. However, the mechanisms leading to vascular stiffening, as well as preventive factors, remain unclear. The aim of the present study was to investigate the consequences of apelin deficiency on the vascular stiffening and wall remodeling of aorta in mice. This factor freed by visceral adipose tissue, is known for its homeostasic role in lipid and vascular metabolisms, or again in inflammation. We compared the level of metabolic markers, inflammation of white adipose tissue (WAT), and aortic wall remodeling from functional and structural approaches in apelin-deficient and wild-type (WT) mice. Apelin-deficient mice were generated by knockout of the apelin gene (APL-KO). From 8 mice by groups, aortic stiffness was analyzed by pulse wave velocity measurements and by characterizations of collagen and elastic fibers. Mann–Whitney statistical test determined the significant data (p
Published: 2021
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4. Carbamylation of elastic fibers is a molecular substratum of aortic stiffness

Author: Manon Doué, Anaïs Okwieka, Alexandre Berquand, Laëtitia Gorisse, Pascal Maurice, Frédéric Velard, Christine Terryn, Michaël Molinari, Laurent Duca, Christine Piétrement, Philippe Gillery, and Stéphane Jaisson
Subjects: Medicine, Science
Abstract: Abstract Because of their long lifespan, matrix proteins of the vascular wall, such as elastin, are subjected to molecular aging characterized by non-enzymatic post-translational modifications, like carbamylation which results from the binding of cyanate (mainly derived from the dissociation of urea) to protein amino groups. While several studies have demonstrated a relationship between increased plasma concentrations of carbamylated proteins and the development of cardiovascular diseases, molecular mechanisms explaining the involvement of protein carbamylation in these pathological contexts remain to be fully elucidated. The aim of this work was to determine whether vascular elastic fibers could be carbamylated, and if so, what impact this phenomenon would have on the mechanical properties of the vascular wall. Our experiments showed that vascular elastin was carbamylated in vivo. Fiber morphology was unchanged after in vitro carbamylation, as well as its sensitivity to elastase degradation. In mice fed with cyanate-supplemented water in order to increase protein carbamylation within the aortic wall, an increased stiffness in elastic fibers was evidenced by atomic force microscopy, whereas no fragmentation of elastic fiber was observed. In addition, this increased stiffness was also associated with an increase in aortic pulse wave velocity in ApoE−/− mice. These results provide evidence for the carbamylation of elastic fibers which results in an increase in their stiffness at the molecular level. These alterations of vessel wall mechanical properties may contribute to aortic stiffness, suggesting a new role for carbamylation in cardiovascular diseases.
Published: 2021
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5. The Elastin Receptor Complex: An Emerging Therapeutic Target Against Age-Related Vascular Diseases

Author: Dignê Tembely, Aubéri Henry, Laetitia Vanalderwiert, Kevin Toussaint, Amar Bennasroune, Sébastien Blaise, Hervé Sartelet, Stéphane Jaisson, Céline Galés, Laurent Martiny, Laurent Duca, Béatrice Romier-Crouzet, and Pascal Maurice
Subjects: extracellular matrix, elastin, receptor, neuraminidase, desialylation, signaling, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: The incidence of cardiovascular diseases is increasing worldwide with the growing aging of the population. Biological aging has major influence on the vascular tree and is associated with critical changes in the morphology and function of the arterial wall together with an extensive remodeling of the vascular extracellular matrix. Elastic fibers fragmentation and release of elastin degradation products, also known as elastin-derived peptides (EDPs), are typical hallmarks of aged conduit arteries. Along with the direct consequences of elastin fragmentation on the mechanical properties of arteries, the release of EDPs has been shown to modulate the development and/or progression of diverse vascular and metabolic diseases including atherosclerosis, thrombosis, type 2 diabetes and nonalcoholic steatohepatitis. Most of the biological effects mediated by these bioactive peptides are due to a peculiar membrane receptor called elastin receptor complex (ERC). This heterotrimeric receptor contains a peripheral protein called elastin-binding protein, the protective protein/cathepsin A, and a transmembrane sialidase, the neuraminidase-1 (NEU1). In this review, after an introductive part on the consequences of aging on the vasculature and the release of EDPs, we describe the composition of the ERC, the signaling pathways triggered by this receptor, and the current pharmacological strategies targeting ERC activation. Finally, we present and discuss new regulatory functions that have emerged over the last few years for the ERC through desialylation of membrane glycoproteins by NEU1, and its potential implication in receptor transactivation.
Published: 2022
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6. Thrombospondin-1 Receptor CD47 Overexpression Contributes to P-Glycoprotein-Mediated Multidrug Resistance Against Doxorubicin in Thyroid Carcinoma FTC-133 Cells

Author: Marie-Pierre Courageot, Laurent Duca, Laurent Martiny, Emmanuelle Devarenne-Charpentier, Hamid Morjani, and Hassan El Btaouri
Subjects: chemo-resistance, doxorubicin, P-glycoprotein, TSP-1, CD47, thyroid carcinoma cells, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: It is now admitted that in addition to acquired resistance, the tumor microenvironment contributes to the development of chemo-resistance and malignant progression. In a previous study, we showed that Dox induced apoptosis in FTC-133 cells by trigging JNK pathway. This process was accompanied by a decrease of thrombospondin-1 (TSP-1) expression. Moreover, exogenous TSP-1 or its C-terminal-derived peptide interact with receptor CD47 and are able to protect FTC-133 cells against Dox-induced apoptosis. Here, we investigated the involvement of TSP-1/CD47 interaction in a context of acquired multidrug resistance in FTC-133 cells. To that end, we established a Dox-resistant cell line (FTC-133R cells) which developed a resistance against Dox-induced apoptosis. Cell viability was evaluated by Uptiblue assay, nuclear Dox was measured by microspectrofluorimetry, caspase activity was measured by fluorescence of cleaved caspase-3 substrate, gene expression was evaluated by RT-PCR and protein expression was examined by western-blot. Our results showed that FTC-133R overexpressed the P-gp and were 15-fold resistant to Dox. JNK phosphorylation and Dox-induced apoptosis were reduced in FTC-133R cells. Expression of CD47 was increased in FTC-133R cells but TSP-1 expression presented similar levels in two cell lines. VPL restored Dox nuclear uptake and FTC-133R cell sensitivity to apoptosis and induced a decrease in CD47 mRNA expression. Moreover, knockdown of CD47 in FTC-133R cells induced an increase in JNK activation and sensitized FTC-133R cells to Dox. Our data suggest that CD47 is able to contribute to the protection of FTC-133R cells against Dox-induced apoptosis and/or to potentiate the acquired Dox resistance.
Published: 2020
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7. Transmembrane Peptides as a New Strategy to Inhibit Neuraminidase-1 Activation

Author: Camille Albrecht, Andrey S. Kuznetsov, Aline Appert-Collin, Zineb Dhaideh, Maïté Callewaert, Yaroslav V. Bershatsky, Anatoly S. Urban, Eduard V. Bocharov, Dominique Bagnard, Stéphanie Baud, Sébastien Blaise, Béatrice Romier-Crouzet, Roman G. Efremov, Manuel Dauchez, Laurent Duca, Marc Gueroult, Pascal Maurice, and Amar Bennasroune
Subjects: neuraminidase-1, sialidase activity, transmembrane domain, membrane protein dimerization, interfering peptides, Biology (General), QH301-705.5
Abstract: Sialidases, or neuraminidases, are involved in several human disorders such as neurodegenerative, infectious and cardiovascular diseases, and cancers. Accumulative data have shown that inhibition of neuraminidases, such as NEU1 sialidase, may be a promising pharmacological target, and selective inhibitors of NEU1 are therefore needed to better understand the biological functions of this sialidase. In the present study, we designed interfering peptides (IntPep) that target a transmembrane dimerization interface previously identified in human NEU1 that controls its membrane dimerization and sialidase activity. Two complementary strategies were used to deliver the IntPep into cells, either flanked to a TAT sequence or non-tagged for solubilization in detergent micelles. Combined with molecular dynamics simulations and heteronuclear nuclear magnetic resonance (NMR) studies in membrane-mimicking environments, our results show that these IntPep are able to interact with the dimerization interface of human NEU1, to disrupt membrane NEU1 dimerization and to strongly decrease its sialidase activity at the plasma membrane. In conclusion, we report here new selective inhibitors of human NEU1 of strong interest to elucidate the biological functions of this sialidase.
Published: 2020
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8. Transmembrane Peptides as Inhibitors of Protein-Protein Interactions: An Efficient Strategy to Target Cancer Cells?

Author: Camille Albrecht, Aline Appert-Collin, Dominique Bagnard, Sébastien Blaise, Béatrice Romier-Crouzet, Roman G. Efremov, Hervé Sartelet, Laurent Duca, Pascal Maurice, and Amar Bennasroune
Subjects: transmembrane peptides, protein-protein interaction, transmembrane protein dimerization inhibition, cancers, peptide delivery strategy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Cellular functions are regulated by extracellular signals such as hormones, neurotransmitters, matrix ligands, and other chemical or physical stimuli. Ligand binding on its transmembrane receptor induced cell signaling and the recruitment of several interacting partners to the plasma membrane. Nowadays, it is well-established that the transmembrane domain is not only an anchor of these receptors to the membrane, but it also plays a key role in receptor dimerization and activation. Indeed, interactions between transmembrane helices are associated with specific biological activity of the proteins as cell migration, proliferation, or differentiation. Overexpression or constitutive dimerization (due notably to mutations) of these transmembrane receptors are involved in several physiopathological contexts as cancers. The transmembrane domain of tyrosine kinase receptors as ErbB family proteins (implicated in several cancers as HER2 in breast cancer) or other receptors as Neuropilins has been described these last years as a target to inhibit their dimerization/activation using several strategies. In this review, we will focus on the strategy which consists in using peptides to disturb in a specific manner the interactions between transmembrane domains and the signaling pathways (induced by ligand binding) of these receptors involved in cancer. This approach can be extended to inhibit other transmembrane protein dimerization as neuraminidase-1 (the catalytic subunit of elastin receptor complex), Discoidin Domain Receptor 1 (a tyrosine kinase receptor activated by type I collagen) or G-protein coupled receptors (GPCRs) which are involved in cancer processes.
Published: 2020
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9. Elastin molecular aging promotes MDA‐MB‐231 breast cancer cell invasiveness

Author: Stéphanie Salesse, Ludivine Odoul, Lise Chazée, Christian Garbar, Laurent Duca, Laurent Martiny, Rachid Mahmoudi, and Laurent Debelle
Subjects: aging, elastin‐derived peptides, invasiveness, matrix metalloprotease‐14, MDA‐MB‐231 breast cancer cells, Biology (General), QH301-705.5
Abstract: Elastin is a long‐lived extracellular matrix protein responsible for the structural integrity and function of tissues. Breast cancer elastosis is a complex phenomenon resulting in both the deposition of elastotic masses and the local production of elastin fragments. In invasive human breast cancers, an increase in elastosis is correlated with severity of the disease and age of the patient. Elastin‐derived peptides (EDPs) are a hallmark of aging and are matrikines – matrix fragments having the ability to regulate cell physiology. They are known to promote processes linked to tumor progression, but their effects on breast cancer cells remain unexplored. Our data show that EDPs enhance the invasiveness of MDA‐MB‐231 breast cancer cells through the engagement of matrix metalloproteases 14 and 2. We therefore suggest that elastosis and/or an aged stroma could promote breast cancer cell invasiveness.
Published: 2018
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10. Identification and Evaluation of New Potential Inhibitors of Human Neuraminidase 1 Extracted from Olyra latifolia L.: A Preliminary Study

Author: Camille Albrecht, Zachée Louis Evariste Akissi, Philomène Akoua Yao-Kouassi, Abdulmagid Alabdul Magid, Pascal Maurice, Laurent Duca, Laurence Voutquenne-Nazabadioko, and Amar Bennasroune
Subjects: Olyra latifolia, natural bioactive molecules, Elastin Receptor Complex, neuraminidase 1, sialidase activity, Biology (General), QH301-705.5
Abstract: Sialidases, also called neuraminidases, are involved in several human pathologies such as neurodegenerative disorders, cancers, as well as infectious and cardiovascular diseases. Several studies have shown that neuraminidases, such as neuraminidase 1 (NEU-1), may be promising pharmacological targets. Therefore, the discovery of new selective inhibitors of NEU-1 are necessary to better understand the biological functions of this sialidase. In the present study, we describe the isolation and characterization of nine known compounds from Olyra latifolia L. leaves. This plant, known to have several therapeutic properties, belongs to the family of Poaceae and is found in the neotropics and in tropical Africa and Madagascar. Among the purified compounds, feddeiketone B, 2,3-dihydroxy-1-(4-hydroxy-3,5-diméthoxyphényl)-l-propanone, and syringylglycerol were shown to present structural analogy with DANA, and their effects on membrane NEU-1 sialidase activity were evaluated. Our results show that they possess inhibitory effects against NEU-1-mediated sialidase activity at the plasma membrane. In conclusion, we identified new natural bioactive molecules extracted from Olyra latifolia as inhibitors of human NEU-1 of strong interest to elucidate the biological functions of this sialidase and to target this protein involved in several pathophysiological contexts.
Published: 2021
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11. Uncoupling of Elastin Complex Receptor during In Vitro Aging Is Related to Modifications in Its Intrinsic Sialidase Activity and the Subsequent Lactosylceramide Production.

Author: Amandine Scandolera, Fanja Rabenoelina, Carine Chaintreuil, Anthony Rusciani, Pascal Maurice, Sébastien Blaise, Béatrice Romier-Crouzet, Hassan El Btaouri, Laurent Martiny, Laurent Debelle, and Laurent Duca
Subjects: Medicine, Science
Abstract: Degradation of elastin leads to the production of elastin-derived peptides (EDP), which exhibit several biological effects, such as cell proliferation or protease secretion. Binding of EDP on the elastin receptor complex (ERC) triggers lactosylceramide (LacCer) production and ERK1/2 activation following ERC Neu-1 subunit activation. The ability for ERC to transduce signals is lost during aging, but the mechanism involved is still unknown. In this study, we characterized an in vitro model of aging by subculturing human dermal fibroblasts. This model was used to understand the loss of EDP biological activities during aging. Our results show that ERC uncoupling does not rely on Neu-1 or PPCA mRNA or protein level changes. Furthermore, we observe that the membrane targeting of these subunits is not affected with aging. However, we evidence that Neu-1 activity and LacCer production are altered. Basal Neu-1 catalytic activity is strongly increased in aged cells. Consequently, EDP fail to promote Neu-1 catalytic activity and LacCer production in these cells. In conclusion, we propose, for the first time, an explanation for ERC uncoupling based on the age-related alterations of Neu-1 activity and LacCer production that may explain the loss of EDP-mediated effects occurring during aging.
Published: 2015
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12. Elastin peptides signaling relies on neuraminidase-1-dependent lactosylceramide generation.

Author: Anthony Rusciani, Laurent Duca, Hervé Sartelet, Aurore Chatron-Colliet, Hélène Bobichon, Dominique Ploton, Richard Le Naour, Sébastien Blaise, Laurent Martiny, and Laurent Debelle
Subjects: Medicine, Science
Abstract: The sialidase activity of neuraminidase-1 (Neu-1) is responsible for ERK 1/2 pathway activation following binding of elastin peptide on the elastin receptor complex. In this work, we demonstrate that the receptor and lipid rafts colocalize at the plasma membrane. We also show that the disruption of these microdomains as well as their depletion in glycolipids blocks the receptor signaling. Following elastin peptide treatment, the cellular GM(3) level decreases while lactosylceramide (LacCer) content increases consistently with a GM(3)/LacCer conversion. The use of lactose or Neu-1 siRNA blocks this process suggesting that the elastin receptor complex is responsible for this lipid conversion. Flow cytometry analysis confirms this elastin peptide-driven LacCer generation. Further, the use of a monoclonal anti-GM(3) blocking antibody shows that GM(3) is required for signaling. In conclusion, our data strongly suggest that Neu-1-dependent GM(3)/LacCer conversion is the key event leading to signaling by the elastin receptor complex. As a consequence, we propose that LacCer is an early messenger for this receptor.
Published: 2010
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13. Polysaccharide-Enriched Electrospun Nanofibers for Salicylic Acid Controlled Release

Author: Antonio Laezza, Antonietta Pepe, Aubéri Henry, Laurent Duca, and Brigida Bochicchio
Published: 2022

14. Supplementary Figure 5 from Fhit Regulates EMT Targets through an EGFR/Src/ERK/Slug Signaling Axis in Human Bronchial Cells

Author: Béatrice Nawrocki-Raby, Myriam Polette, Philippe Birembaut, Véronique Dalstein, Claire Kileztky, Christine Gilles, Laurent Duca, Simon Grelet, and Audrey Joannes
Abstract: PDF file - 117KB, Supplementary figure 5: Rescue of EGFR inhibition by active Src in Fhit siRNA-treated cells. (a) Western blot analysis of phospho-Src, total Src, Fhit and Slug levels in HBE4-E6/E7 cells transduced with control or Src. (b) Analysis by Western blotting and zymography of the effect of Src overexpression on vimentin and MMP-9 levels in Fhit siRNA transfectants treated with DMSO or gefitinib.
Published: 2023

15. Supplementary Figure 2 from Fhit Regulates EMT Targets through an EGFR/Src/ERK/Slug Signaling Axis in Human Bronchial Cells

Author: Béatrice Nawrocki-Raby, Myriam Polette, Philippe Birembaut, Véronique Dalstein, Claire Kileztky, Christine Gilles, Laurent Duca, Simon Grelet, and Audrey Joannes
Abstract: PDF file - 297KB, Supplementary figure 2: Representative fields of cell invasion assays. The invasive capacities of scrambled or Fhit siRNA HBE4-E6/E7 transfectants were tested in a modified Boyden chamber invasion assay either after co-transfection with Slug siRNA 1 (a) or Slug siRNA 2 (b) or in the presence of PD98059 (c), PP1 (d), Gefitinib (e) and anti-EGFR antibody (f). The respective controls for Slug siRNA, inhibitor and neutralizing antibody experiments were scrambled siRNA, DMSO and IgG1. Bar = 100 ?m.
Published: 2023

16. Supplementary Figure 1 from Fhit Regulates EMT Targets through an EGFR/Src/ERK/Slug Signaling Axis in Human Bronchial Cells

Author: Béatrice Nawrocki-Raby, Myriam Polette, Philippe Birembaut, Véronique Dalstein, Claire Kileztky, Christine Gilles, Laurent Duca, Simon Grelet, and Audrey Joannes
Abstract: PDF file - 99KB, Supplementary figure 1: Cell invasion induced by Fhit is Slug-dependent. (a) Analysis of the effect of Slug siRNA 2 or a scrambled siRNA on the invasive capacities of HBE4-E6/E7 transfectants in a modified Boyden chamber invasion assay. (b) Western blot and zymography analysis of the effect of Slug siRNA 2 or a scrambled siRNA on Fhit, Slug, vimentin and MMP-9 levels in HBE4-E6/E7 transfectants.
Published: 2023

17. Supplementary Figure 4 from Fhit Regulates EMT Targets through an EGFR/Src/ERK/Slug Signaling Axis in Human Bronchial Cells

Author: Béatrice Nawrocki-Raby, Myriam Polette, Philippe Birembaut, Véronique Dalstein, Claire Kileztky, Christine Gilles, Laurent Duca, Simon Grelet, and Audrey Joannes
Abstract: PDF file - 108KB, Supplementary figure 4: Effect of pharmacological inhibitors of various signaling pathways on cell invasion induced by Fhit silencing. HBE4-E6/E7 cells were transfected with scrambled or Fhit siRNA as described in the "Materials and Methods" section. The invasive capacities of the transfectants were tested in a modified Boyden chamber invasion assay in the presence of PD98059 (ERK), PP1 (Src), SB203580 (p38), Y27632 (ROCK), KT5720 (PKA), wortmaninn (PI3K), U73122 (PLC) or SP600125 (JNK) inhibitors. A representative experiment is shown. Data are expressed as fold induction relative to the DMSO control. *P < 0.05.
Published: 2023

18. Neuraminidase-1: A Sialidase Involved in the Development of Cancers and Metabolic Diseases

Author: Kévin, Toussaint, Aline, Appert-Collin, Hamid, Morjani, Camille, Albrecht, Hervé, Sartelet, Béatrice, Romier-Crouzet, Pascal, Maurice, Laurent, Duca, Sébastien, Blaise, and Amar, Bennasroune
Abstract: Sialidases or neuraminidases (NEU) are glycosidases which cleave terminal sialic acid residues from glycoproteins, glycolipids and oligosaccharides. Four types of mammalian sialidases, which are encoded by different genes, have been described with distinct substrate specificity and subcellular localization: NEU-1, NEU-2, NEU-3 and NEU-4. Among them, NEU-1 regulates many membrane receptors through desialylation which results in either the activation or inhibition of these receptors. At the plasma membrane, NEU-1 also associates with the elastin-binding protein and the carboxypeptidase protective protein/cathepsin A to form the elastin receptor complex. The activation of NEU-1 is required for elastogenesis and signal transduction through this receptor, and this is responsible for the biological effects that are mediated by the elastin-derived peptides (EDP) on obesity, insulin resistance and non-alcoholic fatty liver diseases. Furthermore, NEU-1 expression is upregulated in hepatocellular cancer at the mRNA and protein levels in patients, and this sialidase regulates the hepatocellular cancer cells' proliferation and migration. The implication of NEU-1 in other cancer types has also been shown notably in the development of pancreatic carcinoma and breast cancer. Altogether, these data indicate that NEU-1 plays a key role not only in metabolic disorders, but also in the development of several cancers which make NEU-1 a pharmacological target of high potential in these physiopathological contexts.
Published: 2022

19. Bio-guided Studies of Lotus maritimus Aerial Parts and Investigation of their Antioxidant, Tyrosinase and Elastase Inhibitory Activities

Author: Jean-Marc Nuzillard, Marie Schmitt, Jane Hubert, Abdulmagid Alabdul Magid, Laurence Voutquenne-Nazabadioko, Laurent Duca, Nicolas Etique, Institut de Chimie Moléculaire de Reims - UMR 7312 (ICMR), SFR Condorcet, Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), and Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)
Subjects: antioxidant, DPPH, Tyrosinase, Flavonoid, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, tyrosinase, 01 natural sciences, Flavones, chemistry.chemical_compound, Flavonols, Drug Discovery, elastase, flavonoid, Lotus maritimus, chemistry.chemical_classification, biology, Traditional medicine, 010405 organic chemistry, food and beverages, Glycoside, Fabaceae, [SDV.BV.BOT]Life Sciences [q-bio]/Vegetal Biology/Botanics, biology.organism_classification, dereplication, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, Complementary and alternative medicine, chemistry, Quercetin
Abstract: Background: Lotus maritimus L. (Fabaceae) is a perennial herb species with yellow flowers, growing in Europe, Asia, Middle East and Maghreb. Some flavones and flavonols have been identified in their leaves and flowers. Their leaf extract was used as a cellulolytic and antiaging cosmetic ingredient. Objective: The aim of this work was to perform antioxidant, anti-tyrosinase and anti-elastase properties of L. maritimus aerial parts and their chemical profile. Methods: A 13C NMR-based dereplication method combined with a bio-guided purification was used for metabolite identification. Chemical structures were determined by NMR and ESI-MS spectroscopic methods. The antioxidant properties of the fractions and purified compounds were measured using CUPRAC, DPPH and hydroxyl radical scavenging assays. Their inhibitory activities against the fungal tyrosinase and human neutrophil elastase enzymes were also evaluated. Results: EtOAc and n-BF fractions were characterized as the most active parts. Twenty-two compounds were identified from these fractions by using a 13C NMR-based dereplication method. This process was completed by the purification of minor compounds in the n-BuOH fraction. Eight known compounds were isolated, including many mono-glycosylated flavonoids with variable substitutions on the B-ring, allowing structure-activity relationships. Conclusion: Twenty-two compounds, including phenolic acids, flavonoids and glycoside derivatives, were firstly described in L. maritimus. Three quercetin and myricetin-type flavonoids exhibited good antioxidant activities and all flavonoids tested have moderate effects on elastase inhibition.
Published: 2022

20. Role of elastin and elastin-derived peptides in arterial stiffness: from synthesis to potential therapeutic interventions

Author: Amandine Wahart, Amar Bennasroune, Christian E.H. Schmelzer, Muriel Laffargue, Sébastien Blaise, Béatrice Romier-Crouzet, Hervé Sartelet, Laurent Martiny, Philippe Gillery, Stéphane Jaisson, Pascal Maurice, and Laurent Duca
Published: 2022

21. Contributors

Author: Elena Aikawa, S.G. Anderson, Livia Silva Araújo Passos, Samsul Arefin, Per M. Arvidsson, Alberto Avolio, Martin Bachler, Magnus Bäck, Michael J. Bashline, Dakota Becker-Greene, Jamie Bellinge, Amar Bennasroune, Sébastien Blaise, Barry A. Borlaug, Pierre Boutouyrie, Y. Breet, Jerome W. Breslin, Matthew J. Budoff, Mark Butlin, Marina Cecelja, Chen-Huan Chen, Hao-Min Cheng, Yi-Bang Cheng, Julio A. Chirinos, Phil Chowienczyk, Shao-Yuan Chuang, Marie-Annick Clavel, Jordana B. Cohen, Alexis M. Corcoran, William K. Cornwell, Vicente F. Corrales–Medina, Nancy Côté, Thais Coutinho, James Cox, J.K. Cruickshank, Lu Dai, Stella S. Daskalopoulou, Kevin P. Davy, Marc L. De Buyzere, Paul B. Dieffenbach, Laurent Duca, Girish Dwivedi, David G. Edwards, William B. Farquhar, Bo Fernhall, John S. Floras, Laura E. Fredenburgh, Masafumi Fukumitsu, L. Gafane-Matemane, Nestor Gahungu, Ahmed K. Ghanem, Thierry C. Gillebert, Philippe Gillery, Delphine Gomez, Ezequiel Guzzetti, Bernhard Hametner, Junichiro Hashimoto, Kevin S. Heffernan, Brooks A. Hibner, Sam Hobson, Nien-Wen Hu, T.M. Hughes, Jay D. Humphrey, Stéphane Jaisson, Nadjia Kachenoura, Kazuomi Kario, Prasad V.G. Katakam, Goro Katsuumi, Avinash Kondiboyina, Sándor J. Kovács, R. Kruger, Karolina Kublickiene, Patrick Lacolley, Muriel Laffargue, Arinola O. Lampejo, Agne Laucyte-Cibulskiene, Stéphane Laurent, Hae-Young Lee, Wesley K. Lefferts, Elizabeth C. Lefferts, Adelino F. Leite-Moreira, Chee H. Liew, Joao A.C. Lima, André P. Lourenço, Kaisa Maki-Petaja, Marcy Maracle, Laurent Martiny, Pascal Maurice, Christopher C. Mayer, Barry J. McDonnell, John W. McEvoy, M.L. Meyer, Jean-Baptiste Michel, Philip J. Millar, Tohru Minamino, Gary F. Mitchell, Walter L. Murfee, Jonathan P. Mynard, Massimo Nardone, Peter M. Nilsson, Kevin O'Gallagher, Yoshiaki Ohyama, Kazunori Omote, Jeong Bae Park, Shayn M. Peirce, Philippe Pibarot, Gary L. Pierce, Stuart B. Prenner, Athanase Protogerou, Reed E. Pyeritz, Michael A. Quail, Yogesh N.V. Reddy, Alban Redheuil, Véronique Regnault, Rakhshinda Rehman, Ernst R. Rietzschel, Béatrice Romier-Crouzet, Jasjit Rooprai, Lucia Salvi, Paolo Salvi, Hervé Sartelet, Christian E.H. Schmelzer, A.E. Schutte, Angelina Schwarz, Patrick Segers, James E. Sharman, Ippei Shimizu, Marc A. Simon, Piera Sosa, Bart Spronck, Peter Stenvinkel, Eric J. Stöhr, M. Strauss-Kruger, Ariana Suarez-Martinez, Masayoshi Suda, Shih-Hsien Sung, Isabella Tan, Dimitrios Terentes-Printzios, Raymond R. Townsend, Andrew H. Tran, Elaine M. Urbina, Bharath Ambale Venkatesh, Charalambos Vlachopoulos, Anton Vonk Noordegraaf, Amandine Wahart, Ji-Guang Wang, Siegfried Wassertheurer, Andrew James Webb, Thomas Weber, Berend E. Westerhof, Ian B. Wilkinson, and Yohko Yoshida
Published: 2022

22. A guide to the composition and functions of the extracellular matrix

Author: Nikolaos A. Afratis, Sylvie Ricard-Blum, Laurent Duca, Spyros S. Skandalis, Achilleas D. Theocharis, Demitrios H. Vynios, Linda Troeberg, Zoi Piperigkou, Madeleine Durbee, Alberto Passi, Maurizio Onisto, Valentina Masola, Christian E.H. Schmelzer, Véronique Orian-Rousseau, Dimitra Manou, Marco Franchi, Nikos K. Karamanos, Karamanos N.K., Theocharis A.D., Piperigkou Z., Manou D., Passi A., Skandalis S.S., Vynios D.H., Orian-Rousseau V., Ricard-Blum S., Schmelzer C.E.H., Duca L., Durbeej M., Afratis N.A., Troeberg L., Franchi M., Masola V., Onisto M., and Publica
Subjects: 0301 basic medicine, collagen, Cell signaling, matrix metalloproteinase, integrin, extracellular matrix, Integrin, elastin, hyaluronidase, Matrix (biology), Matrix metalloproteinase, Biochemistry, heparanase, Extracellular matrix, hyaluronan, 03 medical and health sciences, 0302 clinical medicine, tenascins, laminin, glycosaminoglycan, Animals, Humans, collagens, glycosaminoglycans, hyaluronidases, integrins, laminins, matrix metalloproteinases, proteoglycans, Cell adhesion, Molecular Biology, proteoglycan, biology, Cell growth, Animal, CD44, Cell Biology, Cell biology, 030104 developmental biology, tenascin, 030220 oncology & carcinogenesis, biology.protein
Abstract: Extracellular matrix (ECM) is a dynamic 3-dimensional network of macromolecules that provides structural support for the cells and tissues. Accumulated knowledge clearly demonstrated over the last decade that ECM plays key regulatory roles since it orchestrates cell signaling, functions, properties and morphology. Extracellularly secreted as well as cell-bound factors are among the major members of the ECM family. Proteins/glycoproteins, such as collagens, elastin, laminins and tenascins, proteoglycans and glycosaminoglycans, hyaluronan, and their cell receptors such as CD44 and integrins, responsible for cell adhesion, comprise a well-organized functional network with significant roles in health and disease. On the other hand, enzymes such as matrix metalloproteinases and specific glycosidases including heparanase and hyaluronidases contribute to matrix remodeling and affect human health. Several cell processes and functions, among them cell proliferation and survival, migration, differentiation, autophagy, angiogenesis, and immunity regulation are affected by certain matrix components. Structural alterations have been also well associated with disease progression. This guide on the composition and functions of the ECM gives a broad overview of the matrisome, the major ECM macromolecules, and their interaction networks within the ECM and with the cell surface, summarizes their main structural features and their roles in tissue organization and cell functions, and emphasizes the importance of specific ECM constituents in disease development and progression as well as the advances in molecular targeting of ECM to design new therapeutic strategies.
Published: 2021

23. Apelin expression deficiency in mice contributes to vascular stiffening by extracellular matrix remodeling of the aortic wall

Author: Corinne Garbar, Philippe Valet, Laurent Martiny, Christian Garbar, Cédric Dray, Alizée Dortignac, Béatrice Romier, Laurent Duca, Thinhinane Hocine, Amar Bennasroune, Camille Boulagnon, Sébastien Blaise, Hervé Sartelet, Laetitia Vanalderwiert, Amandine Wahart, Pascal Maurice, Nicole Bouland, Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), Geroscience and rejuvenation research center (RESTORE), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Jean Godinot [Reims], UNICANCER, and MAURICE, Pascal
Subjects: medicine.medical_specialty, Physiology, Science, [SDV]Life Sciences [q-bio], Cardiology, Gene Expression, Adipose tissue, Blood Pressure, Diseases, Pathogenesis, White adipose tissue, Article, Extracellular matrix, Mice, chemistry.chemical_compound, Vascular Stiffness, Endocrinology, Adipocyte, Internal medicine, medicine.artery, medicine, Animals, Aorta, Cathepsin S, Mice, Knockout, Multidisciplinary, Pancreatic Elastase, business.industry, Immunohistochemistry, Extracellular Matrix, Apelin, [SDV] Life Sciences [q-bio], Risk factors, chemistry, Medicine, Aortic stiffness, business, Biomarkers
Abstract: Numerous recent studies have shown that in the continuum of cardiovascular diseases, the measurement of arterial stiffness has powerful predictive value in cardiovascular risk and mortality and that this value is independent of other conventional risk factors, such as age, cholesterol levels, diabetes, smoking, or average blood pressure. Vascular stiffening is often the main cause of arterial hypertension (AHT), which is common in the presence of obesity. However, the mechanisms leading to vascular stiffening, as well as preventive factors, remain unclear. The aim of the present study was to investigate the consequences of apelin deficiency on the vascular stiffening and wall remodeling of aorta in mice. This factor freed by visceral adipose tissue, is known for its homeostasic role in lipid and vascular metabolisms, or again in inflammation. We compared the level of metabolic markers, inflammation of white adipose tissue (WAT), and aortic wall remodeling from functional and structural approaches in apelin-deficient and wild-type (WT) mice. Apelin-deficient mice were generated by knockout of the apelin gene (APL-KO). From 8 mice by groups, aortic stiffness was analyzed by pulse wave velocity measurements and by characterizations of collagen and elastic fibers. Mann–Whitney statistical test determined the significant data (p
Published: 2021

24. Elastic fibers: formation, function, and fate during aging and disease

Author: Christian E.H. Schmelzer and Laurent Duca
Subjects: 0301 basic medicine, Aging, Fibrillin-1, Fibrillins, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Glycation, medicine, Extracellular, Animals, Humans, Molecular Biology, biology, Chemistry, Cell Biology, medicine.disease, Elastic Tissue, Cell biology, Elastin, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, biology.protein, Microfibril, Fibrillin, Function (biology), Elastic fiber, Calcification
Abstract: Elastic fibers are extracellular components of higher vertebrates and confer elasticity and resilience to numerous tissues and organs such as large blood vessels, lungs, and skin. Their formation and maturation take place in a complex multistage process called elastogenesis. It requires interactions between very different proteins but also other molecules and leads to the deposition and crosslinking of elastin's precursor on a scaffold of fibrillin-rich microfibrils. Mature fibers are exceptionally resistant to most influences and, under healthy conditions, retain their biomechanical function over the life of the organism. However, due to their longevity, they accumulate damages during aging. These are caused by proteolytic degradation, formation of advanced glycation end products, calcification, oxidative damage, aspartic acid racemization, lipid accumulation, carbamylation, and mechanical fatigue. The resulting changes can lead to diminution or complete loss of elastic fiber function and ultimately affect morbidity and mortality. Particularly, the production of elastokines has been clearly shown to influence several life-threatening diseases. Moreover, the structure, distribution, and abundance of elastic fibers are directly or indirectly influenced by a variety of inherited pathological conditions, which mainly affect organs and tissues such as skin, lungs, or the cardiovascular system. A distinction can be made between microfibril-related inherited diseases that are the result of mutations in diverse microfibril genes and indirectly affect elastogenesis, and elastinopathies that are linked to changes in the elastin gene. This review gives an overview on the formation, structure, and function of elastic fibers and their fate over the human lifespan in health and disease.
Published: 2021

25. Adverse effects of oseltamivir phosphate therapy on the liver of LDLR-/- mice without any benefit on atherosclerosis and thrombosis

Author: Olivier Bocquet, Thomas Sarazin, Hervé Sartelet, Stéphanie Gayral, Sébastien Blaise, Amar Bennasroune, Pascal Maurice, Pr. Laurent Duca, Camille Boulagnon, Amandine Wahart, Pr. Laurent Martiny, Elise Vincent, Pr. Philippe Gillery, Anne Fougerat, Stéphane Jaisson, Béatrice Romier-Crouzet, Aubéri Henry, Muriel Laffargue, and Christophe Schneider
Subjects: Liver Cirrhosis, 0301 basic medicine, Aortic Diseases, Inflammation, 030204 cardiovascular system & hematology, Pharmacology, Diet, High-Fat, Sialidase, Antiviral Agents, Risk Assessment, 03 medical and health sciences, Oseltamivir, 0302 clinical medicine, Insulin resistance, Fibrosis, Oseltamivir Phosphate, medicine, Animals, Carotid Artery Thrombosis, Adverse effect, Aorta, Mice, Knockout, biology, business.industry, Atherosclerosis, medicine.disease, Plaque, Atherosclerotic, 3. Good health, Disease Models, Animal, 030104 developmental biology, Liver, Receptors, LDL, LDL receptor, biology.protein, Female, Chemical and Drug Induced Liver Injury, medicine.symptom, Cardiology and Cardiovascular Medicine, business, Elastin
Abstract: Desialylation, governed by sialidases or neuraminidases, is strongly implicated in a wide range of human disorders, and accumulative data show that inhibition of neuraminidases, such as neuraminidases 1 sialidase, may be useful for managing atherosclerosis. Several studies have reported promising effects of oseltamivir phosphate, a widely used anti-influenza sialidase inhibitor, on human cancer cells, inflammation, and insulin resistance. In this study, we evaluated the effects of oseltamivir phosphate on atherosclerosis and thrombosis and potential liver toxicity in LDLR-/- mice fed with high-fat diet. Our results showed that oseltamivir phosphate significantly decreased plasma levels of LDL cholesterol and elastin fragmentation in aorta. However, no effect was observed on both atherosclerotic plaque size in aortic roots and chemically induced thrombosis in carotid arteries. Importantly, oseltamivir phosphate administration had adverse effects on the liver of mice and significantly increased messenger RNA expression levels of F4/80, interleukin-1β, transforming growth factor-β1, matrix metalloproteinase-12, and collagen. Taken together, our findings suggest that oseltamivir phosphate has limited benefits on atherosclerosis and carotid thrombosis and may lead to adverse side effects on the liver with increased inflammation and fibrosis.
Published: 2021

26. The high expression of elastases, observed in apelin deficient mice, could contribute to premature wear of elastic fibers and vascular stiffness

Author: Amar Bennasroune, Laurent Martiny, Corinne Garbar, Laetitia Vanalderwiert, Hervé Sartelet, Amandine Wahart, Philippe Valet, Christian Garbar, Laurent Duca, Thinhinane Hocine, Béatrice Romier, Sébastien Blaise, Camille Boulagnon, Nicole Bouland, Alizée Dortignac, Cédric Dray, and Pascal Maurice
Subjects: medicine.medical_specialty, Vascular stiffness, Text mining, Endocrinology, business.industry, Chemistry, Internal medicine, medicine, Deficient mouse, business, Apelin
Abstract: Vascular stiffness is often the main cause of arterial hypertension and its complications including atherosclerosis, observed during obesity. However, the mechanisms leading to this rigidity or the preventing factors are misknown. We hypothesized that apelin, known for its beneficial effects on lipid, inflammatory, and vascular metabolism, could be a protective factor against vascular stiffness. We used mice deficient for the apelin gene (KO-APL) and compared with wild-type mice (WT) at the level of metabolic markers and inflammations of white adipose tissue (WAT), as well as aortic functional and anatomical parameters. KO-APL mice developed an inflammation associated with significant remodeling of WAT, in particular with the protease expressions such as neutrophil elastase or cathepsin S. From a vascular point of view, these same elastases are involved in the fragmentation of elastic fibers, explaining the increase in vascular velocity of pulse wave and arterial hypertension. Interestingly, univariate correlation analysis showed that the inflammation markers and protease expression of WAT were associated with remodeling of the vascular wall. Our results suggest that the modifications induced by the absence of apelin particularly in WAT, could facilitate the expression of elastases and the rupture of elastic fibers, necessary to maintain elastance. This discovery is fundamental because the synthesis of elastic fibers stops as of adolescence and is not renewed during the entire life of human. The preservation of these fibers is therefore critical in maintaining vascular homeostasis. Thus, Apelin could be an interesting therapeutic route to protect the premature wear of elastic fibers.
Published: 2021

27. Chemical characterization, antioxidant, tyrosinase and elastase inhibitory activities of Colutea arborescens aerial parts guided by chemical and biological assays

Author: Marie Schmitt, Abdulmagid Alabdul Magid, Nicolas Etique, Laurent Duca, Jane Hubert, Jean-Marc Nuzillard, Laurence Voutquenne-Nazabadioko, Institut de Chimie Moléculaire de Reims - UMR 7312 (ICMR), SFR Condorcet, Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), and Nuzillard, Jean-Marc
Subjects: glycoside, antioxidant, [CHIM.THER] Chemical Sciences/Medicinal Chemistry, elastase, flavonoid, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, tyrosinase, [SDV.BV.BOT]Life Sciences [q-bio]/Vegetal Biology/Botanics, Colutea arborescens, dereplication, [SDV.BV.BOT] Life Sciences [q-bio]/Vegetal Biology/Botanics
Abstract: International audience; This study presents the bio-guided chemical investigation of 80% methanol extract of aerial parts of bladder tree or Colutea arborescens. Liquid-liquid partitioning in solvents of increasing polarity combined with biological screening showed that the EtOAc and n-BuOH soluble fractions were the most active parts of the extract. These fractions were chemically profiled by a 13 C NMR-based dereplication method, resulting in the identification of fifteen compounds. The dereplication process was completed by purification of minor compounds of the n-BuOH fraction. Fourteen known compounds (1-14) were isolated, including two tri-glycosylated flavonoids containing an apiofuranose unit (12 and 14). Their structures were elucidated by spectroscopic methods including 1D and 2D NMR and high-resolution electrospray ionization mass spectrometry. The antioxidant activity of fractions and isolated compounds were evaluated using 2,2,1-diphenyl-1-picrylhydrazyl and hydroxyl radicals scavenging and by cupric ion reducing antioxidant capacity assays. In parallel, their inhibitory properties against mushroom tyrosinase and human neutrophil elastase enzymes were assessed. Quercetin-type flavonoids showed the best antioxidant activities and a tri-glycosylated quercetin exhibited both antioxidant and anti-elastase activities. Phenylethyl-glucoside exhibited a significant tyrosinase inhibitory activity.
Published: 2021

28. Revealing the elasticity of an individual aortic fiber during ageing at nanoscale by in situ atomic force microscopy †

Author: Laurent Martiny, Sébastien Blaise, Alexandre Berquand, Laëtitia Gorisse, Philippe Gillery, Laurent Duca, Béatrice Romier-Crouzet, Pascal Maurice, Christine Pietrement, Fatouma Touré, Hervé Sartelet, Michael Molinari, Stéphane Jaisson, Aubéri Henry, Amar Bennasroune, Amandine Wahart, Laboratoire de Recherche en Nanosciences - EA 4682 (LRN), SFR Condorcet, Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV), Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Chimie et Biologie des Membranes et des Nanoobjets (CBMN), École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-SFR Condorcet, Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Université de Bordeaux (UB)-École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and MAURICE, Pascal
Subjects: Fluorescence-lifetime imaging microscopy, Aging, Materials science, 030204 cardiovascular system & hematology, Pulse Wave Analysis, Microscopy, Atomic Force, Extracellular matrix, 03 medical and health sciences, Mice, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, medicine.artery, medicine, Animals, General Materials Science, Elasticity (economics), [PHYS.MECA.BIOM]Physics [physics]/Mechanics [physics]/Biomechanics [physics.med-ph], Pulse wave velocity, Aorta, 030304 developmental biology, 0303 health sciences, biology, [PHYS.MECA.BIOM] Physics [physics]/Mechanics [physics]/Biomechanics [physics.med-ph], Stiffness, Elasticity, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Ageing, biology.protein, medicine.symptom, Elastin, Biomedical engineering
Abstract: International audience; Arterial stiffness is a complex process affecting the aortic tree that significantly contributes to cardiovascular diseases (systolic hypertension, coronary artery disease, heart failure or stroke). This process involves a large extracellular matrix remodeling mainly associated with elastin content decrease and collagen content increase. Additionally, various chemical modifications that accumulate with ageing have been shown to affect long-lived assemblies, such as elastic fibers, that could affect their elasticity. To precisely characterize the fiber changes and the evolution of its elasticity with ageing, high resolution and multimodal techniques are needed for precise insight into the behavior of a single fiber and its surrounding medium. In this study, the latest developments in atomic force microscopy and the related nanomechanical modes are used to investigate the evolution and in a near-physiological environment, the morphology and elasticity of aorta cross sections obtained from mice of different ages with an unprecedented resolution. In correlation with more classical approaches such as pulse wave velocity and fluorescence imaging, we demonstrate that the relative Young's moduli of elastic fibers, as well as those of the surrounding areas, significantly increase with ageing. This nanoscale characterization presents a new view on the stiffness process, showing that, besides the elastin and collagen content changes, elasticity is impaired at the molecular level, allowing a deeper understanding of the ageing process. Such nanomechanical AFM measurements of mouse tissue could easily be applied to studies of diseases in which elastic fibers suffer pathologies such as atherosclerosis and diabetes, where the precise quantification of fiber elasticity could better follow the fiber remodeling and predict plaque rupture. † Electronic supplementary information (ESI) available. See
Published: 2021

29. Identification and Evaluation of New Potential Inhibitors of Human Neuraminidase 1 Extracted from Olyra latifolia L.: A Preliminary Study

Author: Zachée Louis Evariste Akissi, Amar Bennasroune, Laurence Voutquenne-Nazabadioko, Abdulmagid Alabdul Magid, Laurent Duca, Philomène Akoua Yao-Kouassi, Camille Albrecht, Pascal Maurice, Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie Moléculaire de Reims - UMR 7312 (ICMR), SFR Condorcet, Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Université Félix Houphouët-Boigny (UFHB)
Subjects: 0301 basic medicine, Bioactive molecules, Medicine (miscellaneous), natural bioactive molecules, sialidase activity, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Sialidase, General Biochemistry, Genetics and Molecular Biology, Article, neuraminidase 1, 03 medical and health sciences, 0302 clinical medicine, Olyra latifolia, Elastin receptor complex, lcsh:QH301-705.5, biology, Elastin Receptor Complex, Sialidase activity, [SDV.BV.BOT]Life Sciences [q-bio]/Vegetal Biology/Botanics, biology.organism_classification, 3. Good health, 030104 developmental biology, Biochemistry, lcsh:Biology (General), 030220 oncology & carcinogenesis, biology.protein, Identification (biology), Neuraminidase
Abstract: International audience; Sialidases, also called neuraminidases, are involved in several human pathologies such as neurodegenerative disorders, cancers, as well as infectious and cardiovascular diseases. Several studies have shown that neuraminidases, such as neuraminidase 1 (NEU-1), may be promising pharmacological targets. Therefore, the discovery of new selective inhibitors of NEU-1 are necessary to better understand the biological functions of this sialidase. In the present study, we describe the isolation and characterization of nine known compounds from Olyra latifolia L. leaves. This plant, known to have several therapeutic properties, belongs to the family of Poaceae and is found in the neotropics and in tropical Africa and Madagascar. Among the purified compounds, feddeiketone B, 2,3-dihydroxy-1-(4-hydroxy-3,5-diméthoxyphényl)-l-propanone, and syringylglycerol were shown to present structural analogy with DANA, and their effects on membrane NEU-1 sialidase activity were evaluated. Our results show that they possess inhibitory effects against NEU-1-mediated sialidase activity at the plasma membrane. In conclusion, we identified new natural bioactive molecules extracted from Olyra latifolia as inhibitors of human NEU-1 of strong interest to elucidate the biological functions of this sialidase and to target this protein involved in several pathophysiological contexts.
Published: 2021

30. Lactosylceramide induced by elastin-derived peptides decreases adipocyte differentiation

Author: Sébastien Blaise, Pascal Maurice, Hassan El Btaouri, Thinhinane Hocine, Béatrice Romier-Crouzet, Laurent Duca, Hervé Sartelet, Alexandre Guillot, Amar Bennasroune, Cathy Hachet, Laurent Martiny, Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), SFR CAP Santé (Champagne-Ardenne Picardie Santé), and Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Cell signaling, Physiology, Cellular differentiation, [SDV]Life Sciences [q-bio], Lactosylceramides, Peroxisome proliferator-activated receptor, Receptors, Cell Surface, 030209 endocrinology & metabolism, adipocyte, Biochemistry, Extracellular matrix, Mice, 03 medical and health sciences, chemistry.chemical_compound, Lactosylceramide, 0302 clinical medicine, 3T3-L1 Cells, Adipocyte, PPAR, Adipocytes, Animals, Elastin derived peptides, music, chemistry.chemical_classification, Adipogenesis, music.instrument, biology, Lactosyl-ceramide, Cell Differentiation, General Medicine, Elastin, Cell biology, ERK, 030104 developmental biology, Gene Expression Regulation, chemistry, Differentiation, biology.protein, Oligopeptides
Abstract: International audience; Elastin, major protein of extracellular matrix, is specially found in cardiovascular tissues and contributing to 30-50% of the dry weight of blood vessels. Elastin regulates cell signalling pathways involved in morphogenesis, injury response, and inflammation. The function of elastin is frequently compromised in damaged or aged elastic tissues. Indeed, elastin degradation, observed during ageing, and the resulting production of elastin derived peptides (EDP), have crucial impacts on cardiovascular disease (atherosclerosis, thrombosis) or on metabolism disease progressions (type 2 diabetes or non-alcoholic steatohepatitis). In the present study, we analysed the EDP effects on 3T3 pre-adipocyte cell differentiation. In a first part, we treated 3T3-L1 cells with EDP and visualized the lipid droplet accumulation by the oil redO staining and measured the expression of various transcription factors and adipocyte-specific mRNAs by real-time RT-PCR. We demonstrated that elastin receptor complex, ERC, is activated by EDPs and decreased adipocyte differentiation by a modulation of crucial adipogenesis transcriptional factor particularly PPARγ. In a second part, we identified the signalling pathway implicated in EDP-reduced cell differentiation. The flow cytometry and immunocytochemistry approaches showed that ERC activated by EDP, produced a second messenger, lactosylceramide (Lac-Cer). Moreover, this Lac-Cer production favoured the phosphorylation of ERK1-2 (p-ERK1-2), to decrease adipocyte differentiation by a modulation of adipogenesis transcriptional factor PPARγ. To conclude, the EDP/Lac-Cer/p-ERK1-2 signalling pathway may be studied further as a critical target for treating complications associated with adipocyte dedifferentiation such as obesity and diabetes insulin resistance. KEY POINTS Elastin Derived Peptides (EDP) decreased PPAR expression. EDP reduced adipocytes differentiation. Adipocytes differentiation is reduced by Lac-cer production and ERK1/2 activation.
Published: 2020

31. Investigation of Antioxidant and Elastase Inhibitory Activities of Geum urbanum Aerial Parts, Chemical Characterization of Extracts Guided by Chemical and Biological Assays

Author: Nicolas Etique, Abdulmagid Alabdul Magid, Laurent Duca, Laurence Voutquenne-Nazabadioko, Marie Schmitt, Jean-Marc Nuzillard, Jane Hubert, Institut de Chimie Moléculaire de Reims - UMR 7312 (ICMR), SFR Condorcet, Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), and Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Geum urbanum, Antioxidant, antioxidant, medicine.medical_treatment, Plant Science, phenols, 01 natural sciences, chemistry.chemical_compound, food, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, Drug Discovery, medicine, NMR dereplication, Bioassay, elastase, Phenols, Pharmacology, Aqueous solution, Chromatography, 010405 organic chemistry, ellagitanins, Elastase, General Medicine, food.food, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, Complementary and alternative medicine, chemistry, Methanol
Abstract: This study presents the bioguided chemical investigation of the 80% aqueous methanol extract of Geum urbanum aerial parts. Liquid–liquid partitioning of this extract in solvents of increasing polarity combined with biological screening showed that the ethyl acetate (EtOAc) soluble fraction was the most active part of the extract. This fraction was chemically profiled by a 13C nuclear magnetic resonance (NMR)-based dereplication method, resulting in the identification of 14 compounds. The dereplication process was followed by the purification of unknown and minor compounds of the EtOAc fraction. A new glycosylated phenol, namely, 3-(3,4-dihydroxyphenyl)propyl-α-l-rhamnopyranoside, together with 6 known compounds were isolated. Their structures were elucidated by spectroscopic methods including NMR and high-resolution electrospray ionization mass spectrometry. The antioxidant activity of fractions and isolated compounds were evaluated by 2,2,1-diphenyl-1-picrylhydrazyl and hydroxyl radical scavenging, and by cupric ion reducing antioxidant capacity assays. In parallel, their enzyme inhibitory property against human neutrophil elastase was assessed. Four subfractions, essentially containing polyphenols and triterpenes, exhibited a significant elastase inhibitory activity and an ellagitannin showed a very high radical scavenging activity.
Published: 2020

32. Bio-guided isolation of new phenolic compounds from Hippocrepis emerus flowers and investigation of their antioxidant, tyrosinase and elastase inhibitory activities

Author: Abdulmagid Alabdul Magid, Laurence Voutquenne-Nazabadioko, Jane Hubert, Nicolas Etique, Marie Schmitt, Laurent Duca, Institut de Chimie Moléculaire de Reims - UMR 7312 (ICMR), SFR Condorcet, Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), and Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Antioxidant, DPPH, Tyrosinase, medicine.medical_treatment, Flavonoid, Plant Science, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 01 natural sciences, Biochemistry, chemistry.chemical_compound, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, Elastase, medicine, Hippocrepis emerus, chemistry.chemical_classification, Chromatography, biology, 010405 organic chemistry, Chemistry, Glycoside, [SDV.BV.BOT]Life Sciences [q-bio]/Vegetal Biology/Botanics, biology.organism_classification, Dereplication, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, Quercetin, Agronomy and Crop Science, Biotechnology
Abstract: This study presents the bio-guided chemical investigation of a 80% methanol extract of Hippocrepis emerus flowers, a perennial non-climbing shrub. Liquid-liquid partitioning in solvents of increasing polarity combined to biological screening enabled to determine the EtOAc and n-BuOH soluble fractions as the most active parts of the extract. These fractions were chemically profiled by using a 13C NMR-based dereplication method, resulting in the identification of twenty-six compounds. The dereplication process was completed by purification of some unknown or minor compounds of the n-BuOH fraction. Three new glycosylated flavonoids, namely kaempferol-3-O-β- d -glucopyranosyl-7-O-β- d -glucopyranosyl-(1→3)-α- l -rhamnopyranoside (1), isorhamnetin-3-O-β- d -glucopyranosyl-7-O-β- d -glucopyranosyl-(1→3)-α- l -rhamnopyranoside (2) and quercetin-3-O-β- d -glucopyranosyl-7,4′-O-α- l -dirhamnopyranoside (3), together with twelve known compounds (4 – 15) were isolated. Their structures were elucidated by spectroscopic methods including NMR, HR-ESI-MS and UV. The antioxidant activity of fractions and isolated compounds were evaluated using DPPH and hydroxyl radical scavenging and CUPRAC assays. In parallel, their inhibitory properties against mushroom tyrosinase and human neutrophil elastase enzymes were assessed. Three quercetin glycosides exhibited a significant radical-scavenging activity and two flavonoids showed a moderate elastase inhibitory activity.
Published: 2020

33. Effect of elastin-derived peptides (EDPS) and carbamylated-EDPS on vascular smooth muscle cells phenotype in relation to atherosclerosis development

Author: Sébastien Blaise, S. Jaisson, Hervé Sartelet, Philippe Gillery, Laurent Duca, A. Berquand, A. Henry, Christine Terryn, Pascal Maurice, Amar Bennasroune, and Béatrice Romier-Crouzet
Subjects: Vascular smooth muscle, biology, Chemistry, biology.protein, Cardiology and Cardiovascular Medicine, Elastin, Phenotype, Cell biology
Published: 2021

34. Characterization of novel interactions with plasma membrane NEU1 reveals new biological functions for the elastin receptor complex in vascular diseases

Author: Olivier Bocquet, Laurent Martiny, Hervé Sartelet, Sébastien Blaise, Christian E.H. Schmelzer, Andrea Heinz, Laurent Duca, D. Tembely, Christine Terryn, Charlotte Kawecki, Pascal Maurice, Amar Bennasroune, and Béatrice Romier-Crouzet
Subjects: biology, Monocyte, Protein subunit, Sialidase, Cell biology, NEU1, Membrane glycoproteins, medicine.anatomical_structure, biology.protein, medicine, Cardiology and Cardiovascular Medicine, Receptor, Elastin, Function (biology)
Abstract: Remodeling of elastin during pathophysiological vascular aging leads to the production of elastin-derived peptides (EDP), also known as elastokines. These peptides trigger biological effects through the elastin receptor complex (ERC). Data from the last decade have brought significant insights on the critical role played by its catalytic subunit, Neuraminidase-1 (NEU1), in the biological effects mediated by EDP in vascular and metabolic diseases. We recently developed a proteomic approach dedicated to the purification and identification of membrane NEU1-associated protein complexes in human macrophages and identified several promising candidates (Kawecki et al, CMLS. 2019). Here, we validated and characterized two novel interactions with NEU1 in human monocytes and endothelial cells involving the β2 integrin and ICAM-1, respectively. We show that binding of EDP to the ERC leads to desialylation of monocyte β2 integrin and endothelial ICAM-1 through membrane NEU1. Importantly, desialylation of either monocyte β2 integrin or endothelial ICAM-1 by EDP is sufficient to potentiate monocyte adhesion to a monolayer of endothelial cells. In conclusion, these results demonstrate, for the first time, that binding of EDP to the ERC modulates the sialylation levels of monocyte β2 integrin and endothelial ICAM-1 through NEU1, and highlight that EDP and the ERC may be important regulators of circulating monocytes recruitment to inflamed vascular sites through this sialidase. By its ability to interact with and to modulate the sialylation of key membrane glycoproteins through NEU1, new biological functions are anticipated for EDP and the ERC in vascular diseases involving elastic fibers and elastin degradation. Keywords: Biochemistry, pathophysiological Biochemistry is both life science and a chemical science - it explores the chemistry of living organisms and the molecular basis for the changes occurring in living cells. It uses the methods of chemistry, "Biochemistry has become the foundation for understanding all biological processes. It has provided explanations for the causes of many diseases in humans, animals and plants." physics, molecular biology, and immunology to study the structure and behaviour of the complex molecules found in biological material and the ways these molecules interact to form cells, tissues, and whole organisms. Biochemists are interested, for example, in mechanisms of brain function, cellular multiplication and differentiation, communication within and between cells and organs, and the chemical bases of inheritance and disease. The biochemist seeks to determine how specific molecules such as proteins, nucleic acids, lipids, vitamins, and hormones function in such processes. Particular emphasis is placed on the regulation of chemical reactions in living cells.
Published: 2021

35. Role of elastin peptides and elastin receptor complex in metabolic and cardiovascular diseases

Author: Thomas Sarazin, Camille Albrecht, Pascal Maurice, Laurent Duca, Laurent Martiny, Sébastien Blaise, Béatrice Romier-Crouzet, Amar Bennasroune, Amandine Wahart, Thinhinane Hocine, Hassan El Btaouri, Aubéri Henry, Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Signalisation et Récepteurs Matriciels (SiRMa), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Laboratoire Interdisciplinaire des Environnements Continentaux (LIEC), Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Terre et Environnement de Lorraine (OTELo), Institut national des sciences de l'Univers (INSU - CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Pennington Biomedical Center, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)
Subjects: AMPK, Heart disease, oxidized Low Density Lipoprotein, EDP, Biochemistry, Matrix MetalloProteinase, Neu-1, WHO, 0302 clinical medicine, cardiovascular continuum, T2D, Left Ventricular Diastolic Pressure, ComputingMilieux_MISCELLANEOUS, LKB-1, NCEP, oxLDL, MMP, Non Alcoholic Fatty Liver Disease, EGIR, NASH, ROS, 3. Good health, Type 2 Diabetes, Cardiovascular Diseases, Non Alcoholic Steato Hepatitis, 030220 oncology & carcinogenesis, PTM, elastin, Receptors, Cell Surface, RPP, Hepatocyte Growth Factor Receptor, PPCA, 03 medical and health sciences, elastin receptor complex, NAFLD, Humans, World Health Organisation Keywords : Elastin, SupraValvular Aortic Stenosis, LVEDP, WBS, Molecular Biology, National Cholesterol Education Program, elastin-derived peptides, medicine.disease, American Association of Clinical Endocrinologists, 030104 developmental biology, Elastin Binding Protein, IR, Metabolic syndrome, Peptides, Reactive Oxygen Species, Supravalvular aortic stenosis, Liver Kinase-B1, Willliams-Beuren Syndrome, 0301 basic medicine, Adenosine Monophosphate-Activated Protein Kinase, Rate Pressure Product, [SDV]Life Sciences [q-bio], European Group for Study of Insulin Resistance, Type 2 diabetes, Bioinformatics, Cerebrovascular Accident, Creatin Kinase, Nonalcoholic fatty liver disease, Reperfusion Injury Salvage Kinase, RISK, Abbreviations : AACE, Metabolic Syndrome, CVA, biology, SVAS, ERC, CC, Extracellular Matrix, CK, Nitric Oxyde, Protective Protein/Cathepsin A, IRS, Insulin Receptor, Myocardal Ischemia, EBP, NO, Diabetes mellitus, medicine, Animals, Post- Translational Modifications, MI, ECM, business.industry, Neuraminidase-1, HGFR, Cell Biology, Insulin Receptor Substrate, ECM-based pharmacology, biology.protein, ELN, business, Elastin
Abstract: The Cardiovascular Continuum describes a sequence of events from cardiovascular risk factors to end-stage heart disease. It includes conventional pathologies affecting cardiovascular functions such as hypertension, atherosclerosis or thrombosis and was traditionally considered from the metabolic point of view. This Cardiovascular Continuum, originally described by Dzau and Braunwald, was extended by O'Rourke to consider also the crucial role played by degradation of elastic fibers, occurring during aging, in the appearance of vascular stiffness, another deleterious risk factor of the continuum. However, the involvement of the elastin degradation products, named elastin-derived peptides, to the Cardiovascular Continuum progression has not been considered before. Data from our laboratory and others clearly showed that these bioactive peptides are central regulators of this continuum, thereby amplifying appearance and evolution of cardiovascular risk factors such as diabetes or hypertension, of vascular alterations such as atherothrombosis and calcification, but also nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. The Elastin Receptor Complex has been shown to be a crucial actor in these processes. We propose here the participation of these elastin-derived peptides and of the Elastin Receptor Complex in these events, and introduce a revisited Cardiovascular Continuum based on their involvement, for which elastin-based pharmacological strategies could have a strong impact in the future.
Published: 2019

36. Identification of CD36 as a new interaction partner of membrane NEU1: potential implication in the pro-atherogenic effects of the elastin receptor complex

Author: Béatrice Romier, Kenneth J. Linton, Christian E.H. Schmelzer, Laurent Duca, Christian Ihling, Christine Terryn, Andrea Heinz, Sébastien Blaise, Pascal Maurice, Laurent Martiny, Olivier Bocquet, Amandine Wahart, Amar Bennasroune, Charlotte Kawecki, Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Martin-Luther-Universität Halle Wittenberg (MLU), University of Copenhagen = Københavns Universitet (KU), Plateforme en Imagerie Cellulaire et Tissulaire (PICT), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV), and Queen Mary University of London (QMUL)
Subjects: CD36 Antigens, Proteomics, THP-1 Cells, CD36, Neuraminidase, Peptide, Receptors, Cell Surface, NEU1, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Sialylation, Sialidase, 03 medical and health sciences, Cellular and Molecular Neuroscience, Chlorocebus aethiops, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Scavenger receptor, Receptor, Molecular Biology, Pharmacology, chemistry.chemical_classification, 0303 health sciences, biology, Catabolism, Chemistry, Macrophages, 030302 biochemistry & molecular biology, Cell Membrane, Cell Biology, Atherosclerosis, N-Acetylneuraminic Acid, Cell biology, Elastin, Elastin-derived peptides, Lipoproteins, LDL, Membrane, COS Cells, biology.protein, Molecular Medicine, Original Article, RNA Interference, Peptides, Protein Binding
Abstract: International audience; In addition to its critical role in lysosomes for catabolism of sialoglycoconjugates, NEU1 is expressed at the plasma membrane and regulates a myriad of receptors by desialylation, playing a key role in many pathophysiological processes. Here, we developed a proteomic approach dedicated to the purification and identification by LC-MS/MS of plasma membrane NEU1 interaction partners in human macrophages. Already known interaction partners were identified as well as several new candidates such as the class B scavenger receptor CD36. Interaction between NEU1 and CD36 was confirmed by complementary approaches. We showed that elastin-derived peptides (EDP) desialylate CD36 and that this effect was blocked by the V14 peptide, which blocks the interaction between bioactive EDP and the elastin receptor complex (ERC). Importantly, EDP also increased the uptake of oxidized LDL by macrophages that is blocked by both the V14 peptide and the sialidase inhibitor 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA). These results demonstrate, for the first time, that binding of EDP to the ERC indirectly modulates CD36 sialylation level and regulates oxidized LDL uptake through this sialidase. These effects could contribute to the previously reported proatherogenic role of EDP and add a new dimension in the regulation of biological processes through NEU1.
Published: 2019

37. Novel short isoforms of adenylyl cyclase as negative regulators of cAMP production

Author: Isabelle Limon, Laurent Duca, Benjamin Vallin, Pierre Vincent, Martine Glorian, Régis Blaise, Yohan Legueux-Cajgfinger, Nathalie Clément, Sorbonne Université (SU), Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Signalisation et Récepteurs Matriciels (SiRMa), Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Université de Reims Champagne-Ardenne (URCA), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), and Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, 0301 basic medicine, Gene isoform, Vascular smooth muscle, [SDV]Life Sciences [q-bio], Interleukin-1beta, Myocytes, Smooth Muscle, Cell, Heterodimerization, Muscle, Smooth, Vascular, Short adenylyl cyclases, Adenylyl cyclase, 03 medical and health sciences, chemistry.chemical_compound, CAMP signaling, Cyclic AMP, medicine, Vascular smooth muscle cells, Animals, Humans, splice, Cloning, Molecular, Molecular Biology, Cells, Cultured, Cell Biology, cAMP signaling, Rats, Vasoprotective, Cell biology, Alternative Splicing, Dominant-negative, HEK293 Cells, 030104 developmental biology, medicine.anatomical_structure, chemistry, Cell Transdifferentiation, Endoplasmic Reticulum, Rough, Protein Multimerization, Cyclase activity, Adenylyl Cyclases
Abstract: International audience; Here, we cloned a new family of four adenylyl cyclase (AC) splice variants from interleukin-1β (IL-1β)-transdifferentiated vascular smooth muscle cells (VSMCs) encoding short forms of AC8 that we have named "AC8E-H". Using biosensor imaging and biochemical approaches, we showed that AC8E-H isoforms have no cyclase activity and act as dominant-negative regulators by forming heterodimers with other full-length ACs, impeding the traffic of functional units towards the plasma membrane. The existence of these dominant-negative isoforms may account for an unsuspected additional degree of cAMP signaling regulation. It also reconciles the induction of an AC in transdifferentiated VSMCs with the vasoprotective influence of cAMP. The generation of alternative splice variants of ACs may constitute a generalized strategy of adaptation to the cell's environment whose scope had so far been ignored in physiological and/or pathological contexts.
Published: 2018

38. Production of Elastin-Derived Peptides Contributes to the Development of Nonalcoholic Steatohepatitis

Author: Jean-Louis Guéant, V. Durlach, Pascal Maurice, Béatrice Romier, Laurent Duca, Roselyne Garnotel, Jean-Pierre Bronowicki, Alexandre Guillot, Eric Bertin, Sébastien Blaise, Andrea Heinz, Laurent Martiny, Jessica Jonquet, Hervé Sartelet, Christian E.H. Schmelzer, Johanne Amoyel, Laurent Debelle, Corinne Ivaldi, Jean Marc Alberto, Thinhinane Hocine, Amar Bennasroune, Université de Reims Champagne-Ardenne (URCA), Centre Hospitalier Universitaire de Reims (CHU Reims), Nutrition, obésité et risque thrombotique (NORT), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Joliot Curie, École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire [Grenoble] (CHU), Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physique de l'ENS Lyon (Phys-ENS), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Martin-Luther-University Halle-Wittenberg, Fraunhofer Institute for Microstructure of Materials and Systems IMWS, SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Publica
Subjects: Male, 0301 basic medicine, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Body Mass Index, Cohort Studies, Liver disease, Non-alcoholic Fatty Liver Disease, Fibrosis, Nonalcoholic fatty liver disease, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Cells, Cultured, ComputingMilieux_MISCELLANEOUS, education.field_of_study, biology, Extracellular Matrix, Obesity, Morbid, 3. Good health, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Liver, Lipogenesis, Disease Progression, Female, medicine.symptom, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, Signal Transduction, medicine.medical_specialty, [PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], Population, Receptors, Cell Surface, Inflammation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Diet, High-Fat, Proof of Concept Study, 03 medical and health sciences, Insulin resistance, Internal medicine, Internal Medicine, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, education, business.industry, medicine.disease, Mice, Mutant Strains, Peptide Fragments, Elastin, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, Diabetes Mellitus, Type 2, Gene Expression Regulation, biology.protein, [SPI.OPTI]Engineering Sciences [physics]/Optics / Photonic, business, Biomarkers
Abstract: Affecting more than 30% of the Western population, nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and can lead to multiple complications, including nonalcoholic steatohepatitis (NASH), cancer, hypertension, and atherosclerosis. Insulin resistance and obesity are described as potential causes of NAFLD. However, we surmised that factors such as extracellular matrix remodeling of large blood vessels, skin, or lungs may also participate in the progression of liver diseases. We studied the effects of elastin-derived peptides (EDPs), biomarkers of aging, on NAFLD progression. We evaluated the consequences of EDP accumulation in mice and of elastin receptor complex (ERC) activation on lipid storage in hepatocytes, inflammation, and fibrosis development. The accumulation of EDPs induces hepatic lipogenesis (i.e., SREBP1c and ACC), inflammation (i.e., Kupffer cells, IL-1β, and TGF-β), and fibrosis (collagen and elastin expression). These effects are induced by inhibition of the LKB1-AMPK pathway by ERC activation. In addition, pharmacological inhibitors of EDPs demonstrate that this EDP-driven lipogenesis and fibrosis relies on engagement of the ERC. Our data reveal a major role of EDPs in the development of NASH, and they provide new clues for understanding the relationship between NAFLD and vascular aging.
Published: 2018

39. Matrix aging and vascular impacts

Author: Laurent Debelle, Béatrice Romier, Laurent Duca, Philippe Gillery, Charlotte Kawecki, Pascal Maurice, Hassan El Btaouri, Sébastien Blaise, Laboratoire de Signalisation et Récepteurs Matriciels (SiRMa), Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Reims Champagne-Ardenne (URCA), SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), and Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Physics, [SDV]Life Sciences [q-bio], [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Hematology, Molecular biology, ComputingMilieux_MISCELLANEOUS
Abstract: La matrice extracellulaire (MEC) est constituee d’un ensemble complexe de macromolecules ; elle est presente dans tous les organes et tissus ou elle forme un reseau tridimensionnel entre les cellules. Longtemps apprehendee comme un simple support architectural pour les cellules, la MEC est desormais consideree comme une structure dynamique, finement regulee entre neosynthese et degradation, et essentielle aux proprietes fonctionnelles des tissus. Le vieillissement matriciel correspond a l’ensemble des alterations moleculaires que subissent les proteines a demi-vie longue, comme les collagenes et l’elastine, principaux constituants de la MEC, et se traduit par un intense remodelage de la MEC. Au niveau vasculaire, ce remodelage matriciel a des consequences majeures sur le developpement de nombreuses pathologies liees a l’âge telles que le diabete, l’hypertension arterielle, les anevrismes, l’atherosclerose ou encore la thrombose. Apres une presentation succincte des principaux constituants de la MEC vasculaire, cette revue abordera les principales modifications vasculaires survenant au cours du vieillissement matriciel puis presentera les principaux effets, rapportes a ce jour, de la degradation de l’elastine et des elastokines sur le developpement de pathologies vasculaires liees a l’âge. De nouvelles approches pharmacologiques ciblant la MEC et reduisant la degradation de l’elastine, la production des elastokines et/ou leurs effets cellulaires, pourraient se reveler prometteuses pour retarder la survenue et la progression des pathologies vasculaires liees au vieillissement.
Published: 2015

40. Saffron extracts alleviate cardiomyocytes injury induced by doxorubicin and ischemia-reperfusion in vitro

Author: Ramez Chahine, Laurent Martiny, Laurent Duca, Moni Nader, and Nathalie Chahine
Subjects: 0301 basic medicine, Cardiotonic Agents, Health, Toxicology and Mutagenesis, Blotting, Western, Myocardial Ischemia, Apoptosis, Caspase 3, Pharmacology, Toxicology, medicine.disease_cause, Mitochondrial Membrane Transport Proteins, Antioxidants, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, medicine, Animals, Myocytes, Cardiac, Doxorubicin, Membrane Potential, Mitochondrial, Cardioprotection, Antibiotics, Antineoplastic, Chemical Health and Safety, Mitochondrial Permeability Transition Pore, Plant Extracts, business.industry, Public Health, Environmental and Occupational Health, General Medicine, Crocus, medicine.disease, Rats, Safranal, Oxidative Stress, 030104 developmental biology, chemistry, Mitochondrial permeability transition pore, Reperfusion Injury, business, Reperfusion injury, Oxidative stress, medicine.drug
Abstract: Doxorubicin (DOX), a highly active chemotherapeutic drug, faces limitations in clinical application due to severe cardiotoxic effects (mainly through increased oxidative stress). Therefore, its effect is exacerbated in subjects with ischemic heart disease. We have recently reported that saffron extract (SAF), a natural compound mainly consisting of safranal and corcins, exerts a protective effect against DOX oxidative cytotoxicity in isolated rabbit hearts. Here, we aimed to investigate whether SAF exerts cardioprotection against combined ischemia-reperfusion (I/R) and DOX toxicity in H9c2 cardiomyocytes. H9c2 were subjected to simulated I/R, with or without DOX treatment at reperfusion, in the presence or absence of SAF prior to ischemia or at reperfusion. We evaluated the effects of these treatments by MTT, LDH and western blot analysis. Apoptosis was assessed by Hoechst 33258 staining, tetramethyl rhodamine methyl ester fluorescence and caspase activity. The results showed that I/R and DOX significantly decreased cardiomyocytes viability, inhibited reperfusion injury salvage kinase cardioprotective pathway, reduced contractile proteins (α-Actinine, Troponine C and MLC), increased caspase-3 expression and induced loss of mitochondrial membrane potential. These effects were remarkably inhibited by treatment with SAF (10 μg/mL) at reperfusion. SAF activated AKT/P70S6K and ERK1/2, restored contractile proteins expression, inhibited mitochondrial permeability transition pore and decreased caspase-3 activity. In conclusion, our findings indicate that SAF treatment exerted cardioprotection against I/R and DOX toxicity by reducing oxidative stress (LDH assay). Thereby, SAF offers a potential novel antioxidant therapeutic strategy to counteract I/R and DOX cardiotoxicity, paving the way for future clinical trials.
Published: 2015

41. Biological activities of triterpenoids from Poraqueiba sericea stems

Author: Lucie Paloque, Elsa Rengifo, Ilhem Zebiri, Jean-Bernard Behr, Mohamed Haddad, Laurence Voutquenne-Nazabadioko, Laurent Duca, Michel Sauvain, Billy Cabanillas, Institut de Chimie Moléculaire de Reims - UMR 7312 (ICMR), Université de Reims Champagne-Ardenne (URCA)-Institut de Chimie du CNRS (INC)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS)-SFR Condorcet, Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Instituto de Investigaciones de la Amazonía Peruana (IIAP), SFR Condorcet, Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), and Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Inhibition zone, secoiridoids, Plant Science, 01 natural sciences, Biochemistry, Analytical Chemistry, Poraqueiba, Magnoliopsida, Triterpenoid, triterpenes, Cytotoxic T cell, Animals, Humans, [CHIM]Chemical Sciences, Leishmania infantum, Secoxyloganin, [SDV.EE]Life Sciences [q-bio]/Ecology, environment, Icacinaceae, Traditional medicine, biology, Pancreatic Elastase, Plant Stems, 010405 organic chemistry, Plant Extracts, beta-Glucosidase, Organic Chemistry, Arjunolic acid, Saponins, biology.organism_classification, 0104 chemical sciences, [SDV.BV.PEP]Life Sciences [q-bio]/Vegetal Biology/Phytopathology and phytopharmacy, 010404 medicinal & biomolecular chemistry, Acetylcholinesterase, Poraqueiba sericea
Abstract: Eleven compounds were isolated from Poraqueiba sericea stems and identified as niga-ichigoside-F1 (1), trachelosperoside B1 (2), 4-epi-niga-ichigoside (7), 19α-hydroxyasiatic acid (3), myrianthic acid (4), hyptatic acid (5), trachelosperogenin B (6), arjunolic acid (8), and trachelosperogenin E (9), secologanoside (10) and secoxyloganin (11). Compounds 1–11 were tested for their antileishmanial activities against Leishmania infantum promastigotes, 1–6 and 8–11 were tested for their cytotoxic activities on fibroblasts, 1–3, 5–6, 8–11 were evaluated for their anti-elastase and anti-acetylcholinesterase assays activities by a spectrophotometric method and 1–2, 5 and 7–10 were tested using bioautography for their β-glucosidase. No antileishmanial activity was detected; compounds 1, 2 and 11 showed a moderate cytotoxic activity with IC50 17.7, 20.5 and 10.9 μg/mL, respectively; compounds 2, 8, 9 and 10 gave a percentage of inhibition ranging from 13 to 16% (at 50 μg/mL) and compounds 1 and 2 showed an inhibition zone on β-glucosidase and anti-acetylcholinesterase assays.
Published: 2017

42. The elastin peptide (VGVAPG)3 induces the 3D reorganisation of PML-NBs and SC35 speckles architecture, and accelerates proliferation of fibroblasts and melanoma cells

Author: Hélène Bobichon, Marianne Lorenzato, Dominique Ploton, Aurore Chatron-Colliet, Laurent Duca, Christine Terryn, Nathalie Lalun, Anthony Rusciani, and Sandrine Kurdykowski
Subjects: Adult, MAPK/ERK pathway, Histology, RNA Splicing, Biology, Matrix metalloproteinase, Cell Line, law.invention, Extracellular matrix, Structure-Activity Relationship, Imaging, Three-Dimensional, Confocal microscopy, law, Humans, Melanoma, Molecular Biology, Cell Proliferation, Cell Nucleus, food and beverages, Cell Biology, Fibroblasts, Molecular biology, Elastin, Cell biology, Medical Laboratory Technology, Cell culture, embryonic structures, RNA splicing, biology.protein, Signal transduction, Oligopeptides
Abstract: During melanoma tumour growth, cancerous cells are exposed to the immediate surrounding the micro- and macro environment, which is largely modified through the degradation of the extracellular matrix by fibroblast-derived metalloproteinases. Among the degradation products, (VGVAPG)3, an elastin peptide is known to stimulate the proliferation of both fibroblasts and cancerous cells by binding to the elastin-binding receptor and activating the MEK/ERK signal transduction pathway. As this process strongly modifies mRNA synthesis, we investigated its effect on the relative three-dimensional organisation of the major partners of the mRNA splicing machinery: promyelocytic nuclear bodies (PML-NBs ) and splicing component 35 speckles (SC35) of normal fibroblasts and melanoma SK-MEL-28 cells. SC35 and PML-NBs proteins were immunolabeled and imaged by confocal microscopy within these cells cultured with (VGVAPG)3. Three-dimensional reconstruction was performed to elucidate the organisation of PML-NBs and SC35 speckles and their spatial relationship. In G0 cells, SC35 speckles were sequestered in PML-NBs. Shortly after (VGVAPG)3 stimulation, the three-dimensional organisation of PML-NBs and SC35 speckles changed markedly. In particular, SC35 speckles gradually enlarged and adopted a heterogeneous organisation, intermingled with PML-NBs. Conversely, inhibition of the elastin-binding protein or MEK/ERK pathway induced a remarkable early sequestration of condensed SC35 speckles in PML-NBs, the hallmark of splicing inhibition. The 3D architecture of speckles/PML-NBs highlights the modulation in their spatial relationship, the multiple roles of PML-NBs in activation, inhibition and sequestration, and provides the first demonstration of the dependence of PML-NBs and SC35 speckles on the elastin peptide for these functions.
Published: 2014

43. Fhit Regulates EMT Targets through an EGFR/Src/ERK/Slug Signaling Axis in Human Bronchial Cells

Author: Philippe Birembaut, Audrey Joannes, Christine Gilles, Claire Kileztky, Myriam Polette, Simon Grelet, B. Nawrocki-Raby, Véronique Dalstein, and Laurent Duca
Subjects: MAPK/ERK pathway, Cancer Research, Epithelial-Mesenchymal Transition, Lung Neoplasms, MAP Kinase Signaling System, Slug, Bronchi, Vimentin, Transfection, Gefitinib, FHIT, Cell Line, Tumor, medicine, Humans, Epithelial–mesenchymal transition, RNA, Small Interfering, Lung cancer, neoplasms, Molecular Biology, biology, Cancer, Epithelial Cells, biology.organism_classification, medicine.disease, Immunohistochemistry, Acid Anhydride Hydrolases, Neoplasm Proteins, ErbB Receptors, Gene Expression Regulation, Neoplastic, src-Family Kinases, Oncology, Gene Knockdown Techniques, Cancer research, biology.protein, Snail Family Transcription Factors, Transcription Factors, medicine.drug
Abstract: In many cancers, including lung carcinomas, Fragile histidine triad (Fhit) is frequently decreased or lost. Fhit status has recently been shown to be associated with elevated in vitro and in vivo invasiveness in lung cancer. Tumor cell invasion is facilitated by epithelial–mesenchymal transition (EMT), a process by which tumor cells lose their epithelial features to acquire a mesenchymal cell-like phenotype. In this study, the mechanism underlying Fhit-regulated EMT was deciphered. Using Slug knockdown, pharmacologic inhibitors PD98059, PP1, and gefitinib as well as an anti-EGFR antibody, it was demonstrated that Fhit silencing in bronchial cells induced overexpression of two primary EMT-associated targets, MMP-9 and vimentin, to regulate cell invasion dependent on an EGFR/Src/ERK/Slug signaling pathway. Moreover, ectopic expression of Fhit in Fhit-deficient lung cancer cells downregulated this pathway. Finally, an inverse correlation was observed between Fhit and phospho-EGFR levels in a cohort of human squamous cell lung carcinoma specimens. These results demonstrate a Fhit-dependent mechanism in the control of EMT-regulated EGFR signaling. Implications: This study adds new insight into the regulatory mechanism of EMT, a process known to increase resistance to conventional and targeted therapies in lung cancer. Mol Cancer Res; 12(5); 775–83. ©2014 AACR.
Published: 2014

44. Zebiriosides A-P, oleanane saponins isolated by LC-SPE-NMR hyphenation from the roots of Dendrobangia boliviana

Author: Elsa Rengifo, Audrey Gratia, Laurent Duca, Ilhem Zebiri, Billy Cabanillas, Laurence Voutquenne-Nazabadioko, Lucie Paloque, Michel Sauvain, Mohamed Haddad, Institut de Chimie Moléculaire de Reims - UMR 7312 (ICMR), SFR Condorcet, Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), Instituto de Investigaciones de la Amazonía Peruana (IIAP), Laboratoire de chimie de coordination (LCC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), CNRS, Conseil Regional Champagne Ardenne, Conseil General de la Marne, Ministry of Higher Education and Research (MESR), Université de Reims Champagne-Ardenne (URCA)-Institut de Chimie du CNRS (INC)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS)-SFR Condorcet, Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de Toulouse (ICT), and Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Pharmacology, Chromatography, [SDV]Life Sciences [q-bio], Organic Chemistry, Pharmaceutical Science, Dendrobangia boliviana, LC-NMR, Analytical Chemistry, Triterpenoid saponins, chemistry.chemical_compound, Complementary and alternative medicine, chemistry, Drug Discovery, Molecular Medicine, Oleanane, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2016

45. Impact of sialic acids on the molecular dynamic of bi-antennary and tri-antennary glycans

Author: Pascal Maurice, Laurent Debelle, Laurent Duca, Jessica Jonquet, Alexandre Guillot, Nicolas Belloy, Béatrice Romier, Stéphanie Baud, V. Durlach, Laurent Martiny, Sébastien Blaise, Manuel Dauchez, Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Signalisation et Récepteurs Matriciels (SiRMa), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), MAURICE, Pascal, Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), and Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé)
Subjects: 0301 basic medicine, Glycan, In silico, [SDV]Life Sciences [q-bio], Molecular Conformation, Molecular Dynamics Simulation, Article, 03 medical and health sciences, Molecular dynamics, Polysaccharides, Monosaccharide, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Receptor, ComputingMilieux_MISCELLANEOUS, chemistry.chemical_classification, Protein function, Multidisciplinary, biology, [SDV] Life Sciences [q-bio], carbohydrates (lipids), 030104 developmental biology, Enzyme, chemistry, Biochemistry, Sialic Acids, biology.protein, Function (biology)
Abstract: Sialic acids (SA) are monosaccharides that can be located at the terminal position of glycan chains on a wide range of proteins. The post-translational modifications, such as N-glycan chains, are fundamental to protein functions. Indeed, the hydrolysis of SA by specific enzymes such as neuraminidases can lead to drastic modifications of protein behavior. However, the relationship between desialylation of N-glycan chains and possible alterations of receptor function remains unexplored. Thus, the aim of the present study is to establish the impact of SA removal from N-glycan chains on their conformational behavior. We therefore undertook an in silico investigation using molecular dynamics to predict the structure of an isolated glycan chain. We performed, for the first time, 3 independent 500 ns simulations on bi-antennary and tri-antennary glycan chains displaying or lacking SA. We show that desialylation alters both the preferential conformation and the flexibility of the glycan chain. This study suggests that the behavior of glycan chains induced by presence or absence of SA may explain the changes in the protein function.
Published: 2016

46. New Insights into Molecular Organization of Human Neuraminidase-1: Transmembrane Topology and Dimerization Ability

Author: Sébastien Blaise, Manuel Dauchez, Maxime Ghirardi, Laurent Martiny, Stéphanie Baud, Pascal Maurice, Béatrice Romier, Olivier Bocquet, Laurent Debelle, Eduard V. Bocharov, Charlotte Kawecki, Laurent Duca, Roman G. Efremov, Andrey S. Kuznetsov, Olga V. Bocharova, Laëtitia Gorisse, Laboratoire de Signalisation et Récepteurs Matriciels (SiRMa), Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Cardiac Research Laboratory, Innsbruck Medical University [Austria] (IMU), Nutrition, obésité et risque thrombotique (NORT), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Reims Champagne-Ardenne (URCA), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), and Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Models, Molecular, Protein Conformation, alpha-Helical, 0301 basic medicine, [SDV]Life Sciences [q-bio], Gene Expression, Neuraminidase, Plasma protein binding, Sialidase, Article, Substrate Specificity, 03 medical and health sciences, NEU1, Protein structure, Chlorocebus aethiops, Escherichia coli, Animals, Humans, Protein Interaction Domains and Motifs, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, Peptide sequence, Binding Sites, Multidisciplinary, Cell-Free System, biology, Ubiquitin, Chemistry, Cell Membrane, Recombinant Proteins, Transmembrane protein, Cell biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], 030104 developmental biology, Structural Homology, Protein, Membrane topology, COS Cells, Phosphatidylcholines, Sialic Acids, biology.protein, Protein Conformation, beta-Strand, Protein Multimerization, Plasmids, Protein Binding
Abstract: Neuraminidase 1 (NEU1) is a lysosomal sialidase catalyzing the removal of terminal sialic acids from sialyloconjugates. A plasma membrane-bound NEU1 modulating a plethora of receptors by desialylation, has been consistently documented from the last ten years. Despite a growing interest of the scientific community to NEU1, its membrane organization is not understood and current structural and biochemical data cannot account for such membrane localization. By combining molecular biology and biochemical analyses with structural biophysics and computational approaches, we identified here two regions in human NEU1 - segments 139–159 (TM1) and 316–333 (TM2) - as potential transmembrane (TM) domains. In membrane mimicking environments, the corresponding peptides form stable α-helices and TM2 is suited for self-association. This was confirmed with full-size NEU1 by co-immunoprecipitations from membrane preparations and split-ubiquitin yeast two hybrids. The TM2 region was shown to be critical for dimerization since introduction of point mutations within TM2 leads to disruption of NEU1 dimerization and decrease of sialidase activity in membrane. In conclusion, these results bring new insights in the molecular organization of membrane-bound NEU1 and demonstrate, for the first time, the presence of two potential TM domains that may anchor NEU1 in the membrane, control its dimerization and sialidase activity.
Published: 2016

47. Elastin-derived peptides potentiate atherosclerosis through the immune Neu1–PI3Kγ pathway

Author: Matthias P. Wymann, Laurent Debelle, Audrey Castaing-Berthou, Sébastien Blaise, Aurélie Montheil, Pascal Maurice, Roselyne Garnotel, Stéphanie Gayral, Alexey V. Pshezhetsky, Elodie Berge, Laurent O. Martinez, Laurent Duca, Nicole Malet, Laurent Martiny, Anne Fougerat, Muriel Laffargue, Departement /u563 : Lipoproteines et Mediateurs Lipidiques, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Reims Champagne-Ardenne (URCA), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Department of Biomedicine, Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Signalisation et Récepteurs Matriciels (SiRMa), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Division of Medical Genetics, CHU Sainte Justine [Montréal], Simon, Marie Francoise, Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), and Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Class I Phosphatidylinositol 3-Kinases, Physiology, [SDV]Life Sciences [q-bio], Neuraminidase, Receptors, Cell Surface, Inflammation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Cathepsin A, Monocytes, Phosphatidylinositol 3-Kinases, NEU1, In vivo, Physiology (medical), medicine, Animals, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Cathepsin, Atherosclerosis, medicine.disease, Elastin, 3. Good health, Cell biology, Mice, Inbred C57BL, Atheroma, Receptors, LDL, Biochemistry, biology.protein, Diet, Atherogenic, medicine.symptom, Peptides, Cardiology and Cardiovascular Medicine, Signal Transduction
Abstract: International audience; AIMS: Elastin is degraded during vascular ageing and its products, elastin-derived peptides (EP), are present in the human blood circulation. EP binds to the elastin receptor complex (ERC) at the cell surface, composed of elastin-binding protein (EBP), a cathepsin A and a neuraminidase 1. Some in vitro functions have clearly been attributed to this binding, but the in vivo implications for arterial diseases have never been clearly investigated. METHODS AND RESULTS: Here, we demonstrate that chronic doses of EP injected into mouse models of atherosclerosis increase atherosclerotic plaque size formation. Similar effects were observed following an injection of a VGVAPG peptide, suggesting that the ERC mediates these effects. The absence of phosphoinositide 3-kinase γ (PI3Kγ) in bone marrow-derived cells prevented EP-induced atherosclerosis development, demonstrating that PI3Kγ drive EP-induced arterial lesions. Accordingly, in vitro studies showed that PI3Kγ was required for EP-induced monocyte migration and ROS production and that this effect was dependent upon neuraminidase activity. Finally, we showed that degradation of elastic lamellae in LDLR(-/-) mice fed an atherogenic diet correlated with atherosclerotic plaque formation. At the same time, the absence of the cathepsin A-neuraminidase 1 complex in cells of the haematopoietic lineage abolished atheroma plaque size progression and decreased leucocytes infiltration, clearly demonstrating the role of this complex in atherogenesis and suggesting the involvement of endogenous EP. CONCLUSION: Altogether, this work identifies EP as an enhancer of atherogenesis and defines the Neuraminidase 1/PI3Kγ signalling pathway as a key mediator of this function in vitro and in vivo.
Published: 2013

48. Zebiriosides A-L, oleanane saponins from the roots of Dendrobangia boliviana

Author: Amandine Scandolera, Mohamed Haddad, Elsa Rengifo, Dominique Harakat, Michel Sauvain, Billy Cabanillas, Lucie Paloque, Ilhem Zebiri, Laurent Duca, Laurence Voutquenne-Nazabadioko, Institut de Chimie Moléculaire de Reims - UMR 7312 (ICMR), Université de Reims Champagne-Ardenne (URCA)-Institut de Chimie du CNRS (INC)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS)-SFR Condorcet, Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Instituto de Investigaciones de la Amazonía Peruana (IIAP), Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Givaudan ACI, Soliance, SFR Condorcet, Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), and Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0106 biological sciences, Stereochemistry, Plant Science, Horticulture, DEPT, Plant Roots, 010603 evolutionary biology, 01 natural sciences, Biochemistry, Triterpenoid saponins, Magnoliopsida, chemistry.chemical_compound, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Oleanolic Acid, Spectral data, Cytotoxicity, Nuclear Magnetic Resonance, Biomolecular, Molecular Biology, Oleanane, Leishmania, chemistry.chemical_classification, Molecular Structure, Cytotoxic activity, Cytotoxins, 010405 organic chemistry, Cardiopteridaceae, Dendrobangia boliviana, Glycoside, General Medicine, Zebirioside C, Fibroblasts, Saponins, Antineoplastic Agents, Phytogenic, Triterpenes, 0104 chemical sciences, 3. Good health, chemistry, Zebirioside I
Abstract: International audience; Twelve oleanane saponins, zebiriosides A-L, were isolated from the roots of Dendrobangia boliviana Rusby, together with two known saponins, talunumoside I and 3-O-beta-D-glucuronopyranosyl serjanic acid. These saponins are glycosides of serjanic or phytolaccinic acid. Their structures were established on two basis: first, their spectral data, mainly HR-TOFESIMS, 1D-NMR (H-1, C-13, DEPT) and 2D-NMR (H-1-H-1 COSY, TOCSY, HSQC, HMBC, and ROESY), and second by comparison with literature data. These compounds were evaluated for their cytotoxic, antileishmanial and hemolytic activities. No antileishmanial or hemolytic activities were revealed, however zebirioside C and zebirioside I showed cytotoxicity against fibroblasts with IC50 of 6.4 and 5.6 mu M, respectively.
Published: 2016

49. Matrix ageing and vascular impacts: focus on elastin fragmentation

Author: Laurent Martiny, Alexandre Guillot, Charlotte Kawecki, Béatrice Romier, Stéphanie Gayral, Sébastien Blaise, Laurent Duca, Laurent Debelle, Hassan El Btaouri, Muriel Laffargue, Pascal Maurice, Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Departement /u563 : Lipoproteines et Mediateurs Lipidiques, Centre de Physiopathologie Toulouse Purpan (CPTP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Signalisation et Récepteurs Matriciels (SiRMa), Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé)
Subjects: 0301 basic medicine, Aging, Serine Proteinase Inhibitors, Physiology, [SDV]Life Sciences [q-bio], Population, Neuraminidase, Nanotechnology, Matrix (biology), Bioinformatics, Extracellular matrix, 03 medical and health sciences, Physiology (medical), Animals, Humans, Medicine, Glycoside Hydrolase Inhibitors, Molecular Targeted Therapy, Vascular Diseases, Fragmentation (cell biology), education, education.field_of_study, Pancreatic Elastase, biology, business.industry, Cardiovascular Agents, Arteries, Elastin degradation, Peptide Fragments, Elastin, Extracellular Matrix, 3. Good health, 030104 developmental biology, Ageing, Proteolysis, Cardiovascular agent, biology.protein, Cardiology and Cardiovascular Medicine, business, Signal Transduction
Abstract: International audience; Cardiovascular diseases (CVDs) are the leading cause of death worldwide and represent a major problem of public health. Over the years, life expectancy has considerably increased throughout the world, and the prevalence of CVD is inevitably rising with the growing ageing of the population. The normal process of ageing is associated with progressive deterioration in structure and function of the vasculature, commonly called vascular ageing. At the vascular level, extracellular matrix (ECM) ageing leads to molecular alterations in long half-life proteins, such as elastin and col-lagen, and have critical effects on vascular diseases. This review highlights ECM alterations occurring during vascular ageing with a specific focus on elastin fragmentation and also the contribution of elastin-derived peptides (EDP) in age-related vascular complications. Moreover, current and new pharmacological strategies aiming at minimizing elastin degradation, EDP generation, and associated biological effects are discussed. These strategies may be of major relevance for preventing and/or delaying vascular ageing and its complications.
Published: 2016

50. The Elastin Receptor Complex: A Unique Matricellular Receptor with High Anti-tumoral Potential

Author: Laurent Martiny, Sébastien Blaise, Béatrice Romier-Crouzet, Ludivine Odoul, Amandine Scandolera, Laurent Debelle, Laurent Duca, Pascal Maurice, Alexandre Guillot, Hassan El Btaouri, Stéphanie Salesse, Charlotte Kawecki, Givaudan ACI, Soliance, Institute of Pathology, University of Bern, Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Laboratoire de Signalisation et Récepteurs Matriciels (SiRMa), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), and Pennington Biomedical Center
Subjects: 0301 basic medicine, Angiogenesis, Mini Review, extracellular matrix, [SDV]Life Sciences [q-bio], Integrin, Biology, therapeutic targets, Extracellular matrix, 03 medical and health sciences, 0302 clinical medicine, elastokines, Pharmacology (medical), [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Receptor, ComputingMilieux_MISCELLANEOUS, Pharmacology, Tropoelastin, Binding protein, lcsh:RM1-950, ERC, 3. Good health, Cell biology, lcsh:Therapeutics. Pharmacology, 030104 developmental biology, Biochemistry, 030220 oncology & carcinogenesis, biology.protein, Signal transduction, neuraminidase-1, Elastin
Abstract: Elastin, one of the longest-lived proteins, confers elasticity to tissues with high mechanical constraints. During aging or pathophysiological conditions such as cancer progression, this insoluble polymer of tropoelastin undergoes an important degradation leading to the release of bioactive elastin-derived peptides (EDPs), named elastokines. EDP exhibit several biological functions able to drive tumor development by regulating cell proliferation, invasion, survival, angiogenesis, and matrix metalloproteinase expression in various tumor and stromal cells. Although, several receptors have been suggested to bind elastokines (αvβ3 and αvβ5 integrins, galectin-3), their main receptor remains the elastin receptor complex (ERC). This heterotrimer comprises a peripheral subunit, named elastin binding protein (EBP), associated to the protective protein/cathepsin A (PPCA). The latter is bound to a membrane-associated protein called Neuraminidase-1 (Neu-1). The pro-tumoral effects of elastokines have been linked to their binding onto EBP. Additionally, Neu-1 sialidase activity is essential for their signal transduction. Consistently, EDP-EBP interaction and Neu-1 activity emerge as original anti-tumoral targets. Interestingly, besides its direct involvement in cancer progression, the ERC also regulates diabetes outcome and thrombosis, an important risk factor for cancer development and a vascular process highly increased in patients suffering from cancer. In this review, we will describe ERC and elastokines involvement in cancer development suggesting that this unique receptor would be a promising therapeutic target. We will also discuss the pharmacological concepts aiming at blocking its pro-tumoral activities. Finally, its emerging role in cancer-associated complications and pathologies such as diabetes and thrombotic events will be also considered.
Published: 2016

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