Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0086543 (cataract)
 29,165 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A high glucose concentration in vivo or an increased glucose of glucose 6-phosphate concentration in vitro has been found to lead to the glycosylation of epsilon-amino groups of lysine residues in bovine and rat lens crystallins. In vitro, this glycosylation imparts an increased susceptibility of the crystallins to sulfhydryl oxidation. Disulfide crosslinks result in the formation of high molecular weight aggregates and an opalescence in the crystallin solutions. The addition of reducing agents prevents as well as reverses the formation of high molecular weight aggregates and the opalescence of the crystallins. These phenomena suggest a new interpretation of previous results on cataract formation and a new approach for development of drugs to prevent cataracts.
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PMID:Diabetic cataract formation: potential role of glycosylation of lens crystallins. 27 62

Short-term incubation of bovine alpha-crystallin with ascorbate alters the protein conformational stability. The denaturation curves with urea and guanidinium-chloride show different patterns, suggesting a deviation from a two-state mechanism owing to the presence of one or more intermediates in the unfolding of ascorbate-modified alpha-crystallin. Furthermore, the latter protein profiles are shifted to lower denaturant concentrations indicating a destabilizing action of ascorbate, which is capable of facilitating protein dissociation into subunits as demonstrated by gel filtration with 1.5 M-urea. The decrease in conformational stability cannot be ascribed to any major structural alteration, but rather to localized changes in the protein molecule. In fact, no difference between native and ascorbate-treated alpha-crystallin can be detected by amino acid analysis but perturbation of the tryptophan and tyrosine environment is indicated by alterations in intrinsic fluorescence. Furthermore, turbidity and light-scattering measurements suggest an involvement of the lysine side chains, since aggregability patterns with acetylsalicylic acid are significantly altered. The ascorbate-destabilizing effect on the conformational stability of alpha-crystallin, probably exerted through oxidative modification of amino acid residues and/or the formation of covalent adducts, provokes unfavourable steric interactions between residues along the polypeptide chains, thus favouring aggregation and insolubilization of crystallins which can lead to cataract formation, as also demonstrated by proteolytic digestion patterns which show a lower rate of degradation of the ascorbate-modified alpha-crystallin.
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PMID:Conformational stability of bovine alpha-crystallin. Evidence for a destabilizing effect of ascorbate. 141 62

Previous investigations indicate that some forms of cataract may be due to the reactions of isocyanate with lens proteins. The present investigation was directed toward identifying the products of these reactions and determining rate constants for their formation. Bovine alpha-crystallins were incubated with isocyanate and separated into alpha A- and alpha B-crystallins by reversed-phase HPLC (high-performance liquid chromatography). Products of the reaction of isocyanate with alpha-crystallins were analyzed by mass spectrometry and isoelectric focusing. Proteolytic digests of carbamylated alpha A were analyzed by HPLC and fast atom bombardment mass spectrometry to determine the extent of reaction of each of the 7 lysyl residues present in alpha A. These results demonstrate that incubation of alpha-crystallins in 0.1 M KNCO leads to partial carbamylation of all 7 lysines of alpha A-crystallin. The extent of modification after 24 h of incubation varied from 7% at Lys 88 to 61% at Lys 11. Rate constants for the reaction of specific lysyl residues with isocyanate ranged from 5 to 54 x 10(-2) M-1 h-1. The distribution of reaction products, as determined by isoelectric focusing, indicates that the physiologically relevant initial stages of carbamylation of the 7 lysyl residues of alpha A proceed in a noncooperative manner.
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PMID:Rates of carbamylation of specific lysyl residues in bovine alpha-crystallins. 146 24

Studies were carried out comparing the ability of urea extraction and sonication to solubilize the water-insoluble (WI) protein fraction from human lens tissue. Sonication and urea extraction were able to solubilize greater than 80% of the insoluble protein whether whole lenses or lens nuclei were used. This was true for normal lens and +1 cataracts; however, only 60% solubilization was obtained with the WI fraction from more advanced cataracts. Equal aliquots of a WI fraction from both pooled normal and pooled cataract lens nuclei were solubilized with and without reducing agents. The addition of dithiothreitol (DTT) had no significant effect on solubilization of the normal lens WI fraction. DTT did increase the protein solubilized from the cataract WI fraction by 30% with urea extraction; however, no increase was seen with sonication. When sodium borohydride was used as the reducing agent, essentially the same results were obtained. The solubilized protein populations were identical by SDS-PAGE and amino acid analysis. The addition of reducing agents had no effect on the amino acid content of the solubilized proteins with the single exception of lysine. This amino acid was markedly decreased in the proteins extracted in the presence of 40 mM sodium borohydride, but not with DTT. These data suggest that the borohydride not only increased the amount of protein solubilized, but likely also stabilized glycated lysine residues during the acid hydrolysis. Therefore, sonication readily provides a soluble preparation of the WI proteins from normal and cataract lens nuclei without the need for denaturing agents, however, disulfide-linked and lysine modified crystallins were best solubilized with urea.
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PMID:Studies on the solubilization of the water-insoluble fraction from human lens and cataract. 148 36

Collagen undergoes progressive browning with age and diabetes characterized by yellowing, fluorescence, and cross-linking. The present research was undertaken in order to investigate the nature of the collagen-linked fluorescence. Human collagen was exhaustively cleaved into peptides by enzymatic digestion. Upon purification, a highly fluorescent chromophore was identified and purified from old human collagen. Structure elucidation revealed the presence of an imidazo [4,5-b] pyridinium-type structure acting as a cross-link between arginine, lysine, and a pentose. This advanced glycosylation end-product and protein cross-link results from the reaction of pentoses with proteins and was named pentosidine. Further work indicated that long-term glycosylation of proteins with hexoses also leads to pentosidine formation through sugar fragmentation. The proposed mechanism of pentosidine formation involves the dehydration of the pentose-derived Amadori compound to form an intermediate which is attacked under base catalysis by the guanido group of arginine. The strict requirement for the Amadori rearrangement is uncertain. However, oxidation is definitely involved since pentosidine is not formed in the absence of oxygen. Five-carbon sugars contributing to pentosidine formation could be formed from larger sugars by oxidative fragmentation or from trioses, tetroses, and ketoses by condensation and/or reverse aldol reactions. Pentosidine increases exponentially in human skin at autopsy. Mean age-adjusted skin levels were significantly increased in subjects with uremia and especially in type 1 diabetics with uremia vs. controls. In skin biopsy, levels were significantly elevated in all diabetic (type 1) vs. control subjects. The highest degree of association was with the cumulative grade of diabetic complication (retinopathy, nephropathy, arterial stiffness, and joint stiffness). Pentosidine also forms in various proteins other than collagen, although to a much lesser extent. In blood, pentosidine is mainly associated with plasma proteins and is highly elevated during uremia. In the lens, it is associated with both water-soluble and -insoluble protein fractions and is especially elevated during brunescent cataract formation. The origin of pentosidine in vivo is uncertain. Evidence suggests that the pentoses are the most reactive sugars in pentosidine formation in vitro; however, the origin and importance of free pentoses in vivo, especially during the diabetic state, are not certain. Possible origins include hemolysis and/or a defect in the primary pentose metabolism.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Pentosidine: a molecular marker for the cumulative damage to proteins in diabetes, aging, and uremia. 181 79

Human lens was found to contain aldehyde dehydrogenase at a level of activity similar to that of bovine lens, namely 1.76 +/- 0.51 IU/g. The enzyme, which appears to be a tetramer of 229 kD, was less susceptible to inhibition by cataractogenic agents than the bovine enzyme. The lipid peroxidation product malondialdehyde was a good substrate of the human lens enzyme. The in vitro aldose reductase reaction, which we have shown is caused by glyceraldehyde-stimulated free-radical NADPH oxidation, is inhibited by the potential anti-cataract agents, bendazac acid and bendazac lysine; these compounds also inhibit ferricytochrome c reduction in the presence of DL-glyceraldehyde and scavenge superoxide radicals. These results are consistent with the hypotheses that aldehyde dehydrogenase is a protective enzyme in the human lens, and that the peroxy radical scavenging effects of bendazac acid and bendazac lysine contribute to their anti-cataract activity.
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PMID:Aldehyde dehydrogenase, aldose reductase, and free radical scavengers in cataract. 182 64

To assess the significance of glycation, nonenzymatic browning, and oxidation of lens crystallins in cataract formation in elderly diabetic patients, we measured three distinct products of glycation, browning, and oxidation reactions in cataractous lens crystallins from 29 diabetic patients (mean +/- SD age 72.8 +/- 8.8 yr) and 24 nondiabetic patients (age 73.5 +/- 8.3 yr). Compounds measured included 1) fructoselysine (FL), the first stable product of glycation; 2) pentosidine, a fluorescent, carbohydrate-derived protein cross-link between lysine and arginine residues formed during nonenzymatic browning; and 3) N epsilon-(carboxymethyl)lysine (CML), a product of autoxidation of sugar adducts to protein. In diabetic compared with nondiabetic patients, there were significant increases (P less than 0.001) in HbA1 (10.2 +/- 3.1 vs. 7.1 +/- 0.7%), FL (7.6 +/- 5.4 vs. 1.7 +/- 1.2 mmol/mol lysine), and pentosidine (6.3 +/- 2.8 vs. 3.8 +/- 1.9 mumol/mol lysine). The disproportionate elevation of FL compared with HbA1 suggests a breakdown in the lens barrier to glucose in diabetes, whereas the increase in pentosidine is indicative of accelerated nonenzymatic browning of diabetic lens crystallins. CML levels were similar in the two groups (7.1 +/- 2.4 vs. 6.8 +/- 3.0 mmol/mol lysine), providing no evidence for increased oxidative stress in the diabetic cataract. Thus, although the modification of lens crystallins by autoxidation reactions was not increased in diabetes, the increase in glycation and nonenzymatic browning suggests that these processes may acclerate the development of cataracts in diabetic patients.
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PMID:Role of glycation in modification of lens crystallins in diabetic and nondiabetic senile cataracts. 190 46

Bendazac is a drug which protects proteins from denaturation induced by different agents. It is also effective in protecting rabbits from X-ray-induced cataract. This study deals with the effects of bendazac on the intense light-induced retinal damage in rats. Four groups of animals received orally 0, 50, 100 or 200 mg/kg of bendazac L-lysine salt three times a day for 3 days and once the fourth day, before 1 h exposure to intense-green filtered light. Fourteen days after housing in a dark room, the rats were sacrificed and the retinae were examined by light microscopy. Retinal damage was graded according to a score severity from 0 to 5. The mean score for control animals was 2.23, whereas a dose-related and statistically significant reduction of retinal damage was detected in bendazac treated rats, i.e. 1.72, 1.54 and 1.40. A protective activity in the distribution of the severity score, i.e. a higher incidence of no damaged retinae and a lower frequency in the most severely affected ones, was also observed in treated versus control rats. These results suggest a potential therapeutic value of bendazac in the treatment of those conditions, such as retinitis pigmentosa and senile macular degeneration, in which the light exposure plays a role as a co-factor.
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PMID:Pretreatment with bendazac attenuates retinal damage induced by intense light in rats. 194 39

In connection with the clinical trial of an anti-cataract drug (Bendazac lysine) a number of examination methods were used to assess the progress of the cataract: slitlamp examination, visual acuity determination, and the measurement of the contrast sensitivity, light scatter in the eye and the autofluorescence and transmission of the lens. In this article the measurements of 43 patients (43 eyes) are presented, taken at the time that medication was started. In this way we can get an impression of the value of these measurements for the study of cataractous lenses. The contrast sensitivity of the cataractous eye is lowered for all spatial frequencies as compared with the normal population. Light scatter is greatly increased. The autofluorescent profile of the lens with nuclear cataract differs markedly from that of the lens with cortical cataract.
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PMID:Clinical and physical measurements of the cataractous lens. 209 Mar 99

The clinical progression of the cataract may be influenced by drugs which reduce the denaturation of lens proteins. One of the most promising drugs is the bendazac-lysine salt. The drug was used in a double-blind study of a group of patients with initial cortical cataract in order to evaluate the changes in visual acuity and contrast sensitivity by means of a psychophysical and an electrophysiological method. After 6 months of treatment with bendazac the mean values of visual acuity showed a statistically significant increase in respect to baseline values, as well as an improvement of the threshold of contrast for most spatial frequencies. In the eyes treated with placebo there was no statistical difference between the visual acuity at baseline and after the treatment, but an increase of the contrast threshold for many spatial frequencies. The treatment with bendazac, when compared to the administration of placebo, leads to a statistically significant improvement of the contrast threshold and induces a global improvement on the visual conditions.
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PMID:Psychophysical and electrofunctional contrast sensitivity in cataractous patients treated with bendazac-lysine salt. 210 31


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