Collagen fibrillogenesis: intermediate aggregates and suprafibrillar order.
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Polymerization of collagen in vitro has been studied with the electron microscope at early time points of fibril assembly. We have found morphologically distinct stages of aggregation, which we suggest represent successive steps in fibril formation. Linear growth of the fibril appears to occur by the tandem addition of aggregates to each other and subsequently to the ends of a subfibril; lateral growth occurs by the entwining, like a rope, of these subfibrils. Fibrillogenesis is also accompanied by extensive development of suprafibrillar order in which various patterns of parallel, spiral, and orthogonal sets of fibrils were frequently observed. (+info)
Collagen synthesis in capsules surrounding dimethylbenzanthracene-induced rat breast tumors and the effect of pretreatment with beta-aminopropionitrile.
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Collagen synthesis is increased over three-fold in capsules surrounding dimethylbenzanthracene-induced rat breast tumors compared to the tumor parenchyma and over six-fold compared to normal breast connective tissue. Increased collagen synthesis is independent of the rate of tumor growth and final tumor size. Pretreatment of animals with beta-aminopropionitrile to inhibit collagen cross-linking caused an 82% decrease in tumor formation and a significant reduction in tumor volume (approximately 0.4 cu cm) compared to controls (approximately 10 cu cm). The four small tumors that did develop in the lathyritic animals had increased collagen synthesis in the interior tumor stroma and reduced collagen synthesis in the tumor capsule. These findings suggest that the collagenous capsule surrounding dimethylbenzanthracene tumors functions as a physical barrier to protect the tumor from the immune system of the host. The apparent antitumor effects of beta-aminopropionitrile may be due to immunopotentiation and/or cytotoxic actions of the drug. (+info)
Analysis of the combined osteolathyritic effects of beta-aminopropionitrile and diethyldithiocarbamate on xenopus development.
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In order to examine the mechanistic basis between combined effects and mechanisms of action, two osteolathyrogens, beta-aminopropionitrile (betaAPN) and diethyldithiocarbamate (DTC), were tested together on Xenopus embryos. In a separate test, DTC was also tested with copper sulfate to determine the importance of copper in DTC-induced osteolathyrism. Frog embryos (Xenopus laevis) were exposed for 96 h, with daily solution removal and replacement. Preserved tadpoles were evaluated for osteolathyritic lesions. For the betaAPN:DTC test, a 1.2-factor matrix design was used, producing two single chemical and seven mixture-response curves. The chi(2) goodness-of-fit test was used to compare the experimental mixture-response curves with theoretical effects for two combined effects models, dose-addition and independence. All seven mixture curves were consistent with expected results for dose-addition, but the correlations were generally not high. For the DTC:copper test, the three mixture-response curves generated showed that added copper increased the DTC-alone EC(50), but there was no corresponding right shift at the top of the response curves, as observed previously with betaAPN and copper. In the betaAPN:DTC and DTC:copper tests, DTC alone showed a biphasic concentration-osteolathyrism curve, and the slope of the response curve for DTC alone in each test was statistically different than the slope for the betaAPN alone response curve. Taken together, the results suggest the potential for a second osteolathyritic effect of DTC that affected the combined toxicity enough to produce a dose-addition correlation without the chemicals necessarily having the same mechanism. (+info)
Pattern and associated factors of the neurolathyrism epidemic in Ethiopia.
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OBJECTIVES: To describe the neurolathyrism epidemic in Ethiopia and to identify associated household factors. METHODS: We interviewed 589 randomly selected heads of household in Debre Sina district of Ethiopia, the area afflicted by the recent neurolathyrism epidemic. Disease information was obtained for 2987 family members. RESULTS: Neurolathyrism patients were detected in 56 (9.5%) households (prevalence rate 2.38%). The mean number of affected family members per household was 1.27 (SD 0.65, range 1-3). Most (77.5%) patients developed the disability during the epidemic (1995-1999). The median age at onset of paralysis was 11 years with a range of 41 (range 3-44). Younger people were more affected during the epidemic than during the non-epidemic period (P=0.01). The presence of a neurolathyrism patient in the family was associated with illiteracy [adjusted OR (95% CI)=2.23 (1.07-5.10)] of the head of household, with owning a grass pea farm [adjusted OR (95% CI)=2.01 (1.04-3.88)] and with the exclusive cooking of grass pea foods using handmade traditional clay pots [adjusted OR (95% CI=2.06 (1.08-3.90)]. CONCLUSION: Males aged 10-14 years were most affected by neurolathyrism. Increased household risk was associated with illiteracy of the head of the household and exclusive cooking of grass pea foods with handmade traditional clay pots. (+info)
Glucosylation of galactosylhydroxylysyl residues in collagen in vitro by collagen glucosyltransferase. Inhibition by triple-helical conformation of the substrate.
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Glucosylation of galactosylhydroxylysyl residues in various collagen polypeptide chains and in small peptides prepared from collagen was studied in vitro using collagen glucosyltransferase purified about 200 to 500-fold from extract prepared from chick embryos. When various denatured polypeptide or peptide chains were compared as substrates for the enzyme, no significant differences were found between citrate-soluble collagens from normal or lathyritic rats and isolated alpha1 and alpha2 chains. In contrast, gelatinized insoluble calf skin collagen, and peptides prepared from collagen and having an average molecular weight of about 500 were clearly less effective substrates as judged from their Km and V values. A marked difference was found between native and heat-denatured citrate-soluble collagen in that no synthesis of glucosylgalactosylhydroxylysine was observed with the native collagen when the reaction was studied at 30 degrees C with different times, enzyme concentrations, and substrate concentrations. When the reaction was studied as a function of temperature, little glucosylation of native collagen was observed below 37 degrees C, but there was a sharp transition in the rate of glucosylation of native collagen at temperatures above 37 degrees C, similar to that observable in the melting curve of collagen. The data suggest that triple-helical conformation of collagen prevents that glucosylation of galactosylhydroxylysyl residues. (+info)
Collagen metabolism in osteolathyrism in chick embryos: site of action of beta-amino-propionitrile.
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Chick embryos were sacrificed at intervals after simultaneous injection of BAPN and proline-C(14), the collagen separated into neutral salt-extractable and residue fractions, and total hydroxyproline and hydroxyproline specific radioactivity determined in each fraction. Extractable collagen, measured as hydroxyproline, increased markedly and had a higher specific activity in BAPN-treated embryos than in corresponding controls. Hydroxyproline of the residue collagen in the treated animals, however, had a lower specific activity. When proline-C(14) was injected 24 hours prior to BAPN, the specific radioactivity of the soluble collagen of treated embryos was similar to that of controls, in spite of the fact that the specific activity of the residue fraction was higher than that of the soluble fraction at the time of BAPN administration. These results suggest that the increased amount of soluble collagen in lathyrism induced by administration of BAPN does not arise from the collagen insoluble prior to administration of the drug, but rather that BAPN acts by blocking the formation of mature collagen fibers, perhaps by preventing the formation of cross-linkages between alpha-collagen chains. (+info)
Experimental lathyrism in the chick embryo. The distribution of beta-aminopropionitrile.
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1. C(14)-labeled beta-aminopropionitrile distributed throughout the egg contents within 10 minutes postinjection. By ion exchange chromatography and electrophoretic analysis three major components of the extractable dialyzable radioactive material could be demonstrated, representing at least 80 per cent of the total. The acidic and basic components were identified as beta-aminopropionitrile and cyanoacetic acid, while the fraction isoelectric at pH 5.3, consisting of two components, remained unidentified. 2. Less than 1 molecule of betaAPN per 100 molecules of protein was present in the highly purified extractable lathyritic bone collagen indicating that binding of the lathyrogen is not a factor in collagen extractability. 3. The proximity of betaAPN to collagen in bone is not essential to its extractability. 4. The effect of incubation temperature of the embryo on collagen extractability suggests the involvement of a metabolic process in this phenomenon. (+info)
METABOLISM OF COLLAGEN IN MAMMALIAN TISSUES.
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The amino acid composition of collagen is described and the status of knowledge about the synthesis of its unique amino acids, hydroxyproline and hydroxylysine, presented. This is followed by a schematic overview of collagen metabolism. Scurvy and lathyrism, the only two abnormalities of collagen metabolism which can now be reasonably elucidated at a molecular level, are then discussed in some detail. The paper concludes by stressing the importance of recognizing the role of histoarchitecture and of interactions of collagen with other compounds when studying collagen or its metabolism in the whole animal. (+info)