Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002895 (sickle cell disease)
 11,747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Factors that influence hemoglobin (Hb)A(Ic) synthesis by intact erythrocytes were studied in vitro. After incubation cells were lysed, and hemoglobins were separated by isoelectric focusing on polyacrylamide slab gels and quantitated by microdensitometry. HbA(Ic) increased with time, glucose concentrations (5-500 mM), and incubation temperature (4 degrees -37 degrees C). Low temperatures allowed prolonged incubations with minimal hemolysis. At 4 degrees C HbA(Ic) increased linearly with time for 6 wk; after incubation at the highest glucose concentration, HbA(Ic) comprised 50% of total hemoglobin. Insulin (1 and 0.1 mU/ml) did not affect HbA(Ic) synthesis in vitro. In addition to glucose, galactose and mannose, but not fructose, served as precursors to HbA(Ic). A good substrate for hexokinase (2-deoxyglucose) and a poor hexokinase substrate (3-O-methylglucose), were better precursors for HbA(Ic) synthesis than glucose, suggesting that enzymatic phosphorylation of glucose is not required for HbA(Ic) synthesis. Autoradiography after erythrocyte incubation with (32)P-phosphate showed incorporation of radioactivity into HbA(Ia1) and A(Ia2), but not HbA(Ib), A(Ic), or A. Acetylated HbA, generated during incubation with acetylsalicylate, migrated anodal to HbA(Ic) and clearly separated from it. Erythrocytes from patients with insulinopenic diabetes mellitus synthesized HbA(Ic) at the same rate as controls when incubated with identical glucose concentrations. Likewise, the rate of HbA(Ic) synthesis by erythrocytes from patients with cystic fibrosis and congenital spherocytosis paralleled controls. When erythrocytes from cord blood and from HbC and sickle cell anemia patients were incubated with elevated concentrations of glucose, fetal Hb, HbC, and sickle Hb decreased, whereas hemoglobins focusing at isoelectric points near those expected for the corresponding glycosylated derivatives appeared in proportionately increased amounts.
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PMID:Synthesis of hemoglobin Aic and related minor hemoglobin by erythrocytes. In vitro study of regulation. 3 12

Butyrate has a dramatic effect on transformed cells in culture. This effect disappears as soon as butyrate is removed from the medium. The other short chain fatty acids are much less effective. Butyrate produces an arrest of cell proliferation at the early G1 phase of the cell cycle. The effect is very general and may be used for cell growth synchronization. This compound increases the expression of the c-fos oncogene and inhibits the expression of c-myc in all phases of the cell cycle. Butyrate modulates the expression of several genes. In general it induces the expression of markers of cell differentiation. Many studies have been devoted to hemoglobin synthesis which is induced in erythroleukemia cells. In general it induces the synthesis of embryonic and of fetal hemoglobin, and delays and even suppresses the switch to adult hemoglobin, which could be useful for the treatment of sickle cell anemia and beta thalassemia. This effect of butyrate seems to require specific DNA regulatory sequences. Butyrate induces the synthesis of alkaline phosphatase, placental and intestinal isozymes, especially in cells where these syntheses are ectopic. It has the same effect on peptidic hormone syntheses and also on receptors of thyroid hormone and insulin. It stimulates their synthesis in cells which are poor in receptor and inhibits the synthesis in cells which have high amounts of these receptors. The use of antibiotics and of the run on method strongly suggest that butyrate acts at the transcriptional level. Butyrate inhibits the induction of proteins, including enzymes, by steroid hormones as has been shown for the induction of tyrosine aminotransferase by glucocorticoids, of ovalbumin and transferrin by estradiol in chick oviduct. Butyrate strongly alters cell morphology, usually it produces an enlargement of the cells with formation of protrusions. In HTC cells alteration of nucleoli and of the nuclear shape are observed. All these alterations are reversible and the cells recover the normal morphology upon removal of butyrate. These alterations result at least partly from modifications of the cytoskeleton: induction of vimentin and cytokeratin, formation of microfilaments, of microtubules and of actin fibers. The external matrix is also modified, as are the cell surface glycoproteins, and gangliosides. Most of these alterations are consistent with the loss of transformation characteristics of the cell. The mechanism of action of butyrate has been studied by many authors. It has been well established that butyrate induces an hyperacetylation of histones by inhibiting histone deacetylases, which is consistent with its stimulatory effect on gene expression.4+ and would require transacting proteins. The use of butyrate in therapeutics would require the synthesis of new molecules including butyrate but more active and metabolized at a slower rate. Several such molecules have been synthesized: monobutyrate 3 (or 6) monoacetate glucose, pivalyloxymethyl-butyrate. The use of such molecules in human therapeutics has been suggested, especially in hematology (sickle cell anemia, beta thalassemia) and in cancerology.
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PMID:[Molecular and cellular action of butyrate]. 145 Sep 86

Insulin and tumor necrosis factor alpha (TNF alpha) produce potent and opposing physiological signals in adipocytes. However, genes that are co-regulated by the hormone and cytokine during and after adipocyte differentiation have not been characterized. Using 3T3-L1 cells, we have studied the regulation of the expression of genes encoding acyl-CoA synthetase (ACS), and stearoyl CoA desaturase-1 (SCD-1), two enzymes that play key roles in the metabolism of long chain fatty acids. Insulin is required for triggering the transcriptional activation of the ACS and SCD-1 genes at an early stage in adipocyte differentiation. In mature adipocytes insulin elicits a 4-fold increase in the rates of transcription of the two genes. However, when 3T3-L1 adipocytes are treated with TNF alpha the cytokine causes a 75-90% decrease in the levels of ACS and SCD-1 mRNAs. The decline in mRNA content is associated with similar decrements in the rates of transcription of the ACS and SCD-1 genes. Thus, the ACS and SCD-1 genes are subject to stimulation and counter-regulation (at the transcriptional level) by insulin and TNF alpha, respectively. The opposing effects of insulin and TNF alpha are observed in developing and terminally differentiated adipocytes. Unlike the ACS and SCD-1 genes, the genes that encode the lipogenic enzymes lipoprotein lipase and malic enzyme are not subject to counter-regulation by insulin and TNF alpha at the transcriptional level in 3T3-L1 adipocytes. These observations on the control of ACS and SCD-1 expression suggest possible mechanisms by which adipocytes can markedly adjust their capacity for long chain fatty acid metabolism in response to external stimuli.
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PMID:Regulation of gene expression by insulin and tumor necrosis factor alpha in 3T3-L1 cells. Modulation of the transcription of genes encoding acyl-CoA synthetase and stearoyl-CoA desaturase-1. 168 80

Intravenous glucose tolerance tests (IVGTT) were performed on 9 adults with sickle cell anemia and 15 normal controls. Blood samples were collected before and 1, 3, 5, 10, 20, 30, 40, 50, and 60 min after intravenous glucose infusion and used for glucose and C-peptide assays. The mean C-peptide concentration after glucose infusion was significantly (p less than 0.05) lower for the SCA patients as compared to the controls. No significant differences were observed in the glucose concentration of IVGTT between the two groups. These results suggest an inadequate insulin secretion by the endocrine pancreas in sickle cell anemia or an independent genetic abnormality in linkage disequilibrium with the beta s gene.
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PMID:Decreased C-peptide secretion in sickle cell anemia. 250 99

Health care practitioners are often faced with the dilemma of whether or not to provide oral contraceptives (OCs) to women who have certain chronic medical conditions. Oral contraceptive use among gestational diabetics who use OCs may be at increased risk for developing insulin- dependent diabetes. It appears that progestins are primarily responsible because they decrease the number of insulin receptors on cell membranes. Norgestrel has a more marked effect on carbohydrate metabolism than norethindrone. Estrogen may also play a role by slowing the uptake of glucose. Findings of available studies show that progestin only OCs, combined, low-dose OCs (35 mcg of ethinyl estradiol), or preparations with norethindrone are relatively safe for gestational diabetics. In mitral valve prolapse (MVP) abnormal hemodynamics at the prolapsed valve may promote formation of thrombi and lead to cerebrovascular accidents (CVAs). Oral contraceptives are also known to increase the incidence of thrombi, especially in the lower extremities. A 1986 study of 11 OC users who had had CVAS found that a specific subject of women with MVP are at risk for CVA, perhaps due to persistent clotting abnormalities, however most could safely use a combined, low-dose pill unless headaches, smoking, and MVP symptoms. Oral contraceptive use has usually been avoided in women with sickle cell disease. The major concern has been the possibility of an additive or synergistic effect of OCs on the blood-clotting mechanism. However sickle cell disease is a relative contraindication. Several studies showed that OC use, even up to 54 months, did not increase sickle cell crises, and only 5 cases of thromboses have been reported. The increase of fetal and maternal mortality, however, is a definite risk, therefore a similar low-dose pill may be safe for women with the sickle cell trait.
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PMID:Oral contraceptive use in women with chronic medical conditions. 267 89

Two pregnant women were treated for both insulin-dependent diabetes and sickle cell disease. Careful application of treatments developed for each of these conditions allowed both pregnancies to be successfully carried to term.
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PMID:Pregnancy associated with both insulin-dependent diabetes mellitus and sickle cell disease. A report of two cases. 358 80

The requirement of zinc for humans was recognized in the early 1960s. The causes of zinc deficiency include malnutrition, alcoholism, malabsorption, extensive burns, chronic debilitating disorders, and chronic renal diseases; use of certain drugs such as penicillamine and, in some cases, diuretics; and genetic disorders such as acrodermatitis enteropathica and sickle cell disease. The requirement of zinc is increased in pregnancy and during growth. The clinical manifestations of severe zinc deficiency include bullous-pustular dermatitis, alopecia, diarrhea, emotional disorder, weight loss, intercurrent infections, and hypogonadism in males; zinc deficiency can be fatal if unrecognized and untreated. A moderate deficiency of zinc is characterized by growth retardation and delayed puberty in adolescents, hypogonadism in males, rough skin, poor appetite, mental lethargy, delayed wound healing, taste abnormalities, and abnormal dark adaptation. In mild cases of zinc deficiency in human subjects, we have observed oligospermia, slight weight loss, and hyperammonemia. Zinc is a growth factor. As a result of its deficiency, growth is affected adversely in many animal species and humans, probably because zinc is needed for protein and DNA synthesis and cell division. The effects of zinc and growth hormone on growth appear to be independent of each other in experimental animals. Whether zinc is required for the metabolism of somatomedin needs further investigation. Thyroid and adrenal functions do not appear to change as a result of zinc deficiency. Glucocorticoids may have an effect on zinc metabolism, although the clinical relevance of this effect is not known at present. In contrast, testicular function is affected adversely as a result of zinc deficiency in both humans and experimental animals. The effect appears to be a direct one since the hypothalamic-pituitary axis is intact, and may relate to the reduction in testicular size as a result of the need for zinc in cell division. In addition, zinc is required for the function of several testicular enzymes, although a specific role in steroidogenesis has not been identified. Zinc appears to have a role in the modulation of prolactin secretion, in the secretion and action of insulin, and in the production and biologic effects of thymic hormones. It is clear that the endocrine consequences of zinc deficiency are multiple, and that continued investigation should provide additional pathophysiologic and therapeutic insights.
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PMID:Clinical, endocrinologic, and biochemical effects of zinc deficiency. 391 98

Recent developments in recombinant DNA research promise to have a substantial impact on medicine. The technology now allows for DNA pieces to be isolated and ligated to other DNA, such as that from bacteria, and be replicated in foreign hosts. The replicated DNA can then be isolated and used to study its structure, to study gene expression and its regulation, to program microorganisms to synthesize medically, agriculturally or industrally important proteins, to transfer genes back into mammalian cells and to diagnose genetic diseases. The DNA used for cloning can be obtained by copying mRNA, by chemically synthesizing it and by isolating chromosomal DNA; each of these types of DNAs serve special uses. The results of studies with the use of these DNAs have provided an enormous amount of information, in some cases of a quite surprising nature, about the structure and function of genes. This information is already providing substantial insights into the mechanisms of diseases such as cancer and hopefully it will lead to newer therapies as well. The technology had already resulted in the synthesis in microorganisms of a number of useful proteins such as vaccines, insulin and interferon. The use of the DNA to diagnose genetic diseases has been applied as for instance to thalassemia and sickle cell anemia. Finally, the ability to transfer genes back into cells and to have these genes function promises to open a new approach with gene therapy that may be useful for treating not only genetic diseases, but a number of other diseases as well.
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PMID:Tan Sri Runme Shaw lecture. Genetic engineering and its impact on medicine. 635 18

Glycosylated hemoglobin in red blood cell hemolysates of five patients homozygous for CC, 18 patients with SC condition, and 13 patients heterozygous for Hb C with or without insulin-dependent diabetes mellitus were separated by Bio-Rex 70 chromatography. The various glycosylated components were identified by analysis of the hemoglobin components for ketoamine and phosphate, in vitro glycosylation studies, and by the quantitative differences in the minor components between the participants with and without diabetes. The percentages of Hb A1a + b, Hb A1c, and Hb C1c were significantly increased in the Hb C heterozygote with diabetes. Similarly, the percentages of Hb S1a + b and Hb S1c were elevated in the SC patient with diabetes. It was noteworthy that the levels of these components became normal after adequate control of diabetes. Moreover, the levels of Hb C1c in the CC participants and Hb S1c (Hb S1c/total Hb S) in the SC patients were significantly higher than the Hb S1c levels previously reported in patients with sickle cell anemia. These findings might reflect the fact that CC and SC patients have less severe hemolytic anemia. Moreover, the relative proportions of Hb A1c and Hb C1c were nearly the same in Hb C heterozygotes, which indicated that Hb A and Hb C were glycosylated in vivo to approximately the same extent.
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PMID:Glycosylated hemoglobins in heterozygotes and homozygotes for hemoglobin C with or without diabetes. 648 Dec 20

The function of the pituitary-adrenal axis and leukocyte alkaline phosphatase activity were evaluated in eight patients with sickle cell disease during a painful crisis and when crisis-free. The leukocyte alkaline phosphatase (LAP) score did not increase during crisis; the scores were in the low-normal range during crisis and noncrisis periods. Insulin-induced hypoglycemia produced normal growth hormone responses during both crisis and crisis-free periods. Plasma cortisol concentrations were diminished in the crisis group. Also impaired was 11-deoxycortisol production in both groups after metyrapone. These findings indicate that a mild defect in the hypothalamic-pituitary-adrenal axis exists in sickle cell disease patients.
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PMID:Pituitary-adrenal axis function in sickle cell anemia and its relationship to leukocyte alkaline phosphatase. 701 Oct 1


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