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PubMed1988

Endometrial and vaginal response to three different oestrogen preparations administered by the transdermal and oral routes.

In a randomized, cross-over study endometrial and vaginal response to transdermal 17 beta-oestradiol (TTS-oestradiol 50 micrograms) and two forms of oral oestrogen replacement therapy (conjugated oestrogens 1.25 mg and oestradiol valerate 2 mg) were studied in 13 peri-menopausal and post-menopausal women. Five (5) of the women exhibited periodic ovarian function as evidenced by peripheral oestradiol and progesterone levels and were considered to be peri-menopausal. In the post-menopausal group of 8 women the bleeding pattern was more regular than among the peri-menopausal women. In the case of the post-menopausal group the number of days on which spotting and bleeding occurred was significantly lower during the administration of TTS-oestradiol than during treatment with conjugated oestrogens. This finding was paralleled by a significantly higher karyopyknotic index in the vaginal epithelium and significantly increased deoxyribonucleic acid (DNA) synthesis in the endometrial cells during treatment with equine oestrogens. No significant difference was seen in these indices when the effect of TTS-oestradiol was compared with that of oestradiol valerate. The study results in the post-menopausal group suggested a relationship between the intensity of the oestrogen treatment and not only the proliferation and maturation of the oestrogen target-organ cells but also the number of days on which bleeding occurred. It was concluded that a clear distinction needs to be made between peri-menopausal and post-menopausal women. In the present study the irregular ovarian activity among the peri-menopausal subjects precluded an unbiased assessment of the exogenous oestrogens. It is also likely that exogenous oestrogens exert a cumulative action with oestrogen secreted endogenously, interfere with the physiological events at the target organ level and induce uncontrollable endometrial bleeding. The complete cessation of ovarian activity may therefore have to be established before exogenous oestrogens are administered to climacteric patients.

Administration, Cutaneous↗
PubMed1994

Bleeding pattern and climacteric symptoms during different sequential combined HRT regimens in current use.

Four sequential combined oestrogen and progestogen regimens were compared in terms of bleeding pattern and relief of climacteric symptoms. Treatment was with either 2 mg 17 beta-oestradiol with 1 mg norethisterone acetate [E2 + NETA]; 2 mg oestradiol valerate with 75 micrograms levonorgestrel [E2V + LNG]; 2 mg oestradiol valerate with 10 mg medroxyprogesterone acetate [E2V + MPA]; or 1.5 mg 17 beta-oestradiol with 150 micrograms desogestrel [E2 + DG]. A placebo-controlled study lasting 12-24 months was completed by 143 healthy early postmenopausal women. Bleeding lengths were not substantially different; in all regimens the majority of women were bleeding for 3-6 days. Bleeding onset showed differences when related to the 11th day of progestogen addition; in the regimen with E2V + LNG, 21% of the women women were bleeding before the 11th day of progestogen addition 26% on, and 53% after that day. In the regimen with E2V + MPA, 56% of the women were bleeding before the 11th day, 28% on, and 17% after that day, whereas in the regimen with E2 + DG, 15% of the women were bleeding before the 11th day, 5% on, and 80% after that day. All regimens reduced climacteric symptoms to the same extent. Breast tenderness occurred in all the regimens, except in the E2 + DG. Conclusively, the differences between the responses to treatment were not conspicuous. However, our data indicate that one regimen (E2 + DG) resulted in optimal bleeding control, optimal effect on climacteric symptoms, and no production of breast tenderness.

Breast↗
PubMed1994

Plasma concentrations of medroxyprogesterone acetate, estradiol and estrone following oral administration of Klimaxil, Trisequence/Provera and Divina. A randomized, single-blind, triple cross-over bioavailability study in menopausal women.

The absorption of estradiol and medroxyprogesterone acetate was investigated in a randomized single-blind, triple cross-over study, in 12 menopausal women, for four different HRT drugs (Klimaxil, a combination tablet containing 17 beta-estradiol 2 mg and medroxy-progesterone acetate 5 mg; Divina, a combination tablet containing 17 beta-estradiol valerate 2 mg and medroxyprogesterone acetate 10 mg; Trisequence, a triphasic preparation containing 17 beta-estradiol 2 mg in the first phase; Provera, a tablet containing medroxyprogesterone acetate 5 mg). Trisequence and Provera were ingested simultaneously. In conclusion, there was no statistically significant difference between the drugs with respect to the estradiol levels. The estrone concentration, however, differed between the different drugs. The serum concentration was higher after intake of tablets containing estradiol than after intake of tablets containing the valerate ester. There was a significant increase in the MPA levels between periods 1 and 3. Finally, Divina produced higher MPA concentrations than Klimaxil and the combination of Trisequence and Provera, although the mean AUC was not twice as high, as might have been expected.

Administration, Oral↗
PubMed1994

Effects of oestradiol administration via different routes on the lipid profile in women with bilateral oophorectomy.

To determine the influence of various oestrogenenic administrations on lipid response, 63 women with total abdominal hysterectomy and bilateral anexectomy were studied before and 6 and 12 months after receiving 17 beta-oestradiol by different means. The effect on the levels of lipids and lipoproteins of the 2 mg/24 h administration of oestradiol valerate was compared with 1.5 mg/day of percutaneous 17 beta-oestradiol and 0.05 mg/day of transdermic oestradiol. The treatments were given continuously over a year. The oestradiol valerate produced a statistically significant increase (P < 0.05) of the HDL-C levels both after 6 and 12 months (10.6% vs. 11.6%). A significant increase was also observed (P < 0.05) in the Apo AI levels during the treatment (18 and 25%). On the other hand, unfavorable side effects with oestradiol were not produced, either percutaneous or transdermic, on lipid plasmatic or lipoprotein levels. These data show the benefit of oral oestrogenic therapy and the maintenance of the lipid profile in percutaneous and transdermic therapies in oophorectomized women.

Administration, Cutaneous↗
PubMed2005

Application of response surface methodology for optimization of acidogenesis of cattail by rumen cultures.

Acidogenesis of cattail using rumen cultures was carried out to produce volatile fatty acids (VFA) in this study. The influences of pH and substrate concentration on cattail degradation, VFA yield and microbial growth were investigated by using response surface methodology (RSM). Experimental results showed that a low substrate concentration and pH of 6.9 were optimal for acidogenesis of cattail. The highest cattail degradation efficiency, VFA yield and microbial yield were 75.9%, 0.41 g/g VS and 0.110 g/g VS, respectively. Further experiments confirmed that the main VFA in the acidogenesis of cattail were acetate, propionate and butyrate, while i-butyrate, valerate and i-valerate were also produced at low levels. The results suggested that acidogenesis using rumen cultures is a promising method for cattail disposal.

Animals↗
PubMed2005

Structure-based design, synthesis, and biological evaluation of novel 1,4-diazepines as HDM2 antagonists.

Crystallographic analysis of ligands bound to HDM2 suggested that 7-substituted 1,4-diazepine-2,5-diones could mimic the alpha-helix of p53 peptide and may represent a promising scaffold to develop HDM2-p53 antagonists. To verify this hypothesis, we synthesized and biologically evaluated 5-[(3S)-3-(4-chlorophenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-2,5-dioxo-7-phenyl-1,4-diazepin-1-yl]valeric acid (10) and 5-[(3S)-7-(2-bromophenyl)-3-(4-chlorophenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-2,5-dioxo-1,4-diazepin-1-yl]valeric acid (11). Preliminary in vitro testing shows that 10 and 11 substantially antagonize the binding between HDM2 and p53 with an IC(50) of 13 and 3.6 microM, respectively, validating the modeling predictions. Taken together with the high cell permeability of diazepine 11 determined in CACO-2 cells, these results suggest that 1,4-diazepine-2,5-diones may be useful in the treatment of certain cancers.

Antineoplastic Agents↗
PubMed2005

The effects of hormone therapy, estrogen therapy and tibolone on apoptosis and cyclin D1 expression in postmenopausal vaginal epithelium.

OBJECTIVE: To investigate the effects of hormone therapy, estrogen therapy and tibolone on markers of apoptosis including bcl-2, and bax and cyclin D(1) expression in postmenopausal vaginal epithelium. STUDY DESIGN: Thirty postmenopausal women were randomized to the treatment protocols (0.625 mg conjugated equine estrogen (CEE) + 2.5 mg medroxyprogesterone acetate (MPA); 2mg estradiol valerate; 2.5mg tibolone). After baseline vaginal biopsy, control biopsies were performed after 70 days following the initiation of the therapy. Bcl-2, bax, Bcl-2/bax ratio, cyclin D(1) measurements were performed immunohistochemically. Data were analyzed by Kruskal-Wallis, Mann-Whitney U and Wilcoxon tests. RESULTS: After the treatment period the above-mentioned parameters were not different among the groups except for cyclin D(1) levels. Cyclin D(1) expression was found to be strong in patients with treated estradiol valerate. CONCLUSIONS: The effects of estrogen on cyclin D(1) expression were not detected with tibolone or with the addition of progesterone to estrogen in the vaginal epithelium. Cyclin D(1) appeared to have stronger effects on the estrogen related proliferation compared to apoptotic markers in vaginal epithelial cells.

Adult↗
PubMed2005

Effect of the cessation of long-term hormone replacement therapy on plasma plasminogen activator inhibitor-1 and fibrinogen.

OBJECTIVE: Hormone replacement therapy (HRT) has generally been documented to reduce plasminogen activator inhibitor-1 (PAI-1) and fibrinogen levels in plasma of postmenopausal women. We used a wash out protocol to study whether stopping long-term HRT with estrogen alone or a combination of estrogen-progestin have different effects on these markers of hemostasis. STUDY DESIGN: Thirty healthy postmenopausal women on HRT participated. Fifteen had estradiol valerate, and 15 had estradiol valerate and levonorgestrel. Each was studied after long-term HRT (period 1), four weeks after cessation of the treatment (period 2, wash out), and three weeks after reintroducing the therapy (period 3). RESULTS: In the estrogen group, PAI-1 increased by 18% during the wash out period (P=0.013) and decreased by 22% after reintroduction of therapy (P=0.001). In the combined therapy group, there was a trend of PAI-1 to increase by 18% when therapy was discontinued (P=0.17), and it decreased by 25% after reintroduction of hormone replacement therapy (P=0.036). Fibrinogen was initially lower in the estrogen group compared with the combined therapy group (p=0.014), and did not change during wash out. CONCLUSION: This wash out study shows that cessation of long-term HRT unfavorably increases PAI-1, but appears to have no adverse effect on fibrinogen.

Drug Combinations↗
PubMed2006

Effect of drug loading on the transformation of vesicular into cubic nanoparticles during heat treatment of aqueous monoolein/poloxamer dispersions.

Colloidal dispersions of the pre-equilibrated cubic phase in the monoolein/poloxamer 407/water system, which are under investigation as potential drug carriers, often contain a considerable fraction of undesired non-cubic particles, particularly when prepared with high concentrations of poloxamer. Recent investigations revealed that the non-cubic particles can be transformed into particles of cubic internal structure by heat treatment. The present study investigates the effect of drug loading on the non-cubic to cubic transformation process during autoclaving of the dispersions. The results indicate that the process can also proceed in dispersions loaded with different concentrations of ubidecarenone, tocopheryl acetate, betamethasone-17-valerate, chloramphenicol or miconazole. At low concentration, none of the drugs had pronounced influence on the autoclaved dispersions whereas with increasing drug concentration different effects were observed. Depending on the type of drug no effects (betamethasone-17-valerate), increasing particle size of the dispersions (chloramphenicol, miconazole) or phase separation upon autoclaving (high load of miconazole) was observed. Except for loading with high amounts of chloramphenicol, which led to the formation of cubic phase particles already without additional heat treatment, the properties of the thermally untreated dispersions were virtually unaffected by drug incorporation.

Glycerides↗
PubMed2005

The influence of microbial metabolites on human intestinal epithelial cells and macrophages in vitro.

Microbial metabolites may influence the metabolic integrity of intestinal epithelial cells and induce mucosal immune responses. Therefore, we investigated the effects of the microbial metabolites butyrate, iso-valerate, and ammonium on Caco-2 cells and macrophages. Barrier functioning was determined by measuring transepithelial electrical resistance and basolateral recoveries of metabolites. The barrier function of Caco-2 cells remained intact after exposures. Basolateral recoveries ranged from 6.2% to 15.2%. Tumour necrosis factor-alpha and interleukin-10 were measured to determine immune reactions. The Caco-2 cells did not secrete both cytokines. Physiological concentrations of butyrate and iso-valerate stimulated the secretion of tumour necrosis factor-alpha and suppressed the secretion of interleukin-10 by macrophages that are not protected by an epithelial barrier. In contrast, ammonium concentrations as high as those produced by microbiotas of IBD patients suppressed the release of both cytokines when the barrier function is impaired.

Ammonium Chloride↗
PubMedDate not supplied

[Acceptability of continuous combined versus cyclical HRT: a French multicentric randomized clinical study].

OBJECTIVES: To describe and compare acceptability of treatment and quality of life over 12 cycles in 2 groups of women randomised to continuous combined Climodiène (estradiol valerate 2 mg/dienogest 2 mg) or cyclic Climène (estradiol valerate 2 mg, from D1 to D21/cyproterone acetate 1 mg, from D12 to D21, followed by 7 days off), switching from previous sequential estroprogestative HRT because of side effects. PATIENTS AND METHODS: One hundred forty three postmenopausal women aged 54.39-years were recruited and randomised to Climène (N=68) or Climodiène (N=75). Acceptability was evaluated by the continuation rate in the 2 groups at the end of the 12 cycles study. Assessment of quality of life was obtained from the responses to the women's health questionnaire (WHQ) and to an ad hoc satisfaction questionnaire at baseline, and at the 12th cycle of treatment. RESULTS: No significant difference in baseline characteristics of volunteers were found in the 2 treatment groups except for the socioeconomic status (more town-dwellers in Climène group). Total WHQ score significantly improved after 12 months of treatment with Climène and Climodiène, respectively decreasing from 68.9 to 64.37 (-4.53) and from 69.95 to 62.06 (-7.89), with a trend towards higher improvement with Climodiène, particularly in the hot flushes subscale. In Climodiène group, a significant decrease in sleep problems and cognitive function subscales was found, which is consistent with previous polysomnography and psycho physiological measures data with Climodiène. The evolution of Satisfaction Index is positive and of the same magnitude in the 2 groups, showing an improvement at 12 months: respectively -2.79 (P=0.002) et -2.26 (P=0.02) for Climène and Climodiène. DISCUSSION AND CONCLUSIONS: Even though the benefit/risk ratio of the hormonal substitutive treatment is recognized effective against climateric symptoms which affect the quality of life, this work is the first randomised prospective study on the effects of Climodiène on quality of life in post-menopausal women assessed by the French validated version of the world-wide used WHQ. Decreases in "sleep problems" and "cognitive function" subscales scores in this study are of a magnitude clinically relevant and consistent with previous data on Climodiène impact on postmenopausal symptoms.

Cyproterone Acetate↗
PubMed2005

Estrogen decreases neointimal hyperplasia and improves re-endothelialization in pigs.

BACKGROUND: 17-Beta-estradiol inhibits smooth muscle cell proliferation and migration and accelerates endothelial cell repair in response to balloon injury. The aim of this study was to determine whether administration of estrogen is associated with decreased neointimal hyperplasia after stenting in the porcine model. METHODS AND RESULTS: Twenty-two farm female pigs 7 months old were oophorectomized and at the third day normal saline (11 pigs) or 20 mg of estradiol valerate (11 pigs), modified release, were administered intramuscularly. At the 10th day after oophorerectomy, 1 or 2 stainless steel stents were implanted in the right coronary artery in each pig, and at the 17th day, normal saline or 10 mg estradiol valerate, modified release, were administered intramuscularly in the two groups. Pigs were sacrificed 28 days after stent implantation and histomorphometric analysis of the coronary arteries was performed (20 stents from the estrogen and 18 stents from the control groups). In the estrogen group, neointimal proliferation area was 1.42+/-0.55 mm(2), whereas in the control group, 1.96+/-0.89 mm(2) (p=0.02). Area stenosis was 39+/-13% and 49+/-16% in the two groups, respectively (p=0.07). Re-endothelialization was 2.67+/-0.34 and 2.22+/-0.46 in the two groups, respectively (p<0.010). The injury score was similar between the two groups. CONCLUSIONS: These data suggest that intramuscular administration of estrogen accelerates the endothelial cell repair in response to injury and reduces intimal hyperplasia in the porcine model.

Animals↗
PubMed2006

Study of the toxic effect of short- and medium-chain monocarboxylic acids on the growth of Saccharomyces cerevisiae using the CO2-auxo-accelerostat fermentation system.

The effect of aliphatic monocarboxylic acids (formic, acetic, propionic, valeric, octanoic and decanoic acids) on the growth and metabolic activity of Saccharomyces cerevisiae S288C was studied, using continuous cultivation method - CO(2)-auxo-accelerostat with smooth increase in the concentration of added monocarboxylic acids. Slow increase in the concentration of these acids resulted in the rapid decrease in the growth yield (Y(ATP)) and specific growth rate (micro), however, the specific ATP production rate (Q(ATP)) increased or stayed almost constant. On the other hand, Q(ATP) decreased if the concentration of formic, acetic or decanoic acids was increased rapidly. The toxic effect of aliphatic monocarboxylic acids on the growth of S. cerevisiae was characterized and quantified from the respective dose-effect curves as the IC(50) value (mM) using two different endpoints: a decrease of 50% in the specific growth rate (IC(50 micro)) and a decrease of 50% in the growth yield based on ATP production (IC(50YATP)). The concentrations of formic, acetic, propionic, valeric, octanoic and decanoic acids causing the 50% reduction in the specific growth rate (IC(50 micro)) were, respectively, 18.1, 47.1, 33.6, 2.3, 0.16 and 0.07 mM. The IC(50 micro) values were notably lower (up to 5-fold) in case of a more rapid increase in the concentration of acid in the medium. The results of the CO(2)-auxo-accelerostat experiments show that the toxic effect depends not only on the nature of the monocarboxylic acid (lipophilicity) but also on the rate at which its concentration changes in the growth environment.

Adaptation, Physiological↗
PubMed2004

Percutaneous absorption of drugs used in atopic eczema: pimecrolimus permeates less through skin than corticosteroids and tacrolimus.

For treatment of skin diseases with topical drugs, penetration of the agents into the relevant layers of the skin is required. Permeation through the skin should, however, be kept to a minimum, in order to avoid the risk of systemic side effects. Here we compared the in vitro skin penetration and permeation of two novel drugs used in the therapy of atopic eczema (pimecrolimus and tacrolimus) and three representative corticosteroids (betamethasone-17-valerate, clobetasol-17-propionate, and diflucortolon-21-valerate). Drug concentrations of pimecrolimus and corticosteroids in human skin were found to be in the same order of magnitude. Permeation of pimecrolimus through human skin was, however, lower by factors of 70-110 as compared to the steroids. When pimecrolimus was compared with tacrolimus in human, pig, or rat skin, similar concentrations of the two compounds were measured in the skin, whereas permeation of pimecrolimus through skin was consistently lower by factors of 9-10. Lipophilicity was found to be highest for pimecrolimus, its octanol-water distribution coefficient being higher by factors of 8 and 25-450 than that of tacrolimus and the corticosteroids, respectively. The low permeation of pimecrolimus may be explained by its higher lipophilicity (compared to tacrolimus and the corticosteroids) and higher molecular weight (compared to steroids). In conclusion, pimecrolimus appears to have a favourable skin penetration/permeation profile, featuring a low degree of percutaneous absorption.

Administration, Cutaneous↗
PubMed2004

Effect of a topical steroid on gene expressions for chemokines in mice with contact hypersensitivity.

Effects of a topical corticosteroid drug, diflucortolone valerate, on the mRNA expressions for four CC- and four CXC-chemokines, which have been reported to be associated with recruitment of different kinds of proinflammatory and inflammatory cells, were investigated by RT-PCR in mice with 2,4,6-trinitrochlorobenzene (TNCB)-induced contact hypersensitivity (CHS) response. All of the eight gene expressions were clearly up-regulated in the lesion site of the CHS response up to 24 h post-challenge of TNCB at which ear swelling response reached a peak, so that heavy infiltration of inflammatory cells consisting mainly of mononuclear cells and neutrophils was likely induced by these chemokines. Topical treatment with diflucortolone valerate suppressed completely the infiltrates as well as the ear swelling response. In addition, the up-regulation of gene expressions for these eight chemokines were suppressed by the treatment, indicating that the corticosteroid drug attenuates the expression of chemokine genes essential for orientating nonspecific skin response to hapten-specific CHS response through the recruitment of inflammatory cells from the circulation into the tissue site.

Administration, Cutaneous↗
PubMed2006

Determination of short-chain fatty acids in serum by hollow fiber supported liquid membrane extraction coupled with gas chromatography.

A method based on hollow fiber supported liquid membrane extraction coupled with a gas chromatograph equipped with flame ionization detector (GC-FID) was developed for the determination of six short-chain fatty acids including acetic acid, propionic acid, i-butyric acid, n-butyric acid, i-valeric acid and n-valeric acid in serum. Hollow fiber supported liquid membrane extraction was employed for preconcentration and clean-up of the samples. The fatty acids were extracted from the acidic donor (diluted serum) into a liquid membrane formed in the wall of the hollow fiber with 10% tri-n-octylphoshphine oxide (TOPO) in di-n-hexyl ether, and then extracted back into a basic acceptor solution filled in the lumen of the hollow fiber. After being acidified with HCl, the acceptor was directly analyzed by GC-FID. The acceptor concentration, donor pH, membrane liquid and extracting time were optimized giving an enrichment factor up to 155 times. The good linearity (r(2)>0.980), reasonable recovery (87.2-121%), and satisfactory intra-assay (8.2-11.5%) and inter-assay (6.1-11.6%) precision illustrated the good performance of the present method. Limits of detection (LOD) ranged from 0.04 to 0.24 microM and limits of quantification (LOQ) varied from 0.13 to 0.80 microM.

Chromatography, Gas↗
PubMed2006

Using vaginal cytology to assess the estrogenic activity of phytoestrogen-rich herb.

To assess the estrogenic activities of synthetic estrogen, synthetic phytoestrogen, Pueraria lobata and three distinct cultivars of Pueraria mirifica, a phytoestrogen-rich herb, a vaginal cytology assay in ovariectomized rats were used. Rats were ovariectomized and treated with DW, estradiol valerate (1 mg/kg BW), genistein (0.25-2.5 mg/kg BW), Pueraria lobata and Pueraria mirifica (10-1,000 mg/kg BW) for 14 days. The vaginal cytology was checked daily and the uteri were dissected and weighed at the end of treatment or post-treatment periods. The treatments of DW, genistein and Pueraria lobata did not influence the vaginal epithelium, but the injection of estradiol valerate induced a vaginal cornification from day-3 of treatment to day-14 of post-treatment period. The occurrence of vaginal cornification after treatment and the recovery after the cessation was dependent on dosages and cultivars of Pueraria mirifica. The increments of uterus weight in all rats agreed with the cornification of vaginal epithelium. Although both uterotropic and vaginal cytology assays can be used to assess the estrogenic activity of phytoestrogen-rich herb, however, using vaginal cytology assay has two advantages: (1) we do not need to kill the animals and (2) we can follow up the recovery after the cessation of treatment.

Animals↗
PubMed2005

Short-chain fatty acids modulate gene expression for vascular endothelial cell adhesion molecules.

OBJECTIVE: Leukocyte infiltration into the intestinal wall is central to the pathogenesis of tissue injury that occurs in patients with a variety of inflammatory bowel diseases. Migration of leukocytes from the intestinal circulation into bowel tissues is mediated by chemotactic substances and adhesion molecules (i.e., intercellular adhesion molecule-1 [ICAM-1] and E-selectin) on the surface of endothelial cells lining blood vessels. Short-chain fatty acids (SCFAs) derived from dietary fiber decrease inflammatory responses in colon cells. However, the effect of SCFAs on vascular adhesion molecules is unknown. We investigated the effects of SCFAs on vascular endothelial cell adhesion molecule expression. METHODS: We assessed the effect of physiologically relevant concentrations of butyrate on expression of ICAM-1 protein and mRNA in cultures of human umbilical vein endothelial cells. We also assessed the effect of butyrate on levels of HLA-DR, E-selectin, vascular cell adhesion molecule-1, and endoglin. In additional experiments, we evaluated the effect of butyrate on ICAM-1 mRNA stability and the effect of valerate, isobutyrate, and propionate on ICAM-1 expression. The effect of butyrate on ICAM-1 expression was compared with that of trichostatin A, a specific inhibitor of histone deacetylase. Data were evaluated with Student's t tests or Tukey's multiple comparison tests, with P < 0.05 considered statistically significant. RESULTS: Butyrate concentrations of 2.5 to 5 mM significantly increased endothelial expressions of ICAM-1 protein and mRNA. The effect of butyrate (5 mM) on ICAM-1 expression was time dependent, with significant increases in levels occurring after 16 h of incubation. Butyrate (5 mM) also increased expression of E-selectin but not of HLA-DR, vascular cell adhesion molecule-1, or endoglin. Isobutyrate had little effect on ICAM-1 expression, whereas valerate and propionate significantly increased expression of ICAM-1 but were weaker stimulants compared with butyrate. Butyrate (5 mM) did not alter stability of ICAM-1 mRNA. The effect of butyrate (5 mM) was comparable to that of trichostatin A. The stimulatory effect of butyrate on ICAM-1 expression was reversed after 48 h of butyrate withdrawal. CONCLUSIONS: Butyrate increases vascular endothelial expressions of ICAM-1 and E-selectin. We speculate that butyrate-induced effects on vascular adhesion molecules modulate gut inflammation. The role of SCFAs and fiber in the pathogenesis and modulation of gut inflammation in vivo requires further study.

Butyrates↗