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)

Age-related or senile human nuclear cataracts were examined using electron microscopy of thin sections prepared from thick vibrating-knife microtome sections of nuclei extracted by extracapsular surgery. The use of extended aldehyde-tannic acid fixation of 80-120-microns thick vibrating-knife microtome sections overcame the difficult problem of preserving the hardened nuclear core of aged lenses. Comparisons were made between a typical nuclear cataract, containing a central opacity and a transparent rim, and a more advanced, or mature, completely opaque nuclear cataract. The typical nuclear cataract contained no obvious cell disruption, cellular debris, or objects that readily could explain the central opacity. The fiber cells had intact uniformly stained cytoplasms with well-defined plasma membrane borders and gap junctions. The transparent rim and the nuclear core appeared similar, except that fiber cells in the nucleus were more condensed with more elaborate intercellular interdigitations. The mature cataract showed various types of cell disruption in the perimeter but not in the core of the nucleus. These disruptions were globules, vacuoles, multilamellar membranes, and clusters of highly undulating membranes. Because these potential scattering centers were not found in the nuclear core, they probably were not the sole cause of the observed opacity. Other potential scattering centers found throughout the mature cataract nucleus included variations in staining density between adjacent cells, enlarged extracellular spaces between undulating membrane pairs, and protein-like deposits in the extracellular space. Similar features, although less pronounced, were present in the typical nuclear cataract. It was concluded that massive cell disruption is not essential to the formation of a central nuclear opacity. Subtle structural changes, especially small fluctuations in protein density between adjacent cells and alterations of the membranes and the extracellular space, probably contribute significantly to the central opacities in human nuclear cataracts.
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PMID:Cellular architecture in age-related human nuclear cataracts. 139 26

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

Collagen shields have been studied in the enhancement of the initial healing of epithelial defects, as an adjunct in the treatment of dry eye, and as a reservoir and delivery system for topical ocular medications. The authors used collagen shields to collect information on the numbers and types of free cells populating the normal and postoperative ocular surface. In addition, correlative microscopic techniques were used to study details of the mechanisms responsible for the dissolution of the shields when applied to the human eye. Collagen shields were applied as a bandage lens on the eyes of patients who underwent extracapsular cataract extraction (n = 10) or penetrating keratoplasty (n = 10) and on normal volunteers (n = 10). The shields were collected at the 1-day postoperative examination and fixed in aldehyde mixtures. Specimens then were processed for correlative light (LM), transmission (TEM), and scanning (SEM) microscopy. Cell accumulation was shown by SEM on both anterior and posterior shield surfaces. Cell adherence occurred primarily on the posterior shield periphery for approximately 2 mm, with the central zone relatively clean. Both LM and TEM evaluation revealed cell counts ranging from 0.066 cells/10(4) microns2 (standard deviation, +/- 0.256) in healthy eyes compared with shields placed on postoperative eyes (194.25 +/- 7.32 cells/10(4) microns2). Various correlative microscopy techniques revealed that most cells were polymorphonuclear leukocytes with a low number of other hematogenous (lymphocytes and monocytes) and exfoliated epithelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Collagen shields as a vehicle for collecting and studying migratory cells on human corneas. 174 Mar 59

Aminoguanidine is being studied as a possible drug to prevent diabetic complications, by blocking the reactive carbonyl group of the Amadori product formed by glycation (non-enzymic glycosylation) of proteins. Thus it prevents the later browning and cross-linking steps. In the present work we show that labelled aminoguanidine becomes bound to glycated lens proteins. We also show that aminoguanidine inhibits the first steps of glycation of lens proteins but has no effect on carbamylation, the reaction with cyanate. It appears, therefore, that aminoguanidine can prevent glycation as well as the browning reactions, and may do so not by acting on the proteins, as other putative anti-cataract drugs do, but by decreasing the concentration of the active aldehyde form of the sugars.
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PMID:The effects of aminoguanidine on the glycation (non-enzymic glycosylation) of lens proteins. 237 49

From studies involving 31 cataracts classified by the CCRG system and eight normal human lenses, it has been found that the adult human lens contains an enzyme system capable of oxidizing 1-2 mumol of glyceraldehyde, acetaldehyde, propionaldehyde, formaldehyde, and malonaldialdehyde per hour to their carboxylic acid form. Roughly 30 mumol G-3-P can be oxidized per hour. Statistically, the level of the oxidase system in nuclear cataracts and deeply pigmented lenses was found to be the same as for normal lenses. The deficiency of an enzyme responsible for the oxidation of highly reactive aldehydes thus seems unlikely to be involved in nuclear cataract formation and the browning of the lens. Evidence that the observed oxidase activity occurs via two separate enzymes: aldehyde dehydrogenase and glyceraldehyde-3-P dehydrogenase was achieved by studying the response of enzyme to substrate and activators (dithiothreitol and arsenate) and by final separation of enzyme activities. Differences in pH optima and heat treatment response further distinguished one enzyme from the other.
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PMID:Aldehyde metabolism in the human lens. 661 79

Cytoplasmic aldehyde dehydrogenase from bovine lens was purified to apparent homogeneity by using ion-exchange and affinity chromatography. Sedimentation-equilibrium ultracentrifugation, gel-filtration chromatography and sodium dodecyl sulphate/polyacrylamide-gel electrophoresis show that the enzyme is a dimer of Mr 114000, with subunits of Mr 57000. The enzyme does not dissociate into monomers in the presence of Ca2+ or Mg2+. The enzyme has a pI of 5.0, an activation energy of 35.1kJ/mmol and a pK value of 8.6 with acetaldehyde as substrate. The enzyme is a prolate ellipsoid with a Stokes radius of 4nm. Progesterone, deoxycorticosterone and chlorpropamide inhibited enzyme activity, and this inhibition may play a role in cataract formation in patients maintained on systemic corticosteroids and in tablet-dependent diabetics.
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PMID:Bovine lens aldehyde dehydrogenase. Purification and preliminary characterization. 665 65

We have previously demonstrated by TLC an additional phospholipid spot between phosphatidylethanolamine (PE) and phosphatidylserine (PS) in human cataract. This was further identified as a fluorescent Schiff-base conjugate resulting from crosslinking of reactive carbonyl groups of malondialdehyde (MDA) with the primary amino groups of membrane phospholipids. Evidence presented here shows that such an adduct could be formed in rabbit lens subjected to oxidative stress in vitro. TLC analysis of a lipid extract of a crude membrane fraction obtained from the lens homogenate incubated with 1 mM H2O2, tert-butyl hydroperoxide (TBHP) or MDA for 1-6 h at 25 degrees C, showed that the oxidants and MDA produced time-dependent crosslinking of aminophospholipids. Under identical conditions of incubation with TBHP or MDA, development of the Schiff-base lipid fluorochrome in lens with peak emission at 470 nm when excited at 360 nm also showed a time-dependent increase. The PE.MDA.PS produced in cellular membranes of the lenses cultured for 3 h in Krebs-Ringer medium was 151 nmol/mumol PE, and addition of 1 mM H2O2, TBHP or MDA, increased it to 881, 610 and 375 nmol/mumol PE, respectively. Adduct was also formed when authentic samples of PE and PS were reacted with pure MDA. From the results it is clear that oxidants viz., H2O2 and TBHP, or MDA were effective in promoting crosslinking of lens membrane aminophospholipids by Schiff-base conjugation of primary amino groups with the carbonyl groups of the aldehyde, a breakdown product of lipid peroxides.
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PMID:Crosslinking of aminophospholipids in cellular membranes of lens by oxidative stress in vitro. 894 71

The purposes of this experiment were to: (1), characterize the peptide aldehyde SJA6017, N-(4-fluorophenylsulfonyl)-L-valyl-L-leucinal, a newly synthesized inhibitor of calpain, and (2) test the effect of SJA6017 in preventing calcium ionophore-induced cataract in cultured rat lenses. In vitro, SJA6017 strongly inhibited purified m-calpain from porcine kidney. Casein zymography confirmed that SJA6017 reversibly bound to the active site of m-calpain. SJA6017 was also confirmed to be a cell-permeable inhibitor in Molt-4 cells. In cultured lenses, SJA6017 reduced nuclear opacity and proteolysis of crystallins and alpha-spectrin caused by calcium ionophore A23187. These results suggested that SJA6017 is a reversible and cell-permeable calpain inhibitor which may possess great efficacy against calcium-induced models of cataract.
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PMID:SJA6017, a newly synthesized peptide aldehyde inhibitor of calpain: amelioration of cataract in cultured rat lenses. 937 5

Kinetic studies on the aldose reductase protein (AR2) have shown that it does not behave as a classical enzyme in relation to ring aldose sugars. These results have been confirmed by X-ray crystallography studies, which have pinpointed binding sites for pharmacological "aklose reductase inhibitors" (ARIs). As with non-enzymic glycation reactions, there is probably a free-radical element involved derived from monosaccharide autoxidation. In the case of AR2, there is free radical oxidation of NADPH by autoxidising monosaccharides, enhanced in the presence of the NADPH-binding protein. Whatever the behaviour of AR2, many studies have showed that sorbitol production is not an initiating aetiological factor in the development of diabetic complications in humans. Vitamin E (alpha-tocopherol), other antioxidants and high fat diets can delay or prevent cataract in diabetic animals even though sorbitol and fructose levels are not modified; vitamin C acts as an AR1 in humans. Protein post-translational modification by glyc-oxidation or other events is probably the key factor in the aetiology of diabetic complications. There is now no need to invoke AR2 in xylitol biosynthesis. Xylitol can be produced in the lens from glucose, via a pathway involving the enzymes myo-inositol-oxygen oxidoreductase, D-glucuronate reductase. L-gulonate NAD(+)-3-oxidoreductase and L-iditol-NAD(+)-5-oxidoreductase, all of which have recently been found in bovine and rat lens. This chapter investigates the molecular events underlying AR2 and its binding and kinetics. Induction of the protein by osmotic response elements is discussed, with detailed analysis of recent in vitro and in vivo experiments on numerous ARIs. These have a number of actions in the cell which are not specific, and which do not involve them binding to AR2. These include peroxy-radical scavenging and recently discovered effects of metal ion chelation. In controlled experiments, it has been found that incubation of rat lens homogenate with glucose and the copper chelator o-phenanthroline abolishes production of sorbitol. Taken together, these results suggest AR2 is a vestigial NADPH-binding protein, perhaps similar in function to a number of non-mammalian crystallins which have been recruited into the lens. There is mounting evidence for the binding of reactive aldehyde moieties to the protein, and the involvement of AR2 either as a 'housekeeping' protein, or in a free-radial-mediated 'catalytic' role. Interfering with the NADPH binding and flux levels--possibly involving free radicals and metal ions--has a deleterious effect. We have yet to determine whether aldose reductase is the black sheep of the aldehyde reductase family, or whether it is a skeleton in the cupboard, waiting to be clothed in the flesh of new revelations in the interactions between proteins, metal ions and redox metabolites.
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PMID:Aldose reductase: a window to the treatment of diabetic complications? 969 97

Carbohydrates with reactive aldehyde and ketone groups can undergo Maillard reactions with proteins to form advanced glycation end products. Oxalate monoalkylamide was identified as one of the advanced glycation end products formed from the Maillard reaction of ascorbate with proteins. In these experiments, we have analyzed human lens proteins immunochemically for the presence of oxalate monoalkylamide. Oxalate monoalkylamide was absent in most of the very young lenses but was present in old and cataractous lenses. The highest levels were found in senile brunescent lenses. Incubation experiments using bovine lens proteins revealed that oxalate monoalkylamide could form from the ascorbate degradation products, 2,3-diketogulonate and L-threose. These data provide the first evidence for oxalate monoalkylamide in vivo and suggest that ascorbate degradation and its binding to proteins are enhanced during lens aging and cataract formation.
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PMID:Immunochemical detection of oxalate monoalkylamide, an ascorbate-derived Maillard reaction product in the human lens. 1040 69


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