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 free radical mechanism of cataractogenesis involving enzymatic and nonenzymatic reactions, is proposed. Supporting experimental evidence is briefly reviewed. H2O2, which is one of the toxic metabolites of oxygen, was significantly increased 2-3 fold in ocular humors in several experimental cataracts and in human senile cataract. Various cataractogenic agents were also found to increase H2O2 in ocular humors in vivo prior to cataract formation. Enzymatic defenses against O2-. and H2O2 provided by superoxide dismutase, catalase and glutathione peroxidase were impaired in cataracts. In some cataracts, catalase and superoxide dismutase were affected earlier. Malondialdehyde (MDA), a major breakdown product of lipid peroxides was significantly increased by 2-4-fold in human senile cataract, in cataracts induced in rabbit and rat, and in hereditary cataracts in mice. All the reactive species of O2 (O2-., H2O2, OH. and 1 delta gO2) may participate in initiating lipid peroxidation of lens in vitro. Various scavengers of these species were capable of preventing lenticular lipid peroxidation, amongst which OH. scavengers were found to be the most effective. Biological antioxidant, vitamin E afforded 44% prevention of lipid peroxidation in lens. The important observation was that vitamin E was therapeutically effective in about 50% of animals in arresting cataract induced in rabbit by 3-aminotriazole. In these rabbits, H2O2 and ascorbic acid of ocular humors and MDA of lens were close to normal. It is our working hypothesis that the carbonyl groups of MDA and amino groups of amino acids, proteins, nucleic acids and their bases, and phospholipids could interact in a cross-linking reaction producing high molecular weight aggregates by Schiff-base conjugate formation in addition to disulfide cross-linking of proteins, and finally resulting in cataract.
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PMID:Molecular mechanism of cataractogenesis: III. Toxic metabolites of oxygen as initiators of lipid peroxidation and cataract. 631 86

Glutathione is present in both the reduced and oxidized form in the cornea, aqueous humor, ocular lens and retina. In these tissues it serves a variety of functions including maintaining normal tissue hydration (in the cornea) detoxifying peroxides and electrophilic compounds via enzymatic pathways and acting as a free radical scavenger to protect against photoinduced damage. In the ocular lens, glutathione levels decrease with aging and cataract formation. Recent evidence which may account in part for this phenomenon suggests that glutathione is altered when subjected to UV radiation in the presence of H2O2. Analyses employing fluorescence, phosphorescence, UV absorption and proton mode NMR spectroscopy demonstrate that UV exposure does alter both the reduced and oxidized forms of glutathione, producing the same final products. Moreover, while H2O2 speeds up the process, it is not essential to the reaction.
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PMID:Glutathione and ocular photobiology. 636 May 41

Metabolic changes may precede changes in lens protein structure and cataract opacification. Since many of the effects associated with cataract are oxidative in nature, changes in the redox state may be caused by alterations in the level of various metabolic intermediates such as ATP and NAD(P)H. Abnormal levels of H2O2 have been found in the aqueous fluid of cataract patients. Lenses have been treated with 1 mM-H2O2 in organ culture as a cataract model. H2O2 in this system uncouples Na+, K+-ATPase. This metabolic stress has been further evaluated non-invasively by 31P NMR to show that H2O2 can reduce ATP levels without any immediate effects on visual transparency. However, further treatment by this oxidant leads to definitive visual changes in lens clarity. These changes may be due to further changes in structural lens proteins caused by denaturation and aggregation induced by H2O2. The effects of H2O2 on isolated lens proteins is being examined in molecular detail by NMR to ascertain how the lens proteins become denatured in solution. The relevance of the H2O2 model to cataract formation can only be evaluated by using several non-invasive techniques beyond NMR, and then critically comparing the model systems with human cataract tissue samples.
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PMID:Non-invasive techniques in the study of cataract development at the metabolic and protein molecular level. 656 77

Previous work has established that oxidation of the constituents of the human lens is an early event in the development of cataract. In old pre-cataractous lenses, oxidation of the fibre membrane polypeptides is observed. Non-disulphide-linked aggregates possibly generated by photo-oxidation are also found. With the development of cataract the oxidation becomes more extensive, affecting many of the proteins of the tissue. High molecular weight, disulphide-linked aggregates are formed, involving cytosol and membrane components. Membrane rupture accompanies the process. Hydrogen peroxide has been found in elevated levels in the aqueous fluid of some cataract patients. H2O2 will cause cataract and has been shown to affect Na+,K+-ATPase. Analyses of available data suggest that (1) oxidation of membrane components may be an initiating event in cataract, and (2) the oxidizing agent may come from the exterior environment of the tissue. The problems involved in proving this hypothesis are discussed and an approach to testing the hypothesis is suggested.
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PMID:Oxidation and cataract. 656 80

The mammalian lens contains an unusually high concentration of glutathione (GSH), the highest level being in the epithelium. GSH is present largely in the reduced state. The high concentration of GSH in a normal lens and the decreased concentration in most types of cataracts have led to many hypotheses on its role in cataract formation. These hypotheses are considered in the light of current evidence. GSH is synthesized and degraded in the lens. Both processes require ATP, derived largely from glycolysis. Carbohydrate metabolism is also involved in the maintenance of GSH in the reduced state. There is a direct link between the rate of formation of oxidized glutathione (GSSG) and the stimulation of the hexose monophosphate shunt through the generation of NADPH. One possible function of GSH in the lens is to maintain the thiol (SH) groups of proteins in the reduced state, thus preventing formation of high molecular weight (HMW) protein aggregates. The formation of HMW proteins in X-ray-induced cataracts through disulphide bond formation and the involvement of SH oxidation in HMW proteins isolated from human cataractous lenses suggest a role for GSH in protecting protein SH groups. GSH in the lens may also protect critical SH groups involved in regulating cation transport and permeability. Studies with mammalian lenses indicate that lowering the lens GSH concentration leads to increased permeability to cations and inactivation of Na+,K+-ATPase. A consequence of the changes in ion distribution is the inhibition of protein synthesis, which may explain the cessation of growth in cataractous lenses. GSH may also protect against oxidative damage to the lens. GSH metabolism is intimately involved in detoxification of H2O2, normally present in the aqueous humour. Lenses with impaired shunt activity or inhibited glutathione reductase are more susceptible to oxidative damage by peroxide. This may contribute to the formation of cataract.
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PMID:Metabolism and function of glutathione in the lens. 656 81

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

The activities of the protective enzymes, superoxide dismutase, catalase and glutathione peroxidase have been measured in the cortical and nuclear sections of 76 human cataractous lenses as well as in calf, rabbit and rat lenses. No changes was observed in the activity of catalase with the progressive development of cataract. However, a precipitous decrease (70%) in both superoxide dismutase and glutathione peroxidase in the nuclear region of the lens was found at the onset of nuclear cataract. Further decreases accompanied the progression of the cataract and similar, but less marked, decreases were observed in the cortical region of the lens. It is suggested that the inactivation of these enzymes may result in an elevation of the H2O2 and O2.- levels in the lens and that this may be responsible for the oxidative modification of lens proteins observed in nuclear cataracts.
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PMID:Superoxide dismutase, catalase and glutathione peroxidase in the human cataractous lens. 682 28

This review examines the hypothesis that oxidative stress is an initiating factor for the development of maturity onset cataract and describes the events leading to lens opacification. Data are reviewed that indicate that extensive oxidation of lens protein and lipid is associated with human cataract found in older individuals whereas little oxidation (and only in membrane components) is found in control subjects of similar age. A significant proportion of lenses and aqueous humor taken from cataract patients have elevated H2O2 levels. Because H2O2, at concentrations found in cataract, can cause lens opacification and produces a pattern of oxidation similar to that found in cataract, it is concluded that H2O2 is the major oxidant involved in cataract formation. This viewpoint is further supported by experiments showing that cataract formation in organ culture caused by photochemically generated superoxide radical, H2O2, and hydroxyl radical is completely prevented by the addition of a GSH peroxidase mimic. The damage caused by oxidative stress does not appear to be reversible and there is an inverse relationship between the stress period and the time required for loss of transparency and degeneration of biochemical parameters such as ATP, GPD, nonprotein thiol, and hydration. After exposure to oxidative stress, the redox set point of the single layer of the lens epithelial cells (but not the remainder of the lens) quickly changes, going from a strongly reducing to an oxidizing environment. Almost concurrent with this change is extensive damage to DNA and membrane pump systems, followed by loss of epithelial cell viability and death by necrotic and apoptotic mechanisms. The data suggest that the epithelial cell layer is the initial site of attack by oxidative stress and that involvement of the lens fibers follows, leading to cortical cataract.
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PMID:Oxidative stress-induced cataract: mechanism of action. 767 10

Caffeic acid phenethyl ester (CAPE) was isolated from propolis (a product of honeybee hives) that has been used in folk medicine as a potent antiinflammatory agent. CAPE is cytotoxic to tumor and virally transformed but not to normal cells. Our main goal was to establish whether CAPE inhibits the tumor promoter (12-O-tetradecanoylphorbol-13-acetate)-induced processes associated with carcinogenesis. Topical treatment of SENCAR mice with very low doses (0.1-6.5 nmol/topical treatment) of CAPE strongly inhibits the following 12-O-tetradecanoylphorbol-13-acetate-mediated oxidative processes that are considered essential for tumor promotion: (a) polymorphonuclear leukocyte infiltration into mouse skin and ears, as quantified by myeloperoxidase activity; (b) hydrogen peroxide (H2O2) production; and (c) formation of oxidized bases in epidermal DNA, as measured by 5-hydroxymethyluracil and 8-hydroxylguanine. A 0.5-nmol dose of CAPE suppresses the oxidative burst of human polymorphonuclear leukocytes by 50%. At higher doses (1-10 mumol), CAPE inhibits edema and ornithine decarboxylase induction in CD-1 and SENCAR mice. Interestingly, we discovered that 12-O-tetradecanoylphorbol-13-acetate-induced H2O2 production in bovine lenses also is inhibited by CAPE. Cumulatively, these findings point to CAPE as being a potent chemopreventive agent, which may be useful in combating diseases with strong inflammatory and/or oxidative stress components, i.e., various types of cancer and possibly cataract development.
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PMID:Inhibition of tumor promoter-mediated processes in mouse skin and bovine lens by caffeic acid phenethyl ester. 768 Feb 81

The enhancement of UVB on the surface of the earth due to stratospheric ozone depletion may increase the risk of photochemically induced cataract. In this study, changes in the content of certain biological parameters were used as a marker to study ocular toxicity. A significant enhancement in the level of H2O2, LP and Pi, along with the depletion of GSH (antioxidant-defence system) in serum, aqueous humor and lens of albino mice exposed to UVB was observed. The level of Ca++ increased in serum and aqueous humor but decreased considerably in the lens due to increase in UVB exposure. These observations provide further clues to support the involvement of oxidative stress and Ca++ in the events leading to the formation of cataract.
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PMID:Ultraviolet-B effects on ocular tissues. 775 17


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