Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019045 (hemoglobinopathies)
 2,704 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interferon-gamma (IFN-gamma) has been shown to influence globin gene expression in cord blood and normal adult progenitor-derived erythroblasts. To explore the influence of IFN-gamma on fetal hemoglobin (HbF) synthesis in the hemoglobinopathies, erythroid progenitors (BFU-E, burst forming unit-erythroid) from patients with sickle cell anemia (SCA) and thalassemia were co-cultured with or without IFN-gamma. Hemoglobin content in progenitor-derived erythroblasts was assessed by radioligand assay (RIA). Co-culture of erythroid progenitors from 12 SCA patients with 200-400 U/ml of IFN-gamma resulted in a significant decrease in picograms of HbF and percent HbF per BFU-E-derived erythroblast. The mean decrease (+/- SEM) of picograms of HbF per cell and percent of HbF was by 42 +/- 9% and 35 +/- 8% of control cultures, respectively. Co-culture of erythroid progenitors from 10 patients with thalassemia major or thalassemia variant (HPFH/thalassemia, sickle/beta 0-thalassemia) with 200 U/ml IFN-gamma also resulted in a significant decrease in picograms and percent of HbF per BFU-E-derived erythroblast. IFN-gamma treatment also inhibited the enhancement in gamma-globin synthesis induced in culture by butyric acid. Erythroid progenitors from 2 patients with SCA, 1 patient with sickle/beta 0-thalassemia, and 1 patient with HbE/beta 0-thalassemia were co-cultured with IFN-gamma, L-alpha-amino-n-butyric acid, or both. HbF content (expressed as picograms HbF/cell) was decreased in samples co-cultured with IFN, increased in cultures with L-alpha-amino-n-butyric acid, but remained at control values in cultures treated with IFN plus L-alpha-amino-n-butyric acid. These data demonstrate that IFN-gamma is an environmental factor that influences gamma-globin gene expression in the beta hemoglobinopathies in vitro.
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PMID:Interferon-gamma modulates fetal hemoglobin synthesis in sickle cell anemia and thalassemia. 170 29

Butyric acid, a naturally occurring fatty acid, has been shown to increase fetal hemoglobin in BFUe cultures, in primates, and in patients with beta chain hemoglobinopathies. The precise mechanism of gamma gene induction by butyrate is unknown. Butyrate may induce fetal hemoglobin production in vivo by reactivation of silenced gamma globin genes, by inhibiting the silencing of gamma genes, or by both mechanisms. We examined the effects of butyrate on gamma gene expression in transgenic mice carrying three types of constructs: microLCRA gamma mice, which continue to express the gamma gene in the adult stage of development at a level of one-third to one-fifth of the expression in the fetus; microLCRA gamma psi beta delta beta mice, which display correct developmental regulation of gamma and beta human globin genes and have low level gamma globin expression in the adult; and beta locus YAC mice, which display correct developmental regulation of epsilon, gamma, and beta globin genes and have a totally silenced gamma gene in the adult stage. Animals were treated with a continuous infusion of alpha-amino butyric acid (alpha-ABA) for 7 days. In microLCRA gamma mice alpha-ABA produced up to a 43-fold induction of gamma and 9-fold induction of mouse alpha globin genes. In contrast, butyrate did not induce gamma globin expression in the beta locus YAC mice. However, the gamma globin genes of beta locus YAC mice were activated after administration of 5-azacytidine (5-azaC), and the level of gamma globin expression was further increased by administration of alpha-ABA. These results suggest that butyrate cannot reactivate a totally silenced gamma gene and that induction of fetal hemoglobin by this compound may require the presence of preactivated gamma globin genes.
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PMID:alpha-Amino butyric acid cannot reactivate the silenced gamma gene of the beta locus YAC transgenic mouse. 752 73

Butyrate, a four-carbon fatty acid, and its two-carbon metabolic product, acetate, are inducers of gamma-globin synthesis. To test whether other short-chain fatty acids share this property, we first examined whether propionic acid, a three-carbon fatty acid that is not catabolized to acetate, induces gamma-globin expression. Sodium propionate increased the frequency of fetal hemoglobin containing erythroblasts and the gamma/gamma + beta mRNA ratios in adult erythroid cell cultures and F reticulocyte production in a nonanemic juvenile baboon. Short-chain fatty acids containing five (pentanoic), six (hexanoic), seven (heptanoic), eight (octanoic), and nine (nonanoic) carbons induced gamma-globin expression (as measured by increase in gamma-positive erythroblasts and gamma/gamma + beta mRNA ratios) in adult erythroid burst-forming unit cultures. There was a clear-cut relationship between the concentration of fatty acids in culture and the degree of induction of gamma-globin expression. Three-, four-, and five-carbon fatty acids were better inducers of gamma globin in culture as compared with six- to nine-carbon fatty acids. These results suggest that all short-chain fatty acids share the property of gamma-globin gene inducibility. The fact that valproic acid, a derivative of pentanoic acid, also induces gamma-globin expression suggests that short-chain fatty acid derivatives that are already approved for human use may possess the property of gamma-globin inducibility and may be of therapeutic relevance to the beta-chain hemoglobinopathies.
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PMID:Stimulation of fetal hemoglobin production by short chain fatty acids. 757 19

The inherited beta-hemoglobinopathies (sickle cell disease and beta thalassemia) are the result of a mutation in the adult (beta) globin gene. The fetal globin chain, encoded by the gamma globin genes, can substitute for the mutated or defective beta globin chain, but expression of the gamma globin gene is developmentally inactivated prior to birth. Re-inducing expression of the normal fetal globin genes is a preferred method of ameliorating sickle cell disease and the beta thalassemias. Stimulation of as little as 4-8% fetal globin synthesis in the bone marrow can produce > 20% fetal hemoglobin in the peripheral circulation, due to enhanced survival of red blood cells containing both sickle and fetal hemoglobin, compared to those containing sickle hemoglobin alone. Butyric acid and butyrate derivatives are generally safe compounds which induce fetal hemoglobin production by stimulating the promoter of the fetal globin genes. An initial trial with the parent compound, delivered as Arginine Butyrate, has demonstrated rapid stimulation of fetal globin expression to levels that have been shown to ameliorate these conditions. Phase 1 trials of an oral butyrate derivative with a long plasma half-life have just begun. These agents now provide a specific new approach for ameliorating these classic molecular disorders and merit further investigation in larger patient populations.
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PMID:Butyrate-induced reactivation of the fetal globin genes: a molecular treatment for the beta-hemoglobinopathies. 768 3

The search for, and discovery of, a physiologic model in which the developmentally regulated switch from fetal to adult globin gene expression could be prevented has resulted in the development of a new class of therapeutic agents, consisting of simple fatty acids, such as butyric acid, for the treatment of the beta-hemoglobinopathies. Butyrate and related drugs stimulate fetal (gamma-) globin gene expression in erythroid cells cultured from patients, and in chicken, ovine, and primate animal models. The butyrates are perhaps the first class of drugs designed to transcriptionally activate specific genes--in this particular case, to reactivate the developmentally silenced fetal globin genes. Phase I-II clinical trials resulting from this basic research have been initiated on a small scale during the past 3 years. Analysis of two butyrate-derived therapeutic agents, one delivered intravenously and one orally, has shown initial efficacy in stimulating fetal hemoglobin expression in 50% to 85% of patients. Correction of the anemia from the beta-hemoglobinopathy has followed induction of fetal globin, and has been adequate to eliminate the need for erythrocyte transfusions in some patients with beta-thalassemia. These compounds have been relatively safe and without generalized cytotoxicity in patients, but drug tolerance develops in some patients after prolonged therapy. Third-generation, small two- to five-carbon butyrate derivatives are in development. The molecular basis for butyrate action is being defined. Binding of putative regulatory proteins to a specific region of the gamma-globin promoter is altered in vivo in patients receiving butyrate therapy. Further analysis of the mode of action may contribute to development of other therapeutic agents designed to regulate gene transcription.
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PMID:Butyrate in the treatment of sickle cell disease and beta-thalassemia. 937 80

Butyrates have been studied as cancer differentiation agents in vitro and as a treatment for hemoglobinopathies. Tributyrin, a triglyceride with butyrate molecules esterified at the 1, 2, and 3 positions, induces differentiation and/or growth inhibition of a number of cell lines in vitro. When given p.o. to rodents, tributyrin produces substantial plasma butyrate concentrations. We treated 13 patients with escalating doses of tributyrin from 50 to 400 mg/kg/day. Doses were administered p.o. after an overnight fast, once daily for 3 weeks, followed by a 1-week rest. Intrapatient dose escalation occurred after two courses without toxicity greater than grade 2. The time course of butyrate in plasma was assessed on days 1 and 15 and after any dose escalation. Grade 3 toxicities consisted of nausea, vomiting, and myalgia. Grades 1 and 2 toxicities included diarrhea, headache, abdominal cramping, nausea, anemia, constipation, azotemia, lightheadedness, fatigue, rash, alopecia, odor, dysphoria, and clumsiness. There was no consistent increase in hemoglobin F with tributyrin treatment. Peak plasma butyrate concentrations occurred between 0.25 and 3 h after dose, increased with dose, and ranged from 0 to 0.45 mM. Peak concentrations did not increase in three patients who had dose escalation. Butyrate pharmacokinetics were not different on days 1 and 15. Because peak plasma concentrations near those effective in vitro (0.5-1 mM) were achieved, but butyrate disappeared from plasma by 5 h after dose, we are now pursuing dose escalation with dosing three times daily, beginning at a dose of 450 mg/kg/day.
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PMID:Phase I study of the orally administered butyrate prodrug, tributyrin, in patients with solid tumors. 953 30

Butyric acid, a short chain fatty acid (SCFA), is a natural component of the animal metabolism. Physiological concentrations induce multiple and reversible biological effects. They concern regulatory mechanisms of gene expression conducing to promote markers of cell differentiation, apoptosis and cell growth control. The described hyperacetylation of histones and the induction of several immune or non-immune cell-activating mediators are consistent with the pleiotropic stimulatory effect of the agent. Butyric acid is considered as a biological response modifier (BRM) and is an interesting tool for biological studies. The history of butyric acid as a putative medication in human health is spanning since 60 years and is confusing in part because of conflicting data between exciting experimental results and clinical trials. In light of minimal impact of systemic therapy and the short half-life of the saline molecule used, it is evident that continuous infusions of butyrate are required to improve the efficacy of the treatment. Butyric acid has been viewed with skepticism because of less convenient for long-term chronic therapy. New experimental data from several studies conduced within the past decade with butyric derivatives, delivery systems, and long-acting prodrugs, have demonstrated the practical value of the therapeutic concept. To support issues regarding clinical development, it was of interest to evaluate the recent information, showing butyric acid currently considered as therapeutic purposes in the treatment of colorectal cancer and hemoglobinopathies.
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PMID:Role of butyric acid and its derivatives in the treatment of colorectal cancer and hemoglobinopathies. 982 Jan 19

Regiospecific synthesis of 12 novel n-butyric and phenylalkylcarboxylic monoesters of mannose and xylitol was achieved. The strategy adopted, avoided a tedious intramolecular transesterification step, previously described for the synthesis of analogous compounds and permitted the facile synthesis of a new generation of stable derivatives. The general tolerance of the drugs has been assayed after intravenous administration of a bolus dose into mice. Monobutyric esters showed a low toxicity commensurate with the requirements for future development. A relationship was observed between chain length and toxicity. In contrast, phenylacetic, 3-phenylpropionic and 4-phenylbutyric esters were found to be toxic. Phenylbutyric esters induced marked and specific neuromuscular damage. Preliminary biological investigations of the new series of monobutyric esters showed them to retain the benificial biological properties of butyric acid whilst remaining relatively non toxic. They induced an inhibition of in vitro proliferation of 10 human cases of de novo acute myeloid leukemia (AML) primary cultures and AML established cell lines. AML blasts growth appeared to be blocked and cell differentiation was established. Transcription and expression of maturation markers and finally apoptosis were observed. Moreover, human gamma-chain hemoglobin (HbF) synthesis in erythroleukemia cells was stimulated by monobutyric esters. Mannose and xylitol butyric derivatives would appear to have exciting potential in treatment of beta-Hemoglobinopathies, sickle cell anemia and cancer.
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PMID:Regioselective synthesis and biological profiling of butyric and phenylalkylcarboxylic esters derivated from D-mannose and xylitol: influence of alkyl chain length on acute toxicity. 984 86

Butyrate, a non-toxic short-chain fatty acid (SCFA) and inhibitor of histone deacetylase (HDAC), has potential as an anti-tumor agent because it imposes a reversible G1 block in normal cells yet induces apoptosis in tumor lines. As a potent reactivator of fetal globin transcription, butyrate is used clinically in the treatment of hemoglobinopathies. The anti-proliferative effect of butyrate and its derivatives on in vivo erythroid cell maturation, however, has limited their utility. The molecular mechanisms underlying the G1 arrest induced by butyrate and related SCFAs remain unclear. One model, drawing on tumor cell data, proposes that HDAC inhibition and subsequent transcriptional induction of cyclin-dependent kinase inhibitor (CKI) p21CIP are required. However, because of potentially confounding genetic mutations present in tumor models, we examined SCFA effects on CKIs in a non-transformed growth control model. Using murine 3T3 fibroblasts, we find p27KIP1 is also strongly induced. Unlike previously described effects of butyrate and HDAC inhibition on p21CIP, p27KIP1 induction did not occur at the transcriptional level; instead, the stability of the p27KIP1 protein increased. Other structurally unrelated HDAC inhibitors, including trichostatin A (TSA), induced p27KIP1 similarly. p27KIP1 was found in cyclin E/Cdk2 complexes, concomitant with suppression of cdk2 activity. Elevation of p27KIP1 is required for the observed G1 blockade, as p27KIP1-deficient fibroblasts were resistant to HDAC inhibition-induced arrest. These data suggest a novel activity for HDAC inhibitors and demonstrate a critical role for p27KIP1 in mediating G1 arrest in response to these drugs.
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PMID:Histone deacetylase inhibition-mediated post-translational elevation of p27KIP1 protein levels is required for G1 arrest in fibroblasts. 1538 42

Butyrate is a prototype of histone deacetylase inhibitors that is believed to reactivate silent genes by inducing epigenetic modifications. Although butyrate was shown to induce fetal hemoglobin (HbF) production in patients with hemoglobin disorders, the mechanism of this induction has not been fully elucidated. Our studies of the epigenetic configuration of the beta-globin cluster suggest that DNA methylation and histone H3 acetylation are important for the regulation of developmental stage-specific expression of the beta-like globin genes, whereas acetylation of both histones H3 and H4 seem to be important for the regulation of tissue-specific expression. These studies suggest that DNA methylation may be important for the silencing of the beta-like globin genes in nonerythroid hematopoietic cells but may not be necessary for their silencing in nonhematopoietic cells. Furthermore, our studies demonstrate that butyrate exposure results in a true reversal of the normal developmental switch from gamma- to beta-globin expression. This is associated with increased histone acetylation and decreased DNA methylation of the gamma-globin genes, with opposite changes in the beta-globin gene. These studies provide strong support for the role of epigenetic modifications in the normal developmental and tissue-specific regulation of globin gene expression and in the butyrate-mediated pharmacologic induction of HbF production.
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PMID:Role of epigenetic modifications in normal globin gene regulation and butyrate-mediated induction of fetal hemoglobin. 1763 55


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