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PubMed1999

Flow cytometric analysis of the molecular mechanisms of immunosuppressive action of the active metabolite of leflunomide and its malononitrilamide analogues in a novel whole blood assay.

Malononitrilamides (MNAs) are a new class of immunomodulatory drug highly effective in in vivo models of allo- and xenotransplantation. Knowledge of their effects on immune cells, however, is limited and has been derived solely from investigations using isolated mononuclear cells. This use of purified cells to investigate drug activity is not ideal, so we have combined the analytical power of flow cytometry with our mitogen-driven, whole blood lymphocyte activation and proliferation assays to investigate the in vitro mechanism of action of MNAs. We first show that MNAs (A77 1726, HMR1279, and HMR1715), as well as brequinar (BQR) and cyclosporine (CsA), effectively inhibit cell activation antigen expression and lymphocyte proliferation. We next show that the inhibitory effects of MNAs and BQR, but not CsA, are reversed by the addition of uridine to the culture. These results suggest that inhibition of pyrimidine biosynthesis may be a mechanism by which MNAs suppress both lymphocyte activation and proliferation since these effects were reversed when uridine nucleotide pools were replenished. This novel finding of suppression of activation antigen expression by MNAs in whole blood expands our understanding of the effects of this new class of drug.

Acrylamides↗
PubMed1999

Saccharomyces cerevisiae cell fatty acid composition and release during fermentation without aeration and in absence of exogenous lipids.

Medium-chain fatty-acids (MCFA) are among the main aroma compounds of fermented beverages. High concentrations of MCFA have been found in sluggish and stuck fermentations. It has been suggested that they arrest cell growth, as they may be toxic, but the causes of sluggish and stuck fermentations are still unclear. The aim of this work was to see whether the production of MCFA is related to fatty acid synthesis in the absence of exogenous lipids and aeration, and whether their increase can be regarded as a consequence, instead of the cause, of sluggish and stuck fermentations. Two possibilities were considered: (i) MCFA are produced to replace unsaturated fatty acids (UFA) for cell membrane fluidity when the lack of oxygen makes desaturation of saturated fatty acids (SFA) impossible; or (ii) MCFA are produced following the release of medium-chain acyl-CoA from the fatty acid synthetase complex (FAS) due to the accumulation of SFA, and their hydrolysis to recycle CoA-SH. In the first hypothesis, MCFA should be active in cell metabolism and be found in cell structures; in the second, MCFA should be a discard and prevalently found outside the cell. We carried out a Saccharomyces cerevisiae fermentation experiment in a synthetic, lipid-free medium without aeration. We measured the fatty acid composition of yeast cells and the amounts of MCFA and their ethyl esters in the medium throughout the fermentation. Cell growth and the oxygen content of the medium were also monitored. We found that MCFA are not immobilized in cell structures, but mainly released into the medium. Cell growth is arrested because fatty acid biosynthesis is prevented by the lack of oxygen. The higher MCFA concentrations found in sluggish and stuck fermentations can be thus regarded as an effect, and not the cause, of this arrest. Some suggestions for the prevention of these events are proposed.

Caproates↗
PubMed2001

Degradation of natural and synthetic polyesters under anaerobic conditions.

Often, degradability under anaerobic conditions is desirable for plastics claimed to be biodegradable, e.g. in anaerobic biowaste treatment plants, landfills and in natural anaerobic sediments. The biodegradation of the natural polyesters poly(beta-hydroxybutyrate) (PHB), poly(beta-hydroxybutyrate-co-11.6%-beta-hydroxyvalerate) (PHBV) and the synthetic polyester poly(epsilon-caprolactone) (PCL) was studied in two anaerobic sludges and individual polyester degrading anaerobic strains were isolated, characterized and used for degradation experiments under controlled laboratory conditions. Incubation of PHB and PHBV films in two anaerobic sludges exhibited significant degradation in a time scale of 6-10 weeks monitored by weight loss and biogas formation. In contrast to aerobic conditions, PHB was degraded anaerobically more rapidly than the copolyester PHBV, when tested with either mixed cultures or a single strained isolate. PCL tends to degrade slower than the natural polyesters PHB and PHBV. Four PHB and PCL degrading isolates were taxonomically identified and are obviously new species belonging to the genus Clostridium group I. The depolymerizing enzyme systems of PHB and PCL degrading isolates are supposed to be different. Using one isolated strain in an optimized laboratory degradation test with PHB powder, the degradation time was drastically reduced compared to the degradation in sludges (2 days vs. 6-10 weeks).

Anaerobiosis↗
PubMed1998

Formation of poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) by PHA synthase from Ralstonia eutropha.

The acetoacetyl-CoA reductase and the polyhydroxyalkanoate (PHA) synthase from Ralstonia eutropha (formerly Alcaligenes eutrophus) were expressed in Escherichia coli, Klebsiella aerogenes, and PHA-negative mutants of R. eutropha and Pseudomonas putida. While expression in E. coli strains resulted in the accumulation of poly(3-hydroxybutyrate) [PHB], strains of R. eutropha, P. putida and K. aerogenes accumulated poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) [poly(3HB-co-3HHx)] when even chain fatty acids were provided as carbon source, and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) [poly(3HB-co-3HV)] when odd chain fatty acids were provided as carbon source. This suggests that fatty acid degradation can be directly accessed employing only the acetoacetyl-CoA reductase and the PHA synthase. This is also the first proof that the PHA synthase from R. eutropha can incorporate 3-hydroxyhexanoate (3HHx) into PHA and has, therefore, a broader substrate specificity than previously described.

3-Hydroxybutyric Acid↗
PubMed2002

Design of poly-epsilon-caprolactone nanospheres coated with bioadhesive hyaluronic acid for ocular delivery.

This study was performed to design a new ocular drug delivery system based on poly-epsilon-caprolactone (PCL) biodegradable nanospheres (NS) coated with a bioadhesive polymer, hyaluronic acid (HA), in order to combine ophthalmic prolonged action with the ease of application. The aim of this work was to investigate three strategies to attach HA on NS surface: (1) coating the core by chain entanglement with HA; (2) coating NS by HA adsorption; (3) coating NS by electrostatic interactions between negatively charged HA and a cationic surfactant (stearylamine, SA, or benzalkonium chloride, BKC). A radioimmunoassay technique, usually used for HA quantification in serum, was transposed to determine the amount of HA on the NS. The results show that HA is strongly attached on NS positively charged by cationic surfactant. This system is stable and not influenced by dilution. These results show the possibility of using cationic surfactants to obtain a HA coating by electrostatic interactions. BKC, approved for ophthalmic administration, was retained because it was more firmly anchored within the PCL matrix and the amount of HA attached was high (41.6 microg HA/mg PCL). Moreover, the yield of fixation reached 50%. Therefore, by using a simple preparation method, it was possible to obtain stable HA and intact HA-coated NS.

Adhesives↗
PubMed2003

Polymeric micelles of poly(2-ethyl-2-oxazoline)-block-poly(epsilon-caprolactone) copolymer as a carrier for paclitaxel.

Polymeric micelles based on amphiphilic block copolymers of poly(2-ethyl-2-oxazoline) (PEtOz) and poly(epsilon -caprolactone) (PCL) were prepared in an aqueous phase. The loading of paclitaxel into PEtOz-PCL micelles was confirmed by 1H-NMR spectra. Paclitaxel was efficiently loaded into PEtOz-PCL micelles using dialysis method, and the loading content of paclitaxel in micelles was in the range 0.5-7.6 wt.% depending on the block composition of block copolymers, organic solvent used in the dialysis, and feed weight ratio of paclitaxel to block copolymer. The higher the content of hydrophobic block in the block copolymers, the higher the loading efficiency of micelles for paclitaxel. When acetonitrile was used as solvent, a higher drug loading efficiency was obtained than with THF. The loading efficiency decreased with increasing feed weight ratio of paclitaxel to block copolymer from 0.1:1 to 0.2:1. The hydrodynamic diameters of paclitaxel-loaded micelles were in the range 18.3-23.4 nm with narrow size distribution. The hemolysis test of PEtOz-PCL performed in vitro indicated that the toxicity of PEtOz-PCLs to lipid membrane was not significant compared with Tween 80, and was comparable to that observed with Cremophore EL. The proliferation inhibition activity of paclitaxel-loaded micelles for KB human epidermoid carcinoma cells was also evaluated in vitro. Paclitaxel-entrapped polymeric micelles exhibited comparable activity to that observed with Cremophore EL-based paclitaxel formulations in inhibiting the growth of KB cells.

Animals↗
PubMed1997

High affinity binding of 125I-neurotensin to dispersed cells from chicken liver and brain.

Dispersed cells from chicken brain and liver were found to possess cell surface binding sites for 125I-neurotensin (125I-NT). Scatchard analyses indicated the presence of high affinity (K4, 25-80 pM) and low affinity (Kd, 250-450 pM) components in adult tissues. Binding capacity was reduced 25-40% by incubation with pertussis toxin. Ontogenetic studies indicated that NT receptor capacity increased approximately 20-fold from the embryonic stage to adult. Cross-linking of 125I-NT to intact cells labeled one major band (52 kDa, > or = 90%) and two minor bands (40 and 90 kDa, < or = 10%) which could represent distinct NT-receptors or one receptor partly degraded or cross-linked to G-protein(s). The binding of 125I-NT to dispersed cells was enhanced by reduction with dithoithreitol and suppressed by alkylation with N-ethyl-maleimide (NEM), maleimidocaproic acid (MCA) and p-chloromercuribenzenesulfonate (PCMBS). Since MCA and PCMBS do not permeate cells, this suggests that the sulfhydryl group(s) critical to binding are located within the NT receptor itself. Preincubation of cells with NT prior to treatment with NEM diminished its inhibitory effect, suggesting that the critical SH-group(s) were within the NT binding pocket or were protected by an allosteric effect. These results suggest that one or more of the nine cysteine residues in the NT receptor is involved in the NT binding reaction.

4-Chloromercuribenzenesulfonate↗
PubMed1997

A novel fluorescent tag for labelling of some antisense oligonucleotides.

A new versatile fluorescent tag, 4-acetylamino-1,8-naphthalimido-N-caproic acid (NCA) has been synthesized and characterized, and the optimal conditions for the maximum fluorescence using this tag allow a sensitivity level of 10(-9) mol/l. Useful fluorescence is observed upon covalent linking of this tag via its activated carboxy end to an alkylamino moiety, activated by the use of carbonyldiimidazole and hexamethylenediamine at the 5'-termini of an octamer, d(TCTTGCTC), a 33-mer, and a 41-mer complementary to the tat initiator of the HIV-1 genome. A new method for the generation of alkylamino function at the 5'-termini of oligonucleotides by the use of N-(4-bromobutyl) phthalimide is also described. The variation in fluorescence with respect to alteration of chain length of the oligonucleotides has also been studied. The fluorescence exhibited by these oligodeoxynucleotide (ODN)-NCA conjugates suggests that they may have a potential application as experimental tools in medicine and molecular biology.

Caproates↗
PubMed1993

Regio- and stereo-selectivity in the induction of peroxisome proliferation by substituted hexanoic acids.

Quantitative structure-activity relationship is an effective tool in order to predict drug potency. A similar approach is actually developed for peroxisome proliferation induced by substituted carboxylic acids issued from plasticizer metabolism in rats. The study is focused on acids found in rat urine after adipic diester dosings. Size, location of the substituted group and length of the chain have been studied. 3-D structure has also been taken in account for 2-ethyl hexanoic acids. The results obtained so far demonstrate that peroxisome proliferation potencies of the considered acids are modified according structure changes. At this time location of the group along the chain appears to be a predominant factor.

Animals↗
PubMed1982

In vitro metabolism of penicillic acid with mouse-liver homogenate fractions.

The metabolism of penicillic acid (PA), a carcinogenic mycotoxin, was studied in vitro using subcellular fractions of mouse-liver homogenates. PA reacted with glutathione (GSH) both enzymatically and non-enzymatically. Each reaction was of equal importance. The in vitro metabolism of PA using different hepatic subcellular fractions was essentially non-enzymatic when GSH was absent, but metabolism was strikingly increased when GSH was available. In the microsomal preparation in the presence of GSH 75% of the added PA was biotransformed within 30 min to metabolite(s) that were not extractable with organic solvents. HPLC analysis indicated that the metabolite(s) were more polar than the parent compound.

Animals↗
PubMed1998

2-Ethylhexanoic acid: subchronic oral toxicity studies in the rat and mouse.

Groups of 10 male and 10 female Fischer 344 rats and B6C3F1 mice were fed diets containing either 0.0, 0.1, 0.5 or 1.5% 2-ethylhexanoic acid (EHA) for 13 wk. Additional groups of 10 male and 10 female rats or mice. were fed either 0.0 or 1.5% EHA for 13 wk followed by a 4-wk recovery (non-treatment) period. Based on food consumption and body weight, the EHA diets provided doses of 61, 303 or 917 mg/kg/day for male rats and 71, 360 or 1068 mg/kg/day for female rats. The EHA diets provided doses of 180, 885 or 2728 mg/kg/day for male mice and 205, 1038 or 3139 mg/kg/day for female mice. No mortality or significant clinical signs of toxicity were observed during the study. Body weights and food consumption of both rats and mice fed 1.5% EHA were lower beginning after the first week of treatment, consistent with a reduction in food consumption. Other groups were unaffected by treatment. After 13 wk, lower triglyceride levels occurred in male mice fed 1.5% EHA and female mice fed 0.5 or 1.5% EHA, but not in other groups. Cholesterol levels were higher in all male rat test groups and in female rats and male and female mice fed either 0.5 or 1.5% EHA, although this effect was reversible following a 28-day recovery period. The principal effects of EHA involved the liver or metabolic processes associated with the liver. The 0.5 and 1.5% diets in both rats and mice were associated with increased relative liver weight and histological changes in hepatocytes, specifically hepatocyte hypertrophy and reduced cytoplasmic vacuolization. Observed histopathological and clinical pathological changes were reversible following recovery. These results indicate that EHA does not produce persistent. overt toxicity in rats or mice following subchronic dietary exposure at concentrations up to 1.5% in feed. The no-observed-adverse-effect level (NOAEL) for male rats was 61 mg/kg/day and the no-observed-effect level (NOEL) for female rats was 71 mg/kg/day, while 180 and 205 mg/kg/day represent NOELs for male and female mice, respectively.

Administration, Oral↗
PubMed2000

Developmental toxicity of 2-ethylhexyl stearate.

2-Ethylhexyl stearate was investigated in an embryo-/foetotoxicity and teratogenicity study on rats according to OECD guidelines for the testing of chemicals (No. 414). Dose levels of 0 (arachidis oil), 100, 300 and 1000mg/kg body weight/day were administered by gavage. Dams tolerated the applied dose levels without any toxic effects. Pre- and post-implantation loss and mean numbers of resorptions were unaffected by treatment. All parameters were comparable with the animals of the control group. Skeletal and visceral investigations revealed no treatment-related malformations. For embryo-/foetotoxicity, teratogenicity and maternal toxicity a NOAEL of 1000mg/kg was deduced.

Abnormalities, Drug-Induced↗
PubMed1998

Altered zinc metabolism contributes to the developmental toxicity of 2-ethylhexanoic acid, 2-ethylhexanol and valproic acid.

It has been hypothesized that the developmental toxicity of certain compounds is, in part, due to maternal toxicity resulting in alterations in zinc (Zn) metabolism that affects the developing conceptus. In the present work the effects of developmentally toxic doses of 2-ethylhexanoic acid (EHXA), 2-ethylhexanol (EHXO), and valproic acid (VPA) on Zn metabolism were investigated in the pregnant rat. In experiment 1, dams were intubated with EHXA (3.13, 6.25, 9.38 or 12.5 mmol/kg), EHXO (6.25, 9.38 or 12.5 mmol/kg), VPA (1.56, 3.13, 6.25 or 9.38 mmol/kg), or corn oil (control; 1.0 ml/kg) at 14:00 h on gestation day (GD) 11.5, intubated with 32 microCi 65Zn at 22:00 h, and then killed at 08:00 h on GD 12.5. At the higher dose levels of EHXA and EHXO, and at all dosages of VPA, the percentage of 65Zn retained in maternal liver was higher, while that in the embryos was lower, than in controls. Chemical-associated changes in 65Zn distribution were associated with increased maternal liver metallothionein (MT) concentrations. In experiment 2, dams were fed diets containing 1, 25 or 97 microg Zn/g from GD 0-16 and intubated with 3.5 mmol EHXA or 1.0 ml corn oil/kg/d from GD 8-15. Dams were killed on GD 16 or 19. High incidences of encephalocele and tail defects were noted in the GD 16 fetuses of EHXA-treated dams fed either the low or adequate Zn diet, the highest incidences being in the low Zn group. On GD 19 the incidence of tail defects tended to be higher in the EHXA groups than in oil-treated controls, the highest incidence occurring in the low Zn EHXA group. Encephalocele was only observed in the low Zn EHXA-treated group. Fetal weight and crown-rump lengths were decreased by EHXA treatment and low dietary Zn. The incidence of rib anomalies was higher in the EHXA-exposed groups than in their respective oil controls. In experiment 3, GD 10.5 embryos collected from control dams were cultured for 48 h in serum from control or EHXA-treated male rats fed 4.5 or 25.0 microg Zn/g diets. Embryos cultured in either EHXA or low Zn sera exhibited delayed development; the addition of Zn to these sera eliminated their developmental toxicity. These results support the hypothesis that certain chemicals which induce maternal toxicity act, in part, to influence embryonic Zn metabolism and trigger abnormal development. Importantly, the teratogenic effects of these chemicals can be modulated by dietary Zn intake.

Animals↗
PubMed1978

Progeston therapy for menstrually related aphthae.

Ten female patients with a history of recurrent aphthous lesions for at least 5 years with the lesions occurring regularly in the latter half at the menstrual cycle were treated with progestogen in the form of an intramuscular depot injection. Medroxyprogesterone acetate and gestronol hexanoate was used. All 10 patients were satisfied with the treatment; the side effects were few.

Adult↗
PubMed2001

The origin of spermatozoa does not affect intracytoplasmic sperm injection outcome.

OBJECTIVE: To assess whether the origin of spermatozoa, ejaculate or testicular, affects intracytoplasmic sperm injection (ICSI) outcome. STUDY DESIGN: Retrospective study of 890 consecutive first ICSI and embryo transfer cycles done for male infertility. The ICSI outcome of ejaculated spermatozoa (n=780) and testicular spermatozoa retrieved from patients with obstructive azoospermia (n=43), non-obstructive azoospermia (n=53) and severe oligoasthenoteratozoospermia (n=14) were compared by using chi-square test, independent t-test and ANOVA with Bonferroni test. RESULTS: All azoospermic males had a diagnostic testicular biopsy at least 6 months before the ICSI procedure. Spermatozoa were successfully retrieved in all 43 patients with obstructive azoospermia and in 72.6% of 73 non-obstructive cases. The cycle characteristics of the four groups were similar apart from a younger mean female age in the non-obstructive azoospermia group when compared with the ejaculated spermatozoa group. The fertilization, implantation and clinical pregnancy rates were comparable among the four groups. CONCLUSION: Testicular spermatozoa recovered from patients with obstructive and all types of non-obstructive azoospermia were as much as effective as ejaculated spermatozoa in ICSI.

17 alpha-Hydroxyprogesterone Caproate↗
PubMed1999

Specific and non-specific binding of long-chain fatty acids to firefly luciferase: cutoff at octanoate.

Firefly luciferase emits a burst of light when the substrates luciferin and ATP are mixed in the presence of oxygen. We (I. Ueda, A. Suzuki, Biophys. J. 75 (1998) 1052-1057) reported that long-chain fatty acids are specific inhibitors of firefly luciferase in competition with luciferin in microM ranges. They increased the thermal transition temperature. In contrast, 1-alkanols of the same carbon chain length inhibited the enzyme non-competitively in mM ranges and decreased the transition temperature. The present study showed that the action of fatty acids switched from specific to non-specific when the carbon chain length was reduced below C8 (octanoate). The fatty acids longer than C10 inhibited the enzyme in microM ranges whereas those shorter than C8 required mM ranges to inhibit it. The longer fatty acids increased whereas shorter fatty acids decreased the transition temperature. The Hill coefficients of longer chain bindings were less than one whereas those of shorter chain were more than one. The shorter fatty acids interacted with the enzyme cooperatively at multiple sites. Binding of the longer fatty acids is limited. Fatty acids longer than C10 are high-affinity specific binders and followed Koshland's induced-fit model. Those shorter than C8 are low-affinity non-specific denaturants and followed Eyring's rate process model. These results contradict the general consensus that the size of the receptor cavity discriminates specific binders.

Animals↗
PubMed2000

Effects of organic acids on lipid synthesis and ecdysis in Triatoma infestans eggs.

Medium chain fatty acids are known inhibitors of the activity of lipogenic enzymes at the transcriptional level. Mature Triatoma infestans eggs incorporate [14C]-acetate into phospholipid (PL), triacylglycerol (TG), and free fatty acid (FFA) fractions. In the presence of sodium octanoate (SO) or sodium phenylethylpropionate (PHEP), lipid synthesis is inhibited in a dose-dependent manner. When eggs are incubated in vivo with [14C]-acetate, the usual fatty acid products are largely palmitic and oleic acids. However, in the presence of SO (5-10 mM), the elongation of [14C]-acetate units is interrupted at [14C] eight total carbons. Eggs incubated in vivo with [14C]-SO, accumulate most of the label in the FFA fraction. SO (> 0.1 mM) but not sodium hexanoate (SH), inhibits the activity of microsomal and cytosolic fatty acid synthetases (FAS's), measured as [14C]-malonyl-CoA incorporation. PHEP (1 mM) and SO (10 mM) also produce major alterations in egg hatching and survival of the emerged insects, after a 1 h immersion bioassay.

Acetates↗