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PubMed1991

Production of analytical quantities of recombinant proteins in Chinese hamster ovary cells using sodium butyrate to elevate gene expression.

Sodium butyrate was used to enhance expression levels and thereby facilitate the generation of analytical quantities of nine different tissue plasminogen activator (tPA) analogues expressed under the control of the cytomegalovirus immediate early (CMV IE) promoter by the Chinese hamster ovary (CHO) mammalian expression system. Production involved growth in roller bottles, using serum free or low serum media formulations, together with repetitive, sodium butyrate inductions. Average inductions in the presence of sodium butyrate ranged from 2 to 9-fold relative to uninduced controls, using cell lines with no previous butyrate exposure. Retardation of growth rate by butyrate minimized the need to split cells during the production runs, extending longevity of roller bottles containing cells secreting at induced levels. SDS-PAGE analyses indicate a consistently high percentage of single-chain material. Measurements of specific activity and fibrinogen fragment enhancement for one of the analogues demonstrate that neither of these two critical parameters are affected by production in the presence of butyrate. Induction kinetic data and growth curves for the expression of sCD4 under control of the SV40 early promoter demonstrate that the benefits of butyrate can be realized with different promoters and heterologous genes, and are additive when used in conjunction with an amplified cell line constitutively expressing at elevated levels. This work demonstrates the practical application of sodium butyrate in the production of analytical quantities of protein from the CHO expression system, and suggests a role for sodium butyrate in commercial scale processes as well.

Animals↗
PubMed1987

Effects of butyric and acetic acids on acetone-butanol formation by Clostridium acetobutylicum.

The actions of butyric and acetic acids on acetone-butanol fermentation are investigated. Production of butyric and acetic acids are controlled by the extracellular concentrations of both acids: acetic acid added to the medium inhibits its own formation but has no effect on butyric acid formation, and added butyric acid inhibits its own formation but not that of acetic acid. The ratio of end metabolites depends upon acetic and butyric acid quantities excreted during the fermentation. In contrast to acetic acid, which specifically increases acetone formation, butyric acid increases both acetone and butanol formations. Acetate and butyrate kinase activities were also examined. Both increase at the start of fermentation and decrease when solvents appear in the medium. Coenzyme A transferase activity is weak in the acidogenic phase and markedly increases in the solvent phase. Acetic and butyric acids appear to be co-substrates. On the basis of these results, a mechanism of acetic and butyric acid pathways, coupled to solvent formation by C. acetobutylicum glucose fermentation is proposed.

Acetate Kinase↗
PubMed1988

Effect of butyrate on thyroid hormone-mediated gene expression in rat pituitary tumour cells.

These studies correlate the effects of (sodium) butyrate on intranuclear thyroid hormone receptor levels, with influences on both endogenous and transfected rat growth hormone (rGH) gene expression and regulation by L-triiodothyronine (T3). In rat anterior pituitary tumour (GH3) cells, 5.0 mM butyrate elicits a biphasic reduction in the number of nuclear T3 receptors. About 75% are depleted rapidly (t1/2 = 7 h), and the remaining receptors are depleted more slowly (t1/2 = 59 h). GH3 cells were treated with increasing concentrations of butyrate (0-5.0 mM), plus or minus 10 nM T3 for 48 h. Total cytoplasmic RNA, cellular protein and medium were analysed for rGH levels with radiolabelled rGH cDNA or antibodies. A greater than 50-fold increase in rGH mRNA level was seen after T3 treatment in the absence or presence of 0.1 mM butyrate. However, 1.0 and 5.0 mM butyrate decreased the stimulation of rGH mRNA levels by T3 to 10- and less than 2-fold, respectively. Control mRNA levels were decreased slightly by increasing butyrate concentrations; rGH mRNA level was 2- to 3-fold higher in the absence of 5 mM butyrate. The pattern of butyrate/T3 response displayed by both cellular and secreted rGH was similar to that seen with mRNA levels. Thus, the predominant effect of butyrate on T3-mediated regulation of growth hormone gene expression is at the level of transcription or mRNA accumulation. A hybrid gene containing 5'-flanking DNA from the rGH gene fused to the bacterial gene coding for chloramphenicol acetyl transferase (CAT), was used to transfect rat pituitary tumour cells with or without butyrate and T3 treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Modulation of the receptor-coupled adenylate cyclase system in HeLa cells by sodium butyrate.

Exposure of HeLa cells to 5 mM sodium butyrate, but not 0.6 mM, resulted in a more efficient coupling between their beta-adrenergic receptors and the guanine nucleotide binding stimulatory (Ns) component of adenylate cyclase. Both concentrations of the fatty acid, however, caused an increase in receptor number. beta receptors from control and butyrate-treated cells had the same affinity for isoproterenol. Modulation of this affinity by GTP was greatly enhanced, however, in cells treated with 5 mM butyrate compared to untreated and 0.6 mM butyrate treated cells. The concentration of isoproterenol required to half-maximally stimulate adenylate cyclase (Kact) was reduced in cells treated with 5 mM butyrate. In addition, the Kact for GTP in the presence, but not the absence, of isoproterenol was reduced. The effect of butyrate on the coupling between beta receptors and Ns was analyzed in detail by monitoring the activation of Ns by guanine 5'-O-(3-thiotriphosphate) (GTP gamma S) in a two-step assay. In the absence of isoproterenol, Ns from control and 5 mM butyrate treated cells was activated to the same extent with the same time course and Kact for GTP gamma S. In the presence of isoproterenol, Ns from 5 mM butyrate treated cells was activated more rapidly and extensively than Ns from control cells. The Kact for both GTP gamma S and isoproterenol also was reduced. The rate of agonist-mediated activation of Ns was strongly dependent on temperature, which accentuated the differences between 5 mM butyrate treated and control cells. At 4 degrees C, the difference in rate was 8.8-fold.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1987

Modulation of placental alkaline phosphatase activity and cytokeratins in human HN-1 cells by butyrate, retinoic acid, catecholamines and histamine.

The effects of butyrate and retinoic acid in combination with catecholamines or histamine on the HN-1 human head and neck squamous carcinoma cell line were investigated analysing cell proliferation, placental alkaline phosphatase (PLAP) activity, and relative cytokeratin content. Butyrate inhibited cell proliferation in agar, whereas retinoic acid induced a small inhibitory effect. Butyrate enhanced PLAP activity in a time related manner in contrast to retinoic acid, which had no significant effect. However, retinoic acid inhibited the efficacy of butyrate to induce PLAP activity. A synergistic enhancement of PLAP activity was demonstrated after treatment of butyrate pretreated cells with catecholamines or histamine. The beta-adrenergic antagonist propranolol partly inhibited the aforementioned enhancement of PLAP activity, whereas the alpha-adrenergic antagonist phentolamine further enhanced PLAP activity. Indirect labeling of keratins with a polyclonal antibody showed that cytokeratin content was enhanced by butyrate but not by retinoic acid. Further analysis of cytokeratin content using four monoclonal antibodies showed that labeling of cytokeratins (5 + 8) was increased by butyrate. PLAP activity could be modulated by a concerted action of either butyrate plus retinoic acid or butyrate plus catecholamines or histamine, indicating a possible role for PLAP in tumour cell proliferation.

Alkaline Phosphatase↗
PubMed1987

Butyrate stimulates tissue-type plasminogen-activator synthesis in cultured human endothelial cells.

Incubation of cultured human endothelial cells with 5 mM-dibutyryl cyclic AMP led to an approx. 2-fold increase in tissue-type plasminogen-activator (t-PA) production over a 24 h incubation period. The stimulating effect of dibutyryl cyclic AMP could be explained by the slow liberation of butyrate, as the effect could be reproduced by addition of free butyrate to the medium, but not by addition of 8-bromo cyclic AMP or forskolin, agents known to raise intracellular cyclic AMP levels. With butyrate, an accelerated accumulation of t-PA antigen in the conditioned medium (CM) was observed after a lag period of about 6 h. Increasing amounts of butyrate caused an increasingly stimulatory effect, reaching a plateau at 5 mM-butyrate. The relative enhancement of t-PA production in the presence of 5 mM-butyrate varied among different endothelial cell cultures from 6- to 25-fold in 24 h CM. Such an increase in t-PA production was observed with both arterial and venous endothelial cells. The butyrate-induced increases in t-PA production were accompanied by increased t-PA mRNA levels. Analysis of radiolabelled CM and cell extracts by SDS/polyacrylamide-gel electrophoresis indicated that the potent action of butyrate is probably restricted to a small number of proteins. The accumulation of plasminogen activator inhibitor type 1 (PAI-1) in CM from butyrate-treated cells varied only moderately. In our study of the relationship between structure and stimulatory activity, we found that a straight-chain C4 monocarboxylate structure with a methyl group at one end and a carboxy moiety at the other seems to be required for the optimal induction of t-PA in cultured endothelial cells.

Butyrates↗
PubMed1987

Butyrate selectively activates the metallothionein gene in teratocarcinoma cells and induces hypersensitivity to metal induction.

The expression of metallothionein genes (MT-I and MT-II) was shown to be enhanced within 2 h of addition of 2.5-5 mM sodium butyrate to cultures of teratocarcinoma cells. Both undifferentiated stem cells (F9 and OC15) and differentiated cells (PSA5E and OC15 END) reacted similarly to butyrate by increased accumulation of MT mRNAs. As expected, all of the teratocarcinoma cells that were tested also responded to Zn2+ and Cd2+ by 5- to 10-fold increases in MT mRNA accumulation within 2-24 h of metal addition to the culture media. Surprisingly, MT genes in cells pretreated with butyrate were hypersensitive to metal induction, and this was demonstrated by accumulated transcript levels and by synthesis of MT protein. The maximal metal response was obtained by exposure of cells to butyrate for around 5-8 h together with 10 microM heavy metals. Metal additions to culture media over a range of concentrations and times only induced half the levels of MT mRNA that were achieved by butyrate plus metals. Butyrate enhanced the rate of accumulation of MT mRNA in response to metals, increased the sensitivity of the MT gene to metals, and protected cells from toxic effects of high concentrations of metals. The butyrate and metal ion responses were selective in that no accumulation of c-myc, c-fms, HSP-70, or AFP mRNA was detected. However, c-fos mRNA accumulated in cells exposed to toxic concentrations of metals (50 microM and higher) and this was also potentiated by butyrate treatment. These results suggest that butyrate alters the chromatin conformation of both the MT-I and MT-II genes leading to an accentuated transcriptional response to metals.

Animals↗
PubMed1998

Selective targeting of Kupffer cells with liposomal butyrate augments portal venous transfusion-induced immunosuppression.

BACKGROUND: Enhanced Kupffer cell production of the immunosuppressive arachidonic acid metabolite prostaglandin E2 (PGE2) has been shown to be a mechanism of the immunosuppressive effect of portal venous transfusions (PVT). Butyrate, a four-carbon short-chain fatty acid, has received increased attention because of its ability to enhance gene transcription. This study tested the hypothesis that the intrahepatic delivery of butyrate enhances Kupffer cell PGE2 production and thus augments the immunosuppressive effect of PVT. METHODS: Butyrate was incorporated into liposomes and administered intravenously to Lewis rats. Control rats were administered liposomes without butyrate. Twenty-four hours after liposome injection, rats were administered a PVT of 1 ml of Wistar-Furth blood. Kupffer cells were isolated, and PGE2 and tumor necrosis factor-alpha levels were measured in the culture medium after 24 hr. Additionally, Kupffer cells from butyrate-treated and control animals were added to one-way mixed lymphocyte reaction cultures. RESULTS: Intrahepatic delivery of butyrate via liposomes increased Kupffer cell PGE2 (3800+/-1220 vs. 1010+/-119 pg/ml, P<0.05) and decreased tumor necrosis factor-alpha (1670+/-81 vs. 3360+/-415 pg/ml, P<0.01) production as compared with controls. Butyrate also augmented the Kupffer cell-mediated immunosuppression as demonstrated by significant depression of the mixed lymphocyte reaction (690+/-119 vs. 3850+/-148 cpm, P<0.01). CONCLUSION: The results support the hypothesis that intrahepatic delivery of butyrate enhances Kupffer cell PGE2 production, and specific targeting of Kupffer cells with liposomes containing immunomodulating agents such as butyrate may be a useful means of augmenting immunosuppression protocols in organ transplantation.

Animals↗
PubMed1988

Comparison of the effects of forskolin and dibutyryl cyclic AMP in neuroblastoma cells: evidence that some of the actions of dibutyryl cyclic AMP are mediated by butyrate.

We have compared the effects of forskolin, N6,2'-O-dibutyryladenosine 3':5'-cyclic monophosphate (dibutyryl cyclic AMP, Bt2-cAMP), and butyrate on several aspects of neuroblastoma cell physiology. The morphology of Neuro 2A cells was similar after incubation with forskolin and Bt2-cAMP, which caused extensive neurite outgrowth, whereas in the presence of butyrate some rudimentary neurites were formed but they were not nearly as extensive. All compounds produced a dose-dependent inhibition of cell proliferation, but the effect of Bt2-cAMP was more marked than that caused by forskolin, thus showing that the effect of Bt2-cAMP is due partially to the butyrate released. Acetylcholinesterase activity was lower in the cells incubated with butyrate or Bt2-cAMP than in untreated cells or in forskolin-treated cells. This suggests that cyclic AMP does not play a role in the regulation of this enzyme. Bt2-cAMP produced histone acetylation, a well-known effect of butyrate in cultured cells, whereas forskolin did not affect this modification. Consequently, the levels of thyroid hormone receptor, a nuclear protein whose concentration is regulated by butyrate through changes in acetylation of chromatin proteins, were decreased in cells incubated with Bt2-cAMP or butyrate, but were unaffected by forskolin. Butyrate elevated the concentration of histone H1(0), a protein that increases in neuroblastoma cells as a result of different treatments that block cell division. The concentration of H1(0) in the cells treated with Bt2-cAMP was at a level intermediate between that found after treatment with butyrate and with forskolin. The present results clearly indicate that some of the effects of Bt2-cAMP on neuroblastoma cells can be attributed to the butyryl moiety of this compound rather than to the cyclic nucleotide itself.

Acetylation↗
PubMed1987

Butyrate-induced changes in nuclease sensitivity of chromatin cannot be correlated with transcriptional activation.

We examined in the H4IIE rat hepatoma cell line the relationship between butyrate-induced changes in the nuclease sensitivity of chromatin and changes in transcriptional activity of specific genes. The butyrate-inducible metallothionein I (MT-I) gene underwent a dramatic increase in DNase I sensitivity after 3 h of butyrate treatment. However, genes not transcribed in H4IIE cells underwent the same changes in DNase I sensitivity. Thus, butyrate-induced increases in DNase I sensitivity are not sufficient for the transcriptional activation of a gene. Butyrate treatment has also been reported to alter the sensitivity of sequences to micrococcal nuclease (MNase) in a manner reflecting their tissue-specific expression. Butyrate exposure caused increased digestion of the MT-I gene by MNase. However, butyrate-induced MNase sensitivity also occurred for genes which are neither transcribed in untreated cells nor butyrate inducible. Moreover, cadmium, a potent transcriptional activator of the MT-I gene, does not alter the sensitivity of the MT-I gene to MNase. Thus, the butyrate-induced alterations in MNase sensitivity are neither sufficient for, necessary for, nor indicative of transcriptional activation.

Animals↗
PubMed1995

Constitutive and cytokine induced expression of HLA molecules, secretory component, and intercellular adhesion molecule-1 is modulated by butyrate in the colonic epithelial cell line HT-29.

Normal colonic epithelial cells play an important part in the mucosal immune system and use butyrate, a bacterial fermentation product, as an important energy source. Butyrate deficiency has been associated with inflammatory bowel disease, diversion colitis, and pseudomembranous colitis. Butyrate effects on important molecules for epithelial immune functions were studied in a colonic epithelial cell line (HT-29): the constitutive and cytokine regulated expression of secretory component (poly-Ig receptor), HLA class I and II molecules, and intercellular adhesion molecule-1 (ICAM-1). Butyrate facilitated the constitutive expression of secretory component and HLA class I. Butyrate furthermore tended to enhance cytokine mediated stimulation of protein expression, although tumour necrosis factor alpha (TNF) and interleukin 4 (IL 4) responses on HLA class I and secretory component, respectively, were relatively inhibited by butyrate. Cytokine mediated accumulation in the various mRNAs usually increased even more in the presence of butyrate, with the exception of TNF response on HLA class I and secretory component mRNA concentrations. In conclusion, butyrate may substantially influence constitutive and cytokine mediated expression of molecules with immune functions in a complex and differentiated manner, and butyrate deficiencies, as seen in various clinical conditions, might influence mucosal immune responses.

Base Sequence↗
PubMed1993

Effect of increasing ruminal butyrate on milk yield and blood constituents in dairy cows fed a grass silage-based diet.

The effects of increased ruminal supply of butyrate on milk yield, milk composition, and blood metabolites were studied in four lactating cows in a 4 x 4 Latin square design. The basal diet comprised grass silage, hay, and concentrate (34:22:42, DM basis) and was supplemented with isoenergetic VFA infusions (3.58 Mcal/d). A 3:1 molar mixture of acetate and propionate was replaced gradually with butyrate at the rates of 0, 200, 400, or 600 g/d. When the amount of infused butyrate increased, isobutyrate, butyrate, and isovalerate in plasma and acetoacetate and beta-hydroxybutyrate in whole blood increased linearly, but plasma glucose concentration decreased. The latter was associated with a trend toward higher plasma urea concentration, suggesting that more AA were used for gluconeogenesis as the supply of propionate decreased and that of butyrate increased. Milk yield was not changed. The concentrations of milk fat and protein increased, and that of lactose decreased linearly, with the rate of butyrate infusion. Milk fat yield increased, and lactose yield tended to decrease, with increased butyrate infusion. These results indicate that changes in the supply of butyrate do not affect markedly milk yield in cows yielding less than 20 kg/d but cause marked changes in milk composition. The increase in ruminal butyrate supply increased ketogenesis and decreased gluconeogenesis in the liver of lactating dairy cows.

3-Hydroxybutyric Acid↗
PubMed1990

Sodium butyrate in combination with insulin or dexamethasone can terminally differentiate actively proliferating Swiss 3T3 cells into adipocytes.

Sodium butyrate arrests the growth of actively proliferating Swiss 3T3 cells. A previous report from our laboratory describes the pattern of expression of a representative group of growth-associated genes following treatment of Swiss 3T3 cells with sodium butyrate. The results of this study suggest that sodium butyrate-induced growth arrest involves events which lead to adipocyte differentiation (Toscani, A., Soprano, D.R., and Soprano, K.J. (1988) Oncogene Res. 3, 233-238). However, while sodium butyrate by itself could apparently initiate adipogenesis, it alone was not sufficient to maintain this differentiation state. We now wish to further characterize the role of sodium butyrate in adipocyte differentiation. Subconfluent cultures of Swiss 3T3 cells were treated with sodium butyrate in combination with other agents known to induce Swiss 3T3 cell adipogenesis (e.g. 1-methyl-3-isobutylxanthine, insulin, and dexamethasone) and then analyzed at various times thereafter for: (a) the presence of high concentrations of intracellular lipid as detected by microscopic examination of treated cells following staining with lipid-specific dyes and (b) the expression of four genes known to be modulated during the differentiation of preadipocytes into mature adipocytes (actin, adipsin, lipoprotein lipase, and adipocyte P2). Our results show that sodium butyrate in combination with either insulin or dexamethasone can fully differentiate Swiss 3T3 cells into adipocytes, at least as determined by accumulation of high levels of intracellular lipid. Moreover, the sodium butyrate-mediated process of differentiation can occur in subconfluent, actively proliferating cells. Thus, these experiments describe a new, previously unidentified activity of sodium butyrate and also suggest that this model system may be a useful one to study the relationship between growth arrest and differentiation.

Actins↗
PubMed1990

Sodium butyrate selectively alters thyroid hormone receptor gene expression in GH3 cells.

High-affinity binding of thyroid hormone (T3) to nuclear receptors influences the transcriptional rate of specific genes. The carboxylic acid, sodium butyrate, is known to reduce nuclear binding of T3 in GH3 rat pituitary cels, and this effect correlates with inhibition of T3 responsiveness. Incubation of GH3 cells with 10 mM, but not 1 mM, sodium butyrate abolishes induction of growth hormone gene expression by T3. The relationship between thyroid hormone receptor (TR) depletion and inhibition of T3 action was further investigated by determining the effects of sodium butyrate on TR gene expression. GH3 cells contain mRNAs encoding at least three thyroid hormone receptors (TRs alpha 1, beta 1, and beta 2), as well as a related non-T3 binding repressor or T3 action (c-erbA alpha 2). Remarkably, 10 mM sodium butyrate reduces TR beta 2 mRNA levels by greater than 95% in the presence or absence of T3. The down-regulation of TR beta 2 mRNA occurs at a concentration of sodium butyrate between 5 and 10 mM and is maximal by 8 h of treatment. In contrast, TR beta 1 mRNA levels are unchanged. Furthermore, sodium butyrate has little effect on the mRNAs encoding TR alpha 1 and c-erbA alpha 2. Nuclear run-on assays indicated that sodium butyrate depletes TR beta 2 mRNA by rapidly repressing TR beta 2 gene transcription. In the presence of the transcriptional inhibitor, actinomycin D, the half-life of TR beta 2 mRNA was approximately 3 h in the presence or absence of sodium butyrate. Thus, the reduction in TR number induced by sodium butyrate is likely to be due to the transcriptionally mediated reduction in TR beta 2 mRNA. These data suggest that TR beta 2 has an important physiological role in the regulation of growth hormone gene expression by T3.

Animals↗
PubMed1987

Butyrate-induced cytoarchitectural reorganization of Mallory body-containing rat hepatic tumor cells.

Diethylnitrosamine (CAS: 55-18-5)-transformed 72/22 rat hepatic tumor cells undergo marked cytoarchitectural changes during exposure to sodium butyrate in vitro. Butyrate treatment of this cell line resulted in an increased cell size, volume, and protein content and in structural reorganization within both the intermediate filament and microfilament networks resulting in the generation of a more normal appearing hepatocytic phenotype. Induced changes in the microfilament system involved the accumulation of F-actin at the cellular margins in the form of a peripheral band and in the development of an extensive, predominantly centralized network of thickened cytoplasmic filament bundles. Such butyrate-induced changes in hepatic tumor cellular morphology and microfilament organization were reflected in a 26-51% increase in the amount of cytoskeletal-associated actin in 72/22 cells, as determined by flow cytofluorimetry of permeabilized intact cells or by scanning densitometry of the electrophoretically separated, detergent-resistant cytoskeletal protein fraction, respectively. It is unlikely that this increase in cellular microfilament content was due to a direct effect of butyrate on actin polymerization per se since butyrate (in final concentrations equal to that used in culture) did not alter either actin monomer-polymer transitions or the nucleation reaction in a defined in vitro polymerization assay. The available data suggest that butyrate may regulate the synthesis or modulate the actin-binding capacity of microfilament-associating proteins in cultured cells. Butyrate-induced "normalization" of 72/22 cytoarchitecture was previously shown to be reflected in a reduction or loss in the expression of specific growth traits characteristic of the transformed phenotype. The experimental reversal of defined cytoarchitectural abnormalities and transformed growth characteristics of 72/22 cells by butyrate provided an in vitro model to elucidate both particular cytoskeletal events associated with epithelial cell transformation and the mechanism of action of apparent differentiation-inducing agents, such as sodium butyrate, on responsive tumor cells.

Actins↗
PubMed1986

Antagonistic effect of butyrate on hexamethylene bisacetamide induced differentiation of murine erythroleukemia cells.

Butyrate, at concentrations greater than 0.75 mM, induces hemoglobin accumulation in murine erythroleukemia cells (MELC). At concentrations below 0.75 mM, butyrate inhibits hemoglobin accumulation induced by hexamethylene bisacetamide (HMBA) as well as HMBA induced commitment to terminal cell division. The blocking of HMBA induced differentiation does not result from growth inhibition. When cells were exposed to HMBA and butyrate for 4 days and then both inducers were removed, the cells did not terminally divide. On the other hand, cells exposed to HMBA for 4 days, with subsequent removal of HMBA, did go on to terminally divide. Thus, butyrate blocks the ability of HMBA to accumulate the intracellular signals for terminal cell division. A 48-h pretreatment of cells with butyrate did not inhibit the ability of subsequent HMBA treatment, after butyrate removal, to induce terminal cell division. These results might suggest that cells do not generate a memory of exposure to HMBA in the presence of butyrate or a memory of exposure to butyrate when used as a pretreatment under these conditions. HMBA, at concentrations below 1.0 mM, does not induce MELC differentiation, but such concentrations actually enhance dimethyl sulfoxide induced differentiation of MELC. Equimolar concentrations of short chain fatty acids (1 to 7 carbons) were tested for their ability to block HMBA induced differentiation of MELC. Butyrate and valerate (4 and 5 carbons, respectively) had blocking activities similar to each other, whereas the other fatty acids exhibited little or no blocking of HMBA induced differentiation.

Acetamides↗
PubMed2000

Release characteristics of a short-chain fatty acid, n-butyric acid, from its beta-cyclodextrin ester conjugate in rat biological media.

6(A)-O-(n-Butanoyl)-beta-cyclodextrin was prepared and its hydrolysis behavior in aqueous solutions and in rat intestinal fluids was investigated. Furthermore, the enzymatic hydrolyses of the n-butyric acid-beta-cyclodextrin conjugate using alpha-amylase and esterase were studied to gain insight into the release behavior of n-butyric acid from the conjugate. The hydrolysis of the conjugate proceeded according to a first-order kinetics in aqueous solution, and gave a V-shaped pH profile, indicating a specific acid-base-catalyzed hydrolysis at acidic and neutral-alkaline regions, respectively. The half-lives (t(1/2)) of the conjugate at pH 4.4, 6.8, and 7.4 at 37 degrees C were approximately 580, 43, and 6 days, respectively, indicating that the conjugate is stable in aqueous solution. No appreciable release of n-butyric acid from the conjugate was observed in the stomach and small intestinal contents of rats, or in the small and large intestinal homogenates of rats. On the other hand, a fast disappearance of the conjugate and an appearance of n-butyric acid were observed in the cecal and colonic contents of rats. The t(1/2) values of the disappearance were approximately 4, 1, and 6 h in 10 and 15% cecal contents and 10% colonic contents, respectively, and the appearance of n-butyric acid after 6 h was approximately 10% in the 15% cecal contents. Aspergillus oryzae alpha-amylase hydrolyzed the conjugate to small saccharide conjugates, such as the triose and maltose conjugates, but there was no appreciable release of n-butyric acid. The conjugate was less susceptible to carboxylic esterase (from porcine live), thus releasing no appreciable amounts of n-butyric acid. On the other hand, a fast release of n-butyric acid was observed when the esterase was employed after amylase hydrolysis, suggesting that two types of enzymes, sugar-degrading and ester-hydrolyzing enzymes, are necessary for the release of n-butyric acid from the conjugate in large intestinal contents.

Animals↗
PubMed2004

Linear relationship between Wnt activity levels and apoptosis in colorectal carcinoma cells exposed to butyrate.

We have reported that butyrate, a fatty acid produced by dietary fiber that induces cell cycle arrest, differentiation and/or apoptosis in colorectal carcinoma (CRC) cells in vitro, modulates Wnt activity in 2 CRC cell lines (Bordonaro et al., Int. J. Cancer, 2002; 97:42-51). Our study determines how changes in the levels of Wnt activity induced by butyrate relate to the effects of butyrate on apoptosis, cell cycle arrest and differentiation of CRC cells. In 10 human CRC cell lines a direct relationship was shown between apoptosis and butyrate-induced increase in Wnt activity, as well as between suppressed clonal growth and increased Wnt activity. No correlation existed between butyrate-induced increase in Wnt activity and differentiation. The direct relationship between apoptosis and Wnt activity was supported by analyses of DLD-1 and HCT-116 cells expressing a dominant negative form of Tcf4, and therefore, with repressed Wnt activity, as well as by measuring the ratio of apoptotic to live cells in flow cytometry-sorted cell fractions with high and low Wnt activity. Novel flow cytometric methodology was utilized to show that butyrate differentially increases the number of cells with Wnt activity in different CRC cell lines. Thus, CRC cell lines in which butyrate upregulated Wnt activity to relatively high levels were most susceptible to the apoptotic effects of butyrate, whereas cell lines in which butyrate modestly modulated Wnt activity were less affected.

Apoptosis↗