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)

Hydrogen peroxide (H2O2) is implicated in human cataract development. At the molecular level H2O2 has been observed to cause damage to DNA, protein and lipid. It is now demonstrated, for the first time in a lens system, that H2O2 at concentrations found in cataract patients induces expression of both c-jun and c-fos. At optimal concentrations of H2O2, mRNA accumulation of c-jun and c-fos in the rat lenses is induced 20- and 18-fold above normal levels respectively, but with distinct kinetics. This induction occurs at the transcriptional level. H2O2 also induces transactivation by activating protein-1 (AP-1) in rabbit lens epithelial cells. The antioxidant N-acetyl-cysteine (NAC) has a dual effect on the induction of c-jun and c-fos. Preincubation of rat lenses with 5 mM NAC inhibits the induction by H2O2, while 30 mM and 50 mM NAC induce expression of these genes and mask the H2O2 effect. H7 (50 microM), genistein (2 microM) and okadaic acid (20 nM), all block the induction of c-jun and c-fos mRNA accumulation in the H2O2-treated rat lenses. These results suggest that H2O2 activates protein kinase and phosphatase dependent signal transduction pathways to induce c-jun and c-fos expression which may regulate lens crystallin genes and other genes containing AP-1 binding sites.
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PMID:The redox active components H2O2 and N-acetyl-L-cysteine regulate expression of c-jun and c-fos in lens systems. 783 7

Hydrogen peroxide, in concentrations of 10-1000 microM, produces two major changes in the current-voltage relationships associated with the equatorial potassium current of the lens. First, the resting and reversal potentials become more negative than they were prior to treatment with hydrogen peroxide and second, the membrane resistance related to the equatorial current is decreased. The shift in the resting and reversal potentials is in the opposite direction from that produced by ouabain. Based on the Nernst equation, the shift in the reversal potential suggests that there is an increase in the concentration of potassium in the lens. The 86Rb uptake and efflux are increased. These observations suggest that hydrogen peroxide stimulates the Na,K-pump. The decrease in membrane resistance is inhibited by 100 microM of quinine, a calcium-dependent potassium channel blocker, and does not decrease in a calcium-free medium. This suggests that the decrease in resistance may be secondary to an increase in lenticular calcium. These effects of hydrogen peroxide are similar to those of p-chloromercuriphenylsulfonate (pCMPS), a nearly impermeant sulfhydryl binding agent, and suggest that permeant hydrogen peroxide may increase calcium influx by acting on sulfhydryl groups on the outer surface of lens membranes. Verapamil, a calcium channel blocker, is reported to prevent cataract formation. D600, the methoxy analogue of verapamil, is a calcium channel blocker that increases the resistance associated with the equatorial current in the presence and absence of hydrogen peroxide. The gadolinium ion has a similar effect. Thus, D600 and Gd3+ partially counteract the reduction in membrane resistance produced by 50 microM hydrogen peroxide.
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PMID:Effects of hydrogen peroxide oxidation and calcium channel blockers on the equatorial potassium current of the frog lens. 817 48

Isolated rat lenses were exposed to oxidative stress generated by 100 microM H2O2, 2 mM ADP and 100 microM ferrous ammonium sulfate. Oxidation-induced cataract formation was followed by measuring loss of transmitted light intensity using quantitative digital image analysis, which offers distinct advantages over conventional photography. In the presence of oxidants, total and average light transmitted by the lens decreased exponentially as a function of time; the cortex showing a greater rate of decline in transmitted light intensity than the nucleus, which led to a change in the distribution pattern of light intensity. Lenses developing oxidative cataracts also showed a significant increase in diameter and an increase in the total wet weight. Maximal increase in lens diameter preceded maximal decrease in light intensity. These studies demonstrate the utility of quantitative image analysis in studying changes in lens geometry and transparency, and suggest that cataract formation is a single rate process.
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PMID:Digital image analysis of cultured rat lens during oxidative stress-induced cataractogenesis. 828 24

Lipid peroxidation (LPO) could be one of the mechanisms of cataractogenesis, initiated by enhanced production of oxygen free radicals in the eye fluids and tissues and impaired enzymatic and non-enzymatic defences of the lens. The increased concentrations of primary molecular LPO products (diene conjugates, lipid hydroperoxides) and end fluorescent LPO products were detected in the lipid moiety of the aqueous humor samples obtained from patients with cataract as compared to normal donors. Isolated human transparent and cataractous lenses and normal mouse and rabbit lenses were incubated with liposomes in organ culture in the presence and absence of LPO inhibitors, free radical scavengers and enzymes (catalase, superoxide dismutase (SOD)) in order to examine the potential of the lenses to induce LPO in the surrounding medium. LPO assayed spectrophotometrically were diene and triene conjugates, and malonaldehydes (MDA) were determined as thiobarbituric acid-reactive material. A chemiluminescence detection catalysed by peroxidase was used to measure H2O2 and O2-. was assayed spectrophotometrically using cytochrome C reduction. The level of lipid peroxides in liposomes was significantly (2.5-4.5-fold) higher after 3 h of incubation of the transparent lenses (or the lenses at the initial stage of cataract) than after the proper time of incubation of human mature cataractous lenses and virtually no oxidation of liposomes was detected in the absence of the lens. LPO in this system was decreased in the presence of free radical scavengers and enzymes that degrade H2O2 (EDTA, SOD, L-carnosine, chelated iron and catalase). The most effective agent was EDTA which chelates the free metal cations required to generate O2-. radicals that initiate the free radical process culminating in LPO. Lenses generated more H2O2 into the medium in the presence of exogenous ascorbate. Release of the oxidants, (O2-., H2O2, OH. and lipid hydroperoxides) by the intact lenses in the absence of respiratory inhibitors indicates that these metabolites are normal physiological products inversely related to the lens life-span potential (maturity of cataract) generated, probably, through the metal-ion catalysed redox-coupled pro-oxidant activation of the lens reductants (ascorbic acid, glutathione).
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PMID:Lipid peroxide and reactive oxygen species generating systems of the crystalline lens. 831 81

The purpose of these experiments was to examine the relationship between oxidation cataract and proteolysis in cultured rat lens. Hydrogen peroxide cataract showed insolubilization of protein, loss of 31 kDa beta B1-crystallin polypeptide, decreases in soluble calpain, and increases in insoluble calpain. This suggested that calpain may be activated in hydrogen peroxide treated lenses, since beta B1 is a known calpain substrate, and calpain undergoes autolysis and degradation when activated. Furthermore, the cysteine protease inhibitor E64 was partially effective in preventing development of H2O2-cataract. E64 also prevented the loss of the 31 kDa beta B1-crystallin polypeptide and decreased the loss of calpain in the lens. These results suggested that development of hydrogen peroxide induced cataract in rat lenses was associated with activation of calpain.
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PMID:Role of calpain in hydrogen peroxide induced cataract. 831 93

Oxidative stress is known to cause cataracts in lens culture systems and is believed to be an important factor contributing to human cataracts. In this communication, it is demonstrated that cataract development of cultured rat lenses produced as a result of photochemically induced oxidation in a 4% oxygen atmosphere similar to the native environment of the lens can be blocked by the transition metal complex AL-3823A. In this system, riboflavin is added to the medium as a photosensitizer. AL-3823A acts primarily as a glutathione peroxidase mimic, which catalytically metabolizes H2O2 and also has low superoxide dismutase-like activity. Measurements of H2O2, O2.-, and OH. indicate that appreciable levels of the first two of these oxidants and low levels of OH. are produced by this photochemical stressing system. The H2O2 concentrations are similar to those found in some patients with cataracts. The development of cataracts was followed over a 96-hr period. Transparency, hydration, glyceraldehyde-3-phosphate dehydrogenase activity, and protein and nonprotein thiol were monitored. All parameters show marked changes during the 96-hr period. However, in the presence of 200 microM AL-3823A, no difference between control and light-exposed lenses was observed with respect to these parameters. The results suggest that in vivo human cataract development caused by oxidative stress may be prevented by compounds of this type.
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PMID:Photochemically induced cataracts in rat lenses can be prevented by AL-3823A, a glutathione peroxidase mimic. 835 43

H2O2 stress is shown to produce cataract in cultured rat lenses. The loss of transparency begins in the equatorial region within 24 hours and the entire superficial cortex is opaque by 96 hours. No involvement of the nuclear region is observed. However after an additional 48 hours, the nuclear region becomes opaque. The loss of transparency is accompanied by a large uptake of H2O which occurs gradually over the 96 hour period, complete loss of glyceraldehyde phosphate dehydrogenase (GPD) activity, almost complete loss of non-protein thiol and a slight decrease in protein thiol. Control lenses show no change other than the establishment of a new non-protein thiol base line approximately 60% lower than 0 time levels. The Alcon glutathione peroxidase type mimic, AL-3823A, completely eliminates almost all of the H2O2 induced effects and the lens remains transparent. Utilizing a more severe photochemical model than may be anticipated physiologically with 10 microM riboflavin and exposure to daylight fluorescent lamps, significant concentrations of superoxide and low levels of OH. are produced as well as extraordinarily high concentrations of H2O2 ranging from about 400 to 1000 microM. As with the H2O2 model, opacification begins at the equator but the cataract develops more rapidly, the lens being completely opaque by 68 hours. Hydration, GPD activity, non-protein and protein thiol all decrease more rapidly than in the H2O2 model. AL-3823A prevents loss of transparency until approximately 92 hours and markedly decreases changes in other parameters. At 92 hours, slight loss of transparency is observed. Catalase is somewhat less effective. AL-3823A is shown to also significantly decrease superoxide levels. The marked delay in the onset of changes in lens biochemistry and physiology in the severe photochemical stress model and the maintenance of normal parameters in the H2O2 model in the presence of AL-3823A suggests that such compounds may prevent cataract caused by oxidative stress under physiological conditions.
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PMID:The prevention of cataract caused by oxidative stress in cultured rat lenses. I. H2O2 and photochemically induced cataract. 838 89

Oxidative stress has long been speculated to play an important role in cataractogenesis. In the H2O2-induced cataract model, rat lens showed extensive biochemical damage but very mild morphological changes after being exposed to H2O2 (0.5 mM) for 24 hr in culture. This damage included reduced glutathione (GSH) depletion, protein-GSH mixed disulfide (PSSG) elevation but not protein-protein disulfide (PSSP) formation. In order to understand the role of protein-thiol mixed disulfide formation in relation to the sequence of events during cataract induction, we conducted a long term H2O2 exposure study for up to 96 hr to monitor the dynamic changes in GSH and PSSG levels, the formation of PSSP aggregate, protein solubility, and the progression in lens opacity. Rat lenses were cultured in 0.5 mM H2O2 and harvested at intervals of 24, 48, 72 and 96 hr for the examination of morphological and biochemical changes. Contralateral lenses cultured in H2O2-free media were used as controls. It was found that the lenses had only patchy opacity at the equator after 24 hr, but became hydrated suddenly at 48 hr (31% heavier than the control), with an opacity which involved the entire outer cortical region. By 72 hr incubation, the nucleus was opacified. Lens GSH progressively decreased with time of H2O2 exposure, 40% was lost by 24 hr and over 95% by 48 hr. There was a concomitant elevation of PSSG, 16-fold over the controls by 24 hr and 45-fold by 48 hr followed by a decline to 34-fold after 72 hr. In addition, the level of protein-cysteine mixed disulfide (PSSC) was elevated after 48 hr incubation in H2O2. At this time point, PSSP aggregates began to appear both in water soluble (WS) and urea soluble (US) fractions along with a drastic reduction in protein solubility. Western blot analysis of the protein fractions identified beta and gamma, but not alpha-crystallin in the disulfide-containing aggregates. The lens clarity and biochemical changes partially recovered if the oxidant was removed within 24 hr, indicating a potential therapeutic role for antioxidants. The complete normalization of PSSG level under this recovery condition signifies that cells may have a natural defense system for controlling PSSG elevation.
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PMID:The effect and recovery of long-term H2O2 exposure on lens morphology and biochemistry. 840 82

Porcine and bovine lens GSTs were compared in the stability against various oxidative stress which is a major factor of cataract formation in order to clarify the role of lens glutathione S-transferase (GST) and its relation to cataractogenesis. Class pi porcine lens GST was inactivated reversibly by biological disulfides, cystine and cystamine, and also inactivated by active oxygen species such as O2- generated through xanthine-xanthine oxidase system and H2O2. On the other hand, class mu bovine lens GST was insensitive to such applied oxidative stress. Furthermore, 1,2-naphthoquinone, which is a metabolite of naphthalene and an actual inducer of naphthalene cataract, strongly inactivated porcine lens GST though it did not affect bovine enzyme. Thus, porcine and bovine lens GSTs had different sensitivity to various oxidative stress which could induce cataract formation. The results suggest that the differential expression of GST isozymes among animals may explain the variation in the cataract formation caused by oxidative stress.
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PMID:Difference in glutathione S-transferase response to oxidative stress between porcine and bovine lens. 847 85

To further investigate the role of protein-thiol mixed disulfides in cataractogenesis, an in vitro H2O2 cataract model was used with rat lenses to study the effect of aging, and the dynamic changes in the cortex, nucleus and the lens protein fractions. A group of lenses was exposed to H2O2-containing media (0.6 mM) for 1 to 3 days so that cortical cataract was induced gradually. Another group of lenses was first subjected to H2O2 exposure for one day and then recovered in the oxidant-free media for one or two days. These lenses were examined for the distribution of free glutathione and protein-thiol mixed disulfides (protein-glutathione and protein-cysteine) in the cortical and nuclear regions as well as in the water soluble and water insoluble fractions. Similar to the results reported earlier, the glutathione depletion in the whole lens occurred immediately and extensively during the 3-day H2O2 exposure. This loss was evenly distributed in the cortical and nuclear fractions. The level of protein-glutathione increased rapidly and continued throughout the 3 days. Most of the accumulation was found in the cortex and in both lens protein fractions. The protein-cysteine modification responded more slowly and less to oxidative stress. The delayed formation occurred mainly in the nucleus and in both lens protein fractions. In the recovery group, glutathione depletion was less drastic in the cortical and nuclear regions, but the elevated protein-glutathione in both regions and both protein fractions spontaneously decreased to its respective basal level within 1 day. Protein-cysteine on the other hand remained quite high, and in some cases it continued to rise in the absence of oxidation. Aging showed little effect on the response of rat lenses to oxidative stress. Similar patterns in glutathione and protein-thiol mixed disulfides occurred in both age groups (1, 23 months) and in both chronic oxidative stress and recovery conditions.
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PMID:Further studies on the dynamic changes of glutathione and protein-thiol mixed disulfides in H2O2 induced cataract in rat lenses: distributions and effect of aging. 854 61


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