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)

Using phosphorous-31 nuclear magnetic resonance (31P-NMR) spectroscopy, we observed the metabolic kinetics of organophosphate compounds in the rat lens during cataract development induced by different doses of galactose (5%, 15%, 25%, and 40%) added to rat chow. The metabolic and histologic changes in the lenses were compared among the rats fed with different doses of galactose. alpha-Glycerophosphate significantly increased in response to the galactose doses, followed by a decrease to steady values of approximately 120% of the base line value, except in the 40% galactose group, which had a marked decrease to 68% of the base line value. Choline phosphate decreased rapidly during dosing in all but the 5% group, but no changes in those levels were observed after 2 weeks of galactose dosing. ATP decreased significantly when the histologic destruction progressed in the entire lens. Although inorganic phosphate increased significantly in a dose-dependent manner, it did not exceed the peak level. The histologic changes were closely related to the dynamic changes in the phosphorous compounds in the rat lens during formation of the galactose-induced cataract. Our results indicated that the development of a galactose-induced cataract was associated with the metabolic changes of the phosphate compounds.
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PMID:Organophosphate metabolic changes in the rat lens during the development of galactose-induced cataract. 1064 92

Galactokinase (GALK) deficiency is an autosomal recessive disorder characterized by hypergalactosemia and cataract formation. Through mass screening of newborn infants, we identified a novel and prevalent GALK variant (designated here as the "Osaka" variant) associated with an A198V mutation in three infants with mild GALK deficiency. GALK activity and the amount of immunoreactive protein in the mutant were both 20% of normal construct in expression analysis. The K(m) values for galactose and ATP-Mg(2+) in erythrocytes with homozygous A198V were similar to those of the healthy adult control subjects. A population study for A198V revealed prevalences of 4.1% in Japanese and 2.8% in Koreans, lower incidence in Taiwanese and Chinese, no incidence in blacks and whites from the United States, and a significantly high frequency (7.8%; P < .023) in Japanese individuals with bilateral cataract. This variant probably originated in Japanese and Korean ancestors and is one of the genetic factors that causes cataract in elderly individuals.
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PMID:A genetic factor for age-related cataract: identification and characterization of a novel galactokinase variant, "Osaka," in Asians. 1123 2

In galactokinase (GALK) deficiency, galactose cannot be phosphorylated into galactose-1-phosphate, which leads to cataract formation. Neonatal screening for hypergalactosemia in Berlin has been performed by thin-layer chromatography since 1978, which detects classical galactosemia and GALK deficiency. Until 1991, GALK deficiency has not been identified in a total of approximately 260,000 samples. In contrast, from 1992 to 1999, nine patients were detected in a total of approximately 240,000 screened newborns. One Turkish patient was homozygous for two novel S142I/G148C GALK mutations in close proximity to the putative ATP-binding site of the enzyme. The other eight children were born to five families belonging to the Bosnian refugee population consisting of approximately 30,000 individuals who have arrived in Berlin since 1991. In two of these families, GALK deficiency was subsequently diagnosed in siblings who had cataract surgery at 4 and 5 y of age, respectively. In all these 10 Bosnian patients, a homozygous P28T mutation located near the active center of the enzyme was identified. We propose that neonatal screening of populations with a significant proportion of Bosnians and possibly other southeastern Europeans, e.g. Romani, should be particularly directed toward GALK deficiency, an inborn error of metabolism that is readily amenable to effective treatment.
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PMID:An unexpectedly high frequency of hypergalactosemia in an immigrant Bosnian population revealed by newborn screening. 1197 83

On the basis of the data about possible potentiation of polychromatic light cataractogenic effect by adrenaline and dimethylsulfoxide preparations, obtained by us earlier (increasing of animals number with changes of lenses and metabolic disturbances, of the first clinical signs of cataract in more earlier terms, more rapid development occurred in lenses opacities, more intensive changes of lenses substance), we have studied some biochemical parameters (peroxide resistance of erythrocyte, the level of free amine nitrogen, activity of Na,K-ATP-ase, gamma-glutamiltranspeptidase, ceruloplasmin) in blood, liver and tissues of rabbits eyes, during modelling of the light cataract on the background of supplementary application of adrenalin and dimethylsulfoxide. It was shown that one of the possible mechanisms of cocataractogenic action of the studied substances is the revealed fact of increasing the metabolic systems disturbances, caused by long-term irradiation of the animals.
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PMID:[Potentiation of the cataractogenic effect of light by dimethylsulfoxide and adrenaline]. 1203 17

In the ocular lens, cataract formation is associated with an elevated intracellular Ca(2+) concentration (Ca(2+)(i)) resulting from the loss of lens cell Ca(2+) regulation. The mechanisms regulating Ca(2+)(i) have been characterized previously in lens epithelial cells, but have not been well characterized in the more differentiated lens fiber cells. The mechanisms regulating Ca(2+)(i) in clusters of fiber-like cells (lentoids) in a sheep lens primary cell culture system in which the epithelial cells differentiate into enlarged fiber-like cells were investigated. Only approximately 50% of the lentoids responded to thapsigargin and/or agonists (ATP and epinephrine), compared to>95% of the epithelial cells. Remarkably, most (90%) lentoids exhibited a resting cytosolic Ca(2+)(i) that was approximately three-fold greater than that in epithelial cells (approximately 100n M). This elevated resting cytosolic Ca(2+)(i) was not affected by thapsigargin treatment, but decreased upon removal of extracellular Ca(2+) or addition of the Ca(2+) channel blocker Gd(3+) (5mM ). These results suggest that a plasma membrane Ca(2+) channel is more active in lentoids than in epithelial cells. Indeed, when plasma membrane cation channel activity was monitored by Mn(2+) influx and quenching of fura-2 fluorescence, quenching was faster in lentoids than epithelial cells. Following thapsigargin treatment, capacitative Ca(2+) entry was activated in epithelial cells but not lentoids. In conclusion, during differentiation in primary cell culture, lens cells lose their ability to respond to agonists and exhibit an elevated resting Ca(2+)(i) that was dependent on the activation of a Ca(2+) influx pathway. The results of this study support the possibility that a sustained elevation in resting Ca(2+)(i) is one of the factors controlling lens cell differentiation, possibly by triggering events such as calpain activation.
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PMID:Ca(2+) regulation in differentiating lens cells in culture. 1212 39

The ABCA subfamily of ABC transporters includes ten members to date. In this study, we describe an additional gene, ABCA12. Four full-length cDNA sequences have been obtained from human placenta that contain two different polyadenylation sites and two splicing forms, coding for ABCA12 isoforms of 2,595 and 2,516 amino acid residues. Both isoforms are predicted to have two ATP-binding domains (nucleotide binding domain, NBD) and two transmembrane (TM) domains, features shared by all other ABCA subfamily proteins. ABCA12 is most closely related to ABCA1, with an amino acid similarity of 47%. Northern blot analysis demonstrates that a 9.5-kb transcript is mainly expressed in the stom- ach. ABCA12 was mapped to human chromosome 2q34. Two other genes from ABCA subfamily are associated with human inherited diseases, ABCA1 with the cholesterol transport disorders Tangier disease and familial hypoalphalipoproteinemia, and ABCA4 with several retinal degeneration disorders. The ABCA12 gene is located in a region of chromosome 2q34 that harbors the genes for lamellar ichthyosis, polymorphic congenital cataract, and insulin-dependent diabetes mellitus (IDDM13), and therefore is a positional candidate for these pathologies.
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PMID:Identification and characterization of a novel ABCA subfamily member, ABCA12, located in the lamellar ichthyosis region on 2q34. 1269 99

The purpose of this study was to determine if high ascorbate of the human aqueous protects the lens against oxidative stress. Previous studies with the rat lens have been inconclusive because of its fortification with aldose reductase (AR), an important antioxidant. The human lens is deficient in this activity. These studies were hence done with the mouse lens, a species deficient in this enzyme. The reactive oxygen species (ROS)-induced physiological damage to the tissue was assessed in organ culture, by measuring its ability to actively transport 86Rb(+) ions, in the absence and presence of ascorbate. In addition, the status of tissue metabolism and its antioxidant reserve were assessed by quantitating ATP and glutathione (GSH). As expected, ROS decreased the membrane transport activity as well as the levels of ATP and GSH. Ascorbate minimized these toxic effects substantially. The presence of high ascorbate, therefore, appears highly beneficial in protecting the lens against oxidative damage and cataract formation, despite a deficiency of AR. The findings therefore appear to be significant from the point of view of using this nutrient for delaying the onset of cataract development in human beings, therapeutically as well as nutritionally.
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PMID:Protective effect of ascorbate against oxidative stress in the mouse lens. 1472 37

The UPL rat is a newly developed hereditary cataract model. We previously found that Ca2+ concentrations in UPL rat lenses increase with the development of cataract, and that the administration of disulfiram and aminoguanidine ameliorates the increase in Ca2+ and the development of cataract in UPL rats. In this study, we determined the expression and activity of plasma membrane Ca2+-ATPase (PMCA) in lenses of normal and UPL rats. We also determined the ATP content in UPL rat lenses and the effects of disulfiram and aminoguanidine administration. Expression of PMCA mRNA in UPL rat lenses, determined by a reverse transcription-PCR method, increased during the development of cataract. Ca2+-ATPase activity in UPL rat lenses also increased with the progression of lens opacification. On the other hand, ATP decreased markedly in UPL rat lenses, and the administration of disulfiram and aminoguanidine attenuate the ATP decrease. These results suggest that an ATP decrease cause cataract development and an increased Ca2+ may upregulate PMCA expression in UPL rat lenses. Disulfiram and aminoguanidine attenuate the decrease in ATP, resulting in a delay in cataract development.
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PMID:Changes in plasma membrane Ca2+ -ATPase expression and ATP content in lenses of hereditary cataract UPL rats. 1500 27

The cataractogenic potential of the thiazolidinedione ciglitazone (CIG) was investigated in vivo and in vitro. In the rat, CIG caused a dose-dependent (30-300 mg/kg/day) increase in incidence and severity of nuclear cataract formation during a 3-month nonclinical safety assessment study. Potential mechanisms of toxicity were surveyed using whole rat lens explants exposed to CIG with or without various inhibitors of cataract formation. In vitro, CIG caused a concentration-(0.375-30 muM) and time-dependent (3-24 h) change in biochemical [ATP content or mitochondrial reduction of the tetrazolium dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) and reduced glutathione (GSH) content] and morphometric (lens wet weight and clarity) markers of damage. Within 3 h of exposure, 7.5 muM CIG decreased lens ATP content 37 +/- 7% (percentage of difference from control, p < 0.05). After 24 h of exposure, lens ATP content, MTT reduction, and GSH content declined 57 +/- 5, 30 +/- 28, and 42 +/- 8%, respectively. Lens wet weight increased 17 +/- 4% with a concomitant decrement in lens clarity. Pretreating lenses with the mitochondrial calcium uniport inhibitor ruthenium red (RR) partially or fully protected lenses from toxicity. In contrast, the antioxidant dithiothreitol, aldose reductase inhibitor sorbinil, and selective cell-permeable calpain inhibitors [calpain II inhibitor and (2S,3S)-trans-epoxysuccinyl-l-leucylamido-3-methylbutane ethyl ester (E64d)] were ineffective in providing protection under the present testing conditions. Early and selective changes in lenticular ATP content and the partial or full protective effect of RR suggest that alterations in lens bioenergetics may play an important role in CIG-induced cataract formation. Lens explant cultures were successfully used to select two thiazolidinediones that lacked cataractogenic activity when evaluated in 3-month rat safety assessment studies.
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PMID:Ciglitazone-induced lenticular opacities in rats: in vivo and whole lens explant culture evaluation. 1552 2

We have previously shown that pyruvate protects against reactive oxygen species (ROS) induced damage to lens in vitro. It has also a significant effect against cataract development. Its effectiveness has been ascribed to the presence of alpha-keto-carboxylate group in the molecule, acting as a scavenger of ROS. Hence, it was felt desirable to determine if other alpha-keto-acids could have similar effects. These studies have hence been conducted with alpha-ketoglutarate (alpha-KG), a compound with greater stability and without any known significant effect on the glycolysis. Its effectiveness has been assessed by monitoring cataract development in rat pups given sodium selenite. A large percentage of such animals (about 80%) developed nuclear opacity 7-8 days after its administration. In animals treated with alpha-ketoglutarate, the incidence of cataracts was only 23%. The agent therefore has a very substantial anticataractogenic effect, as apparent by direct slit lamp examination followed by photography, as well as by examination of the isolated lenses through transillumination. The significance of the ophthalmologic findings was apparent also by better physiological maintenance of the tissue, reflected by higher levels of ATP and GSH. In view of these in vivo beneficial effects, studies are in progress to identify the biochemical and metabolic sites of its action. Whether the effectiveness is related only to its action as a ROS scavenger or it could be contributed also by some metabolic effects independent of ROS remains to be determined.
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PMID:Effect of alpha-ketoglutarate against selenite cataract formation. 1564 29


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