Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Among aging disabilities, the one associated with the progressive decline of vision is functionally most disadvantageous. Cataracts are one of the more common causes of such visual disability. Several predisposing factors have been identified in the genesis of this disease. While it is perhaps a multifactorial process, significant developments have taken place in recent years suggesting that oxygen radicals are involved in the development of this aging manifestation. Antioxidant enzymes, such as catalase and superoxide dismutase, have been demonstrated to protect the lens cell membrane from oxidative stress as reflected by the prevention of the Na(+)-K(+)-ATPase-dependent pump deterioration due to oxyradical-dependent oxidation of its proteins and lipids. From the nutritional point of view, antioxidants such as ascorbate and vitamin E also offer significant protection to the lens against damage due to oxidative stress. Evidence regarding the protective effect of these nutrients has been based on lens organ culture studies in the presence of active oxygen, generated photochemically as well as enzymatically. The experiment involving photochemical environs simulate the status of the eye during the photopic vision. In vivo, the effectiveness of ascorbate against cataracts has been tested in rat pups developing cataracts under the oxidative influence of sodium selenite. Certain antioxidants produced metabolically also may be useful in protecting against cataracts. Pyruvate produced in glucose metabolism seems to be an important antioxidant. The efficacy of this compound has been tested within in vitro organ culture as well as in vivo, the latter experiments being done with selenite-treated rats. There is a hope that these and other nutritional and metabolic antioxidants may one day be useful in delaying or even preventing cataract formation in human beings.
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PMID:Prevention of cataracts by nutritional and metabolic antioxidants. 774 71

It has been reported that antipsychotic drugs such as phenothiazine derivatives, dibenzyl derivatives and others with calmodulin antagonism induce cataracts, which are generically called phenothiazine-induced cataracts. In the ophthalmologic field, the mechanism of cataractogenesis by such drugs is a problem urgently requiring a solution. This paper reports the relationship between the properties of such drugs and cataract formation. In this experiment, phenothiazine derivatives (chlorpromazine, trifluoperazine, prochlorperazine and perphenazine), dibenzyl derivatives (imipramine and amitriptyline), and other drugs (cyproheptadine and calmidazolium) were investigated. As a result, it was clarified that phenothiazine derivatives and calmidazolium have high lipophilicity, strong inhibition activity against phosphodiesterase, and a large permeability constant, and that those drugs induce high levels of Ca2+ accumulation in the lens. It was also revealed that those drugs were distributed only at the peripheral region of the lens after they had penetrated into the lens. From these findings, we inferred that the cataract formation may be caused by lens protein aggregation followed by the inactivation of calmodulin-dependent Ca-ATPase and subsequent Ca2+ accumulation in the lens. Furthermore, we have been convinced that it is necessary to lower at least the lipophilicity of these drugs to suppress the side effect of antipsychotic drugs inducing cataractic formation.
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PMID:The relationship between properties of antipsychotic drugs and cataract formation. 791 71

In 743 cases, the TCM and WM susceptible factors of senile cataract (SC) was studied by the clinical epidemiological investigation. By single factor analysis, the result showed that in WM, the susceptible factors of SC mostly related to (1) case history: coronary heart disease, old ages, smoking, multiple offsprings; (2) physical sign: short build, with coronary sulcus, higher systolic pressure, pulse pressure and average arterial pressure; (3) cardiovascular function: abnormal EKG, higher heart beat index, short microcirculatory stasis time, lower carrier viscosity of blood; (4) dysfunction of brain; (5) deficiency of pulmonary function; (6) lower RBC ATPase, higher whole blood reduction viscosity. While in TCM, it was related to (1) old aged and general asthenia, (2) deficiency of Qi, Heart, Liver or Kidney, (3) Blood Stasis. By stepwise regression analysis, the result showed that SC occurred through the combination with 13 factors of TCM and WM, including Yin Deficiency, senility index, hemorheology index, brain function, pulmonary function, blood pressure, body height, character, optical fundus, etc.
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PMID:[Investigation on traditional Chinese medicine and Western medicine susceptible factors on senile cataract]. 795 Feb 14

We used an animal model of hypocalcemic cataract to investigate the changes of the cation levels and the Ca2+ pump (Ca(2+)-ATPase) function in the lens. Wistar rats (4 weeks old) were fed with a low calcium and no vitamin D3 diet. After 4 weeks on this diet, anterior subcapsular cataract was recognized, when calcium concentration in the aqueous humor and serum had significantly decreased. Calcium content in the lens decreased and sodium content increased. Ca(2+)-ATPase activity detected by [gamma-32P] ATP assay did not show significant change. We concluded that cataract during the early stage of hypocalcemia is caused by membrane damage with low calcium level in the aqueous humor and sodium content increase in the lens. We also studied the ultracytochemical localization of Ca(2+)-ATPase activity and found it in the plasma membrane of the lens epithelium and cortex and also in the epithelium organelles.
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PMID:[Ca(2+)-ATPase activity in the hypocalcemic cataract]. 810 58

The excised rat crystalline lens opacified when incubated aerobically with phenazine methosulfate, but no opacification was observed under anaerobic conditions. Morphological studies revealed development of opacification in the cortex. The opacification resembled that often seen in the early period of senile cataract as well as in naphthalene-induced and UV cataract. Both an increase in hydration and in electrolyte imbalance accompanied this opacification. Na,K-ATPase activity of the opacified lens was found to decrease. In order to investigate if activated oxygen is involved in these processes, we conducted an electron spin resonance study by means of a spin trapping technique. When the lens homogate was incubated with phenazine methosulfate, OH radicals were generated under aerobic but not under anaerobic conditions. Reduced pyridine nucleotides must be involved in the process, because the mixture of nicotinamide adenine dinucleotide phosphate [NAD(P)] and phenazine methosulfate did not generate OH radicals, but the mixture of NAD(P)H and phenazine methosulfate generates OH radicals, indicating that reduced phenazine methosulfate was involved in the OH radical generation. Probably, the generated OH radicals inactivated Na,K-ATPase residing in the epithelium of the lens, which eventually caused opacification of the lens. The present experiment system may be used for the elucidation of lens opacification (cataract) involved with reactive oxygen species.
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PMID:Reactive oxygen species involved in phenazine-methosulfate-induced rat lens opacification. An experimental model of cataract. 813 88

It was reported previously that dietary ascorbate (ASC) delays the development of galactose-induced cataract in guinea pigs compared to the rate which is observed in ASC-deficient animals. Experiments were conducted to explore the possible mechanism of this phenomenon. Guinea pigs were fed for a period of up to 4 weeks either a normal diet (1 g ASC/kg diet) or a scorbutic diet (< 0.04 g ASC/kg diet) combined with 10% galactose in the drinking water. After 2 weeks, levels of ASC in animals on the scorbutic diet decreased by 95% in the aqueous humor and by 78% in the lens. Slit lamp examination showed that galactose-induced vacuoles in the lens equator formed at a significantly faster rate in the scorbutic animals. However, examination of biochemical parameters in whole lenses of the two groups of animals after 2 weeks showed no significant differences with regard to accumulation of galactose and galactitol, decreases in the levels of myoinositol, taurine and GSH or changes in cation concentrations. In order to examine possible regional changes in the lenses, various parameters were studied in the lens capsule-epithelium. On day 4, the capsule epithelia of scorbutic animals on a galactose diet had a content of galactitol two-and-a-half times higher than that of normal galactose-fed animals. Scorbutic conditions also intensified the loss of Na(+)-K+ ATPase activity in the lens capsule-epithelium caused by galactose feeding. Oxidized glutathione was not detectable in the lens capsule epithelia of any of the animals studied. Hexose monophosphate shunt activity was elevated in lenses of normal galactose-fed animals during the first hour of culture after death whereas lenses of scorbutic galactose-fed animals were not. Consistent with the in vivo findings, galactitol accumulation in dog lens epithelial cells exposed to 30 mM galactose was significantly inhibited by the presence of either ASC or dehydroascorbate (DHA) in the medium. Hexose monophosphate shunt activity in the cells was stimulated to two-and-a-half times its initial level by either 1 mM DHA or 30 mM galactose and slightly more than three-fold by a combination of the two challenges. The results suggest that decreased polyol accumulation in the lens epithelium of the normal galactose-fed guinea pig, which has a high level of ASC in the aqueous humor, accounts for the delay in onset of cataract compared to that for the ASC-deficient animal.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:A physiological level of ascorbate inhibits galactose cataract in guinea pigs by decreasing polyol accumulation in the lens epithelium: a dehydroascorbate-linked mechanism. 815 13

Aldose reductase is a rate limiting enzyme in the polyol pathway associated with the conversion of glucose to sorbitol. The enzyme is located in the eye (cornea, retina, lens), kidney, myelin sheath, and also in other tissues less involved in diabetic complications. Experiments in diabetic animals have implicated sorbitol accumulation in the lens to the development of cataracts. The use of inhibitors of aldose reductase in animal studies has demonstrated that diabetic complications such as cataracts, nephropathy, and slowing of nerve conduction can be ameliorated. While an osmotic effect can explain the physical changes in the lens leading to cataract formation, the effect of sorbitol accumulation in other tissues and the resulting diabetic complications has been linked to the depletion of myoinositol content resulting in a derangement of sodium-potassium adenosine triphosphatase activity. Since glucose and other hexoses are poor substrates for aldose reductase, it is only in hyperglycemia when the enzyme hexokinase is saturated that aldose reductase is activated, leading to accumulation of sorbitol. The kinetics of inhibition of aldose reductase by a variety of inhibitors has been delineated. The dose required varies from inhibitor to inhibitor and is consistent with their inhibition constants. Toxicity is a consideration in the use of some of the inhibitors, as was demonstrated with sorbinil which caused hypersensitivity reactions in 10 percent of patients. Other inhibitors such as tolerant have shown efficacy and are under clinical investigation. Interpretation of results obtained with aldose reductase inhibitor therapy in human subjects suggest that these inhibitors are effective at early stages of diabetic complications.
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PMID:Aldose reductase and its inhibition in the control of diabetic complications. 845 42


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