Structural Analysis of Periodate-Oxidized Heparin

Conrad, H. Edward; Guo, Yangyang

doi:10.1007/978-1-4899-2444-5_3

Cited by 19 publications

(17 citation statements)

References 9 publications

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“…A well-characterized one is the oxidation with metaperiodate that breaks the bond between 2 hydroxyl groups present on nonsubstituted uronic acids (glycol-split). This alters the essential GlcA residue within the ATBR and drastically reduces the 45 A similar effect is obtained by N-acetylation, which modifies the essential fully sulfated glucosamine of the ATBR sequence. The nonanticoagulant heparins produced in these ways retain biological activities unrelated to coagulation, such as antiheparanase, 55 anti-inflammatory 43 and antiangiogenesis activity.…”

Section: Discussionmentioning

confidence: 72%

“…Here we studied the functionality of chemically modified heparins with different degrees of sulfation, N-acetylation, and chain flexibility that lost antithrombin binding affinity and have a strongly reduced anticoagulant activity. [44][45][46] We found that "reduced oxy-heparins," alias "glycol-split" heparins (gs-heparins), have strong antihepcidin activity in vivo.…”

Section: Introductionmentioning

confidence: 99%

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Glycol-split nonanticoagulant heparins are inhibitors of hepcidin expression in vitro and in vivo

Poli

Asperti

Naggi

et al. 2014

Blood

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Key Points• Chemically modified nonanticoagulant heparins are strong inhibitors of hepcidin expression in normal and Bmp6 2/2 mice. • These heparins abolish hepcidin induction caused by LPS, a model of inflammation, and are candidates for treatment of inflammatory anemia.Hepcidin controls systemic iron availability, and its excess contributes to the anemia of chronic diseases, the most prevalent anemia in hospitalized patients. We previously reported that heparins are efficient hepcidin inhibitors both in vitro and in vivo, but their anticoagulant activity limits therapeutic use. We studied nonanticoagulant heparins produced by N-acetylation and oxidation/reduction (glycol-split) that lost antithrombinbinding affinity. Four nonanticoagulant heparins inhibited hepcidin expression in hepatic HepG2 cells and primary hepatocytes. The 2 most potent ones used in mice suppressed liver hepcidin expression and serum hepcidin in 6 hours, with a significant decrease of spleen iron. This occurred also in lipopolysaccharide (LPS)-treated animals that mimic inflammation, as well as after chronic 1-week treatments, without evident adverse effects on coagulation. Heparin injections increased iron mobilization and facilitated the recovery from the anemia induced by heat-killed Brucella abortus, a model of inflammatory anemia. The heparins were used also in Bmp6 2/2 mice. A single dose of heparin reduced the already low level of hepcidin of these mice and prevented its induction by LPS. These nonanticoagulant compounds impair bone morphogenetic protein /sons of mothers against decapentaplegic signaling with no evident adverse effect in vivo, even when administered chronically. They may offer a strategy for the treatment of diseases with high hepcidin levels. (Blood. 2014;123(10):1564-1573

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Section: Discussionmentioning

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Glycol-split nonanticoagulant heparins are inhibitors of hepcidin expression in vitro and in vivo

Poli

Asperti

Naggi

et al. 2014

Blood

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“…The ethical guidelines that were followed meet the standards required by Cancer Research UK guidelines (Workman et al, 1998). Figure 2B, the PT of rabbit plasma without any heparinoid is about 7 s. While Hep strongly prolonged PT to about 27 s at the concentration of 100 mg ml 71 , IO 4 -Hep, IO 4 -LMW-Hep and NAC-HCPS only prolonged the PT to 8 to 10 s. Since the periodate oxidation of Hep is known to destruct a penta-saccharide structure which interacts with antithrombin III (Conrad and Guo, 1991), the remainder of the anticoagulant activities of IO 4 -Hep, IO 4 -LMW-Hep and NAC-HCPS may result from interactions with other anticoagulant factors, such as heparin co-factor II (Bourin and Lindahl, 1993).…”

Section: Discussionmentioning

confidence: 94%

“…If Hep could be modified to minimise its anti-coagulant property and to enhance its activities to inhibit tumour growth and metastasis, then such a modified Hep would be a very useful drug in treating malignant diseases. Periodate-oxidised (IO 4 -) Hep and periodate-oxidised, alkaline-degraded low molecular weight (IO 4 -LMW-) Hep (Fransson and Carlstedt, 1974;Fransson, 1978) are known for not having a specific pentasaccharide structure to interact with antithrombin III (Conrad and Guo, 1991), and therefore its anti-coagulant activity (APTT and PT) is much lower than Hep (Figure 2). We previously reported the preparation of NAC-HCPS using the IO 4 -LMW-Hep (Ishihara et al, 2000a).…”

Section: Discussionmentioning

confidence: 99%

“…Our additional studies also have revealed that IO 4 -LMW-Hep and NAC-HCPS have about a 10-fold smaller anticoagulant activity (APTT) than native Hep. The residual anticoagulant activity of NAC-HCPS is probably mediated by interaction with heparin cofactor II, and not antithrombin III (Conrad and Guo, 1991;Lapierre et al, 1996). In many tumour types, fibrin is a major component of the initial stroma (Costantini and Zacharski, 1992).…”

Section: Discussionmentioning

confidence: 99%

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Periodate-treated, non-anticoagulant heparin-carrying polystyrene (NAC-HCPS) affects angiogenesis and inhibits subcutaneous induced tumour growth and metastasis to the lung

et al. 2002

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Periodate-treated, non-anticoagulant heparin-carrying polystyrene consists of about ten periodate-oxidized, alkaline-degraded low molecular weight-heparin chains linked to a polystyrene core and has a markedly lower anti-coagulant activity than heparin. In this study, we evaluated the effect of non-anticoagulant heparin-carrying polystyrene on tumour growth and metastasis. Non-anticoagulant heparin-carrying polystyrene has a higher activity to inhibit vascular endothelial growth factor-165-, fibroblast growth factor-2-or hepatocyte growth factor-induced human microvascular endothelial cell growth than heparin, ten periodate-oxidized-heparin and ten periodate-oxidized-low molecular weight-heparin, which is probably due to the heparin-clustering effect of non-anticoagulant heparin-carrying polystyrene. Non-anticoagulant heparin-carrying polystyrene inhibited human microvascular endothelial cell, B16 melanoma and Lewis lung cancer cell adhesion to Matrigel-coated plates. Non-anticoagulant heparin-carrying polystyrene also showed strong inhibitory activities in the tubular formation of endothelial cells on Matrigel and B16-melanoma and Lewis lung cancer cell invasion in a Matrigel-coated chamber assay. In vivo studies showed that growth of subcutaneous induced tumours and lung metastasis of B16-melanoma and Lewis lung cancer cells were more effectively inhibited by non-anticoagulant heparin-carrying polystyrene than ten periodate-oxidized-heparin and ten periodate-oxidized-low molecular weight-heparin. Furthermore, non-anticoagulant heparin-carrying polystyrene markedly reduced the number of CD34-positive vessels in subcutaneous Lewis lung cancer tumours, indicating a strong inhibition of angiogenesis. These results suggest that non-anticoagulant heparin-carrying polystyrene has an inhibitory activity on angiogenesis and tumour invasion and may be very useful in cancer therapy.

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Specificities of Heparin-binding Sites from the Amino-Terminus and Type 1 Repeats of Thrombospondin-1

Tyrrell

Cashel

et al. 2000

Archives of Biochemistry and Biophysics

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Structural Analysis of Periodate-Oxidized Heparin

Cited by 19 publications

References 9 publications

Glycol-split nonanticoagulant heparins are inhibitors of hepcidin expression in vitro and in vivo

Glycol-split nonanticoagulant heparins are inhibitors of hepcidin expression in vitro and in vivo

Periodate-treated, non-anticoagulant heparin-carrying polystyrene (NAC-HCPS) affects angiogenesis and inhibits subcutaneous induced tumour growth and metastasis to the lung

Specificities of Heparin-binding Sites from the Amino-Terminus and Type 1 Repeats of Thrombospondin-1

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