UMLS:C0086543 - FACTA Search

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Query: UMLS:C0086543 (cataract)
29,165 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to examine the influence of exogenously administered melatonin on cataract formation and lipid peroxidation in newborn rats treated with buthionine sulfoximine (BSO), a drug which inhibits the rate-limiting enzyme in glutathione (GSH) synthesis, gamma-glutamylcysteine synthase, thereby depleting animals of their stores of the important intracellular antioxidant, GSH. BSO (3 mmol/kg BW) was given for three consecutive days beginning on postnatal day 2; melatonin (4 mg/kg) was injected daily beginning on postnatal day 2 and continuing until the animals were killed (either day 9 or day 17 after birth). None of the control animals (rats treated with neither BSO nor with melatonin) developed lenticular opacification during the observation period. In the BSO-treated rats, 16 of 18 animals (89%) had observable cataracts when they were examined. In rats that received both BSO and melatonin, the incidence of cataracts was highly significantly decreased, i.e., only 3 of 18 rats (7%) had observable cataracts. In addition to cataracts, the level of lipid peroxidation products (malondialdehyde (MDA) and 4-hydroxyalkenals (4-HDA)) was examined in the lens, brain, liver, lung, and kidney of control and experimental animals. In BSO-treated rats, the lens, kidney, and lung exhibited increased levels of MDA plus 4-HDA relative to those measured in the control rats; these increases were reversed in the BSO-treated rats who were injected with melatonin daily. While BSO administration did not increase basal levels of MDA plus 4-HDA in either the brain or liver, melatonin reduced levels of lipid peroxidation products below those measured in the control rats (at 17 days after birth). The changes induced by melatonin are consistent with the free-radical scavenging and antioxidative properties of this indole.
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PMID:Cataractogenesis and lipid peroxidation in newborn rats treated with buthionine sulfoximine: preventive actions of melatonin. 921 64

It has been previously shown in H2O2-induced cataract model in the rat lens that protein-GSH (PSSG) formation precedes protein-protein disulfide (PSSP) conjugation and lens opacity. This elevated PSSG spontaneously reduces to a normal level when H2O2 is removed. To verify if thioltransferase (TTase), an enzyme that is known in other tissues to dethiolate PSSG, takes part in this recovery process, we examined the relationship of PSSG and TTase in this cataract model. To ensure enough tissue would be available for various biochemical studies, H2O2 induced cataract in pig lens was established and validated with the rat lens model. The study was divided into two parts. One part was to examine the effect of H2O2 concentration, ranging from 0.1 mM-10 mM, during 24 hr. Another part was to study the H2O2 (1.5 mM) induced cataract progression and recovery, parallel to the long-term study in rat lenses reported previously. These lenses were compared for transparency, wet weight, GSH, PSSG levels and the activity of two redox regulating enzymes, glutathione reductase (GR) and TTase. For the most part, pig lens responded to oxidation parallel to the rat lens except that a higher concentration of H2O2 was needed to achieve the same results. Damage induced by H2O3 was concentration dependent. In general TTase activity and GSH level were depleted with a concomitant increase in PSSG. The D50 (50% damage) for GSH in pig lens was 1.5 mM H2O2 (0.5 mM for rat lens) which was chosen for further studies in cataract progression and recovery. At 1.5 mM H2O2, pig lens showed superficial opacity within 24 hr and deeper cortical opacity in 48 hr. The pre-exposed lens became less cloudy when H2O3 was removed from the medium. Incubation of the lens in 1.5 mM H2O2 for one day also induced 50% GSH depletion and four fold PSSG elevations. This accumulated PSSG was dethiolated spontaneously in the absence of H2O2, similar to the findings in the rat lens and human lens models. In contrast protein-cysteine (PSSC) showed little change and did not respond to the recovery condition. TTase lost 50% activity in these lenses during 24-hr H2O3 exposure but regained most of it under recovery. The study on rat lens showed similar results as before, therefore only data on the relationship of TTase activity to PSSG level during cataract development and recovery is reported here. It was found that in the H2O2 (0.5 mM)-exposed rat lenses, the TTase activity was depleted but PSSG accumulation was accelerated within 8 hr. Both recovered quickly (within 8 hr) as soon as the oxidant was removed. Therefore, protein thiolation and dethiolation processes in the cultured rat or pig lenses display a mirror image with the activity pattern of TTase. Based on the close relationship between lens TTase and PSSG indicated above, it is speculated that TTase may regulate PSSG and maintain it at a low concentration in situ. This repair process may contribute to the improved transparency during recovery. Further studies are planned to substantiate this hypothesis.
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PMID:Relationship of protein-glutathione mixed disulfide and thioltransferase in H2O2-induced cataract in cultured pig lens. 924 98

Mouse lens cultures were employed to study the progression of cataracts initiated by injection of buthionine sulfoximine, an inhibitor of glutathione (GSH) biosynthesis. Culture of lenses removed from untreated mice on postnatal day 7, for 48 hr in the presence of 4 mm BSO, resulted in only limited cataractous changes. To enable substantial progression of cataracts in vitro, it was therefore necessary to pretreat the mice with BSO prior to lens culture. A single injection of BSO (4 nmol mg-1 lens), administered on day 7, resulted in >90% depletion of lens GSH within 3 days, but no visible cataractous changes. The clear lenses were incubated for 29+/-1 hr at 37 degrees C in Medium HL-1, supplemented with EGF, insulin and Ca2+, in the presence or absence of BSO, and were scored for cataract development by previously described criteria. In the absence of BSO, only 4 of 10 lenses developed large opacities. However, in the presence of 4 mm BSO, 40 out of 45 experimental lenses developed opacities affecting at least 50% of the lens visual field and were scored as stages 1C-4, depending upon the extent and density of the cataracts. In addition, three lenses had opacities involving 20-50% of the field (stage 1B). By contrast, less than 10% of lenses from untreated mice incubated in the absence of BSO developed opacities. The cataracts developed in 4 mm BSO were accompanied by reduction of lens glutathione levels to <0.010 nmol mg-1 lens. They were almost completely prevented by 1 mm ascorbate, 2 mm GSH, 2 mm GSH monoethyl ester and 2 mm cysteamine. GSH and GSH ester maintained lens glutathione content between 0.1 and 0.2 nmol mg-1 in the presence of BSO, whereas ascorbate did not prevent near-total GSH depletion. The prevention of cataracts by thiols and ascorbate was confirmed by lens Na/K ratios not significantly different from those in control lenses. The above combination of GSH depletion in vivo by a single injection of BSO, followed 3 days later with lens culture in the presence of BSO, may yield a useful system to elucidate and control the biochemical mechanisms involved in oxidative cataract induction by this GSH-depleting agent.
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PMID:Progression of mouse buthionine sulfoximine cataracts in vitro is inhibited by thiols or ascorbate. 929 71

The preventive action of vitamin E (Vit. E)-containing liposomes on cataractogenesis was examined in male Wistar rats (five weeks old) fed a 25% galactose diet. Vit. E-containing liposomes prepared with dipalmitoylphosphatidylcholine were instilled into both eyes three times a day over a 45-day period. Cataract appeared at 18-day galactose feeding and developed gradually thereafter. Simultaneous Vit. E-containing liposome instillation delayed this cataractogenesis. Lenses of 18-day galactose-fed rats showed decreases in Vit. E and reduced glutathione (GSH) contents and Na+, K(+)-ATPase activity and increases in lipid peroxide (LPO), galactitol, and water contents. Lenses of 45-day galactose fed rats showed decreases in GSH content and Na+,K(+)-ATPase activity and increases in Vit. E, LPO, galactitol, and water contents. Serum Vit. E and cholesterol levels decreased in 18-day galactose-fed rats, while both levels increased in 45-day galactose-fed rats. Simultaneous Vit. E-containing liposome instillation prevented these changes except for the changes of lenticular galactitol and water contents and serum Vit. E and cholesterol levels. These results indicate that simultaneously instilled Vit. E-containing liposomes can delay cataractogenesis in young adult rats fed a 25% galactose diet mainly by the antioxidative action of Vit. E contained in the instilled liposomes.
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PMID:Preventive action of vitamin E-containing liposomes on cataractogenesis in young adult rats fed a 25% galactose diet. 943 57

microPx-11, a ferriheme undecapeptide proteolytic degradation product of cytochrome C is shown to be a peroxidase with broad specificity degrading H2O2 and tertiary butyl hydroperoxide. It is also capable of effectively eliminating superoxide and hydroxyl radical. The peroxidase loses activity in the presence of peroxide unless it is stabilized by ascorbate (Asc) or solutions such as aqueous humor or medium 199. While thiol but not disulfides inactivates the microPx-11, it is not inhibited in the presence of the rat lens which has a high GSH content. microPx-11 at concentrations 10 to 50 fold greater than are required to achieve good protective activity exhibits no toxicity based on cell viability, ATP levels and lens transparency after long-term incubations of alpha TN4-1 cells or cultured rat lens. The peroxidase is capable of protecting cultured rat lenses from photochemical stress where H2O2, O2.- and OH. are generated based on transparency, choline transport, epithelial cell viability and protein integrity as indicated by SDS-PAGE of the rat lens protein. In the absence of the peroxidase, extensive epithelial cell death and other degradative changes are observed. The DNA of alpha TN4-1 cells can also be protected from H2O2 induced single strand breaks by the microPx-11. The overall results suggest that a number of cytochrome C proteolytic degradation products are peroxidases which may be effective anti-cataract agents protecting the lens from oxidative stress.
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PMID:Microperoxidases catalytically degrade reactive oxygen species and may be anti-cataract agents. 946 80

The prevailing view regarding the mechanism of steroid cataract formation holds that glucocorticoids are covalently bound to lens proteins resulting in destabilization of the protein structure allowing further modification (i.e. oxidation) leading to cataract. Alternative hypotheses (e.g. that cataracts result from glucocorticoid receptor mediated effects) have been difficult to test since protein binding does in fact occur for many cataractogenic steroids. A glucocorticoid lacking the typical glucocorticoid hydroxy group at C21 (fluorometholone, FML), other steroids which can bind to proteins but lack glucocorticoid activity, and a glucocorticoid antagonist (RU486) have been utilized to discriminate between these two hypotheses. Purified bovine beta-crystallin incubated with three different 3H-steroids, dexamethasone (Dex), aldosterone or progesterone demonstrated that the C-21 hydroxyl group is not essential for steroid binding. Progesterone (with no C-21 OH) bound to the greatest extent. Pretreatment of the protein with aspirin to acetylate the free protein amino groups blocked this binding, demonstrating the probability of a Schiff base mechanism. Lens culture studies with the same three radiolabeled steroids demonstrated much the same result. Rat lenses cultured for 48 hr-11 days, demonstrated that loss of GSH is an early and significant effect of several glucocorticoids (Dex, prednisolone and FML) but is not seen with other non-glucocorticoid steroids. However, none of the steroids tested consistently produced lenticular opacification (i.e. cataracts) in this in vitro system, nor did they alter rubidium transport. We suggest that a mechanism other than covalent binding of steroids to lens proteins is responsible for glucocorticoid induced cataracts because: (1) non-glucocorticoids were demonstrated to bind lens proteins as well or better than the glucocorticoid Dex and (2) only glucocorticoids, and not other steroids, lowered lens reduced glutathione content which has been demonstrated to be associated with other forms of cataract.
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PMID:Steroid-induced cataract: new perspective from in vitro and lens culture studies. 946 84

Injection of acetaminophen (APAP) (350 mg/kg body weight) into C57BL/6 mice in which cytochrome P450 (CYP) 1A1/1A2 had been induced produced acute cataract and other ocular tissue damage. Treatment of APAP-injected mice with one of the major organosulfides in garlic oil, diallyl disulfide (DADS) (200 mg/kg body weight), prevented cataract development and prolonged survival time. N-acetyl L-cysteine (NAC) (500 mg/kg body weight), a prodrug that stimulates glutathione synthesis, also prolonged survival time but was effective only weakly to prevent cataract formation. A combination of DADS and NAC completely prevented cataractogenesis, and all of the treated animals survived APAP toxicity. Neither DADS nor NAC inhibited CYP 1A1/1A2 induction as determined by their effect on the induction of hepatic microsomal ethoxyresorufin O-dealkylase (ERD) activity. However, in the in vitro enzyme assay, DADS, but not NAC, was a potent inhibitor of ERD activity (IC50 = 3.5 mM). Treatment with DADS or NAC slowed but did not stop the decrease of hepatic glutathione (GSH) content. At 4 hours after APAP injection, hepatic GSH began to increase only when DADS and NAC were administered together. These results suggest that the protective effect of DADS is due to its inhibition of biotransformation of APAP to the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI) by CYP 1A1/1A2 enzymes and that NAC provides protection by increasing cellular cysteine level and GSH synthesis, thus facilitating detoxification of NAPQI by glutathione conjugation. Assay of plasma glutamate-pyruvate transaminase activity, an indicator of liver necrosis, showed that treatment with DADS and NAC together effectively protected the liver. Therefore, the decrease of GSH as much as 30% of normal concentration, by itself, is not responsible for liver damage. The primary cause of hepatic necrosis is rapid accumulation of NAPQI.
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PMID:Prevention of acetaminophen-induced cataract by a combination of diallyl disulfide and N-acetylcysteine. 971 38

There is strong evidence to show that diabetes is associated with increased oxidative stress. However, the source of this oxidative stress remains unclear. Using transgenic mice that overexpress aldose reductase (AR) in their lenses, we found that the flux of glucose through the polyol pathway is the major cause of hyperglycemic oxidative stress in this tissue. The substantial decrease in the level of reduced glutathione (GSH) with concomitant rise in the level of lipid peroxidation product malondialdehyde (MDA) in the lens of transgenic mice, but not in the nontransgenic mice, suggests that glucose autoxidation and nonenzymatic glycation do not contribute significantly to oxidative stress in diabetic lenses. AR reduction of glucose to sorbitol probably contributes to oxidative stress by depleting its cofactor NADPH, which is also required for the regeneration of GSH. Sorbitol dehydrogenase, the second enzyme in the polyol pathway that converts sorbitol to fructose, also contributes to oxidative stress, most likely because depletion of its cofactor NAD+ leads to more glucose being channeled through the polyol pathway. Despite a more than 100% increase of MDA, oxidative stress plays only a minor role in the development of cataract in this acute diabetic cataract model. However, chronic oxidative stress generated by the polyol pathway is likely to be an important contributing factor in the slow-developing diabetic cataract as well as in the development of other diabetic complications.--Lee, A. Y. W., Chung, S. S. M. Contributions of polyol pathway to oxidative stress in diabetic cataract. FASEB J. 13, 23-30 (1999)
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PMID:Contributions of polyol pathway to oxidative stress in diabetic cataract. 987 26

Human age-related nuclear cataract is associated with progressive and widespread oxidation of proteins, particularly in the centre of the lens. The reasons for the onset of cataract and why this disease should take place only in the lenses of older individuals remain unclear. However, a common feature of nuclear cataract is the low concentration of reduced glutathione (GSH) in the centre of the lens. GSH is the principal lenticular antioxidant of the lens and it is synthesized and regenerated in the lens cortex. In this study we investigated the diffusion of glutathione within the human lens as a function of age. Normal human lenses were incubated in artificial aqueous humor containing [35S]cysteine and the label was metabolically incorporated into GSH. After 48-h incubation, lenses were sectioned and phosphorimaging was used to determine the distribution of 35S label. In young lenses, label appeared to diffuse uniformly throughout the whole lens. By contrast, in lenses over the age of 30, very little 35S had penetrated to the centre of the lens. A distinct zonal pattern of label distribution was noted in the older lenses after 48 h incubation, which had dimensions of approximately 7.2 mm (diameter) by 2.8 mm (axial). In some older lenses this pattern was noticeable even after 96-h incubation. Thus a barrier to the diffusion of GSH was observed in older normal lenses which was not present in younger lenses. Furthermore, the internal zone thus delineated has dimensions that coincide with those of the coloured and sclerotic zone present in nuclear cataract lenses. Since nuclear cataract is a disease of the elderly, and maintenance of GSH is known to be vital for lens clarity, we propose that the development of a barrier to the movement of GSH from its site of synthesis and regeneration in the cortex, into the nucleus in older normal lenses, may over time allow oxidative modification of protein to take place in the nucleus, resulting ultimately in nuclear cataract.
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PMID:An impediment to glutathione diffusion in older normal human lenses: a possible precondition for nuclear cataract. 987 21

It has previously been shown that TEMPOL, n-propyl gallate and deferoxamine, compounds that limit the availability of Fe+2 and prevent the generation of hydroxyl radicals, protect cultured rabbit lens epithelial cells from H2O2-induced damage. In view of the importance of glutathione as an antioxidant and the decrease in GSH that is known to accompany most forms of cataract, we investigated whether these compounds protected cultured lens epithelial cells from H2O2 when the cells were artificially depleted of glutathione. Treatment of lens epithelial cells with 1-chloro-2,4-dinitrobenzene (CDNB), a compound that irreversibly binds to glutathione, or buthionine sulfoximine (BSO), an inhibitor of glutathione biosynthesis, reduced the glutathione content to an average of 15-20% of the control values without a concomitant increase in oxidized glutathione. Morphological changes were assessed by phase contrast and electron microscopy. In order to assess growth, cells in 5 ml serum-free MEM were exposed to an initial concentration of 0. 05 mm H2O2 (for 50,000 cells) or 2 doses of 0.5 mm H2O2 (for 800,000 cells). After exposure to H2O2, medium was replaced with MEM plus 8% rabbit serum; cells were fed on days 3 and 6 and counted on day 7. When 50,000 or 800,000 cells with decreased glutathione were exposed to 0.05 or 0.5 mm H2O2 the H2O2 was cytotoxic, whereas cells treated with H2O2 alone remained viable but showed inhibited proliferation. An unexpected finding was that cells continued to remove H2O2 from the medium at normal rates even when the GSH level was reduced. Cells treated with CDNB or BSO alone exhibited morphological and growth properties comparable to untreated cells. Cells treated with CDNB or BSO and then with H2O2 exhibited decreased cell-to-cell contact, nuclear shrinkage, and arborization when viewed with phase-contrast microscopy and showed extensive nuclear and cytoplasmic degeneration at the EM level. Cell death was determined by dye exclusion and confirmed by video microscopy. When cells were treated with CDNB or BSO and subsequently treated with TEMPOL, n-propyl gallate or deferoxamine and then challenged with H2O2 cytotoxicity was prevented and the cells were capable of growth. The data show that H2O2 was not lethal to glutathione-depleted lens epithelial cells when they were treated with compounds that prevented the generation of reactive oxygen species. In addition, the results indicate that GSH has an important protective role independent of its ability to decompose H2O2 via glutathione peroxidase.
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PMID:Protection from oxidative insult in glutathione depleted lens epithelial cells. 998 49

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