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At least 217 records · Page 12Linked to original sources

PubMed1981

Blood levels of branched-chain alpha-keto acids in uremia: effect of an oral glucose tolerance test.

The effect of an oral glucose tolerance test (oGTT) on serum levels of branched-chain keto acids (BCKA), i.e. alpha-keto-isocaproic acid (KICA), alpha-keto-isovaleric acid (KIVA) and alpha-keto-beta methyl-n-valeric acid (KMVA) as well as on serum insulin, C-peptide and blood glucose levels was determined in uremic patients and in healthy control subjects. In controls, blood levels of KICA, KMVA and KIVA declined significantly following oral administration of 100 glucose. In uremic patients no decline of KICA was observed. The fall of KMVA was diminished, while suppression of KIVA blood levels in response to the oGGT remained unimpaired. Although serum insulin and C-peptide levels in uremic patients were not significantly different from the controls before and throughout the oGTT, six out of eight displayed abnormal glucose tolerance. It is suggested that the response of blood BCKA levels to an oGTT is altered in uremia, an abnormality restricted primarily to KICA and possibly explained by insulin antagonism and/or by insufficient insulin secretion.

Adult↗

PubMed1977

Carboxylesterases of human brain extract. Purification and properties of a butyrylesterase.

1. A carboxylesterase (carboxylic-ester hydrolase, EC 3.1.1.1) from human brain extract was prepared to purity using DEAE-cellulose, Sephadex G-200, and fractionation with (NH4)2SO4. The yield was about 20%. 2. Esters of butyric acid were split faster than esters of acetic, propionic and valeric acid, and the enzyme is tentatively designated as a butyrylesterase. Thiocholine esters were split at low rates. 3. The molecular weight was estimated as 340 000 using gel chromatography on Sephadex G-200. In isoelectric focussing the enzyme was resolved into several peaks (pI 4.0--4.7). The low isoelectric point does not seem to be due to terminal sialic acid residues. 4. The enzyme was irreversibly inhibited by diethyl-p-nitrophenyl phosphate (ki = 206 mol-1 - 1 - s-1) and by diisopropylfluorophosphate. The carboxylesterase inhibitor bis-p-nitrophenyl phosphate and eserine did not inhibit the enzyme. 5. The enzyme was progressively inhibited by p-hydroxy-mercuribenzoate, and reactivated by dithiothreitol and 2-mercaptoethanol. N-Ethylmaleimide inactivated the enzyme very slowly, whereas iodoacetate and iodoacetamide were without effect. 6. Ca2+, Mg2+, and Zn2+ or EDTA did not influence the enzyme activity.

Brain↗

PubMed1989

Kynurenic acid inhibits the activation of kainic and N-methyl-D-aspartic acid-sensitive ionotropic receptors by a different mechanism.

The action of kynurenic acid on currents elicited by the activation of amino acid receptors was investigated in primary cultures of cortical neurons prepared from neonatal rats. Kynurenic acid was tested on currents elicited by both N-methyl-D-aspartic acid (NMDA) and kainate, using patch-clamp recording techniques in "outside-out" and "whole-cell" configurations. The inhibition by kynurenic acid was compared with that elicited by amino-phosphono-valeric acid (APV). Whole-cell currents, elicited by increasing doses of NMDA, were antagonized competitively by APV and non-competitively by kynurenic acid (ID50 70 microM); in contrast, kynurenic acid inhibited competitively the whole-cell currents elicited by kainic acid (ID50 500 microM). The non-competitive inhibition by kynurenic acid of the whole cell currents elicited by NMDA was antagonized competitively by glycine, a specific positive allosteric modulator of NMDA receptors; on the other hand glycine failed to change the inhibition by APV of the NMDA-elicited responses. Thus, kynurenic acid inhibits NMDA receptors allosterically (non-competitively) and kainic acid receptors isosterically (competitively).

Animals↗

PubMed1987

Relative importance of physiological precursors for ketogenesis in the nutritional homeostasis of the development of the embryonic chick.

This paper investigates the relative importances of specific amino acids, and, in particular, branched chain amino acids and their keto derivatives as possible ketogenic precursors in suspensions of liver cells isolated from chick embryos. Addition of the branched chain keto acids stimulated ketogenesis. The order of potency was alpha-ketoisocaproic acid greater than alpha-ketoisovaleric acid greater than DL-alpha-keto-beta-methyl-n-valeric acid. The relative order of effectiveness for branched chain keto acids was maintained at all comparable concentrations, and in each case maximum rates were observed with concentrations of 1-2 mM. In contrast to the stimulation of ketogenesis by their keto derivatives, branched chain amino acids were ineffective as precursors for ketogenesis. Of the other amino acids (utilised at concentrations present in chick embryo plasma) only Tyr, Lys, Phe and Arg produced significant increases in ketone body formation above the endogenous rate. At these physiological concentrations, the effectiveness of the amino acids were in the order of Tyr greater than Lys = Phe greater than Arg. The interactions between three groups of ketogenic precursor (fatty acids, amino acids and keto amino acids, all at physiological concentrations), produced rates of ketogenesis that were purely additive. These results indicate that high concentrations of hydroxybutyrate and acetoacetate found in plasma of developing chick embryos may arise from hepatic metabolism of several distinct precursors. The relative importance of each category of precursor may vary with the precise developmental status of animals.

Amino Acids↗

PubMed2005

Intrahippocampal administration of the branched-chain alpha-hydroxy acids accumulating in maple syrup urine disease compromises rat performance in aversive and non-aversive behavioral tasks.

Maple syrup urine disease (MSUD) is an inherited metabolic disease predominantly characterized by neurological dysfunction. Although a variable degree of psychomotor/delay/mental retardation is found in a considerable number of MSUD patients, the mechanisms underlying the neuropathology of this disorder are yet not defined. The present study investigated the effect of acute intrahippocampal administration of the branched-chain alpha-hydroxy acids (BCHA) accumulating in MSUD on rat behavior in non-aversive (open field) and aversive (inhibitory avoidance) tasks. Cannulated 60-day-old male Wistar rats received bilateral intrahippocampal injection of alpha-hydroxyisocaproic acid (HIC, 1.5 micromol), alpha-hydroxyisovaleric acid (HIV, 2.5 micromol), alpha-hydroxy-beta-methyl-n-valeric acid (HMV, 1.5 micromol), or NaCl (2.5 micromol)(controls) immediately after or 10 min before training. Testing session was performed 24 h later. Administration of the hydroxy acids immediately after training caused no effect on the cognitive performance of the rats. In contrast, HIV and HMV administered 10 min before training provoked a habituation deficit in the open field task. Motor activity, assessed by crossing responses, was the same for the groups infused with BCHA and NaCl. The effect of MK-801, succinate, creatine, and the antioxidants ascorbic acid plus alpha-tocopherol on the behavioral alterations provoked by HIV in the open field task revealed that only the energetic substrates (succinate and creatine) prevented these effects, reflecting a possible compromise of brain energy production by HIV. We also observed that rats pretreated with HIC, HIV, or HMV did not increase their latency in the testing session in the step-down inhibitory avoidance task, revealing an impairment of retrieval (memory retention or acquisition) in this task. Furthermore, no differences between controls and rats receiving BCHA were detected in the latency to leave the platform in the training test, suggesting similar motor activity of all groups. The data indicate that the alpha-hydroxy acids accumulating in MSUD impair cognition and may be implicated in the neuropathology and psychomotor delay/mental retardation observed in the affected patients.

Animals↗

PubMed1986

Feeding frequency for lactating cows: effects on rumen fermentation and blood metabolites and hormones.

1. The present paper reports the effects on rumen fermentation and plasma metabolites and hormones of giving fixed rations of hay and high-cereal concentrates at different meal frequencies to lactating cows. In Expt 1 the total ration was given in two and twenty-four meals daily and in Expts 2-4 the concentrates were given in two and five or six meals and the hay in two meals daily. The diets contained 600-920 g concentrates/kg. 2. In Expt 1, minimum rumen pH was higher but mean pH was lower when cows were given their ration in twenty-four meals/d rather than two meals/d. 3. In all the experiments, the effects of increased meal frequency on the molar proportions of rumen volatile fatty acids (VFA) were small and not significant, although there was a general tendency for the proportion of acetic acid to increase and that of propionic acid to fall. Increasing the proportion of concentrates in the diet reduced the proportion of acetic acid and increased the proportions of propionic and n-valeric acids. 4. In Expt 3, more frequent feeding was found to reduce the concentration of non-esterified fatty acids in the blood, but changes in other metabolites were small and not significant. Increasing the proportion of concentrates in the diet reduced the concentrations of acetic acid and 3-hydroxybutyric acid and increased the concentrations of propionic acid and glucose. 5. The mean daily concentration of insulin in the blood was reduced by more frequent feeding of the higher-concentrate diet but not of the lower-concentrate diet. The concentration of glucagon also tended to fall with more frequent feeding. Increasing the proportion of concentrates in the diet increased the concentration of insulin. 6. More frequent feeding reduced the depression in milk-fat concentration caused by feeding the low-roughage diets. About three-quarters of the variation in milk-fat concentration could be related to changes in rumen VFA proportions, but the relations for the two meal frequencies had different intercepts although similar curves. The results suggest that milk-fat depression on low-roughage diets with twice-daily feeding was due to a change in rumen VFA proportions accompanied by elevated plasma insulin concentrations. The improvement in milk-fat concentration due to more frequent feeding could be explained partly by the small change in rumen VFA proportions and partly by a reduction in mean plasma insulin concentrations, but these mechanisms did not fully account for the milk-fat responses observed.

Animals↗

PubMed2005

Biological properties of fructooligosaccharides with different contents of kestose and nystose in rats.

In a four-week experiment on rats' diets containing 5% of sucrose or fructooligosaccharides (FOS) diversified in terms of kestose and nystose contents: 6:1 (FOS-K), 3:1 (FOS-KN), and 0.5:1 (FOS-N) were applied. All FOS preparations, primarily FOS-N, considerably increased the mass of caecum, lowered pH of caecal digesta, and increased concentrations of protein. The glycolytic activity of the caecal digesta was generally alike in all groups, except for the control group where the activity of beta-glucosidase was negligibly lower and that of alpha-galactosidase higher. The administration of FOS preparation with a diet increased the concentration and the pool of total VFA in the caecal digesta, especially in the case of butyric and propionic acids and decreased the concentration of iso-butyric and valeric acids. When compared with the kestose-rich preparation, the nystose-rich preparation increased the production of total VFA in the caecum, primarily of n-butyrate and propionate. Different length of kestose and nystose chains had no effect on the activity of bacterial enzymes in the caecum nor the biochemical indices of serum, concentration of cholesterol, glucose, urea, Ca, P and Mg.

Animals↗

PubMed1976

Microbiological degradation of bile acids. The conjugation of a certain cholic acid metabolite with amino acids in Corynebacterium equi.

1. (4R)-4[4alpha-(2-Carboxyethyl)-3aalpha-hexahydro-7abeta-methyl-5-oxoindan-1beta-yl]valeric acid (II) could not be utilized by Arthrobacter simplex, even though the acid was one of the metabolites formed from cholic acid (I) by this organism. Therefore the further degradation of the acid (II) by Corynebacterium equi was investigated to identify the intermediates involved in the cholic acid degradation. 2. The organism, cultured in a medium containing the acid (II) as the sole source of carbon, produced unexpected metabolites, the conjugates of this original acid (II) with amino acids or their derivatives, although the yield was very low. These new metabolites were isolated and identified by chemical synthesis as the Na-((4R)-4-[4alpha-(2-carboxyethyl)-3a alpha-hexahydro-7a beta-methyl-5-oxoindan-1 beta-yl]-valeryl) derivatives of L-alanine, glutamic acid, O-acetylhomoserine and glutamine, i.e. compounds (IIIa), (IIIb), (IIId) respectively. 3. The possibility that the bacterial synthetic reaction observed in the acid (II) metabolism with C. equi is analogous to peptide conjugation known in both animals and higher plants is discussed. A possible mechanism for this bacterial conjugation is also considered.

Alanine↗

PubMed1995

Determination of portal short-chain fatty acids in rats fed various dietary fibers by capillary gas chromatography.

A simple, rapid and sensitive capillary gas chromatographic method was investigated to measure portal short-chain fatty acids (SCFAs). A 20-microliters sample of portal plasma was denatured with sulfosalicylic acid and then extracted with diethyl ether before the removal of protein precipitate. The resultant extract was concentrated by a transfer to 50 microliters of 0.2 M NaOH, thus avoiding tedious further concentration steps. This reduced the sample volume to one-fourth. Since the ratio of acetic acid, a major SCFA, to other acids varies widely, ranging from 10-fold to 100-fold, acrylic and methacrylic acids were used as internal standards to simultaneously measure SCFAs having a carbon number of 2-6. As a result, good recovery (90.38-103.17%) and reproducibility (coefficient of variation 0.83-8.85%) were observed over a wide range. Furthermore, portal SCFAs in rats fed various dietary fibers were determined by the present method. We showed that the amounts not only of the major acids such as acetic acid and propionic acid, but also of the minor fermented products such as n-valeric acid and n-caproic acid, could be significantly changed by dietary manipulation. Thus, the present method is simple and reliable, and requires only a small amount of sample.

Animals↗

PubMed2004

Determination of some aliphatic carboxylic acids in anaerobic digestion process waters by ion-exclusion chromatography with conductimetric detection on a weakly acidic cation-exchange resin column.

The determination of seven aliphatic carboxylic acids, formic, acetic, propionic, isobutyric, n-butyric, isovaleric and n-valeric acids in anaerobic digestion process waters was examined using ion-exclusion chromatography with conductimetric detection. The analysis of these biologically important carboxylic acids is necessary as a measure for evaluating and controlling the process. The ion-exclusion chromatography system employed consisted of polymethacrylate-based weakly acidic cation-exchange resin columns (TSKgel OApak-A or TSKgel Super IC-A/C). weakly acidic eluent (benzoic acid), and conductimetric detection. Particle size and cation-exchange capacity were 5 microm and 0.1 meq./ml for TSKgel OApak-A and 3 microm and 0.2 meq./ml for TSKgel Super IC-A/C, respectively. A dilute eluent (1.0-2.0 mM) of benzoic acid was effective for the high resolution and highly conductimetric detection of the carboxylic acids. The good separation of isobutyric and n-butyric acids was performed using the TSKgel Super IC-A/C column (150 mm x 6.0 mm i.d. x 2). The simple and good chromatograms were obtained by the optimized ion-exclusion chromatography conditions for real samples from mesophilic anaerobic digestors, thus the aliphatic carboxylic acids were successfully determined without any interferences.

Acids↗

PubMed1995

Rumen fermentation and metabolic profile in conventional and gnotobiotic lambs.

Observations were carried out of actual acidity, volatile fatty acid (VFA) concentrations, enzyme activity in the rumen, total protein, urea, total lipid and glucose in the serum of conventional (CL) and gnotobiotic lambs (GL) in the period of milk nutrition. The inoculum of gnotobiotic lambs contained Streptococcus bovis, Prevoxella ruminicola, Butyrivibrio fibrisolvens and Selenomonas ruminantium at a concentration of 1.10(6) each. Throughout the observation period the pH of the rumen contents of gnotobiotic lambs ranged within 6.5-6.8 with a significant difference at an age of 7 weeks. Total VFA concentrations in the rumen contents were increased in the CL throughout milk nutrition: the differences at 4 and 5 weeks of age were significant. Total VFA in the conventional lambs revealed an increasing tendency between weeks 4 and 7, reaching higher levels at 7 weeks of age (57.1 mmol.l-1), whereas in the gnotobiotic animals the range (24.3-30.1 mmol.l-1) was narrow and the peak occurred at 6 weeks of age. In GL significantly increased molar proportions of acetic acid were observed whereas in CL the molar proportions of propionic acid proved to be significant increased. The molar proportions of butyric and valeric acids were increased in CL but the group differences were not significant. In GL no isoacids were found. Alpha amylase (E.C.3.2.1.1.) activity of the rumen contents was significantly increased in GL between weeks 2 and 6 of age whereas cellulase (endoglucanase E.C.3.2.1.4. and cellobiohydrolase E.C.3.2.1.91.) activity was significantly increased in 4-week-old CL. Over the whole period of milk nutrition no significant differences were observed in urease (E.C.3.5.1.5.) activity of the rumen contents in the examined groups. At 5 weeks of age significantly increased total protein levels were observed in the conventional animals with maximum levels occurring at 4 weeks of age (CL-59.5 g.l-1 GL-55.3 g.l-1). Urea levels in 6-week old conventional lambs were significantly higher than in the gnotobiotic animals (CL-6.4 mmol.l-1 vs. GL-1.9 mmol.l-1). As to glycaemia no significant group differences were recorded. In the conventional animals total lipid levels were significantly increased at 1 and 6 weeks of age with a peak occurring in the first week of life (7.5 g.l-1) whereas in the gnotobiotic lambs a significant increase was observed at 3 weeks of age, the peak being recorded in 4 week-old animals (4.3 g.l-1). Throughout the period of interest the mean daily weight gains in the conventional and gnotobiotic lambs presented 0.164 and 0.162 kg, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

Animal Feed↗

PubMed1988

Determination of gamma-aminobutyric acid and associated amino acids in mouse brain by liquid chromatography.

A rapid method is described for the analysis of amino acids containing in mouse brain by high performance liquid chromatography equipped with a fluorescence detector. Pre-column o-phthalaldehyde-2-mercaptoethanol derivatives of the amino acids were injected onto an ODS C-18 column. 5-Amino-n-valeric acid, a non-endogenous amino acid, was used as an internal standard. Separation and elution of amino acid derivatives were achieved by varying the ratio of organic phase by a step gradient. Significant increases in gamma-aminobutyric acid, glutamine and glycine levels in the brain were detected 2 h after injection of 800 mg/kg valproic acid (VPA). A high dose administration of VPA was correlated with Reye's syndrome.

Amino Acids↗

PubMed1975

The lipids of four unusual non-pathogenic host-associated spirochetes.

The lipid compositions of two spirochetes isolated from the human oral cavity and two isolated from pig feces were examined. These isolates were unusual in that they did not require long-chain fatty acids for growth, as do the other host-associated spirochetes, but rather required isobutyric and valeric acids. Therefore, they could be cultured in a medium free of serum or fatty acid - albumin supplements. The major fatty acids synthesized were normal and iso fatty acids with 14 and 16 carbons. No unsaturated fatty acids were detected, nor were chain lengths longer than 16 carbons. The major complex lipids found were monogalactosyl diglyceride, phosphatidyl glycerol, and bis-phosphatidyl glycerol. Nitrogenous phospholipids, present in Treponema and Leptospira, were not synthesized by these novel strains. The data indicate an intermediate position of these isolates between Treponema and free-living Spriochaeta.

Animals↗

PubMed1990

In vivo evidence for an inhibitory glutamatergic control of serotonin release in the cat caudate nucleus: involvement of GABA neurons.

The local effect of L-glutamic acid (5 x 10(-5) M) on the release of [3H]serotonin continuously synthesized from [3H]tryptophan was examined in the caudate nucleus of 'encéphale isolé' unanaesthetized cats implanted with push-pull cannula. L-Glutamic acid (5 x 10(-5) M) decreased [3H]serotonin release from nerve terminals of the dorsalis raphe-striatal serotonergic neurons. The effect was antagonized by 2-amino-6-trifluoromethoxybenzothiazole (PK 26124) (10(-6) M), an antagonist of glutamatergic transmission. This effect was mimicked by N-methoxy-D-aspartic acid NMDA (5 x 10(-5) M) and prevented by DL-2-phosphono-valeric acid (APV) (5 x 10(-6) M), indicating that L-glutamic acid decreased serotonin release via a N-methoxy-D-aspartate type receptor. The superfusion of serotonergic nerve terminals in the caudate nucleus with tetrodotoxin prevented the inhibitory L-glutamic acid-induced effect on serotonin release. Furthermore, L-glutamic acid-induced inhibition of [3H]serotonin release was antagonized by bicuculline (5 x 10(-5) M). These data suggest that the glutamatergic receptors involved were not located directly on serotonin nerve terminals. The inhibitory control exerted by L-glutamic acid on serotonergic transmission could involve gamma-aminobutyric acid interneurons. Since no reduction of spontaneous [3H]serotonin release was observed in the presence of bicuculline, GABAergic neurons appeared to exert a phasic influence on serotonin release. Indirect inhibitory presynaptic control on serotonin release mediated by corticostriatal glutamatergic fibers is discussed in light of previous findings.

2-Amino-5-phosphonovalerate↗

PubMed1982

The effects of cyclic dicarboxylic acids on spontaneous and amino acid-evoked activity of rat cortical neurones.

1 A series of cyclic dicarboxylic acids were applied by microiontophoresis to neurones in the cerebral cortex of rats anaesthetized with urethane. The object was to examine effects on spontaneous firing rates and any ability to antagonize responses to excitatory amino acids. 2 At relatively low ejecting currents (10-25 nA) cis-2,3-piperidine dicarboxylic acid (cis-2,3-PDA) had no effect on spontaneous firing but selectively antagonized the excitation evoked by n-methyl-D-aspartate (NMDA) without affecting responses to quisqualaife or kainate. At higher ejecting currents (60-100 nA) responses to all three agonists were reduced. 3 Other cis-piperidine dicarboxylic acids and piperazine-2,3-dicarboxylic acid had only weak and variable effects on cell firing and responses to NMDA, quisqualate, kainate, glutamate and aspartate. 4 2, 3-Pyridine dicarboxylic acid (quinolinic acid) produced excitation of all cortical neurones tested. 5 2-Amino-5-phosphono-valeric acid, an NMDA antagonist, reduced responses to quinolinate, implying that this compound can act at NMDA receptors. 6 It is suggested that quinolinic acid may be of physiological interest as a potential endogenous excitant in the nervous system and that cis-2,3-PDA and its N-methyl derivative may be of use in studies of receptor pharmacology and the identification of synaptic transmitters.

Amino Acids↗

PubMed1987

Short-chain fatty acids in seven sterile thioglycollate media.

Short-chain fatty acids (SCFAs) were analysed by gas chromatography in 7 sterile fluid thioglycollate media. The total SCFA concentration varied from 250 mumol/l to 1720 mumol/l. Acetic acid (52.0%-91.3% of total SCFA concentration) and n-butyric acid (5.8%-48.0% of total concentration) were the main acids in all sterile media; low concentrations of propionic, isobutyric, isovaleric, and n-valeric acid were present in most media. In studies of bacterial metabolism, or when analyses of SCFAs are used for identification of bacteria, testing of the sterile medium is necessary.

Chromatography, Gas↗

PubMed1991

Optical detection of postsynaptic potentials evoked by vagal stimulation in the early embryonic chick brain stem slice.

1. A voltage-sensitive dye and multiple-site optical recording of changes in membrane potential were used to reveal the postsynaptic potentials in the early embryonic chick brain stem slice preparation. 2. Vagus-brain stem preparations were isolated from 8-day-old chick embryos and then transverse slice preparations were prepared with both the right and left vagus nerve fibres intact. The slice preparations were stained with a voltage-sensitive merocyanine-rhodanine dye (NK2761). 3. Voltage-related optical (absorbance) changes evoked by vagus nerve stimulation with positive square current pulses using a suction electrode were recorded simultaneously from 127 contiguous loci in the preparation, using a 12 x 12-element photodiode array. Optical responses appeared in a limited area near the dorsal surface of the stimulated side. 4. When relatively large stimulating currents were applied, optical changes having two (or sometimes three) components were recorded. One component was the fast spike-like signal and another the delayed, long-lasting slow signal. 5. The size of the slow signal was decreased by continuous stimulation, reduced by low external calcium ion concentrations and eliminated in the presence of manganese or cadmium ions. 6. The slow signals were eliminated in the presence of kynurenic acid, and they were reduced by 2-APV (DL-2-amino-5-phosphono-valeric acid) and by CNQX (6-cyano-7-nitroquinoxaline-2,3-dione). We conclude that the slow signals correspond to excitatory postsynaptic potentials which are glutamate mediated.

Action Potentials↗

PubMed1994

Augmentation of gamma-globin gene promoter activity by carboxylic acids and components of the human beta-globin locus control region.

Butyric acid increases fetal hemoglobin synthesis in adult animals and in erythroid cells in culture and induces the gamma-globin gene promoter in transient expression experiments in K562 cells (McDonagh KT, Nienhuis AW, Blood 78:255a, 1992 [abstr, suppl 1]). We compared the effect of butyrate and other short-chain carboxylic acids in transient expression studies with K562 cells using an expression plasmid bearing a luciferase reporter gene driven by the normal human A gamma-globin gene promoter. Butyrate (4 carbons) increased the activity of the human A gamma-globin gene promoter up to 123 times. Marked augmentation of the normal gamma-promoter activity was also noted with 5-carbon valeric acid (up to 394 times) and 3-carbon propionic acid (up to 129 times). The branched isobutyric acid as well as phenylacetate showed less ability to increase promoter activity. Addition of the tandemly repeated AP-1/NF-E2 (AP) enhancer sequences from hypersensitive site 2 (HS2) of the locus control region (LCR) increased gamma-promoter activity up to 24 times. Addition of a nearby 16-bp conserved motif (CM) in HS2 (Safaya S, Rieder RF, Blood 78:146a, 1992 [abstr, suppl 1]) to the AP-containing plasmid construct further increased gamma-promoter activity. In the presence of butyrate, the plasmid bearing both the AP and CM sequences showed gene expression up to 477 times greater than that of the basal gamma-promoter-driven luciferase plasmid in the absence of inducer. A plasmid bearing the herpes simplex thymidine kinase promoter was also tested and gene expression was markedly increased by the same organic acids. MEL cells responded to butyrate, valerate, and propionate with induction of hemoglobin synthesis. Responses to isobutyrate and 6-carbon caproate required higher concentrations of the compounds. Thus, other short-chain organic acids as well as butyrate increase gamma-promoter activity in the transient expression system, and this activity can be further augmented by incorporating LCR elements into the expression vector. Nonglobin promoters also respond to the same carboxylic acids.

Animals↗