The Experts below are selected from a list of 264 Experts worldwide ranked by ideXlab platform

Elizabeta Nemeth - One of the best experts on this subject based on the ideXlab platform.

  • design synthesis and characterization of cyclic analogues of the iron regulatory Peptide Hormone hepcidin
    Biopolymers, 2013
    Co-Authors: Richard J Clark, Gloria C Preza, Tomas Ganz, Elizabeta Nemeth, Chia Chia Tan, Johannes W A Van Dijk, Eileen Fung, David J Craik
    Abstract:

    The Peptide Hormone hepcidin is a key regulator of iron homeostasis in vertebrates. Hepcidin acts by binding to ferroportin, the sole known iron exporter, causing it to be internalized and thus trapping iron within the cell. Dysregulation of hepcidin concentrations is associated with a range of iron-related diseases and hepcidin-based therapeutics could be developed as candidate treatments for these diseases. However Peptide-based drugs, despite their many advantages, are often limited by their susceptibility to degradation within the body. Here we describe the design, synthesis and characterization of a series of backbone cyclized hepcidin analogues as an approach to produce stable hepcidin-based leads. The cyclic Peptides were shown by NMR to be structurally analogous to native hepcidin. Comparison of the stability of hepcidin with one of the cyclic analogues in human serum revealed that 77% of the cyclic Peptide but only 18% of linear hepcidin remained after 24 h. The cyclic Peptides were tested for their ability to induce internalization of GFP-ferroportin in vitro but were all found to be inactive. This study demonstrates that backbone cyclization of disulfide-rich Peptides is a suitable approach for increasing stability. However, careful consideration of a number of factors, including location of important residues and their bioactive conformation, is required to generate biologically active lead molecules. (C) 2013 Wiley Periodicals, Inc.

  • cellular catabolism of the iron regulatory Peptide Hormone hepcidin
    PLOS ONE, 2013
    Co-Authors: Gloria C Preza, Rogelio Pinon, Tomas Ganz, Elizabeta Nemeth
    Abstract:

    Hepcidin, a 25-amino acid Peptide Hormone, is the principal regulator of plasma iron concentrations. Hepcidin binding to its receptor, the iron exporter ferroportin, induces ferroportin internalization and degradation, thus blocking iron efflux from cells into plasma. The aim of this study was to characterize the fate of hepcidin after binding to ferroportin. We show that hepcidin is taken up by ferroportin-expressing cells in a temperature- and pH-dependent manner, and degraded together with its receptor. When Texas red-labeled hepcidin (TR-Hep) was added to ferroportin-GFP (Fpn-GFP) expressing cells, confocal microscopy showed co-localization of TR-Hep with Fpn-GFP. Using flow cytometry, we showed that the Peptide was almost completely degraded by 24 h after its addition, but that lysosomal inhibitors completely prevented degradation of both ferroportin and hepcidin. In addition, using radio-labeled hepcidin and HPLC analysis we show that hepcidin is not recycled, and that only degradation products are released from the cells. Together these results show that the Hormone hepcidin and its receptor ferroportin are internalized together and trafficked to lysosomes where both are degraded.

Matthijs Verhage - One of the best experts on this subject based on the ideXlab platform.

  • the role of munc18 1 in docking and exocytosis of Peptide Hormone vesicles in the anterior pituitary
    Biology of the Cell, 2005
    Co-Authors: Niki Korteweg, Ascanio S Maia, Brenda Thompson, Eric W Roubos, Peter J H Burbach, Matthijs Verhage
    Abstract:

    Background information. Many neurons secrete classical transmitters from synaptic vesicles as well as Peptide transmitters from LDCVs (large dense-core vesicles). Little is known about the mechanistic differences between these two secretory pathways. The soluble protein Munc18-1 is essential for synaptic vesicle secretion [Verhage, Maia, Plomp, Brussaard, Heeroma, Vermeer, Toonen, Hammer, van den Berg, Missler, et al. (2000) Science 287, 864–869.]. Results. In the present study, we tested if Munc18 genes are also involved in Peptidergic secretion from LDCVs using the anterior pituitary as a model system. We show that Munc18-1 is the dominant isoform expressed in the anterior pituitary. In Munc18-1 null mutant mice, the anterior pituitary developed normally and the five major endocrine cell types had a normal distribution. However, circulating Peptide Hormone levels were decreased by up to 50-fold in the null mutant, whereas the intracellular levels were significantly higher than that in controls. Ultrastructural analysis using the tannic acid method revealed striking differences in the distribution of secretory vesicles: (i) the number of exocytotic figures was mostly decreased in the null mutants and (ii) the LDCVs accumulated near but not at their target membrane. This is in contrast with the apparently normal distribution of synaptic vesicles in developing synapses in the null mutant (Verhage et al., 2000). Conclusions. We conclude that Munc18-1 is involved in the secretion of Peptide Hormones and in the docking of LDCVs. These results unmask an apparent mechanistic difference between LDCVs and synaptic vesicles.

Gloria C Preza - One of the best experts on this subject based on the ideXlab platform.

  • design synthesis and characterization of cyclic analogues of the iron regulatory Peptide Hormone hepcidin
    Biopolymers, 2013
    Co-Authors: Richard J Clark, Gloria C Preza, Tomas Ganz, Elizabeta Nemeth, Chia Chia Tan, Johannes W A Van Dijk, Eileen Fung, David J Craik
    Abstract:

    The Peptide Hormone hepcidin is a key regulator of iron homeostasis in vertebrates. Hepcidin acts by binding to ferroportin, the sole known iron exporter, causing it to be internalized and thus trapping iron within the cell. Dysregulation of hepcidin concentrations is associated with a range of iron-related diseases and hepcidin-based therapeutics could be developed as candidate treatments for these diseases. However Peptide-based drugs, despite their many advantages, are often limited by their susceptibility to degradation within the body. Here we describe the design, synthesis and characterization of a series of backbone cyclized hepcidin analogues as an approach to produce stable hepcidin-based leads. The cyclic Peptides were shown by NMR to be structurally analogous to native hepcidin. Comparison of the stability of hepcidin with one of the cyclic analogues in human serum revealed that 77% of the cyclic Peptide but only 18% of linear hepcidin remained after 24 h. The cyclic Peptides were tested for their ability to induce internalization of GFP-ferroportin in vitro but were all found to be inactive. This study demonstrates that backbone cyclization of disulfide-rich Peptides is a suitable approach for increasing stability. However, careful consideration of a number of factors, including location of important residues and their bioactive conformation, is required to generate biologically active lead molecules. (C) 2013 Wiley Periodicals, Inc.

  • cellular catabolism of the iron regulatory Peptide Hormone hepcidin
    PLOS ONE, 2013
    Co-Authors: Gloria C Preza, Rogelio Pinon, Tomas Ganz, Elizabeta Nemeth
    Abstract:

    Hepcidin, a 25-amino acid Peptide Hormone, is the principal regulator of plasma iron concentrations. Hepcidin binding to its receptor, the iron exporter ferroportin, induces ferroportin internalization and degradation, thus blocking iron efflux from cells into plasma. The aim of this study was to characterize the fate of hepcidin after binding to ferroportin. We show that hepcidin is taken up by ferroportin-expressing cells in a temperature- and pH-dependent manner, and degraded together with its receptor. When Texas red-labeled hepcidin (TR-Hep) was added to ferroportin-GFP (Fpn-GFP) expressing cells, confocal microscopy showed co-localization of TR-Hep with Fpn-GFP. Using flow cytometry, we showed that the Peptide was almost completely degraded by 24 h after its addition, but that lysosomal inhibitors completely prevented degradation of both ferroportin and hepcidin. In addition, using radio-labeled hepcidin and HPLC analysis we show that hepcidin is not recycled, and that only degradation products are released from the cells. Together these results show that the Hormone hepcidin and its receptor ferroportin are internalized together and trafficked to lysosomes where both are degraded.

Tomas Ganz - One of the best experts on this subject based on the ideXlab platform.

  • design synthesis and characterization of cyclic analogues of the iron regulatory Peptide Hormone hepcidin
    Biopolymers, 2013
    Co-Authors: Richard J Clark, Gloria C Preza, Tomas Ganz, Elizabeta Nemeth, Chia Chia Tan, Johannes W A Van Dijk, Eileen Fung, David J Craik
    Abstract:

    The Peptide Hormone hepcidin is a key regulator of iron homeostasis in vertebrates. Hepcidin acts by binding to ferroportin, the sole known iron exporter, causing it to be internalized and thus trapping iron within the cell. Dysregulation of hepcidin concentrations is associated with a range of iron-related diseases and hepcidin-based therapeutics could be developed as candidate treatments for these diseases. However Peptide-based drugs, despite their many advantages, are often limited by their susceptibility to degradation within the body. Here we describe the design, synthesis and characterization of a series of backbone cyclized hepcidin analogues as an approach to produce stable hepcidin-based leads. The cyclic Peptides were shown by NMR to be structurally analogous to native hepcidin. Comparison of the stability of hepcidin with one of the cyclic analogues in human serum revealed that 77% of the cyclic Peptide but only 18% of linear hepcidin remained after 24 h. The cyclic Peptides were tested for their ability to induce internalization of GFP-ferroportin in vitro but were all found to be inactive. This study demonstrates that backbone cyclization of disulfide-rich Peptides is a suitable approach for increasing stability. However, careful consideration of a number of factors, including location of important residues and their bioactive conformation, is required to generate biologically active lead molecules. (C) 2013 Wiley Periodicals, Inc.

  • cellular catabolism of the iron regulatory Peptide Hormone hepcidin
    PLOS ONE, 2013
    Co-Authors: Gloria C Preza, Rogelio Pinon, Tomas Ganz, Elizabeta Nemeth
    Abstract:

    Hepcidin, a 25-amino acid Peptide Hormone, is the principal regulator of plasma iron concentrations. Hepcidin binding to its receptor, the iron exporter ferroportin, induces ferroportin internalization and degradation, thus blocking iron efflux from cells into plasma. The aim of this study was to characterize the fate of hepcidin after binding to ferroportin. We show that hepcidin is taken up by ferroportin-expressing cells in a temperature- and pH-dependent manner, and degraded together with its receptor. When Texas red-labeled hepcidin (TR-Hep) was added to ferroportin-GFP (Fpn-GFP) expressing cells, confocal microscopy showed co-localization of TR-Hep with Fpn-GFP. Using flow cytometry, we showed that the Peptide was almost completely degraded by 24 h after its addition, but that lysosomal inhibitors completely prevented degradation of both ferroportin and hepcidin. In addition, using radio-labeled hepcidin and HPLC analysis we show that hepcidin is not recycled, and that only degradation products are released from the cells. Together these results show that the Hormone hepcidin and its receptor ferroportin are internalized together and trafficked to lysosomes where both are degraded.

Jens J Holst - One of the best experts on this subject based on the ideXlab platform.

  • small molecule agonists for the glucagon like Peptide 1 receptor
    Proceedings of the National Academy of Sciences of the United States of America, 2007
    Co-Authors: Lotte Bjerre Knudsen, Jens J Holst, Dan Kiel, Min Teng, Carsten Behrens, Dilip Bhumralkar, Janos Tibor Kodra, Claus Bekker Jeppesen, Michael David Johnson, Johannes Cornelis De Jong
    Abstract:

    The Peptide Hormone glucagon-like Peptide (GLP)-1 has important actions resulting in glucose lowering along with weight loss in patients with type 2 diabetes. As a Peptide Hormone, GLP-1 has to be administered by injection. Only a few small-molecule agonists to Peptide Hormone receptors have been described and none in the B family of the G protein coupled receptors to which the GLP-1 receptor belongs. We have discovered a series of small molecules known as ago-allosteric modulators selective for the human GLP-1 receptor. These compounds act as both allosteric activators of the receptor and independent agonists. Potency of GLP-1 was not changed by the allosteric agonists, but affinity of GLP-1 for the receptor was increased. The most potent compound identified stimulates glucose-dependent insulin release from normal mouse islets but, importantly, not from GLP-1 receptor knockout mice. Also, the compound stimulates insulin release from perfused rat pancreas in a manner additive with GLP-1 itself. These compounds may lead to the identification or design of orally active GLP-1 agonists.

  • The Physiology of Glucagon-like Peptide 1
    Physiological reviews, 2007
    Co-Authors: Jens J Holst
    Abstract:

    Glucagon-like Peptide 1 (GLP-1) is a 30-amino acid Peptide Hormone produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon, the gene which is expressed in ...

  • Secretion of glucagon-like Peptide-1 and reactive hypoglycemia after partial gastrectomy
    Digestion, 1994
    Co-Authors: Jan Jesper Andreasen, Cathrine Orskov, Jens J Holst
    Abstract:

    Glucagon-like Peptide-1 is a Peptide Hormone from the distal small intestine which stimulates insulin secretion and inhibits glucagon secretion and thereby lowers blood glucose. This Hormone, therefor