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)

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

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

Increasing the expression of the gamma globin genes is considered a useful therapeutic approach to the beta globin diseases. Because butyrate and alpha-amino-n-butyric acid (ABA) augment gamma globin expression in normal neonatal and adult erythroid progenitors, we investigated the effects of sodium butyrate and ABA on erythroid progenitors of patients with beta thalassemia and sickle cell anemia who might benefit from such an effect. Both substances increased fetal hemoglobin (Hb F) expression in Bfu-e from 7% to 30% above levels found in control cultures from the same subjects with sickle cell anemia. The fraction of cultured erythroblasts producing Hb F increased more than 20% with sodium butyrate treatment in 70% of cultures. In most cultures, this produced greater than 20% total Hb F and greater than 70% F cells, levels which have been considered beneficial in ameliorating clinical symptoms. Alpha: non-alpha (alpha-non-alpha) imbalance was decreased by 36% in erythroid progenitors of patients with beta thalassemia cultured in the presence of butyrate compared with control cultures from the same subjects. These data suggest that sodium butyrate may have therapeutic potential for increasing gamma globin expression in the beta globin diseases.
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PMID:Sodium butyrate enhances fetal globin gene expression in erythroid progenitors of patients with Hb SS and beta thalassemia. 247 1

Butyrate induces fetal hemoglobin (HbF) synthesis in cultures of erythroid progenitors, in primates, and in man. The mechanism by which this compound stimulates gamma-globin synthesis is unknown. In the course of butyrate catabolism, beta oxidation by mitochondrial enzymes results in the formation of two acetate molecules from each molecule of butyrate. Studies were performed to determine whether acetate itself induces HbF synthesis. In erythroid burst-forming unit (BFU-E) cultures from normal persons, and individuals with sickle cell disease and umbilical-cord blood, dose-dependent increases in gamma-globin protein and gamma mRNA were consistently observed in response to increasing acetate concentrations. In BFU-E cultures from normal adults and patients with sickle cell disease, the ratio of gamma/gamma + beta mRNA increased twofold to fivefold in response to acetate, whereas the percentage of BFU-E progeny staining with an anti-gamma monoclonal antibody (MoAb) increased approximately twofold. Acetate-induced increases in gamma-gene expression were also noted in the progeny of umbilical cord blood BFU-E, although the magnitude of change in response to acetate was less because of a higher baseline of gamma-chain production. The effect of acetate on HbF induction in vivo was evaluated using transgenic mouse and primate models. A transgenic mouse bearing a 2.5-kb mu locus control region (mu LCR) cassette linked to a 3.3-kb A gamma gene displayed a near twofold increase in gamma mRNA during a 10-day infusion of sodium acetate at a dose of 1.5 g/kg/d. Sodium acetate administration in baboons, in doses ranging from 1.5 to 6 g/kg/d by continuous intravenous infusion, also resulted in the stimulation of gamma-globin synthesis, with the percentage of HbF-containing reticulocytes (F reticulocytes) approaching 30%. Surprisingly, a dose-response effect of acetate on HbF induction was not observed in the baboons, and HbF induction was not sustained with prolonged acetate administration. These results suggest that both two-carbon fatty acids (acetate) and four-carbon fatty acids (butyrate) stimulate synthesis of HbF in vivo.
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PMID:Fetal hemoglobin induction by acetate, a product of butyrate catabolism. 754 74

Butyrate analogues have been shown to increase fetal hemoglobin (HbF) production in vitro and in vivo. Sodium phenylbutyrate (SPB), an oral agent used to treat individuals with urea-cycle disorders, has been shown to increase HbF in nonanemic individuals and in individuals with sickle cell disease. We have treated eleven patients with homozygous beta thalassemia (three transfusion dependent) and one sickle-beta-thalassemia patient with 20 g/d (forty 500-mg tablets) of SPB for 41 to 460 days. All patients showed an increase in the percent of F reticulocytes associated with treatment, but only four patients responded by increasing their Hb levels by greater than 1 g/dL (mean increase, 2.1 g/dL; range, 1.2 to 2.8 g/dL). None of the transfusion-dependent thalassemia subjects responded. Increase in Hb was associated with an increase in red blood cell number (mean increase, 0.62 x 10(12)/L), and mean corpuscular volume (mean increase, 6 fL). Changes in percent HbF, absolute HbF levels, or alpha- to non-alpha-globin ratios as measured by levels of mRNA and globin protein in peripheral blood did not correlate with response to treatment. Response to treatment was not associated with the type of beta-globin mutation, but baseline erythropoietin levels of greater than 120 mU/mL was seen in all responders and only two of eight nonresponders to SPB. Compliance with treatment was greater than 90% as measured by pill counts. Side effects of the drug included weight gain and/or edema caused by increase salt load in 2/12, transient epigastric discomfort in 7/12, and abnormal body odor in 3/12 subjects. Two splenectomized patients who were not on prophylactic antibiotics developed sepsis while on treatment. We conclude that SPB increases Hb in some patients with thalassemia, but the precise mechanism of action is unknown.
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PMID:Oral sodium phenylbutyrate therapy in homozygous beta thalassemia: a clinical trial. 752 72

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

This communication reviews the effects of short-chain carboxylic acids on human cells of importance to the periodontium. The central hypothesis is that these acids can alter both cell function and gene expression, and thus contribute to the initiation and prolongation of gingival inflammation. Short-chain carboxylic acids [CH3-(CH2)x-COOH, x < 3] are metabolic intermediates with a broad range of apparently paradoxical biological effects. For example, lactic acid (CH3-CHOH-COOH), a 3-carbon alpha-hydroxy-substituted acid, is widely recognized for its cariogenicity. Lactic acid, however, also occurs in tropical fruits, and is the active ingredient in a variety of anti-wrinkle creams developed by dermatologists. In marked contrast, the unsubstituted 3-carbon propionic acid (CH3-CH2-COOH) is used as a food preservative and is the active principle for one class of non-steroidal anti-inflammatory agents. Interestingly, the addition of one carbon to propionic acid dramatically changes the biological effects. The unsubstituted 4-carbon butyric acid (CH3-CH2-CH2-COOH) is used by hematologists as a de-differentiating agent for the treatment of sickle cell anemia, but by oncologists as a differentiating agent for cancer chemotherapy. Finally, acting either individually or in concert, these acids can increase vascular dilation. Clearly, these acids, while metabolically derived, have a number of very divergent activities which are cell-type-specific (Fig. 1). It may be telling that periodontal bacteria produce these acids in millimolar concentrations, and that these bacteria can be characterized by their acid production profiles. It is no less interesting that these acids occur in the gingival crevices of human subjects with severe periodontal disease at millimolar levels which are > 10-fold higher than those found in mildly diseased subjects, and are undetectable in healthy subjects. Further, when applied directly to healthy human gingiva, short-chain carboxylic acids stimulate a gingival inflammatory response and inflammatory cytokine release. At the cellular level, these acids inhibit proliferation of gingival epithelial and endothelial cells, and inhibit leukocyte apoptosis and function, but can stimulate leukocyte cytokine release. At the molecular level, these acids can stimulate neutrophil gene transcription, translation, and protein expression. Thus, the likelihood is high that these acids, in addition to their cariogenic activity, can promote and prolong gingival inflammation. Our challenge will be to identify the cell or cells of the periodontium which respond to short-chain carboxylic acids, to delineate their responses and the molecular mechanism(s) of these effects, and to categorize the aspects of the inflammatory components which damage and those which protect the host. With this information, it may be possible to begin to rationally identify and test pharmaceutical agents which diminish the harmful aspects, while enhancing the beneficial components, of the inflammatory response.
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PMID:Short-chain carboxylic-acid-stimulated, PMN-mediated gingival inflammation. 926 44

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

Butyric acid (BA) is known to induce overexpression of fetal hemoglobin and then erythroid differentiation. Therefore, BA is currently under clinical investigation as a potential therapy for the treatment of sickle cell disease and cancer. Nevertheless, the molecular mechanisms involved in BA-induced differentiation remain largely unknown. Previous reports have shown that BA-induced overexpression of erythroid genes occurred at the transcriptional level, suggesting the involvement of erythroid transcription factors. Here, we intend to demonstrate the requirement of GATA-1 and NF-E2 transcription factors in the BA-induced erythroid differentiation of human leukemic K562 cells. Time-course experiments showed that nuclear levels of GATA-1 and p45 NF-E2 proteins increased during BA treatment. Moreover, antisense oligodeoxynucleotides targeting either GATA-1 or p45 NF-E2 proteins inhibited both protein expression and BA-induced differentiation. In contrast, BA-induced cell growth inhibition was not affected. These results provide the first direct evidence for the requirement of GATA-1 and NF-E2 in BA-induced differentiation process.
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PMID:Requirement of GATA-1 and p45 NF-E2 expression in butyric acid-induced erythroid differentiation. 991 24

High levels of fetal hemoglobin (Hb F) protect from many of the complications of sickle cell disease and lead to improved survival. Butyrate and other short chain fatty acids were previously shown to increase Hb F production in erythroid cells in vitro and in animal models in vivo. However, butyrates are also known to inhibit the proliferation of many cell types, including erythroid cells. Experience with the use of butyrate in animal models and in early clinical trials demonstrated that the Hb F response may be lost after prolonged administration of high doses of butyrate. We hypothesized that this loss of response may be a result of the antiproliferative effects of butyrate. We designed a regimen consisting of intermittent or pulse therapy in which butyrate was administered for 4 days followed by 10 to 24 days with no drug exposure. This pulse regimen induced fetal globin gene expression in 9 of 11 patients. The mean Hb F in this group increased from 7.2% to 21.0% (P <.002) after intermittent butyrate therapy for a mean duration of 29.9 weeks. This was associated with a parallel increase in the number of F cells and F reticulocytes. The total hemoglobin levels also increased from a mean of 7.8 g/dL to a mean of 8.8 g/dL (P <.006). The increased levels of Hb F were sustained in all responders, including 1 patient who has been on pulse butyrate therapy for more than 28 months. This regimen, which resulted in a marked and sustained increase in Hb F levels in more than two thirds of the adult sickle cell patients enrolled in this study, was well tolerated without adverse side effects. These encouraging results require confirmation along with an appropriate evaluation of clinical outcomes in a larger number of patients with sickle cell disease.
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PMID:Sustained induction of fetal hemoglobin by pulse butyrate therapy in sickle cell disease. 1006 48


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