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  1. Article ; Online: C-peptide and zinc delivery to erythrocytes requires the presence of albumin: implications in diabetes explored with a 3D-printed fluidic device.

    Liu, Yueli / Chen, Chengpeng / Summers, Suzanne / Medawala, Wathsala / Spence, Dana M

    Integrative biology : quantitative biosciences from nano to macro

    2015  Volume 7, Issue 5, Page(s) 534–543

    Abstract: People with type 1 diabetes (T1D) must administer insulin exogenously due to the destruction of their pancreatic β-cells. Endogenous insulin is stored in β-cell granules along with C-peptide, a 31 amino acid peptide that is secreted from these granules ... ...

    Abstract People with type 1 diabetes (T1D) must administer insulin exogenously due to the destruction of their pancreatic β-cells. Endogenous insulin is stored in β-cell granules along with C-peptide, a 31 amino acid peptide that is secreted from these granules in amounts equal to insulin. Exogenous co-administration of C-peptide with insulin has proven to reduce diabetes-associated complications in animals and humans. The exact mechanism of C-peptide's beneficial effects after secretion from the β-cell granules is not completely understood, thus hindering its development as an exogenously administered hormone. Monitoring tissue-to-tissue communication using a 3D-printed microfluidic device revealed that zinc and C-peptide are being delivered to erythrocytes by albumin. Upon delivery, erythrocyte-derived ATP increased by >50%, as did endothelium-derived NO, which was measured downstream in the 3D-printed device. Our results suggest that hormone replacement therapy in diabetes may be improved by exogenous administration of a C-peptide ensemble that includes zinc and albumin.
    MeSH term(s) Adenosine Triphosphate/chemistry ; Albumins/chemistry ; Animals ; C-Peptide/administration & dosage ; Calorimetry ; Cell Communication ; Cell Line ; Diabetes Mellitus, Type 1/drug therapy ; Diabetes Mellitus, Type 1/metabolism ; Enzyme-Linked Immunosorbent Assay ; Erythrocytes/cytology ; Humans ; Insulin-Secreting Cells/cytology ; Lab-On-A-Chip Devices ; Microfluidics ; Peptides/chemistry ; Printing, Three-Dimensional ; Rats ; Zinc/administration & dosage
    Chemical Substances Albumins ; C-Peptide ; Peptides ; Adenosine Triphosphate (8L70Q75FXE) ; Zinc (J41CSQ7QDS)
    Language English
    Publishing date 2015-05
    Publishing country England
    Document type Journal Article
    ZDB-ID 2480063-6
    ISSN 1757-9708 ; 1757-9694
    ISSN (online) 1757-9708
    ISSN 1757-9694
    DOI 10.1039/c4ib00243a
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: C-peptide-stimulated nitric oxide production in a cultured pulmonary artery endothelium is erythrocyte mediated and requires Zn(2+).

    Giebink, Adam W / Vogel, Paul A / Medawala, Wathsala / Spence, Dana M

    Diabetes/metabolism research and reviews

    2013  Volume 29, Issue 1, Page(s) 44–52

    Abstract: Background: C-peptide has been shown to stimulate the production of nitric oxide (NO) in aortic endothelial cells via activation of endothelial nitric oxide synthase (eNOS) through an increased calcium influx. Here, results obtained using cultured ... ...

    Abstract Background: C-peptide has been shown to stimulate the production of nitric oxide (NO) in aortic endothelial cells via activation of endothelial nitric oxide synthase (eNOS) through an increased calcium influx. Here, results obtained using cultured bovine pulmonary artery endothelial cells (bPAECs) suggest that C-peptide does not induce eNOS activation directly in cultured pulmonary artery endothelium. However, C-peptide has been shown to stimulate the release of ATP from erythrocytes, a well-documented stimulus of eNOS activity in the pulmonary endothelium. Therefore, studies were performed to examine if C-peptide can indirectly stimulate NO production in a cultured pulmonary endothelium that is erythrocyte mediated.
    Methods: NO production and free intracellular calcium changes were monitored in immobilized bPAECs using specific intracellular fluorescent probes after stimulation with adenosine triphosphate (ATP), calcium ionophore A23187, or C-peptide. A microfluidic device enabled immobilized bPAECs to interact with flowing erythrocytes in the presence and absence of C-peptide to determine the role of the erythrocyte in C-peptide-stimulated NO production in cultured bPAECs.
    Results: ATP and the calcium ionophore stimulate significant increases in both intracellular NO production and influx of free calcium in cultured bPAECs. In contrast, C-peptide, ranging from physiological to above physiological concentrations, was unable to stimulate NO production or calcium influx in the bPAECs. However, when erythrocytes were pre-incubated with a mixture containing physiological concentrations of C-peptide with Zn(2+) and haemodynamically pumped beneath bPAECs cultured on a microfluidic device, an 88.6 ± 7.5% increase in endothelial NO production was observed.
    Conclusions: C-peptide does not affect NO production in bPAECs directly but can impact NO production through an erythrocyte-mediated mechanism. Furthermore, in the absence of Zn(2+), C-peptide does not stimulate this NO production directly or indirectly. These results suggest that C-peptide, in the presence of Zn(2+), may be a determinant in purinergic receptor signalling via its ability to stimulate the release of ATP from erythrocytes.
    MeSH term(s) Adenosine Triphosphate/pharmacology ; Animals ; C-Peptide/pharmacology ; Calcimycin/pharmacology ; Calcium/metabolism ; Calcium Ionophores/pharmacology ; Cattle ; Cells, Cultured ; Endothelial Cells/cytology ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism ; Endothelium, Vascular/cytology ; Endothelium, Vascular/drug effects ; Endothelium, Vascular/metabolism ; Erythrocytes/drug effects ; Erythrocytes/metabolism ; Humans ; Nitric Oxide/biosynthesis ; Pulmonary Artery/cytology ; Pulmonary Artery/drug effects ; Pulmonary Artery/metabolism ; Zinc/metabolism
    Chemical Substances C-Peptide ; Calcium Ionophores ; Nitric Oxide (31C4KY9ESH) ; Calcimycin (37H9VM9WZL) ; Adenosine Triphosphate (8L70Q75FXE) ; Zinc (J41CSQ7QDS) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2013-01
    Publishing country England
    Document type Journal Article
    ZDB-ID 1470192-3
    ISSN 1520-7560 ; 1520-7552
    ISSN (online) 1520-7560
    ISSN 1520-7552
    DOI 10.1002/dmrr.2359
    Database MEDical Literature Analysis and Retrieval System OnLINE

    Full text online

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2119: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  3. Article: C-peptide and zinc delivery to erythrocytes requires the presence of albumin: implications in diabetes explored with a 3D-printed fluidic device

    Liu, Yueli / Chen, Chengpeng / Summers, Suzanne / Medawala, Wathsala / Spence, Dana M

    Integrative biology. 2015 May 11, v. 7, no. 5

    2015  

    Abstract: People with type 1 diabetes (T1D) must administer insulin exogenously due to the destruction of their pancreatic β-cells. Endogenous insulin is stored in β-cell granules along with C-peptide, a 31 amino acid peptide that is secreted from these granules ... ...

    Abstract People with type 1 diabetes (T1D) must administer insulin exogenously due to the destruction of their pancreatic β-cells. Endogenous insulin is stored in β-cell granules along with C-peptide, a 31 amino acid peptide that is secreted from these granules in amounts equal to insulin. Exogenous co-administration of C-peptide with insulin has proven to reduce diabetes-associated complications in animals and humans. The exact mechanism of C-peptide's beneficial effects after secretion from the β-cell granules is not completely understood, thus hindering its development as an exogenously administered hormone. Monitoring tissue-to-tissue communication using a 3D-printed microfluidic device revealed that zinc and C-peptide are being delivered to erythrocytes by albumin. Upon delivery, erythrocyte-derived ATP increased by >50%, as did endothelium-derived NO, which was measured downstream in the 3D-printed device. Our results suggest that hormone replacement therapy in diabetes may be improved by exogenous administration of a C-peptide ensemble that includes zinc and albumin.
    Keywords adenosine triphosphate ; albumins ; amino acids ; c-peptide ; erythrocytes ; granules ; hormone replacement therapy ; humans ; insulin-dependent diabetes mellitus ; islets of Langerhans ; monitoring ; nitric oxide ; peptides ; secretion ; three-dimensional printing ; zinc
    Language English
    Dates of publication 2015-0511
    Size p. 534-543.
    Publishing place The Royal Society of Chemistry
    Document type Article
    ZDB-ID 2480063-6
    ISSN 1757-9708 ; 1757-9694
    ISSN (online) 1757-9708
    ISSN 1757-9694
    DOI 10.1039/c4ib00243a
    Database NAL-Catalogue (AGRICOLA)

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  4. Article ; Online: Structural and Metal Ion Effects on Human Topoisomerase IIα Inhibition by α-(N)-Heterocyclic Thiosemicarbazones.

    Morris, William H / Ngo, Lana / Wilson, James T / Medawala, Wathsala / Brown, Anthony R / Conner, Jennifer D / Fabunmi, Florence / Cashman, Derek J / Lisic, Edward C / Yu, Tao / Deweese, Joseph E / Jiang, Xiaohua

    Chemical research in toxicology

    2018  Volume 32, Issue 1, Page(s) 90–99

    Abstract: Our previous research has shown that α-(N)-heterocyclic thiosemicarbazone (TSC) metal complexes inhibit human topoisomerase IIα (TopoIIα), while the ligands without metals do not. To find out the structural elements of TSC that are important for ... ...

    Abstract Our previous research has shown that α-(N)-heterocyclic thiosemicarbazone (TSC) metal complexes inhibit human topoisomerase IIα (TopoIIα), while the ligands without metals do not. To find out the structural elements of TSC that are important for inhibiting TopoIIα, we have synthesized two series of α-(N)-heterocyclic TSCs with various substrate ring segments, side chain substitutions, and metal ions, and we have examined their activities in TopoIIα-mediated plasmid DNA relaxation and cleavage assays. Our goal is to explore the structure-activity relationship of α-(N)-heterocyclic TSCs and their effect on TopoIIα. Our data suggest that, similar to Cu(II)-TSCs, Pd(II)-TSC complexes inhibit plasmid DNA relaxation mediated by TopoIIα. In TopoIIα-mediated plasmid DNA cleavage assays, the Cu(II)-TSC complexes induce higher levels of DNA cleavage than their Pd(II) counterparts. The Cu(II)-TSC complexes with methyl, ethyl, and tert-butyl substitutions are slightly more effective than those with benzyl and phenyl groups. The α-(N)-heterocyclic ring substrates of the TSCs, including benzoylpyridine, acetylpyridine, and acetylthiazole, do not exhibit a significant difference in TopoIIα-mediated DNA cleavage. Our data suggest that the metal ion of TSC complexes plays a predominant role in inhibition of TopoIIα, the side chain substitution of the terminal nitrogen plays a secondary role, while the substrate ring segment has the least effect. Our molecular modeling data support the biochemical data, which together provide a mechanism by which Cu(II)-TSC complexes stabilize TopoIIα-mediated cleavage complexes.
    MeSH term(s) Copper/chemistry ; Copper/pharmacology ; DNA Topoisomerases, Type II/metabolism ; Heterocyclic Compounds/chemical synthesis ; Heterocyclic Compounds/chemistry ; Heterocyclic Compounds/pharmacology ; Humans ; Ions/chemistry ; Ions/pharmacology ; Molecular Docking Simulation ; Molecular Structure ; Palladium/chemistry ; Palladium/pharmacology ; Thiosemicarbazones/chemical synthesis ; Thiosemicarbazones/chemistry ; Thiosemicarbazones/pharmacology ; Topoisomerase II Inhibitors/chemical synthesis ; Topoisomerase II Inhibitors/chemistry ; Topoisomerase II Inhibitors/pharmacology
    Chemical Substances Heterocyclic Compounds ; Ions ; Thiosemicarbazones ; Topoisomerase II Inhibitors ; Palladium (5TWQ1V240M) ; Copper (789U1901C5) ; DNA Topoisomerases, Type II (EC 5.99.1.3)
    Language English
    Publishing date 2018-12-11
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 639353-6
    ISSN 1520-5010 ; 0893-228X
    ISSN (online) 1520-5010
    ISSN 0893-228X
    DOI 10.1021/acs.chemrestox.8b00204
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2320: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  5. Article ; Online: A Molecular Level Understanding of Zinc Activation of C-peptide and its Effects on Cellular Communication in the Bloodstream.

    Medawala, Wathsala / McCahill, Patrick / Giebink, Adam / Meyer, Jennifer / Ku, Chia-Jui / Spence, Dana M

    The review of diabetic studies : RDS

    2009  Volume 6, Issue 3, Page(s) 148–158

    Abstract: Inspired by previous reports, our group has recently demonstrated that C-peptide exerts beneficial effects upon interactions with red blood cells (RBCs). These effects can be measured in RBCs obtained from animal models of both type 1 diabetes and type 2 ...

    Abstract Inspired by previous reports, our group has recently demonstrated that C-peptide exerts beneficial effects upon interactions with red blood cells (RBCs). These effects can be measured in RBCs obtained from animal models of both type 1 diabetes and type 2 diabetes, though to different extents. To date, the key metrics that have been measured involving C-peptide and RBCs include an increase in glucose uptake by these cells and a subsequent increase in adenosine triphosphate (ATP) release. Importantly, to date, our group has only been able to elicit these beneficial effects when the C-peptide is prepared in the presence of Zn2+. The C-peptide-induced release of ATP is of interest when considering that ATP is a purinergic signaling molecule known to stimulate the production of nitric oxide (NO) in the endothelium and in platelets. This NO production has been shown to participate in smooth muscle relaxation and subsequent vessel dilation. Furthermore, NO is a well-established platelet inhibitor. The objective of this review is to provide information pertaining to C-peptide activity on RBCs. Special attention is paid to the necessity of Zn2+ activation, and the origin of that activation in vivo. Finally, a mechanism is proposed that explains how C-peptide is exerting its effects on other cells in the bloodstream, particularly on endothelial cells and platelets, via its ability to stimulate the release of ATP from RBCs.
    Language English
    Publishing date 2009-11-10
    Publishing country Singapore
    Document type Journal Article
    ZDB-ID 2168938-6
    ISSN 1614-0575 ; 1613-6071
    ISSN (online) 1614-0575
    ISSN 1613-6071
    DOI 10.1900/RDS.2009.6.148
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5992: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
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    ab Jg. 2022: Lesesaal (EG)

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