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Biomedical subjects

A Cerami

Publications and source records attributed to A Cerami.

At least 325 records · Page 18Linked to original sources
PubMed1977

Structure of carbohydrate of hemoglobin AIc.

Hemoglobin AIc is a minor component of normal adult erythrocytes whose concentration is elevated approximately 2-fold in patients with diabetes mellitus. Previous work suggested that the unique structural feature of hemoglobin AIc is the presence of a low molecular weight sugar moiety at the NH2-terminal valine of the beta chain. In this study the structure of the carbohydrate moiety and the nature of its linkage of the beta chain were investigated. Enzymatic digestion of borohydride-reduced betaAIc chains followed by ion exchange chromatography led to the isolation of two distinct NH2-terminal glycovalylhistidines. Comparison of these glycodipeptides with synthetic glycovalylhistidines by thin layer chromatography, gas-liquid chromatography, and proton magnetic resonance spectroscopy gave direct evidence that the naturally derived materials correspond to glucitol and mannitol valylhistidines. Model reactions showed that glucose and mannose react with valine under mild conditions to form an adduct which upon sodium borohydride reduction yields in both cases glucitol and mannitol valines. This suggests a common intermediate, 1-deoxy-1-(N-valyl)fructose, for both reactions. From these studies we conclude that hemoglobin AIc has, as the NH2 terminus of the beta chain, 1-deoxy-1-(N-valyl)fructose. The possible biosynthetic pathways of hemoglobin AIc are discussed.

Adult↗
PubMed1977

Nonenzymatic glycosylation of hemoglobin.

The incubation of dialyzed hemoglobin A with a number of phosphorylated glycolytic intermediates leads to the formation of covalent hemoglobin adducts that co-chromatograph with hemoglobin AIb. Phosphorylated hexoses (glucose-6-P, fructose-6-P, fructose-1,6-P2) and trioses (glyceraldelyde-3-P, dihydroxyacetone-P) containing a free aldehyde or ketone can glycosylate hemoglobin A nonenzymatically. From 7 to 12% of the hemoglobin can be modified after a 72-h incubation of an equimolar mixture of hemoglobin A and the phosphorylated intermediate. No significant formation of adduct was seen with a sugar alone (glucose, fructose) or glycolytic intermediate which had a blocked aldehyde (glucose-1-P, glucose-1,6-P2, UDP-glucose). The addition of an equimolar amount of 2,3-diphosphoglycerate reduced adduct formation. Evidently, the phosphate is needed to orient and stabilize the intermediate in the bisphosphoglycerate pocket of hemoglobin so that the addition reaction can proceed. All of the hemoglobin A adducts were indistinguishable form hemoglobin AIb by ion exchange chromatography and isoelectric focusing. The hemoglobin A-glucose-6-P adduct and hemoglobin AIb had a NaB3H4-reducible linkage in the beta chain. The concentration of hemoglobin AIb is elevated in patients with diabetes mellitus. This presumably reflects the increased concentrations of glycolytic intermediates (glucose-6-P, fructose-6-P, fructose-1,6-P2, dihydroxyacetone-P) which were found to be significantly elevated in the red cells of diabetic patients as compared with normal controls.

Adult↗
PubMed1977

Correlation of serum triglyceride levels and hemoglobin AIc concentrations in diabetes mellitus.

Studies in 10 nonketotic diabetic subjects (five juvenile- and five adult-onset) before and after control of carbohydrate metabolism showed a high degree of correlation between hemoglobin AIc (HbAIc) concentrations and serum triglyceride levels. Serum triglyceride levels were found to correlate more closely with Hb AIc (r = 0.91, p less than 0.001) than did serum cholesterol (r = 0.47, p greater than 0.05), thus indicating a more direct relationship to carbohydrate metabolism.

Adult↗
PubMed1976

Correlation of glucose regulation and hemoglobin AIc in diabetes mellitus.

We studied the increased levels of hemoglobins AIa+Ib and AIc in five hospitalized diabetic patients to determine whether changes in diabetic control would cause parallel changes in the levels of these hemoglobins. Before control of diabetes the mean fasting blood sugar for all patients was 343 mg per deciliter (range, 280 to 450), and hemoglobin AIc concentration 9.8 per cent (range, 6.8 to 12.1). During optimal diabetic control the blood sugar concentration was 84 mg per deciliter (range, 70 to 100), and hemoglobin AIc concentration 5.8 per cent (range, 4.2 to 7.6). Hemoglobin AIc concentration appears to reflect the mean blood sugar concentration best over previous weeks to months. The periodic monitoring of hemoglobin AIc levels provides a useful way of documenting the degree of control of glucose metabolism in diabetic patients and provides a means whereby the relation of carbohydrate control to the development of sequelae can be assessed.

Adult↗
PubMed1976

Inhibition of membrane peroxidation in thalassaemic erythrocytes by 2,3-dihydroxybenzoic acid.

Both iron and precipitated haemoglobin may catalyse the formation of free radicals, which in turn react with the polyunsaturated fatty acids of membranes leading to membrane failure and cell death. 2,3-Dihydroxybenzoic acid (2,3-DHB), a recently identified, orally effective iron-chelating drug, inhibited membrane peroxidation in vitro in H2O2-stressed erythrocytes from patients with beta-thalassaemia major, beta-thalassaemia intermedia, haemoglobin Köln disease and sickle cell disease. We present evidence suggesting that the inhibition of peroxidation is due to ability of 2,3-DHB to scavenge free radicals via quinone formation, a mechanism analogous to that proposed for vitamin E.

Cell Membrane↗
PubMed1976

Chelation studies with 2,3-dihydroxybenzoic acid in patients with beta-thalassaemia major.

2-3-Dihydroxybenzoic acid was evaluated as a potentially useful, orally effective iron-chelating drug by performing iron balance studies in patients with beta-thalassaemia major. The administration of this substance at 25 mg/kg/d to five patients for 8 d caused an average increase in iron excretion of 4.5 mg/d. When the drug was administered at 25 mg/kg q.i.d. to eight patients for 21 d, iron excretion increased to 6.5 mg/d. Chelation was highly specific for iron with changes in magnesium and calcium excretion being insignificant. The drug was well tolerated with side effects limited to gastrointestinal complaints which ameliorated when the drug was taken with food. These studies provide a rationale for further evaluation of 2,3-dihydroxybenzoic acid in patients with iron overload.

Administration, Oral↗
PubMed1976

The use of chang cells cultured in vitro to evaluate potential iron chelating drugs.

A number of iron chelating agents, consisting largely of hydroxamic acid and benzoic acid derivatives, have been studied in an in vitro Chang cell culture system to determine their effect on cellular iron uptake, ferritin synthesis and the incorporation of iron into ferritin. The results have been compared with those of a previous study in which iron balance was determined in hypertransfused rats. Both techniques appear to be of value in screening new iron chelating agents for potential therapeutic use in patients with iron overload.

Benzoates↗
PubMed1976

Increased hemoglobin AIc in diabetic mice.

The minor hemoglobins AIa, AIb, and AIc were studied in mice with either genetic or chemically induced diabetes. Hemoglobin AIc was elevated approximately twofold in all the phenotypically diabetic mice studied (C57BL/KsJ-db/db, C57BL/KsJ-ob/ob, C57BL/6J-db/db, and alloxan- and streptozotocin-treated mice). Elevation of the hemoglobin AIc in C57BL/6J-db/db mice was of short duration, reflecting the transitory diabetes characteristic of these mice. The degree of increase of hemoglobin AIc levels was unrelated to severity of hyperglycemia, duration of diabetes, age of mouse, or body weight. It is not known what factor(s) dictates the steady-state concentration of hemoglobin AIc.

Age Factors↗
PubMed1976

Hemoglobin AIc as an indicator of the degree of glucose intolerance in diabetes.

Hemoglobin AIc concentration, fasting blood sugar, response to an oral glucose tolerance test, and skeletal muscle capillary basement membrane thickness were measured in diabetic patients. Hemoglobin AIc concentration correlates with both response to a glucose tolerance test (r = 0.82, p less than 0.001) and fasting blood sugar (r = 0.62, p less than 0.001). The correlation of hemoglobin AIc concentration with glucose tolerance is independent of fasting blood sugar concentration (partial r = 0.61, p less than 0.005), whereas that of hemoglobin AIc with fasting blood sugar probably reflects the relationship between fasting blood sugar levels and glucose tolerance (partial r = 0.22, p less than 0.05). Hemoglobin AIc levels do not correlate with basement membrane thickness ( r = 0.15, p less than 0.05).

Basement Membrane↗
PubMed1976

The effect of chelating agents on iron mobilization in Chang cell cultures.

The investigation of chelating agents with potential therapeutic value in patients with transfusional iron overload has been facilitated by the use of Chang cell cultures. These cells have been incubated with [59Fe]transferrin for 22 hr, following which most of the intracellular radioiron is found in the cytosol, distributed between a ferritin and a nonferritin form. Iron release from the cells depends on transferrin saturation in the medium, but when transferrin is 100% saturated, which normally does not allow iron release, desferrioxamine, 2,3-dihydroxybenzoic acid, rhodotorulic acid, cholythydroxamic acid, and tropolone all promote the mobilization of ferritin iron and its release from cells. They are effective to an approximately equal degree. The incubation of [59Fe]transferrin with tropolone in vitro at a molar ratio of 1:500 results in the transfer of most of the labeled iron to the chelator, reflecting the exceptionally high binding constant of this compound. How far these phenomena relate to therapeutic potentially remains to be seen.

Anemia, Hypochromic↗
PubMed1976

The development of new iron-chelating drugs.

2,3-Dihydroxybenzoic acid has been identified as a potentially useful iron-chelating drug. Accordingly, we have evaluated a series of derivatives of hydroxylated benzoic acids for their ability to induce iron excretion in the iron-overloaded rat. In addition, we have examined a number of hydroxamic acids and some other naturally occurring iron-chelating agents. Of the 26 benzoic acid derivatives studied, none appeared to be more effective than 2,3-dihydroxybenzoic acid, for reasons which are discussed. Rhodotorulic acid, a hydroxamic acid produced by and isolated from cultures of Rhodotorula pilimanae, was the most effective of all the compounds studied in inducing iron excretion. When administered parenterally, rholotorulic acid induced iron excretion via both the urinary and the fecal routes and was more than twice as potent (on a weight basis) as desferrioxamine. Two ferrous chelators, alpha, alpha-dipyridyl ad 1,10-phenanthroline, induced a moderate amount of iron excretion, suggesting that a pool of ferrous iron may be available for chelation.

Animals↗