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PubMed1997

Sodium butyrate induces NIH3T3 cells to senescence-like state and enhances promoter activity of p21WAF/CIP1 in p53-independent manner.

Sodium butyrate, a histone deacetylase inhibitor, has been shown to induce differentiation of many cancer cells and senescence-like state of human fibroblasts. Here we show that sodium butyrate also induces senescence-like state of NIH3T3 cells. The treated cells were blocked at G1 phase and featured morphologically like senescent cells with enlarged cytoplasm and multiple nuclei. The expression of p21(WAF/CIP1) (p21) increased after sodium butyrate treatment at transcriptional level. To analyze the induction of promoter activity, we isolated 4.6 kb of murine p21 promoter and inserted it upstream of a luciferase reporter gene. When this construct was transiently transfected into NIH3T3 cells, sodium butyrate enhanced the luciferase activity. p53 independency of sodium butyrate-inducible p21 promoter activity was confirmed by using the deletion mutants lacking p53 binding sites and p53 deficient cells in transfection experiments.

3T3 Cells↗
PubMed1998

A protein phosphatase is involved in the inhibition of histone deacetylation by sodium butyrate.

Treatment of cells with sodium butyrate is known to increase histone acetylation by inhibiting deacetylases. Here we have observed, in cultured hepatoma cells, that the potent serine-threonine phosphatase inhibitors, okadaic acid or calyculin A, inhibited phosphatase activity and concomitantly decreased the histone acetylation classically maintained by sodium butyrate. These results suggest that a protein phosphatase may mediate the sodium butyrate effect on deacetylases. Since we have previously found that such a protein would also mediate the sodium butyrate effect on gene expression, we propose that a phosphatase activity constitutes an early and essential step in the sodium butyrate-triggered signalling pathway.

Acetyltransferases↗
PubMed1997

Modulation of heat-shock protein 70 (HSP70) gene expression by sodium butyrate in U-937 promonocytic cells: relationships with differentiation and apoptosis.

The administration of sodium butyrate at 0.75 mM induced the functional differentiation of U-937 human promonocytic leukemia cells with negligible cell mortality. However, the drug rapidly caused cell death with characteristics of apoptosis when used at concentrations of 5 mM and above. In addition, butyrate stimulated the expression of the stress-responsive heat-shock protein 70 (HSP70) gene when applied at both differentiation-inducing and apoptosis-inducing concentrations. The induction of HSP70 by butyrate was inhibited by the simultaneous addition of cAMP-increasing agents (dibutyryl cAMP or the combination of forskolin plus theophylline). However, these agents did not prevent differentiation and only partially reduced apoptosis. Moreover, the DNA topoisomerase II inhibitor etoposide, which provoked U-937 cell differentiation and apoptosis with the same or greater efficiency than butyrate, failed to stimulate HSP70 expression. Finally, it was observed that cAMP-increasing agents also abrogated the induction of HSP70 and reduced the apoptosis caused by cadmium chloride, a typical inducer of the stress response. Taken together, these results indicate that HSP70 expression is not required for differentiation of promonocytic cells, as earlier proposed, and that butyrate probably triggers the stress response in these cells.

Antineoplastic Agents, Phytogenic↗
PubMed1994

Butyrate increases colonocyte protein synthesis in ulcerative colitis.

Butyrate promotes epithelial cell healing and improves symptoms when administered rectally in patients with distal ulcerative colitis (UC). It was hypothesized that butyrate may enhance healing in patients with UC by stimulating colonocyte proliferation and/or protein production. Mucosa from the descending colon was obtained from patients with UC (n = 5), Crohn's disease (n = 8), diverticulitis (n = 6), and cancer (normal tissue 10 cm from tumor; n = 10). Epithelial cells were isolated using dispase/collagenase and differential sedimentation and incubated for 4 hr at 37 degrees C with either Na butyrate (10 mM) or NaCl (10 mM). Protein synthesis was assessed by [14C]leucine incorporation and proliferation was determined with [3H]thymidine. Mean viability and purity were >88%. Spontaneous proliferation was significantly increased in UC when compared to diverticulitis and normal controls. Butyrate significantly increased protein synthesis in UC epithelial cells when compared to saline control. The therapeutic effects of butyrate in patients with UC may be due to its use by epithelial cells as a metabolic fuel to increase protein production and promote healing.

Aged↗
PubMed1996

Induction of alloantigen-specific hyporesponsiveness in vitro by n-butyrate: antagonistic effect of cyclosporin A.

The short-chain fatty acid n-butyrate has recently been shown in vitro to specifically downregulate T cell reactivity to nominal antigen or to alloantigen, which possibly results from inhibition of cell cycle progression in early G1 phase during antigen contact. In the present study, we investigated the effect of cyclosporin A (CyA) on the modulation of alloreactivity in human mixed lymphocyte culture (MLC) by n-butyrate. Whereas in primary culture, CyA additively enhanced inhibition of DNA synthesis by n-butyrate, the effect of this agent on secondary T cell reactivity was clearly antagonized by CyA. Thus, specific downregulation of proliferative responsiveness to restimulation with antigen from the original donor, observed in cultures pretreated with n-butyrate alone, was at least partially prevented by the addition of CyA to the primary culture. Our in vitro finding indicates that specific downregulation of T cell alloreactivity by n-butyrate might depend on a calcium-dependent T cell receptor (TCR)-mediated signal sensitive to the immunosuppressive action of CyA.

Butyrates↗
PubMed1991

Sodium butyrate causes reexpression of three membrane proteins on glycolipid-anchoring mutants.

Murine Thy-1-negative lymphoma mutants synthesize membrane proteins that normally bear glycolipid anchors but do not express these proteins on the cell surface. This phenotype may reflect altered regulation of gene(s) required for anchor biosynthesis. Since tissue culture cells treated with sodium butyrate transcribe new DNA sequences and since these transcripts are translated, it was of interest to determine whether butyrate treatment could restore surface expression of lipid-anchored proteins. When Thy-1-negative lymphoma mutants (complementation groups A-C, E, F, and H) were cultured for three days in 1.5 mM butyrate, a small percentage of the class H cells acquired phosphatidylinositol-specific phospholipase C-releasable surface Thy-1 and J11d. Membrane-associated Thy-1 was not observed before 24 h of treatment. Induction was reversible. Cell fusion studies have shown that murine LM (TK-) fibroblasts can be assigned to the class H lymphoma complementation group. Although these cells synthesize Ly-6, this normally lipid-anchored protein is absent from the cell surface. When LM (TK-) cells were cultured for three days in butyrate, 10% of the cells reversibly expressed Ly-6. In addition, LM (TK-) cells transfected with a plasmid encoding Thy-1 do not express Thy-1, but could be induced to express both Ly-6 and Thy-1 by butyrate treatment. Northern analysis of total RNA from Ly-6/Thy-1-expressing cells indicates that increased steady-state transcript levels cannot account for surface expression of these proteins. We conclude that the lack of expression of three proteins at the surface of class H mutant and the LM (TK-) cells is not due to gross structural lesions in genes along the anchor biosynthetic pathway.

Animals↗
PubMed1989

Effects of butyrate and insulin and their interaction on the DNA synthesis of rumen epithelial cells in culture.

Rumen epithelial cells (REC) were incubated in the presence of various concentrations of butyrate or insulin or with both of them, to obtain information on their effect on the DNA synthesis of cultured cells. The 24-h values of 3H-thymidine incorporation into cellular DNA were measured in the presence of butyrate, insulin or butyrate plus insulin. While butyrate reduced DNA synthesis, insulin produced an increase over the control. Combined butyrate plus insulin treatment influenced the incorporation of label in accordance with the relative proportion of these two substances.

Animals↗
PubMed1983

Effect of media composition on the induction of chorionic gonadotropin by sodium butyrate in HeLa cells.

Production of the glycoprotein hormone alpha-subunit by HeLa cells and its induction by sodium butyrate are dependent on the choice of culture medium. Under identical growth conditions it was found that subunit synthesis in the presence of butyrate was highest in RPMI 1640, lowest in Medium 199 (M199), and intermediate in minimum essential medium (MEM) and Waymouth's MB 752/1. Cell growth was similar in all media examined and was retarded in the presence of butyrate. Alkaline phosphatase activity was also lower in M199 than in RPMI 1640, although, in general, the magnitude of this difference was less than that for the hormone subunit. Incorporation of [1-14C]butyrate by HeLa cells was similar in both M199 and RPMI 1640, indicating that uptake and metabolism of the fatty acid were not significantly different under these conditions. In the presence of 3 mM butyrate, mixtures of RPMI 1640 and M199 gave intermediate levels of alpha-subunit and alkaline phosphatase compared to each medium alone. Intracellular levels of alpha-subunit as well as that of the culture medium were reduced in M199 compared to RPMI 1640 indicating that synthesis rather than secretion was altered.

Alkaline Phosphatase↗
PubMed1988

Butyric acid: inhibition of non-leukemic and chronic myeloid leukemia granulocyte macrophage clonal growth.

Butyric acid has been shown to inhibit the growth of several established tumor cell lines and to induce either granulocytic or erythroid differentiation in different human and murine leukemic cell lines. The dose-dependent effect of butyric acid was tested in vitro on the clonal growth of granulocyte macrophage progenitors in 13 patients with chronic myeloid leukemia (CML) and compared with control bone marrow and peripheral blood responses. The growth of myeloid progenitors from both healthy donors and non-leukemic and leukemic patients was almost completely inhibited by 1.0 mM butyric acid. At 0.5 mM butyric acid, inhibition of CML progenitors, both from chronic phase and blastic phase patients, was significantly greater (P less than 0.01) than bone marrow from non-leukemic patients and peripheral blood controls. Butyric acid, a 4-carbon compound, was the most potent inhibitor of six short chain fatty acids tested on CML myeloid progenitors.

Adult↗
PubMed1990

Enhancement by theophylline of the butyrate-mediated induction of choriogonadotropin alpha-subunit in HeLa cells. I. Lack of correlation with cAMP.

The glycoprotein hormone common alpha-subunit can be induced in HeLa and other nontrophoblastic tumor cell lines by sodium butyrate. This report demonstrates that production of alpha-subunit can be further modulated by theophylline, especially in conjunction with butyrate. This synergism was not observed with other phosphodiesterase inhibitors such as xanthine, caffeine, theobromine, or methylisobutylxanthine. Induction by a combination of the short chain fatty acid plus the methylxanthine results from a decrease in the lag time after effector addition as well as a change in the rate of subunit accumulation. The increase in alpha-subunit is correlated with an increase in the levels of alpha-subunit mRNA, suggesting that induction is manifest at a pretranslational stage. The production of alpha-subunit was only marginally affected in cultures treated with 8-Br-cAMP or forskolin. Intracellular levels of cAMP were increased approximately threefold by methylisobutylxanthine, twofold by theophylline, fourfold by forskolin, and about 50% by butyrate, yet significant induction was achieved only by butyrate and theophylline. Taken together, these data suggest that the synergism between butyrate and theophylline is not mediated by cAMP.

Alkaline Phosphatase↗
PubMed1990

Enhancement by theophylline of the butyrate-mediated induction of choriogonadotropin alpha-subunit in HeLa cells. II. Effect of both agents on mRNA turnover.

In the accompanying paper it was demonstrated that among several methylxanthine phosphodiesterase inhibitors, only theophylline significantly increased production of the glycoprotein hormone alpha-subunit in HeLa cells, and that this action was synergistic with that of sodium butyrate. A correlation between alpha-subunit induction and cAMP concentrations was not evident. In this report we characterized the effect of these two drugs on the metabolism of alpha-subunit mRNA. Sodium butyrate decreased the apparent half-life of mRNAs encoding alpha-subunit, beta 2-microglobulin, and alpha-tubulin, as well as that of total poly(A)+ RNA and rRNA. Theophylline produced a two- to threefold increase in the apparent half-life of alpha-subunit mRNA but had no effect on the turnover of beta 2-microglobulin, alpha-tubulin, or total poly(A)+ mRNA. An inverse correlation was noted between the apparent half-life of the mRNA and the degree of destabilization elicited by butyrate. It is concluded that alpha-subunit induction by theophylline is in large part due to mRNA stabilization, and that the concerted effect of theophylline and butyrate results from inhibition by theophylline of the butyrate-mediated destabilization of alpha-subunit mRNA combined with the elevation in alpha-subunit gene transcription known to be produced by the fatty acid.

Blotting, Northern↗
PubMed1985

Pretranslational regulation of ectopic hCG alpha production in ChaGo lung cancer cells by sodium butyrate.

Ectopic production of hCG and its free alpha subunit by ChaGo lung cancer cells is stimulated by sodium butyrate. To investigate pretranslational regulation in this system, we examined the response of the hCG alpha and beta subunit mRNAs in ChaGo-K1 cells, a clone that produces free hCG alpha but no hCG or hCG beta in the basal state. When a Northern blot of total RNA from ChaGo cells was hybridized to a [32P]- labeled hCG alpha cDNA probe, a single band was detected that was identical in size (approximately 850 bases) to placental hCG alpha mRNA. RNA from butyrate-stimulated (5 mM, 24 h) ChaGo cells contained 7.7 times as much hCG alpha mRNA as RNA from control ChaGo cells. This increase appeared to be relatively selective since no difference in total polyA-containing mRNA levels was detected between butyrate-treated and control cells by [32P]oligo(dT) hybridization. In addition, no hCG beta mRNA was detected when Northern and dot blots were hybridized to an hCG beta cDNA probe. In a time course experiment, hCG alpha mRNA accumulation in butyrate-treated cells increased significantly by 8 h with a maximum increase of 6.1-fold at 24 h compared to control values. Major differences in immunoactive hCG alpha accumulation were not apparent, however, until after 24 h. These studies show that stimulation of ChaGo hCG alpha production by butyrate can be completely accounted for by pretranslational events and that failure to detect hCG or free hCG beta production by these cells is not due to poorly translatable RNA or post-translational protein degradation. Thus, exclusive ectopic production of only one of the hCG subunits is likely to be due to selective genomic expression.

Butyrates↗
PubMed1988

Effect of n-butyrate on the synthesis of sulfated glycosaminoglycans and hyaluronate by rat liver fat-storing cells (Ito cells).

The effect of naturally occurring aliphatic carboxylic acid n-butyrate on total and type-specific synthesis of sulfated proteoglycans and hyaluronic acid by rat liver fat-storing cells (Ito cells, vitamin A-storing cells), the main connective tissue producing cell type in liver, was studied. Concentrations of n-butyrate equal to and higher than 5 mM inhibited significantly in a dose-dependent manner the incorporation of [35S]sulfate and [3H]glucosamine into the carbohydrate chains of sulfated proteoglycans. Maximum inhibition of 70% was reached at 15 mM. Similarly, the formation of hyaluronic acid was impaired by n-butyrate. The synthesis profile of specific sulfated proteoglycans was not affected by the compound. beta-Xyloside, an artificial carbohydrate chain initiator, reversed only partially the inhibitory effect of n-butyrate. Thus, the mechanism of n-butyrate inhibition may involve an impairment of both proteoglycan core protein formation and glycosaminoglycan chain elongation.

Adipose Tissue↗
PubMed1989

Stimulation of choline acetyltransferase activity by retinoic acid and sodium butyrate in a cultured human neuroblastoma.

Choline acetyltransferase (Acetyl-CoA:choline O-acetyltransferase, EC 2.3.1.6, abbreviated ChAT), the biosynthetic enzyme for acetylcholine and acetylcholinesterase (EC 3.1.1.7, abbreviated AChE) are expressed in a human cholinergic neuroblastoma cell line, MC-IXC. We have shown that ChAT activity can be regulated in culture by retinoic acid, an active metabolite of vitamin A, and by sodium butyrate, an organic fatty acid. Optimal concentrations of these agents produce 4.3-fold and 1.6-fold increases in ChAT activity, respectively. The effects of retinoic acid are statistically significant after 24 h, whereas for sodium butyrate significant differences are seen only after 48 h. Since retinoic acid stimulation of ChAT activity was reversed only by trypsin treatment and not by removal of retinoic acid from the medium, this suggests that this agent may be acting at the level of the cell surface. Other differentiating conditions, such as culture in serum-free medium or addition of 1-2% dimethylsulfoxide did not increase ChAT activity. Acetylcholinesterase activity was shown to increase only in the presence of sodium butyrate, suggesting that retinoic acid and sodium butyrate may be acting via different pathways. Retinoic acid and sodium butyrate both seem to be permissive rather than instructive in regulating ChAT activity in that they are unable to induce ChAT expression de novo in cell lines which do not already express ChAT activity.

Butyrates↗
PubMed1990

Differential effects of sodium butyrate and hyperosmolality on the modulation of alkaline phosphatases of LoVo cells.

LoVo cells produce term-placental and intestinal alkaline phosphatases. Hyperosmolality and sodium butyrate increase the levels of both, but the effect of sodium butyrate is more pronounced on the intestinal enzyme. When applied together, induction of term-placental alkaline phosphatase is additive and that of the intestinal enzyme is synergistic. Induction by either stimulus or by their mixture is independent of cell density. However, whereas the effect of hyperosmolality is readily reversible, induction by sodium butyrate is not. No synergistic increase in intestinal alkaline phosphatase activity occurs when cells are sequentially treated with hyperosmolality and sodium butyrate or vice versa. This indicates that only when applied concurrently does one inducer amplify the effect of the other. Since the normal colonic mucosa produces intestinal alkaline phosphatase, its predominant induction by sodium butyrate in LoVo cells may reflect a more differentiated state.

Alkaline Phosphatase↗
PubMed1990

The induction of vimentin gene expression by sodium butyrate in human promonocytic leukemia U937 cells.

The administration of 1 mM sodium butyrate induced the phenotypic differentiation of human promonocytic leukemia U937 cells, as judged by the expression of cD11b and cD11c antigens, two differentiation-specific surface markers. At the same time, butyrate greatly induced the expression at the mRNA level of the vimentin gene. The increase in the level of this RNA started at 6 h of treatment and reached the maximum at Hour 24. Such an increase was caused at least in part by a stimulation in the rate of gene transcription, as suggested by transcription assays in isolated nuclei. Experiments in the presence of cycloheximide suggested that vimentin induction is probably a direct response to the action of butyrate, not mediated by the prior induction of other gene products. Unlike the case of vimentin, the levels of other RNAs, namely beta-actin, ornithine decarboxylase, and c-myc, were not enhanced, but they decreased at different times of treatment with butyrate. Finally, we observed that butyrate induced also the differentiation of HL60 cells, another human myeloid cell type. Nevertheless, the drug failed to stimulate the expression of vimentin in this cell line.

Butyrates↗
PubMed1989

n-butyrate and dexamethasone synergistically modulate the surface expression of epidermal growth factor receptors in cultured rat hepatocytes.

n-Butyrate was previously found to increase the epidermal growth factor (EGF) receptor binding in primary cultures of rat hepatocytes. We show here that butyrate and dexamethasone synergistically modulate the surface expression of the EGF receptors. The butyrate-induced enhancement of high-affinity EGF binding was only slight in the absence of glucocorticoid, but was strongly and dose-dependently amplified by dexamethasone. Butyrate counteracted the inhibition by insulin of the dexamethasone-induced increase in EGF binding. The results indicate that the glucocorticoid has a permissive effect on a butyrate-sensitive process that determines the surface expression of the high-affinity class of EGF receptors.

Animals↗
PubMed1992

Effect of butyrate enemas on the colonic mucosa in distal ulcerative colitis.

Short-chain fatty acid irrigation has been shown to ameliorate inflammation in diversion colitis. In this study the effect of butyrate enemas was tested in 10 patients with distal ulcerative colitis who had been unresponsive to or intolerant of standard therapy for 8 weeks. They were treated for 2 weeks with sodium butyrate (100 mmol/L) and 2 weeks with placebo in random order (single-blind trial). Before and after treatment, clinical symptoms were noted and the degree of inflammation was graded endoscopically and histologically. Rectal proliferation was assessed by autoradiography. After butyrate irrigation, stool frequency (n/day) decreased from 4.7 +/- 0.5 to 2.1 +/- 0.4 (P less than 0.01) and discharge of blood ceased in 9 of 10 patients. The endoscopic score fell from 6.5 +/- 0.4 to 3.8 +/- 0.8 (P less than 0.01). The histological degree of inflammation decreased from 2.4 +/- 0.3 to 1.5 +/- 0.3 (P less than 0.02). Overall crypt proliferation was unchanged, but the upper crypt-labeling index fell from 0.086 +/- 0.019 to 0.032 +/- 0.003 (P less than 0.03). On placebo, all of these parameters were unchanged. These data support the view that butyrate deficiency may play a role in the pathogenesis of distal ulcerative colitis and that butyrate irrigation ameliorates this condition.

Adult↗