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At least 1,333 records · Page 74Linked to original sources
PubMed1984

Carbohydrate composition of erythrocyte membranes and glycosidase activities in serum in patients with myotonic dystrophy, limb-girdle dystrophy and congenital myotonia.

A number of abnormalities in cell membrane function, including cells other than muscle cells, have been described in patients with inherited muscular diseases such as myotonic dystrophy and congenital myotonia. The basic molecular defects are, however, still unknown. The complex carbohydrates of membrane-bound glycoconjugates are of vital importance for the normal performance of the cell membrane. In this study the concentrations of the three major carbohydrates (sialic acid, galactose and hexosamines) of the erythrocyte membrane were therefore determined in patients with myotonic dystrophy, limb-girdle dystrophy and congenital myotonia. The activities of relevant glycosidases in serum were also assayed. In each of the three diseases pertinent changes of the carbohydrate pattern were found. In patients with myotonic dystrophy the sialic acid and in patients with limb-girdle dystrophy the hexosamine concentration was significantly reduced (P less than 0.0005). The sialic acid, galactose and hexosamine concentrations were all significantly increased in patients with congenital myotonia. No increase of the neuraminidase (sialidase) activity was found in sera from patients with myotonic dystrophy. In patients with limb-girdle dystrophy, the activities of serum hexosaminidases were normal. These results support the contention that certain inherited muscular diseases may represent generalized membrane disorders, and suggests that disturbances of membrane-bound glycoproteins and/or glycolipids might be of importance in the pathogenesis of some of these disorders.

Acetylglucosaminidase↗
PubMed1983

Estimates and implications of co-operativity for enzyme kinetics in the intact liver: method of flow invariants.

For substrates rapidly equilibrated between blood and liver cells, steady-state co-operative enzyme kinetics determines combinations of inlet and outlet substrate concentrations which do not change with the rate of blood flow recirculating through an isolated perfused liver. The mathematical forms of these combinations (here called flow invariants) are different for each value of the Hill co-operativity constant which can therefore be estimated, on a set of intact perfused preparations, from that flow invariant which is stochastically least dependent on experimental changes in the flow rate. This estimate, made in a narrow range of substrate concentrations, is illustrated using previously published data on the phosphorylation of galactose by galactokinase in rat liver. Changes (if any) of hepatocellular Hill constants in liver disease could be of clinical interest. A conspicuous difference between effects of negative and positive cooperativity in the intact perfused organ is found: for negative (but not for positive) co-operativity, complete extraction of the substrate in a single pass through a shunt-free liver is predicted from Hill's equation for a specified range of finite input concentrations and flow rates. Substrates with negative co-operativity in vivo would therefore facilitate the quantification of intrahepatic shunts.

Animals↗
PubMed1979

CP-45,634: a novel aldose reductase inhibitor that inhibits polyol pathway activity in diabetic and galactosemic rats.

In some tissues containing aldose reductase, increased flux through the polyol pathway has been implicated as being causative in diabetic complications (e.g., cataracts, peripheral neuropathy). We have found CP-45,634 (d-6-fluoro-spiro[chroman-4,4'-imidazolidine]-2',5'-dione) to be a highly potent, structurally novel, uncompetitive inhibitor of calf lens aldose reductase (IC50 approximately 5 X 10(-7)M). In a system in which sorbitol accumulation in isolated rat sciatic nerves was monitored in the presence of high (50 mM) glucose concentrations, CP-45,634 produced inhibition of polyol accumulation at levels as low as 1 X 10(-6)M. To determine if in vitro activity would translate to in vivo models, sorbitol accumulation in rat sciatic nerves was measured 27 hr after induction of diabetes with streptozotocin. Orally administered CP-45,634 was effective at dose levels as low as 0.25 mg/kg, t.i.d., and at 0.75 mg/kg produced an 85% inhibition of sorbitol accumulation. Two weeks after induction of diabetes by streptozotocin, sorbitol levels in rat lens and the sciatic nerve rose to 21,203 nmole/gm and 1,161 nmole/gm, respectively. Subsequent oral administration of CP-45,634 (2.5 mg/kg, b.i.d.) for 1 wk reduced these levels by 92% in nerves and 90% in lenses. In galactosemic rats, CP-45,634 inhibited the rise in lens galactitol and effectively delayed cataract formation at oral doses as low as 5 mg/kg/day. These high levels of in vivo activity suggest that CP-45,634 has potential for assessing the role of the polyol pathway in diabetic complications.

Aldehyde Reductase↗
PubMed1984

The effects of aldose reductase inhibition on nerve sorbitol and myoinositol concentrations in diabetic and galactosemic rats.

The interrelationship between sorbitol excess and myoinositol deficiency in the peripheral nerve was examined in acutely diabetic rats. Nerve myoinositol concentration was also studied in galactosemic rats. Polyol pathway blockade with Sorbinil (Pfizer, Connecticut) prevented nerve myoinositol reduction in both groups of animals. This conclusion was independent of alteration in the fluid content of the peripheral nerve. It is likely that myoinositol loss from nerves is causally related to the sorbitol and galactitol accumulation.

Aldehyde Reductase↗
PubMed1986

Aldose reductase activity and basement membrane thickening.

Rats fed a high-galactose diet develop marked thickening of their retinal capillary basement membranes. The effect is prevented if the animals also receive the aldose reductase inhibitor sorbinil. The effect does not appear to be due to aldose reductase itself, since immunoreactive aldose reductase has not been found in the retinal microvasculature of the rat but rather to a related enzyme with similar substrate specificity. The detailed biochemical mechanism for basement membrane thickening is obscure, involving an alteration of the extracellular matrix, where aldose reductase and similar enzymes have not been described; osmotic damage to the microvascular cells, such as has been described following aldose reductase-induced sugar alcohol accumulation in lens epithelial cells, is not apparent in diabetic or galactosemic animals. It is possible that concentrations of intracellular sugar alcohols that do not substantially change the osmolarity of the cell cytosol alter intracellular enzyme activities. This, in turn, could affect the biosynthesis of extracellular matrix macromolecules, as suggested, for example, by the hypothesis of Rohrbach et al, based on studies of a basement membrane-producing tumor implanted in diabetic mice, which proposes that the hyperglycemia of diabetes mellitus causes a reduced synthesis of the heparan sulfate BM-1 proteoglycan with a subsequent overproduction of type IV collagen. This and other hypotheses of basement membrane thickening can be tested in diabetic or galactosemic rats, some of which receive aldose reductase inhibitors, or in retinal microvascular pericytes and endothelial cells grown in culture.

Aldehyde Reductase↗
PubMed1990

Vascular filtration function in galactose-fed versus diabetic rats: the role of polyol pathway activity.

These studies were undertaken to assess the effects of increased galactose (v increased glucose) metabolism via the polyol pathway on vascular filtration function in the kidneys, eyes, nerves, and aorta. Quantitative radiolabeled tracer techniques were used to assess glomerular filtration rate (GFR) and regional tissue vascular clearance of plasma 131I-bovine serum albumin (BSA) in five groups of male Sprague-Dawley rats: nondiabetic controls, streptozotocin-diabetic rats, nondiabetic rats fed a 50% galactose diet, diabetic rats treated with sorbinil (an aldose reductase inhibitor), and galactose-fed rats treated with sorbinil. Sorbinil was added to the diet to provide a daily dose of approximately .2 mmol/kg body weight. After 2 months of diabetes or galactose ingestion, albumin clearance was increased twofold to fourfold in the eye (anterior uvea, choroid, and retina), sciatic nerve, aorta, and kidney; GFR was increased approximately twofold and urinary excretion of endogenous albumin and IgG were increased approximately 10-fold. Sorbinil treatment markedly reduced or completely prevented all of these changes in galactose-fed, as well as in diabetic rats. These observations support the hypothesis that increased metabolism of glucose via the sorbitol pathway is of central importance in mediating virtually all of the early changes in vascular filtration function associated with diabetes in the kidney, as well as in the eyes, nerves, and aorta. On the other hand, renal hypertrophy in diabetic rats and polyuria, hyperphagia, and impaired weight gain in galactose-fed and in diabetic rats were unaffected by sorbinil and therefore are unlikely to be mediated by increased polyol metabolism.

Animals↗
PubMedDate not supplied

Sugar metabolism in the crystalline lens.

Research on the sugar metabolism of the crystalline lens, past and preent, is reviewed. The chief energy source in the lens is the Embden-Meyerhof pathway; respiration and oxidative phosphorylation become more important as the lens ages. The function of the alpha-glycerophosphate cycle is not fully understood. The mechanisms involved in cataract formation, including those of hypoglycemic cataract and osmotic cataracts, are discussed. Sugar cataracts can be delayed or prevented with such aldose reductase inhibitors as flavonoids. By inhibiting aldose reductase, the formation and accumulation of sugar alcohols is stopped. This approach may be useful as a medical therapy for human diabetic senile cataracts.

Aldehyde Reductase↗
PubMed1990

Proteins of slow axonal transport in sciatic motoneurones of rats with streptozotocin-induced diabetes or galactosaemia.

This study examined the distribution of axonally transported tubulin and a 68 kDa polypeptide in the sciatic nerve 34 days after injection of labelled methionine into the ventral horn of the spinal cord of control rats, rats with streptozotocin-induced diabetes mellitus and rats fed a diet containing 40% galactose. The proteins were separated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) of pellets produced by treatment of nerve extracts with Triton X-100 followed by differential ultra-centrifugation. The most marked effect of both diabetes and galactosaemia was to reduce the amount of activity present in tubulin transported at a rate of 1.4 to 2.1 mm/day. The distribution of activity in the 68 kDa polypeptide band was not markedly affected by either of the experimental conditions. These findings, taken together with those of other studies, indicate that the polyol pathway may contribute to the development of some defects of nerve function in diabetic rats, but is uninvolved in others.

Animals↗
PubMed1983

Galactosaemia and major burn--a case report.

The management of burns in an adult patient with galactosaemia is described and the problem of lactose-containing drugs in this condition highlighted. The unique problem of hypokalaemia is discussed. Small amounts of lactose contained in various oral drugs which the patient received over a prolonged period caused proximal renal tubular dysfunction. This, combined with the tendency of potassium loss in major burns, resulted in severe hypokalaemia, in spite of large amounts of potassium supplements being given. This case history also supports the view that lactose restriction in patients with galactosaemia should be total and lifelong.

Adolescent↗
PubMed1995

Purification method for alpha-1-acid glycoprotein with subsequent high-performance liquid chromatographic determination of monosaccharides in plasma of healthy subjects and patients with renal insufficiency.

A simple purification method for human plasma alpha-1-acid glycoprotein (AAG) using an ion-exchange and hydroxyapatite column was developed. The recovery of the method was found to be high. We also improved a determination method for N-acetylneuraminic acid and monosaccharides in the carbohydrate moiety of AAG by using an ion-exchange column and pulse-amperometric detection. By this method, a composition analysis of the carbohydrate moiety of AAG (N-acetylneuraminic acid, fucose, N-acetyl glucosamine, galactose and mannose) was possible with 1.0 ml of plasma. We compared these carbohydrate concentrations in the AAG of patients with renal insufficiency with those of healthy subjects. In the AAG of the patients, the concentrations of N-acetylglucosamine, galactose and mannose were significantly higher than those in the AAG of the healthy subjects.

Acetylglucosamine↗
PubMed1995

Galactose biosensors using composite polymers to prevent interferences.

A biosensor using a composite polymer to prevent interferences was used in a flow injection analysis system for the detection of galactose in human plasma. The biosensor consisted of galactose oxidase immobilized on a platinized carbon electrode that had been modified with a composite polymer. The composite polymer showed improved selectivity to hydrogen peroxide compared with either of its individual polymeric components, Nafion and a copolymer of diaminobenzene and resorcinol. The composite polymer minimized the effect of possible interference from urate, ascorbate, and acetaminophen. This analytical system had a minimum detection limit of 50 microM, linearity to 6 mM, a storage stability of greater than 30 days, and a high sample throughput (approx. 120 samples/h).

Biosensing Techniques↗
PubMedDate not supplied

Tolrestat pharmacokinetics in rat peripheral nerve.

The clinical efficacy of an aldose reductase (AR) inhibitor in diabetic polyneuropathy depends on its bioavailability at the site(s) of AR in peripheral nerves. Accordingly, the link between the concentration of the AR inhibitor, tolrestat, and the extent of its inhibition of the AR-catalyzed polyol production was investigated in sciatic nerves of galactosemic rats. Tolrestat was administered by gavage (1 x 150 mg/kg, or 5, and 15 mg/kg/day for 15 days to attain steady state as estimated from the 53-h half-life of tolrestat determined in rat nerve); subsequently, at six time intervals, ranging from 4 to 59 days, rats were given access for 4 days to a 20% galactose diet, and killed. At every time point, the composite tolrestat concentration in the nerve correlated with the percentage decrease in nerve galactitol (r = 0.857, p = 0.0015). Because the latter should reflect the extent of nerve AR inhibition by tolrestat, the concentration of "free" tolrestat available at the site(s) of AR in the nerve was estimated from the tolrestat concentration/percent AR inhibition plot obtained in vitro. The estimated amount of tolrestat present at the site(s) of nerve AR represented 0.4% of the composite tolrestat concentration measured in the nerve. The results support the view that the effectiveness of an AR inhibitor in peripheral nerve depends on its pharmacokinetics in the nerve, i.e., on its uptake, nonspecific binding to cellular constituents, and elimination.

Administration, Oral↗