The ageing of connective tissues involves modifications of collagen, which are currently generating much interest amongst protein researchers. Protein glycation, a non-enzymic reaction involving sugar, appears to play a role in the evolution of age-related physical changes and diabetic complications-retinopathy, neuropathy, renal failure and atherosclerosis. Our studies show that the glycation of human corneal and scleral collagen produces increases in the collagen intermolecular spacing-these increases are similar to those we previously reported on the ageing of collagen in these tissues. The present investigation employs X-ray diffraction to look at the structural effects of various substances that are believed in inhibit protein glycation. Aspirin-like compounds and certain vitamins successfully prevented the sugar-induced molecular changes from occurring in corneal and scleral collagen, suggesting that such compounds could have a useful role in this aspect of ageing.
Objectives: To determine whether dietary vitamin E intake in childhood or mid-life was predictive of adult hypertension and high waist circumference, as two important risk factors for cardiovascular disease. Design: Longitudinal study of a social class stratified random sample of all the legitimate, singleton births in the week of 3-9 March 1946. Settings: England, Scotland and Wales. Subjects: The 2980 survey members who provided information on diet, health and sociodemographic information at two time points; age 4 y in 1950 (24-h dietary recall) and 43 y in 1989 (48-h dietary recall). Main outcome measures: Outcomes were adjusted odds ratios (ORs) for hypertension and high waist circumference at age 43 y by thirds of vitamin E intake, relative to the highest intake thirds at both ages. Results: The lowest consumers of vitamin E in both childhood and adulthood were more likely to be hypertensive (OR 1.8, 95% confidence interval (CI): 1.03-3.08) and have high waist circumference (OR 1.6, 95% CI: 1.02-2.43) than those consuming high levels at both ages. A low intake of vitamin E at just one time point was not associated with a statistically significant increased risk of hypertension or high waist circumference. Social class was also an independent and equally strong predictor of these coronary risk factors, indicating that the relation between social class and cardiovascular risks was not mediated solely by the current measures of diet and lifestyle. Conclusions: Unique data on vitamin E intake from foods in both childhood and adulthood have indicated that relatively low intake of vitamin E at both ages predicted hypertension and high waist circumference at age 43 y.
In aging and diabetes, glycation of collagen molecules leads to the formation of cross-links that could alter the surface charge on collagen fibrils, and hence affect the properties and correct functioning of a number of tissues. The electron-optical stain phosphotungstic acid (PTA) binds to positively charged amino acid side-chains and leads to the characteristic banding pattern of collagen seen in the electron microscope; any change in the charge on these side-chains brought about by glycation will affect the uptake of PTA. We found that, upon glycation, a decrease in stain uptake was observed at up to five regions along the collagen D-period; the greatest decrease in stain uptake was apparent at the c1 band. This reduction in PTA uptake indicates that the binding of fructose leads to an alteration in the surface charge at several sites along the D-period. Not all lysine and arginine residues are involved; there appear to be specific residues that suffer a loss of positive charge.
Keratoconus is an eye disease characterized by a slow progressive thinning and cone shaped protrusion of the central region of the cornea. rcsulting in loss of vision due t o irregular astigmastism and scarring [ I ] . It usually begins in the early teens, is more prevalent in women, and most estimates of its frequency are within the range 4-230 per 100000 individuals 121. At the present time there is no definitive explanation as to the origin of this disorder although it is known that patients with atopic diseases have a higher incidcnce of keratoconus 121. It has also been suggested that the condition may result from ocular trauma such as contact lens wear o r eye rubbing [2]. although the evidence for this is not as strong. There appear to be no differences in collagen type between normal and keratoconus specimens 131, although there is evidence to suggest that there is some alteration in collagen cross-linking 141. A n altcrcd relative biosynthesis o f collagen, proteoglycan, and glycoprotein has also been reported in keratoconus corneas Our investigations have centred on the nature and distribution of the proteoglycans relative t o the collagen fibrils within the corneal stroma. T h e proteoglycans within keratoconus and normal human corneas were stained with Cuprolinic Blue using the 'critical electrolyte' method [ 61. Normal corneas showed clearly stained proteoglycan filaments. thc majority of which were oriented crosswise to the collagen fibrils ( Fig. 1 u). Keratoconus corneas also exhibited this pattern of staining ovcr most of their stroma; howcvcr. in some regions keratoconus corneas had fewer filaments than normal and those present were orientated parallel t o the collagen fibrils (Fig. I h).T h e results from the Cuprolinic Blue staining clearly demonstrate an abnormal arrangement of proteoglycans in keratoconus corneas. This arrangement may be duc t o
151.stresses within the stroma causing slipping between adjacent collagen fibrils and thus displacing the proteoglycans into a parallel arrangement with respect to collagen fibrils; this explanation obviously supports the theory that keratoconus results from ocular trauma. An alternative possibility is that the abnormal arrangement is due to a difference in the nature of the proteoglycans; this is supported by a recent report (71 which states that in keratoconus corneas the keratan sulphate proteoglycan core has fewer keratan sulphate chains attached. This difference in proteoglycan structure could explain the lower levels of staining and abnormal proteoglycan arrangement which we have observed. Corneas were also investigated by X-ray diffraction using the SERC synchroton source at Daresbury U.K. X-Ray diffraction has the advantage ovcr electron microscopy of allowing examination of tissues in their natural state without the need for fixation, dehydration, and embedding. T h e first-order diffraction ring in the low-angle X-ray pattern allows the mean centre-to-centre spacing of the fibrils t o be calculated. Wide-angle X-ray diffraction allows the m...
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