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

---

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

Impaired pancreatic duct secretion is frequently observed in insulin-dependent diabetes mellitus (IDDM), although the cellular mechanism(s) of dysfunction remains unknown. Studies in other tissues have suggested that a hyperglycemia-induced decrease in Na, K-ATPase activity could contribute to the metabolic complications of IDDM and that increased polyol metabolism is involved in this response. The present studies examined the effects of glucose on Na, K-ATPase activity and on expression and activity of aldose reductase (AR), a primary enzyme of polyol metabolism, in Capan-1 human pancreatic duct cells. Increasing medium glucose from 5.5 to 22 mM caused a 29% decrease in Na,K-ATPase activity. The decrease was corrected by 100 microM sorbinil, a specific AR inhibitor. Increasing glucose from 5.5 to 110 mM also resulted in concentration-dependent increases in AR mRNA and enzyme activity that could be resolved into two components, one that was glucose specific and observed at pathophysiological concentrations (< 55 mM) and a second that was osmotically induced at high concentrations (> 55 mM) and which was not glucose specific. The present study demonstrates that pathophysiological levels of glucose specifically activate polyol metabolism with a consequent decrease in Na,K-ATPase activity in pancreatic duct epithelial cells, and that this response to hyperglycemia could contribute to decreased pancreatic secretion observed in IDDM. This is the first report of AR regulation in the pancreatic duct epithelium.
...
PMID:Glucose-specific regulation of aldose reductase in capan-1 human pancreatic duct cells In vitro. 931 66

FK506 (tacrolimus), a potent immunosuppressant, is used for inhibiting allograft rejection in the organ transplantation field. In a preclinical toxicity study in rats, FK506 induced various toxicities, including renal and pancreatic injuries. One of these toxic findings was cataract, and we have found that cataract appeared in rats dosed orally with FK506 for 13 weeks and more. Therefore, to better elucidate the onset mechanism of FK506-induced cataract, we measured biochemical parameters, such as sorbitol, Na,K-ATPase and glutathione in the lens of rats. Rats were dosed with FK506 in oral daily doses of 0.2, 1 or 5 mg/kg for 13 weeks, the lowest dose of which approximated the expected clinical dosage. Cataract developed in the 5-mg/kg/day group, with an incidence of 25%, whereas no cataract formation was observed in the 0.2- or 1-mg/kg/day groups. Five mg/kg/day led an increase of sorbitol and a decrease of reduced type glutathione, but did not affect Na,K-ATPase activity of the lens. FK506 is known to have diabetogenicity mediated through pancreatic injury, which appears as vacuolation of islet cell in rats. Five mg/kg/day of FK506 induced an elevation of blood glucose associated with glucose intolerance, and decrease of both basal insulin level and insulin content in the pancreas, and the changes were in parallel with the cataract development in the present study. On the other hand, diabetic parameters did not change in the 0.2- or 1-mg/kg/day groups. These observation suggest that diabetes developed in the rats dosed with 5 mg/kg/day of FK506. Coadministration of a novel aldose reductase inhibitor, Zenarestat, at an oral dose of 50 mg/kg/day resulted in a reduction of incidence of the FK506-induced cataract and a decrease of sorbitol levels in the lens when compared to that in the lens of rats dosed with 5 mg/kg/day of FK506. These results suggest that FK506-induced cataract in rats is due to an accumulation of sorbitol in the lens, secondary to the diabetogenic effect of FK506. FK506 treatment at the doses of 0.2 and 1 mg/kg/day neither affected parameters indicative of diabetes nor induced cataract in rats, suggesting that the cataract would not develop with FK506 if diabetic parameters were kept under control.
...
PMID:Cataract development induced by repeated oral dosing with FK506 (tacrolimus) in adult rats. 935 35

Cisplatin is the most active anticancer agent for lung cancer. It has been reported that intracellular accumulation of cisplatin is important in determining resistance to cisplatin, which may be modulated by Na+, K(+)-ATPase activity. On the other hand, it is well-known that sorbitol, a metabolite of glucose mediated by aldose reductase, reduces Na+, K(+)-ATPase in diabetic neuropathy. In this study, the effect of exogenous sorbitol on Na+, K(+)-ATPase activity and sensitivity to cisplatin was evaluated using human non-small-cell lung cancer (NSCLC) cell lines. In the NSCLC cell lines, EBC-1, PC-3, and RERF-LC-MS the cytotoxicities of cisplatin were impaired by exposure to sorbitol in these cell lines. Na+, K(+)-ATPase was inactivated and intracellular accumulation of cisplatin was decreased by the exposure. These results suggest that accumulation of sorbitol may induce resistance to cisplatin in NSCLC cells, and diabetes poorly controlled may be one of the determinants of the antitumor effect of cisplatin in NSCLC.
...
PMID:Exposure to sorbitol induces resistance to cisplatin in human non-small-cell lung cancer cell lines. 941 70

Long-term prospective studies comparing the effects of conventional and intensive insulin therapy have linked diabetic hyperglycemia to the development of diabetic retinopathy, nephropathy, and neuropathy. The mechanisms through which glucose metabolism leads to the development of these secondary complications, however, are incompletely understood. In animal models of diabetic neuropathy, the loss of nerve function in myelinated nerve fibers has been related to a series of biochemical changes. Nerve glucose, which is in equilibrium with plasma glucose levels, rapidly increases during diabetic hyperglycemia because glucose entry is independent of insulin. This excess glucose is metabolized in large part by the polyol pathway. Increased flux through this pathway is accompanied by the depletion of myo-inositol, a loss of Na/K ATPase activity and the accumulation of sodium. Supportive evidence linking these biochemical changes to the loss of nerve function has come from studies in which aldose reductase inhibitors block polyol pathway activity, prevent the depletion of myo-inositol and the accumulation of sodium and preserve Na/K ATPase activity, as well as nerve function. The kidney and red blood cells (RBCs) are two additional sites of diabetic lesions that have been reported to develop biochemical changes similar to those in the nerve. We observed that polyol levels in the kidney cortex, medulla, and RBCs increased two- to ninefold in rats following 10 weeks of untreated diabetes. Polyol accumulation was accompanied by a 30% decrease in myo-inositol levels in the kidney cortex, but no change in RBCs or the kidney medulla. Na/K ATPase activity was decreased by 59% in RBCs but was unaffected in the kidney cortex or medulla. Aldose reductase inhibitor treatment that preserved myo-inositol levels, Na/K ATPase, and conduction velocity in the sciatic nerve also preserved Na/K ATPase activity in RBCs. Our results suggest that the pathophysiologic mechanisms underlying diabetic neuropathy are different from those of diabetic nephropathy. Our results also suggest that RBCs maybe a surrogate tissue for the assessment of diabetes-induced changes in nerve Na/K ATPase activity.
...
PMID:Effect of the aldose reductase inhibitor tolrestat on nerve conduction velocity, Na/K ATPase activity, and polyols in red blood cells, sciatic nerve, kidney cortex, and kidney medulla of diabetic rats. 961 71

Motor and sensory nerve conduction velocities (MNCV and SNCV) were reduced in the sciatic nerve of rats after 4 weeks of untreated streptozotocin-induced diabetes, and declined further during the following 4 weeks. Treating diabetic rats with the novel peptide HP228 had no effect on the decline of MNCV after the first 4 weeks of diabetes but attenuated the decline in SNCV. HP228 treatment also prevented any further decline in MNCV or SNCV between weeks 4 and 8 of diabetes. Consequently, at the conclusion of the study, the nerve conduction velocities (NCVs) in treated rats were significantly (both P < .001) higher than in untreated diabetic rats. Reduced nerve homogenate Na+,K+-adenosine triphosphatase (ATPase) activity in diabetic rats was significantly (P < .05) increased by HP228 but remained significantly (P < .05) lower than in untreated controls. HP228 treatment also reduced nerve Na+,K+-ATPase activity of control rats compared with untreated controls (P < .05). There was no effect of HP228 on the hyperglycemia, nerve polyol accumulation, myo-inositol depletion, reduced nerve laser Doppler blood flow, thermal hypoalgesia, or reduced mean axonal caliber in diabetic rats or on any of these parameters in control rats. These data demonstrate that a novel peptide may protect against the slowing of nerve conduction in prolonged diabetes and that the mechanism of action is unrelated to aldose reductase inhibition, prevention of nerve ischemia, or axonal atrophy. HP228 may prove a potential therapeutic agent for the treatment of prolonged diabetic neuropathy.
...
PMID:Effects of the peptide HP228 on nerve disorders in diabetic rats. 962 61

Oxidative damage, through increased production of free radicals, is believed to be involved in UV-induced cataractogenesis (eye lens opacification). The possibility of UVB radiation causing damage to important lenticular enzymes was assessed by irradiating 3 months old rat lenses (in RPMI-1640 medium) at 300 nm (100 microWcm(-2)) for 24 h, in the absence and presence of ascorbic acid, alpha-tocopherol acetate and beta-carotene. UVB irradiation resulted in decreased activities of hexokinase, glucose-6-phosphate dehydrogenase, aldose reductase, and Na, K- ATPase by 42, 40, 44 and 57% respectively. While endopeptidase activity (229%) and lipid peroxidation (156%) were increased, isocitrate dehydrogenase activity was not altered on irradiation. In the presence of externally added ascorbic acid, tocopherol and beta-carotene (separately) to the medium, the changes in enzyme activities (except endopeptidase) and increased lipid peroxidation, due to UVB exposure, were prevented. These results suggest that UVB radiation exerts oxidative damage on lens enzymes and antioxidants were protective against this damage.
...
PMID:Protection against UVB inactivation (in vitro) of rat lens enzymes by natural antioxidants. 1039 Nov 22

Streptosotocin-induced diabetes in rats is accompanied by the development of diabetic complications such as neuropathies. [2-14C]serotonin and [U-14C]GABA release from the neurotransmitter pre-loaded synaptosomes showed significant elevation. Aldose reductase inhibitors (AL-1576, sorbinil) administration leads to partial restoration of serotonin and GABA release, while picamilon restored only GABA release. It was shown that Na+,K(+)-ATPase activities decreased in synaptosomes, synaptic membranes and sciatic nerve of diabetic rats compared to control. Administration of AL-1576 normalized Na+, K(+)-ATPase activity, while sorbinil and picamilon less effectively. Sorbitol level are increased in streptozotocin-diabetic rats as compared to control. The picamilon and aldose reductase inhibitors administration to diabetic rats is accompanied by the partial reduction of brain sorbitol level. The findings confirm the important role of picamilon and aldose reductase inhibitors in the prevention and treatment of diabetic neuropathy.
...
PMID:[Correction of diabetic neuropathies using aldose reductase inhibitors and pikamilon]. 1059 42

This study was designed to evaluate the changes and the role of lens epithelium in sugar cataract formation, in regard to the fact that the highest level of aldose reductase is found in this layer of lens. By light and electron microscopy, we examined the histological changes of central epithelium in lens of rats made diabetic with streptozotocin (STZ) with or without AL1576, an aldose reductase inhibitor, at varying periods of time ranging from 5 to 40 days after intraperitoneal injection of STZ. Also, we examined Na-K-ATPase activity in lens epithelium of rats with diabetes, diabetes plus AL1576 and normal controls at the time of 30 days. The results showed that the first detectable abnormalities occurred after 15 days of STZ injection and were limited to the lens epithelium; cell edema, intracellular vacuoles and extention of rough endoplasmic reticulum pool were remarkable; that AL1576 could prevent almost all of the lesion mentioned above; and that Na-K-ATPase activity in lens epithelium of rats with diabetes increased at the time of 30 days. The findings suggest that lens epithelium may play an important role in sugar cataractogenesis.
...
PMID:[The role of lens epithelium in cataract formation in diabetic rats]. 1068 12

To investigate the characteristic features of diabetic neuropathy in type 2 diabetes mellitus, Otsuka Long-Evans Tokushima fatty (OLETF) rats, an animal model of human type 2 diabetes mellitus, and non-diabetic Long-Evans Tokushima Otsuka (LETO) rats were fed with or without sucrose and/or an aldose reductase inhibitor, [5-(3-thienyl) tetrazol-1-yl] acetic acid (TAT), for 24 weeks, and physiological, biochemical and morphological assessments were performed. Sucrose administration caused remarkable hyperglycemia in OLETF rats but not in LETO rats. Sucrose-fed OLETF rats demonstrated delayed nerve conduction velocity, decreased coefficient of variation of R-R interval, reduced sciatic nerve blood flow, increased platelet aggregation activity, a lower concentration of erythrocyte 2,3-diphosphoglycerate, and decreased Na+/K+-ATPase activity in sciatic nerves, compared with the non-sucrose-fed OLETF and LETO rats. TAT prevented all these deficits except hyperglycemia. Sorbitol and fructose accumulation and myo-inositol depletion in tail nerves of sucrose-fed OLETF rats were ameliorated by TAT. Myelinated fiber size and density in sural nerves of sucrose-fed OLETF rats were decreased and increased, respectively, compared with non-sucrose-fed OLETF and LETO rats. These morphological abnormalities were normalized by TAT. These observations suggest that the sucrose-fed OLETF rat developed diabetic neuropathy not only electrophysiologically but also histologically, and that an aldose reductase inhibitor, TAT, possesses therapeutic value for the treatment of diabetic neuropathy.
...
PMID:Physiological and morphometric analyses of neuropathy in sucrose-fed OLETF rats. 1113 77

A protein isolated from goat testis cytosol is found to inhibit Na+,K+-ATPase from rat brain microsomes. The inhibitor has been purified by ammonium sulphate precipitation followed by hydroxyapatite column chromatography. The purified fraction appears as a single polypeptide band on 10% SDS-PAGE of approximate molecular mass of 70 kDa. The concentration at which 50% inhibition (I50) occurs is in the nanomolar range. The inhibitor seems to bind Na+,K+-ATPase reversibly at ATP binding site in a competitive manner with ATP, but away from ouabain binding site. It does not affect p-nitrophenyl-phosphatase activity. The inhibitor is found to inhibit the phosphorylation step of the Na+,K+-ATPase. The enhancement of tryptophan fluorescence and changes in CD pattern suggest conformational changes of Na+,K+-ATPase on binding to the inhibitor. Amino acid sequence of the trypsinised fragments show some homology with aldehyde reductase.
...
PMID:Purification, characterization and partial amino acid sequencing of a 70 kD inhibitor protein of Na+,K+-ATPase from goat testis cytosol. 1168 23


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---