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)

We examined 9 cataracts from maturity onset diabetics and 4 senile posterior subcapsular cataracts by scanning electron microscopy, transmission electron microscopy, immunofluorescence for crystallin proteins and actin, histochemical methods and x-ray diffraction. The cataractous regions contained spherical globules up to 20 mu in diameter, often in a fibrous matrix. Some were extracellular Morgagnian globules, apparently formed by blebbing from the cell surface; others appeared to have been formed intracellularly. The area of globular degeneration was usually 300 mu deep, but had deeper fusiform extensions. Morphological changes in the cell cytoplasm varied according to their depth in the cataract. Electron microscopy showed intracellular and extracellular globules, many of them were bounded by lipid bilayer membranes. Immunofluorescent staining showed that all the globules contained gamma-crystallin; some contained alpha- and beta-crystallins and actin. All the globules contained higher concentrations of cysteine or cystine than the surrounding lens tissue but they did not react to stains for carbohydrate or calcium. X-ray diffraction studies showed that crystalline calcium salts were absent. Globules and cavities averaged 45% of the total area in cross section. Assuming an area of cataract to be 300 micron thick and that globules 1 mu in diameter scattered, while 2--20 mu in diameter reflected light, we calculated that light passing through such a thickness would be reduced by 65%. Thus the globules could account for most of the opacity of the cataractous area. Presumably the fibrous degeneration of the cells causes enough light scattering to account for the remainder of the reduction. Cataract patients complain of decreased visual acuity, a golden halo around objects, and difficulties when driving while facing oncoming traffic at night. These probably result from light scattering. In our previous experiments, globular bodies containing gamma-crystallin were found in cells grown in tissue culture, and blebs with increased acitn content similar to Morgagnian globules were formed in tissue culture by treating differentiated rat lens cells of stage 2 by cytochalasin D (which impaired microfilament function). These results suggest the possibility of simulating in tissue culture the morphological alterations seen in the cataractous cell.
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PMID:Globular bodies: a primary cause of the opacity in senile and diabetic posterior cortical subcapsular cataracts? 69 89

1. Proteins from the cortex and nucleus of the human lens were studied to determine if any changes could be detected in their amino acids during senile cataract formation. 2. Senile nuclear cataract formation was found to be accompanied by a progressive oxidation of cysteine and methionine. The oxidation of methionine and changes in the distribution of the nuclear proteins did not appear to start until about 60% of the cysteine had been oxidized. 3. In the advanced nuclear cataractous lens, about 90% of the cysteine has been oxidized and 45% of the methionine is present as the sulphoxide in the nuclear proteins. The levels of other amino acids appeared to remain constant. 4. Similar, but smaller, changes were found in the cortical proteins in advanced nuclear cataractous lenses, suggesting that the oxidation spreads from the nucleus to the cortex. 5. These changes were discussed with regard to current views on cataract formation and it was concluded that they are probably the result of simple oxidation of the proteins with O2 or H2O2.
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PMID:Oxidative changes in human lens proteins during senile nuclear cataract formation. 86 Dec 52

The author presents a case with spontaneous perforation of the cornea after extracapsular cataract extraction in a female patient with rheumatoid arthritis. Systemic disorganization of the connective tissue and elevated collagenase activity essentially contribute to the pathogenesis of corneal perforation. Therefore, besides antibacterial drugs, collagenase inhibitors, 3% aqueous solution of cysteine, antimeasles gamma-globulin, and a regeneration stimulant, 5% ascorbic acid aqueous solution, were used in the treatment. The pathogenetic therapy was conducive to early healing of the corneal defect and helped save the eye and preserve its good function (0.8 s + 10.0 diopters).
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PMID:[Pathogenetic therapy of spontaneous corneal perforation after extracapsular cataract extraction]. 128 54

E64, an inhibitor of calpain (EC 3.4.22.17) and other cysteine proteases, slows the rate of formation of cataract in cultured rat lenses. The purpose of this study was to determine (1) why E64, a charged compound with little cell permeability, was effective in reducing cataract in cultured lens and (2) whether uncharged more permeable protease inhibitors are more effective than E64 in preventing cataract. Results showed that E64 entered the lens, but only after the lens was treated with the calcium ionophore, A23187, or sodium selenite, both of which cause cataracts. Therefore, the uptake and subsequent effectiveness of E64 may be related to a generalized increase in membrane permeability during induction of cataract in culture. Three protease inhibitors, reported to have improved cell permeability, were compared with E64 for their ability to prevent cataracts in cultured lenses. cBz-ValPheH, calpain inhibitors I and II, are uncharged-aldehyde inhibitors of calpain. Calpain inhibitors I and II even at high concentrations were not effective at reducing lens opacity caused by calcium ionophore and were toxic to the lens. cBz-ValPheH, which is slightly toxic to the lens, was able to significantly reduce lens opacity induced by calcium ionophore. The presented data suggest that while E64 decreases cataract formation in cultured lens, the more cell permeable inhibitor, cBz-ValPheH, may have greater efficacy as an anticataract drug in vivo.
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PMID:Comparison of cell-permeable calpain inhibitors and E64 in reduction of cataract in cultured rat lenses. 144 Jun 13

A sensitive assay, utilizing high performance liquid chromatography and sulfhydryl (SH) fluorescence labeling, was used for the quantitative determination of reduced glutathione (GSH) and cysteine (CySH) in senile cataractous lens epithelial cells. The capsule-epithelia (CE), obtained following cataract surgery, were soaked in 0.3 ml saline at room temperature for 1 hour. Detached epithelial cells and the capsule with attached residual cells were assayed for GSH and CySH. Regression analysis of the relation between epithelial protein content and capsule wet weight was performed to evaluate the amount of contamination of the CE samples with lens cortex. GSH levels in the cataractous lens epithelial cells were 23.0 +/- 11.2 (Mean +/- S.D.) nmol/mg protein (n = 15); CySH levels were 0.51 +/- 0.50 nmol/mg protein (n = 12). No differences in GSH levels were observed between immature and mature cataracts. Thus, GSH levels in the lens epithelial cells did not appear to decrease with the progression of the senile cataracts.
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PMID:Reduced glutathione levels in senile cataractous lens epithelial cells. 152 93

Selenite (Se) cataract in rabbit lenses was investigated in vitro to define target sites of Se that might be involved in calcium elevation and lens opacification. Experiments in which the anterior or the posterior surface of the lens was exposed to Se showed that anterior exposure led to ionic imbalances and opacification in the whole lens. Posterior exposure to Se (1 mM, 2 hr) had no effect. Se treatment (0.1 mM) of epithelial homogenates led to a 56% loss of thiol (SH) groups, and treatment of lenses cultured in Se led to a 22% loss. Experiments to assess the effects of Se on SH groups of Ca-ATPase showed that the transport enzyme was not affected by the poison. To determine whether this negative finding was due to the lack of accessibility of Se for SH sites in an ordered membrane, Ca-ATPase was also assayed in homogenate preparations treated with Se; still no inhibition of Ca-ATPase activity was observed. Therefore, an alternative explanation of calcium elevation was explored. The passive movement of labeled chloride (36Cl) was found to be twice as fast in Se-treated lenses as it was in control lenses. Measurement of the lens voltage indicated an 18-mV depolarization in Se-treated lenses, suggesting that Se increased membrane permeability. All cataractogenic changes that occurred after Se treatment were irreversible-despite intervention with external application of reduced glutathione or cysteine. This finding suggests that irreversible loss of SH groups in lens membranes is important in maintaining ion homeostasis.
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PMID:Effect of selenite on epithelium of cultured rabbit lens. 182 4

Cataracts were produced in cultured rat lenses by either 10 microM calcium ionophore A23187, 25 microM sodium selenite, or 30 mM xylose. E64, an inhibitor of cysteine proteases, such as calpain (EC, 3.4.22.17), reduced severity of cataract and proteolysis of crystallins when included at a 500 microM concentration in the culture medium along with cataractogenic agents. Calpain II enzyme activity and the amount of calpain antigen were decreased in the cytosol of cataractous lens. However, E64 caused an increase in the amount of an 80-kD calpain subunit associated with the ethyleneglycol-bis-(beta-aminoethylether) tetraacetic acid/ethylenediaminetetraacetic acid-washed insoluble proteins when lenses were incubated with cataractous agents. These data indicate that E64 was at least partially effective in inhibiting lens calpain, and that activation of lens calpain may involve binding to the insoluble fraction. These results provide strong evidence for the activation of calpain in rodent cataracts and suggest testing inhibitors of calpain as anticataract drugs.
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PMID:Amelioration of cataracts and proteolysis in cultured lenses by cysteine protease inhibitor E64. 184 10

The purpose of this experiment was to test the effectiveness of E64 in prevention of selenite nuclear cataract in the whole animal. E64 is an inhibitor of cysteine proteases such as calpain (EC.3.4.22.17). In the whole animal, daily intraperitoneal injection of E64 was mildly effective in slowing the rate of formation of selenite nuclear cataract, although prevention was not permanent. Frequency of the nuclear cataract in selenite group at 5 days post selenite injection was significantly decreased from 40% to 17% in the selenite + E64 group, and the density of cataract in the Se + E64 group was reduced. However, crystallins and calpain were still degraded in the selenite + E64 group. E64 was more effective against selenite cataract when present continuously during lens culture, where it slowed the rate of formation of nuclear opacity. Amelioration of cataract occurred both in vitro and in vivo even though lens calcium concentrations were elevated. The results supported the idea that application of calpain inhibitor is beneficial in prevention of rodent selenite cataracts.
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PMID:Cysteine protease inhibitor E64 reduces the rate of formation of selenite cataract in the whole animal. 191 2

Protein-thiol mixed disulfides in lenses have been implicated in the mechanism of protein-protein disulfide and other cross-linking leading to protein aggregation. The methodology for the detection and quantitation of protein-thiol mixed disulfides has been successfully established in our laboratory. Examination of mixed disulfides at different stages during development of a cataract may give relevant information on the mechanism of cataractogenesis, and whether oxidation is a part of that mechanism. In this study we investigated the involvement of mixed disulfides in cataract formation by using the H2O2-exposed lens as a model. Rat lenses, after being exposed to 0.5 mM H2O2 in culture showed an inverse relationship between the GSH loss and the protein-GSH formation with no effect on the protein-cysteine level. The H2O2-induced protein modification was also demonstrated indirectly by isoelectric focusing. The rate of protein-GSH production is dependent on the time of exposure and the concentration of H2O2. Age also plays some role as the lens GSH level decreases and the protein-thiol mixed disulfides increase as the animal becomes older. Lenses of older rats did not display more susceptibility to H2O2-induced mixed disulfide formation. The two protein-thiol mixed disulfides have a well-defined pattern of distribution in the rat lens. Most of the protein-GSH was found in the cortex and the water-soluble protein fraction whereas more protein-cysteine was found in the nucleus and water-insoluble protein fraction. Lens of older rat has more protein-cysteine as well as more water-insoluble proteins.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The role of protein-thiol mixed disulfides in cataractogenesis. 237 74

The role of the plasma membrane in the regulation of lens fiber cell cytosolic Ca2+ concentration has been examined using a vesicular preparation derived from calf lenses. Calcium accumulation by these vesicles was ATP dependent, and was releasable by the ionophore A23187, indicating that calcium was transported into a vesicular space. Calcium accumulation was stimulated by Ca2+ (K1/2 = 0.08 microM Ca2+) potassium (maximally at 50 mM K+), and cAMP-dependent protein kinase; it was inhibited by both vanadate (IC50 = 5 microM) and the calmodulin inhibitor R24571 (IC50 = 5 microM), indicating that this pump was plasma-membrane derived and likely calmodulin dependent. Valinomycin, in the presence of K+, stimulated calcium uptake, suggesting that the calcium pump either countertransports K+, or is regulated in an electrogenic fashion. Inhibition of calcium uptake by selenite and p-chloromercuribenzoate demonstrates the presence of an essential -SH group(s) in this enzyme. Calcium release from calcium-filled lens vesicles was enhanced by Na+, demonstrating that these vesicles also contain a Na:Ca exchange carrier. p-Chloromercuribenzoate and p-chloromercuribenzoate sulfonic acid also promoted calcium release from calcium-filled vesicles, suggesting that this release, like calcium uptake, is in part mediated by a cysteine-containing protein. We conclude that lens fiber cell cytosolic Ca2+ concentration could be regulated by a number of plasma membrane processes. The sensitivity of both calcium uptake and release to -SH reagents has implications in lens cataract formation, where oxidation of lens proteins has been proposed to account for the elevated cytosolic Ca2+ in this condition.
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PMID:Calcium regulation by lens plasma membrane vesicles. 284 Aug 57


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