Effect of sulphated polysaccharides on the alpha 1-antitrypsin inhibition of amidolysis catalysed by coagulation cascade proteinases.

1 The ability of several sulphated polysaccharide anticoagulants to prevent alpha 1-antitrypsin inhibition of thrombin paralleled their ability to potentiate antithrombin III inhibition of thrombin. None of the compounds examined altered the ability of alpha 1-antitrypsin to inhibit activated coagulation factor X (Xa). 2 These results are consistent with the possibility that a direct polysaccharide-proteinase interaction may be involved in the sulphated polysaccharide-modulated inhibition of thrombin by antithrombin III.

The anticoagulant activity of dermatan sulphates: evidence against the involvement of antithrombin III.

Anticoagulant activity of dermatan sulphates is unaffected by antiserum specific for antithrombin III (AT III) unless the glycosaminoglycan preparation contains demonstrable heparin. 2 Only dermatan sulphate preparations of considerable heparin content potentiate AT III inhibition of thrombin, factor Xa and plasmin. 3 These data suggest that dermatan sulphates exert anticoagulant activity which, unlike that of heparin, is largely or totally independent of AT III.

Anticoagulant effects of sulphated polysaccharides in normal and antithrombin III-deficient plasmas.

1 Comparison of the effects of sulphated polysaccharides on thrombin-induced clotting of normal and antithrombin III-deficient plasmas suggests the involvement of antithrombin III (AT III) in the anticoagulant activities of cellulose, dextran and xylan sulphates. 2 AT III appears to play little or no role in the anticoagulant activity of carrageenans.

Evidence for antithrombin III involvement in the anticoagulant activity of cellulose sulphate.

1 Cellulose sulphate, like heparin, prolonged the clotting time in partial thromboplastin time (PTT) assays, inhibited the amidolytic activity of thrombin, was without effect on amidolysis catalysed by activated coagulation factor X(Xa), and potentiated the inhibition of both thrombin and Xa by antithrombin III (AT). 2 The anticoagulant activity of cellulose sulphate in PTT assays was, like that of heparin and heparin sulphate, but unlike that of dermatan sulphate, reduced by prior incubation of plasma with antiserum specific for AT. 3 These results, which suggest that the anticoagulant activity of cellulose sulphate is at least partially mediated through AT, are discussed in terms of the structural features of polysaccharides required for AT activation.

Heparan structure and the modulation of angiogenesis.

It is postulated that the angiogenic potential of tissues is influenced by the fine structure of heparan glycosaminoglycans present in the tissues. Possible mechanisms involved are discussed. It is suggested that compounds chemically related to heparans might usefully act as inhibitors of pathological angiogenesis.

Glycosaminoglycans and the control of cell surface proteinase activity.

It is postulated that the metabolically variable fine structure of pericellular heparan glycosaminoglycans affects the ability of these molecules to influence cell proliferation-associated proteinase-catalysed reactions occurring at cell surfaces. Evidence suggesting the possibility of a wide repertoire of glycosaminoglycan-mediated positive and negative effects on such reactions is reviewed. It is suggested that clinical administration of compounds related chemically to heparins might usefully modulate cell proliferation-associated proteinase activity.

A putative role for colloidal silicates in primitive evolution deduced in part from their relevance to modern pathological afflictions.

Biogenic and bioactive silicas have structural subtleties that are only now beginning to be appreciated. Their ability to interact with particular biological systems is related to these structures. Some of these interactions result in pathological effects. It is suggested that such interactions mirror events occurring in a prebiotic environment.

A comparison of the antioxidant requirements of proteins with those of synthetic polymers suggests an antioxidant function for clusters of aromatic and bivalent sulphur-containing amino acid residues.

Many proteins which function in extracellular environments potentially rich in oxygen-derived free radicals contain clustered tyrosine and cysteine residues which, by analogy with the chemistry of antioxidants used with synthetic polymers, may provide an appreciable antioxidant and redox stabilization activity. Such proteins may function as antioxidants, and as ligand binding sites for free radicals and other active molecules employed in normal biochemical processes.

Degenerative and inflammatory diseases may result from defects in antimineralization mechanisms afforded by glycosaminolglycans.

Many human cellular and tissue compartments are supersaturated with respect to calcium oxyanion salts. In order to prevent the formation of injurious crystals efficient anti-crystallization protective mechanisms must be necessary. We suggest that depletion of such systems, particularly in ageing organisms and under conditions of oxidative stress, plays an important role in degenerative and inflammatory diseases, including cancer.

A model of two conformational forms of heparins/heparans suggested by infrared spectroscopy.

Results of infrared spectroscopy of complexes between cations and heparins, heparans and chemically-modified polymers suggest the existence of two conformational forms of heparins/heparans, differing in their modes of interaction with cations. Functions of heparans at normal and cancer cell surfaces are discussed in the light of this model.

Pericellular heparans may contribute to the protection of cells from free radicals.

The variation of fine structure and quantity of heparans at cell surfaces could endow cells of different tissues, and in different growth states, with varying degrees of competence in reacting to extracellular free radicals known to be associated with neoplasia.

kappa-Carrageenase from Pseudomonas carrageenovora.

A kappa-carrageenase was isolated from the cell-free medium of cultured Pseudomonas carrageenovora. From dodecylsulphate/polyacrylamide gel electrophoresis, a single protein (identified as the kappa-carrageenase) was detected in the medium. Activity against nominal carrageenan types and inspection of the products indicate the enzyme to be a kappa-carrageenase. Purification is described here by ammonium sulphate precipitation and subsequent CM-Sepharose CL-6B ion-exchange chromatography. Molecular weight was estimated as 35,000 by dodecylsulphate/polyacrylamide gel electrophoresis. Products of degradation were analysed by gel filtration, spectrophotometric assays and 13C nuclear magnetic resonance. These results are consistent with the product of limit digest being neocarrabiose 4-O-sulphate.