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)

In contrast to other tissues, the lens exists in a milieu containing relatively high (micromolar) concentrations of H2O2. It has been demonstrated that activation of H2O2 to more-potent oxidant species via the heme-undecapeptide from cytochrome c produces alterations in lens crystallin polypeptides similar to the changes found in cataract. These include crystallin polypeptide crosslinking and the development of a blue fluorescence not attributable to tryptophan. Of the three classes of mammalian crystallins, gamma-crystallin is crosslinked by heme peptide-H2O2, whereas alpha and beta are not. Heme peptide plus H2O2 generates dityrosine from free tyrosine, and, concomitant with crosslinking, the gamma-crystallin exposed to this system develops a new fluorophor with the the characteristics of dityrosine. The findings with bovine and human crystallins are identical in this regard. In addition to the oxidation of tyrosine, exposure to heme peptide-H2O2 results in the oxidation of tryptophan. The intrinsic fluorescence of alpha, beta, and gamma-crystallins is due primarily to tryptophan, and the intrinsic fluorescence of each is decreased by heme peptide-H2O2. Thus, tryptophan oxidation occurs in all crystallins, but crosslinking occurs only in gamma-crystallin and is associated with oxidation of tyrosine.
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PMID:An analysis of the H2O2-mediated crosslinking of lens crystallins catalyzed by the heme-undecapeptide from cytochrome c. 673 43

Raman spectra have been measured for the lenses from cac-strain mice. These mice possess a hereditary defect and provide lenses at various stages of opacification. The Raman spectra of normal mouse lenses have been obtained also for comparison purposes. The amide I and III bands appear in very similar positions in the Raman spectra of cataractous and normal lenses, suggesting that the peptide backbone of main lens proteins does not undergo a major conformational change upon lens opacification. However, lens opacification causes significant changes in the intensity ratio of the tyrosine doublet near 840 cm-1 and in that of the Raman bands at 881 and 760 cm-1 due to tryptophan residues. These changes could be observed even in the incipient stage of hereditary cataract and became more pronounced with cataract development. These observations indicate that in the course of lens opacification some tyrosine residues undergo a change in their hydrogen-bonding environment and some buried tryptophan residues became exposed. In addition, the present Raman spectroscopic study provides insight into the 2SH leads to S-S conversion in lens proteins. It was found that the conversion proceeded at a faster rate in a hereditary cataractous lens than in a normal lens; however, this difference was fairly small at the early stage of cataract development. Importantly, the 2SH leads to S-S conversion was accelerated after nuclear cataract formation. These observations support the hypothesis that the formation of S-S linkages is not a predominant factor for initiating lens opacification. Probably the formation of S-S linkages plays an important role in stabilizing the protein aggregates which are the cause of lens opacification. The intensity of the SH stretching mode (2579 cm-1) was very weak or absent in the Raman spectrum of a well-developed cataractous lens, suggesting that most sulfhydryl groups form disulfide bonds. Moreover, the fact that this occurs without major conformational changes of peptide backbones implies that most cysteine residues in lens crystallins are accessible to solvent or are clustered closely together.
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PMID:Structural changes in the lens proteins of hereditary cataracts monitored by Raman spectroscopy. 684 84

In order to clarify the role of tryptophan in the patogenesis of senile cataract, we have studied the serum total and free levels of tryptophan in cataract patients as compared with age and sex-matched controls, and the urinary excretion of 10 metabolites after oral load of the amino acid. This excretion increases in the cataract group both as total per cent and as kynurenine. No difference has been found in the free and total serum tryptophan between normal subjects and cataract patients. A possible role of the kynurenines in the pathogenesis of senile cataract is suggested.
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PMID:Metabolism and serum levels of tryptophan in senile cataract patients. 708 72

The prevalence of cataracts is significantly lower in patients with rheumatoid arthritis receiving aspirin (mean of 2,700 mgs daily for an average of 10.4 years) as compared to the matched population not receiving aspirin. Similarly, fewer cataracts were found among a population with diabetes and rheumatoid arthritis receiving aspirin (mean of 2,340 mgs daily for an average of 8.8 years) as compared to the matched population on no aspirin. The effects of aspirin on cataract formation may result from 1) lowering of plasma tryptophan levels and increased excretion of tryptophan metabolites, 2) inhibition of aldose reductase and sorbitol formation in the diabetic lens, 3) inhibition of tryptophan or kynurenine binding to lens protein.
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PMID:Aspirin effect on cataract formation in patients with rheumatoid arthritis alone or combined with diabetes. 726 27

A method is described for determining the natural progression of senile cataracts in humans and whether certain factors accelerate or decelerate this progression. The method consists in plotting the age of the patient against the degree of opacity of the cataract to find the regression relation. A comparison of cataracts from diabetic and nondiabetic patients revealed that diabetes accelerated senile cataract formation, so that there was a difference of 9.6 years in the age of the two groups with more dense cataracts. Plasma tryptophan levels, which are increased in cataract patients, are lowered by acetylsalicylic acid (ASA). In this study ASA decelerated cataract formation in diabetic and nondiabetic patients. Among the nondiabetic patients cataract formation in a group with osteoarthritis was delayed by an average of 10 years. Deceleration of cataract formation resulting from ASA administration may reduce the need for surgical removal of cataracts.
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PMID:Senile cataracts: evidence for acceleration by diabetes and deceleration by salicylate. 729 56

The xanthomatine analogue, pyrphenoxone, which is known to diminish the incidence of cataract in animals and in man, was applied in two different in vivo models of cataract induced in rabbits by tryptophan-free dietary regimen and in rats by hypergalactosemic diet. The drug was also applied at different concentrations in an in vitro model of cataract. It was found that soluble proteins and sulphurated amino acids of the lens in all in vivo and in vitro models of cataract were higher after pyrphenoxone was applied. Furthermore, the drug treatment was followed by a dose-dependent increase in reduced glutathione content in the lens of rabbits and rats. The same was found in the in vitro model of cataract. These results suggest that pyrphenoxone may act by inducing various biochemical changes that lead to a protection of lens against oxidative processes.
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PMID:Biochemical changes induced by pyrphenoxone in the lens of rabbits and rats. 747 31

The major eye-lens protein alpha-crystallin is known to possess a remarkable sequence homology to the low molecular weight heat-shock proteins and has been shown to protect several proteins against thermally induced aggregation. In this work we demonstrate that the rapid aggregation of rabbit muscle phosphoglycerate kinase during incubation at 52 degrees C is completely inhibited in presence of 1/3 moles alpha-crystallin monomer per mole enzyme. Upon irradiation by UV light, tryptophan fluorescence intensity of alpha-crystallin declines, reflecting the destruction of these residues. A remarkable correlation is revealed between the reduction in alpha-crystallin fluorescence during UV-irradiation and the loss of its ability to protect phosphoglycerate kinase against aggregation. Since a loss of tryptophan fluorescence in intact eye lenses in vivo has been demonstrated to occur upon exposure to UV light, as well as during aging, it is proposed that the enhanced rate of lens opacification and cataract formation, as well as the increased levels of damaged lens proteins, which accumulate under these conditions, are the result of the gradual loss of the chaperone-protein efficacy of alpha-crystallin.
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PMID:Photodegradation of tryptophan residues and attenuation of molecular chaperone activity in alpha-crystallin are correlated. 762 28

There are two approaches to the question of whether solar radiation contributes to human cataract. The first, epidemiological studies, investigates correlations between man's environmental UV dose and cataract frequency. The second, animal models, investigates the effects of varying UV strengths and spectra on lens opacification in vivo or in vitro. While the latter approach typically provides for direct evidence, the data must still be extrapolated to human lenses. Results of physiological studies suggest that UV photons interact with proteins of the epithelial cell membranes, in particular tryptophan residues, transport ATPases and cytoskeletal proteins. One hypothesis is that damage to ion pumps and channels accumulates over the years as repair processes incompletely restore membrane function. Peroxidative damage is likely in view of the formation of UV-induced lipid peroxides in the lens epithelial membranes. Loss of homeostatic control of ions, particularly Ca++, leads to crystallin disorder in small regions of the underlying fiber cells. In our diabetic cataract studies, intracellular Ca++ electrodes detected large shifts in intracellular Ca++ before bulk-lens changes were apparent. Similar occurrences likely characterize UV cataract. Our lab is one of few studying lens physiology and how it is altered following transient exposures to UV-B and UV-A, both of which pass through the cornea. Some changes include: loss of epithelial cell GSH; elevated Ca++; loss of membrane voltage; impaired transport of Na+; increased permeability to ions and water; inhibition of critical enzymes; and a decrease in the rate of membrane synthesis.
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PMID:A review of the evidence that ultraviolet irradiation is a risk factor in cataractogenesis. 763 90

The excess prevalence of cataract in third world countries led early this century to the hypothesis that sunlight causes cataract. The hypothesis, which ignored differences in diet, culture, poverty and prevalence of other diseases such as diarrhoea, received little support until about thirty years ago when biochemical studies were set up to explore the browning of lens proteins, which is a common feature of cataract on the Indian subcontinent. Initially these studies were encouraging in that exposure to sunlight caused some changes seen in cataractous lenses, but eventually the hypothesis was rejected because the first change in the laboratory was the destruction of tryptophan, but this was not found in brown cataract lenses. A brown nuclear cataract could not be produced artificially in the laboratory using sunlight or UV exposure. Exposure of laboratory animals has produced lens opacities, but in most experiments the doses required have also caused keratitis, conjunctivitis, iritis and inflammation. The cornea seems more sensitive than the lens, which is not surprising, as it gets the first chance to absorb damaging UV. The biochemical rejection of the hypothesis coincided with the re-start of the epidemiological studies. Most of these are simply latitude studies and are no more than a repeat of what was available sixty years ago. They do not help to find a cause. Two studies showed that cataract was less common at higher altitude in the Himalayas, but unfortunately led to opposing conclusions. On the basis of common knowledge that UV exposure was greater at higher altitude, the first altitude study led to the rejection of the sunlight hypothesis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The untenability of the sunlight hypothesis of cataractogenesis. 763 2

The effect of malondialdehyde on structural features of bovine alpha-crystallin has been investigated by absorption and fluorescence spectroscopy as well as by far-UV circular dichroism. Experimental evidence suggests the occurrence of intermolecular cross-linking induced by malondialdehyde. This cross-linking does not seem to affect the tryptophan environment, as suggested by intrinsic protein fluorescence. On the contrary, the time dependence of far-UV dichroic activity indicates that the cross-linking is accompanied by a secondary structure change. The formation of high molecular mass aggregates, evidence by electrophoresis in denaturing conditions, leads to irreversible alpha-crystallin aggregation due to extensive intermolecular cross-linking. Since malondialdehyde is produced in vivo as a breakdown product of lipid peroxidation the possible involvement of this molecule in the pathological mechanism of cataract formation has been briefly discussed.
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PMID:In vitro cross-linking of calf lens alpha-crystallin by malondialdehyde. 787 36


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