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PubMed2006

The unfolded protein response in lens epithelial cells from galactosemic rat lenses.

PURPOSE: Diabetic complications are associated with hypoglycemia and hyperglycemia. The purpose of this study was to investigate the effect of both glucose deprivation and hyperglycemia on the induction of endoplasmic reticulum (ER) stress and the subsequent activation of the unfolded protein response (UPR) that results in apoptosis in in vitro cultured lens epithelial cells (LECs) and in vivo cataract formation in galactose-fed rats. METHODS: Lenses from rats fed a standard diet containing 50% galactose with or without an aldose reductase inhibitor (ARI) were investigated. Transformed human LECs were cultured in standard 10% FCS-DMEM containing various concentrations of sugar. UPR-specific proteins from both the rat lenses and lens cultures were quantified by protein blot analysis. Cell death was evaluated with TUNEL staining and ethidium homodimer-1 (EthD) dyes. Reactive oxygen species (ROS) were quantified with H2-DCF, and free glutathione (GSH) levels were measured with a commercial GSH quantification kit. RESULTS: Increased apoptosis of the LECs was observed in the lenses of rats fed the galactose diet for 5 to 9 days, and nuclear cataracts subsequently developed in these lenses after 13 to 15 days. Protein blot analysis of the LECs from these galactose-fed rats showed higher levels of the UPR-specific proteins Bip/GRP78, ATF4, and CHOP. These LECs also demonstrated activation of the UPR-specific procaspase-12 and the increased presence of ROS, whereas GSH was reduced. Because these results indicate that the UPR is activated in LECs along with the production of ROS and apoptosis during cataract formation in the galactose-fed rats, subsequent studies were conducted to determine the role of nonenzymatic glycation, osmotic stress, and oxidative stress on these biochemical processes. In vitro cultures of human LECs showed that the UPR was induced by osmotic and oxidative stress, but not by glycation. In addition, the UPR and apoptosis in LECs was induced by glucose deprivation. The ARI blocked the induction of the UPR, cell death, and cataract formation. CONCLUSIONS: The UPR that is induced by abnormally high or low concentrations of sugar is linked to the production of ROS, increased apoptosis in LECs, and cataract formation. The inhibition of the UPR induction by ARI suggests that osmotic stress may be the primary inducer of the UPR. Modulation of the UPR pathways may offer novel methods for the development of therapeutic tools to delay cataracts.

Activating Transcription Factor 4↗
PubMed1969

Galactose-1-phosphate uridyltransferase and galactokinase activity in cultured human diploid fibroblasts and peripheral blood leukocytes. I. Analysis of transferase genotypes by the ratio of the activities of the two enzymes.

The specific activities of galactokinase and galactose-1-phosphate uridyltransferase were determined in peripheral blood leukocytes directly after separation from whole blood, and in cultured skin fibroblasts at various times during the subculture growth period. Growth curves were obtained for fibroblasts based on three different parameters: direct cell counts, total protein, and total deoxyribonucleic acid (DNA) content. At the time in culture when the specific activity of both enzymes was maximal and least variable, the ratio of transferase to galactokinase correlated well with the transferase genotypes of the original tissue donors. Leukocyte transferase: galactokinase ratios gave a similar distribution pattern. Whereas transferase activity in both fibroblasts and leukocytes was similar, galactokinase was approximately three times as active in fibroblasts as in leukocytes. All fibrobast cell strains tested had similar galactokinase activity regardless of transferase genotype.The kinetic properties of fibroblast galactokinase were examined. Galactose-1-phosphate inhibits galactokinase activity in both normal and galactosemic cell strains, whereas other glycolytic intermediates have no effect. There was no detectable transferase activity in eight galactosemic (Gt(G)/Gt(G)) cell strains when transferase activity was maximal in cell strains of other transferase genotypes. Inhibitors responsible for the absence of transferase activity could not be demonstrated. In addition, transferase activity in galactosemic cell lysates was not observed in cells during logarithmic growth; measurable uridine diphosphate galactose (UDPgal) pyrophosphorylase activity was found in human diploid fibroblast cultures, as well as significant levels of endogenous uridine triphosphate (UTP) in lysates of fibroblast cultures.

Black People↗
PubMed1978

Quantitative estimation of clinically important monosaccharides in plasma by rapid thin layer chromatography.

A method is described for the quantitative estimation of clinically important monosaccharides in plasma or whole blood by direct densitometry of chromatographically-separated zones on silica gel layers. Simple modifications of technique originally introduced to improve the reproducibility of paper chromatography have now been adapted for thin layers. The present method is based on peak height measurement with an internal marker correction. Galactose, fructose, D-xylose, and 3-O-methyl glucose can be estimated in addition to glucose, either singly or in combination, within three or four hours, using an initial sample volume of 0.5 ml. With reasonable experience and skill a coefficient of variation of 3 to 6%, depending on sugar concentration, can be achieved without replication, and the limit of sensitivity is about 0.05 mmol/l. When the performance was compared with an automated glucose oxidase/peroxidase system for glucose and the recovery for the other monosaccharides was calculated, the results were satisfactory.

Blood Glucose↗
PubMed1987

Galactosaemia.

This paper reviews galactosaemia and describes the experience of the Willink Biochemical Genetics Unit in the management of classical galactosaemia. Galactokinase and UDPgalactose-4-epimerase deficiency are dealt with briefly. The former disorder is readily treated with a galactose free diet and if this is started early in life, the only complication, cataracts, is avoided. Epimerase deficiency is a relatively 'new' disorder and little is known about the eventual outcome of affected patients. Early observations suggest that the prognosis is likely to be poor even in those patients diagnosed and treated soon after birth. Classical galactosaemia leads to a number of long term complications. The prognosis for normal mental development in affected patients is poor. Unfortunately this does not appear to be reversible by early diagnosis and treatment and whilst every effort should be made to establish an early diagnosis our experience suggests that there is no difference in the ultimate mental development between those who are detected within the first two weeks of life and those before the age of six weeks. In addition female homozygotes are at a very high risk of developing ovarian failure at an early age.

Female↗
PubMed1982

Health economic analysis of the Swedish neonatal metabolic screening programme. A method of optimizing routines.

A benefit-cost analysis was carried out to optimize the routines for neonatal metabolic screening. The basis of the study was provided by results of the Swedish neonatal screening programme from 1965 to 1979. During this period over one million infants were screened by the Guthrie test for phenylketonuria and galactosaemia, and for limited periods also for tyrosinaemia, homocystinuria and histidinaemia. The benefit-cost ratio was calculated for combinations of different screening tests, recall routines, and varying degrees of coverage. The largest benefit-cost ratio was obtained with combined screening for phenylketonuria and galactosaemia, using a borderline blood phenylalanine level of 0.50 mmol/L in the Guthrie test for phenylketonuria. However, the inaccuracy of this test necessitated the use of a lower blood phenylalanine level of 0.25 mmol/L and the acceptance of a lower benefit-cost ratio. An increase in the present 98% coverage of newborns by the screening programme was found to be an effective means of improving the benefit-cost ratio in the present programme.

Amino Acid Metabolism, Inborn Errors↗
PubMed1975

Arylsulfatase B deficiency in Maroteaux-Lamy syndrome: Cellular studies and carrier identification.

Arylsulfatase B deficiency was demonstrated in peripheral leukocytes, cultured skin fibroblasts, and a lymphoid line derived from a patient with MLS. The patient's parents demonstrated levels of arylsulfatase B that were intermediate between those found in patient and those in control subjects. The activity (mean plus or minus SD) in leukocytes from normal subjects, the patient's parents, and the patient was 113.7 plus or minus 36.2, 31.0, and 5.2 nmol 4-nitrocatechol/mg protein/hr, respectively. In skin fibroblasts of the same subjects the activity was 145.2 plus or minus 41.6, 58.5, and 7.0, respectively. Nine other lysosomal enzymes were normal in skin fibroblasts of the patient. No arylsulfatase B activity was detected in a lymphoid line established from the patient with MLS. The arylsulfatase B activity in cultured amniotic fluid cells from 10 normal pregnancies was 203.2 plus or minus 49.9.

Amniotic Fluid↗
PubMed1977

The activity of galactose-1-phosphate uridyltransferase and galactokinase in human fetal organs.

The activity of galactose-1-phosphate uridyltransferase (transferase) and galactokinase in several organs from human fetuses 7-28 weeks old was measured by using radioactive substrates and column chromatography for product identification. The specific activity of transferase and galactokinase increased with gestational age and reached, at the 28th week, a maximal level of 30.0 and 7.9 nmol/min/mg protein (units) in liver, 4.7 and 2.5 units in kidney, 6.0 and 4.0 units in lung, 6.7 and 2.9 units in spleen, 5.2 and 2.6 units in cardiac muscle, and 4.0 and 1.4 units in skeletal muscle, respectively. The activity in brain, on the other hand, remained quite constant with 1.2 units in the case of transferase and 0.5 units in the case of galactokinase during this period. The activities of both enzymes in the liver of children were slightly lower than the highest fetal level during the period of pregnancy studied. Galactokinase activity in fetal erythrocytes was approximately 4 times higher and the transferase activity approximately 30% higher than in adults. The Km value of fetal liver transferase for galactose-1-phosphate was found to be 0.330-0.357 mM and that of galactokinase for galactose, 0.265-0.277 mM.

Child↗
PubMed1988

Galactose, glucose, and lactate concentrations in the portal venous and arterial circulations of newborn lambs after nursing.

We have used the newborn lamb prepared with chronic indwelling catheters to study carbohydrate metabolism in the unstressed, postprandial state. Lambs were fasted 5 h and then allowed to nurse ad libitum from their mothers for 20 min. Serial determinations of whole blood galactose, glucose, and lactate concentration were then made from the portal venous and arterial circulations. Portal venous galactose concentration increased significantly after milk ingestion, but arterial galactose concentration did not increase from baseline unless the portal venous galactose concentration exceeded 10-12 mg/dl suggesting a threshold effect for hepatic galactose clearance. Glucose concentration increased significantly in both circulations with portal venous galactose concentration greater than arterial galactose concentration in all cases. Galactose and glucose were absorbed from the intestine at approximately equal rates. Lactate was not absorbed into the portal venous circulation to any great extent after lactose ingestion.

Animals↗
PubMed1992

Regional activity of galactose-1-phosphate uridyltransferase in rat brain.

The sp act of galactose-1-phosphate uridyltransferase has been measured in individual regions of adult rat brain to see if site-specific differences in enzyme activity can aid in the understanding of brain abnormalities observed in well-treated galactosemic patients. The sp act in the cerebellum, brain stem, and midbrain were higher than in the cortex, hippocampus, and striatum. Activity in the cerebellum was 2-fold greater than that found in the cortex. Steady state levels of mRNA of the enzyme in the cerebellum were twice that of the cortex corresponding to the ratio of enzyme sp act in the two regions. Measurement of the kinetic parameters in tissue from the cerebellum and cortex revealed that the regional specificity in enzyme activity observed in the brain represents differences in the Vmax. Inhibition of the enzyme by uridine and uridine triphosphate was essentially the same for all regions and was not influenced by the 2-fold differences observed in the levels of enzyme. Inhibition by uridine was significantly greater than that for uridine triphosphate.

Animals↗