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PubMed1993

The limitations of paradigms: studies on the intermediary metabolism of Trypanosoma cruzi.

We review the development of our knowledge and interpretations of the intermediary metabolism of Trypanosoma (Schizotrypanum) cruzi. Already in the 1950's it was clearly established that when this organism was exposed to large external concentrations of carbohydrates it was unable to catabolize them completely, even in the presence of oxygen, producing a mixture of CO2, dicarboxylic acids (succinic, malic) and alanine as end products. However, subsequent work tended to emphasize such paradigmatic features as a full complement of glycolytic enzymes in all stages of the life cycle of the parasite, a functional Kreb's cycle, a cytochrome-dependent electron transport chain and phosphorylative oxidation which suggested that T. cruzi had the basic metabolic properties of classical glucose-utilizing cells, in contrast with the degenerate glycolytic metabolism of bloodstream African trypanosomes. Only in the 1980's interest revived on the how and why of the incomplete carbohydrate catabolism by this parasite. The primary reason for this anomaly was found to be the presence of a constitutive phospho-enol-pyruvate carboxykinase (PEPCK, ATP-dependent, E.C.4.1.1.49), present in all stages of the parasite's life cycle, and the lack of regulation of the glycolytic route at its classical control points, hexokinase and phosphofructokinase. On the other hand, the presence of two distinct glutamate dehydrogenases (NAD+ and NADP(+)-dependent), the former being strictly regulated by the energy charge of the cell and the Krebs' cycle activity, indicated that amino acids can be a primary source of energy for this organism.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1992

Acute toxic effects of oxamyl in the rat.

The effects of single acute oral doses of 1, 2.1, and 3.5 mg/kg oxamyl (a carbamate insecticide) on selected biochemical parameters in male Sprague-Dawley rats were investigated. The animals exhibited significantly decreased weight gain when compared to control animals. The compound inhibited brain and blood acetylcholinesterase significantly in the first few hours of exposure. Liver glucose-6-phosphatase was inhibited substantially after 7 and 4 days at the levels of 2.1 and 3.5 mg/kg, respectively. Maximum inhibition of liver succinic acid dehydrogenase was noted after 1 day at the level of 1 mg/kg and after 6 hr at the level of 2.1 and 3.5 mg/kg. Significant changes in serum total lipids and glucose were observed when oxamyl was given at 2.1 and 3.5 mg/kg, but serum protein was not affected at any dose level. However, the absence of statistically significant effects between Days 7 and 14 in most of the investigated parameters is indicative of an overall moderate degree of toxicity of oxamyl following acute oral administration of the selected doses.

Acetylcholinesterase↗
PubMed2005

Novel IMP-1 metallo-beta-lactamase inhibitors can reverse meropenem resistance in Escherichia coli expressing IMP-1.

IMP-1 metallo-beta-lactamase is a zinc metalloenzyme that confers antibiotic resistance to bacteria through the hydrolysis of beta-lactam antibiotics. Pathogens that express the enzyme show reduced susceptibility to carbapenems, such as meropenem and imipenem. In order to identify novel IMP-1 inhibitors, the National Cancer Institute (NCI) chemical diversity set was screened using 96-well high throughput screening format. The collection yielded several novel succinic acid derivatives that exhibited mixed inhibition of IMP-1 with compound 20707 having the highest affinity with a Ki value of 3.3 microM+/-1.7. The compounds are moderately potent inhibitors of IMP-1 with IC50 values ranging from 5.0 to 17 microM. An original chemical class of IMP-1 inhibitor, 2-((E)-(1,3-dihydroxy-2-methylpropan-2-ylimino)methyl)-4,6-diiodophenol, was discovered and was the most potent with an IC50 of 1.2 microM. NCI compounds, 20707, 140905 and 9746 sensitized a carbapenem-resistant laboratory strain of Escherichia coli to clinically achievable levels of meropenem.

Anti-Bacterial Agents↗
PubMed1996

Potentiation of GLP-1 insulinotropic action by a nonglucidic nutrient in the pancreas of diabetic GK rats.

Glucagon-like peptide 1 (GLP-1) is often referred to as a glucose-dependent insulinotropic agent and is currently under investigation as a tool in the treatment of noninsulin-dependent diabetes. This report shows that, in the absence of glucose, a nonglucidic nutrient, namely succinic acid dimethyl ester (SAD), allows full expression of the insulinotropic potential of GLP-1 in the perfused pancreas from diabetic GK rats. Thus, whereas the insulin and glucagon responses to GLP-1 in GK rats differ from those previously documented in nondiabetic animals when tested in the absence of exogenous nutrient, the secretory response of the endocrine pancreas to GLP-1 is virtually normalized in the GK rats when SAD is incorporated into the perfusate. It is proposed, therefore, that nonglucidic nutrients, such as SAD, may optimalize the B-cell secretory response to GLP-1 in noninsulin-dependent diabetes mellitus.

Animals↗
PubMed2006

Validation of an HPLC method for the simultaneous determination of DZ5 and its active metabolite in dog plasma and its pharmacokinetics.

A validated HPLC method is described for the simultaneous determination of daidzein 7,4'-di-succinic acid mon-ester-O-ethoxy (DZ5) and its active metabolite daidzein 7,4'-dioxy-ethoxy (DZ4) in dog plasma. DZ5 and DZ4 were determined by reversed-phase HPLC (column: Hypersil C18 5 microm silica, 200 mm x 4.6 mm i.d.; eluent: 400 ml water, 500 microl 85% phosphoric acid, 600 ml methanol) and photometric detection (250 nm), with Kaempferol as the internal standard. The calibration curve was linear over the range 0.1-50.0 microg/ml in dog plasma. The average extraction recoveries were 84.6% (DZ5), 82.7% (DZ4) and the within-day and between-day precisions were less than 10.93%. The assay was applied to the analysis of samples from a pharmacokinetic study. Following the oral administration and intravenous administration of DZ5, DZ5 was eliminated rapidly from the plasma and DZ4 was found in plasma. The absolute bioavailability of total DZ5 and DZ4 was 41.5%. The method was demonstrated to be feasible for pharmacokinetic studies of DZ5 in dogs.

Animals↗
PubMed1989

Bifunctional oligonucleotide probes synthesized using a novel CPG support are able to detect single base pair mutations.

A novel multifunctional controlled pore glass, MF-CPG (Fig. 1), has been synthesized and used to incorporate 3' terminal primary aliphatic amines into synthetic oligonucleotides. MF-CPG consists of a unique succinic acid linking arm which possesses both a masked primary amine for label attachment and a dimethoxytrityl protected hydroxyl for nucleotide chain elongation. Using MF-CPG, we have devised a simple and convenient technique to attach non-radioactive labels to the 3' terminus of oligonucleotides. Bifunctional probes can then be constructed by 32P labeling the 5' terminus with T4 kinase and gamma 32P-ATP. Using such bifunctional oligonucleotide probes in conjunction with polymerase chain reaction (PCR) amplification, we were able to detect single base substitutions in a target segment of the human H-ras protooncogene employing either functionality. Our technique thus expands the potential applications for oligonucleotides as hybridization probes.

Amines↗
PubMed1988

DNA methylation in rat liver by daminozide, 1,1-dimethylhydrazine, and dimethylnitrosamine.

[methyl-14C]Daminozide (succinic acid 2',2'-dimethylhydrazide; 37 mg/kg), 1,1-[14C]dimethylhydrazine (UDMH; 19 mg/kg), and [14C]dimethylnitrosamine (DMNA; 0.1 mg/kg) were administered by oral gavage to male Sprague-Dawley rats. After 24 hr, the animals were killed and DNA was purified from the livers to constant specific radioactivity. After enzymatic degradation of the DNA to the 3'-deoxynucleotides the level of DNA methylation was determined by HPLC analysis. Radiolabeled 7-methylguanine (7mG) was identified by cochromatography with unlabeled 7mG added as standard after acidic depurination of DNA and HPLC analysis of purines and apurinic acid. All three compounds were found to methylate DNA. The relative potencies were 1:47:4900 for daminozide:UDMH:DMNA. With [methyl-3H]UDMH, the formation of 7mG was investigated as a function of dose administered, at 20, 2, and 0.2 mg/kg. The methylation of DNA was strictly proportional to the dose. The data were used to compare the level of DNA alkylation derived from residues of daminozide and UDMH in treated apple with the genotoxicity of the intake of N-nitroso compounds in Germany and Japan. It is estimated that these residues could lead to a DNA methylation in the liver of about 6% of an average exposure to DMNA.

Animals↗
PubMed1995

Restricted effect of formycin A and non-glucidic nutrients upon insulin release in islets from rats with hereditary or acquired non-insulin-dependent diabetes.

Pancreatic islets isolated from control rats, Goto-Kakizaki rats and adult rats that were injected with streptozotocin during the neonatal period were incubated for two successive period of 90 min each in the presence of D-glucose (11.1 mM) with or without formycin A (1.0 mM), and in the presence of the dimethyl ester of succinic acid (SAD, 10.0 mM) with or without palmitate (1.0 mM). Although formycin A augmented glucose-stimulated insulin release in both control and diabetic rats, it failed to compensate for the impaired secretory response to D-glucose in the latter animals. Likewise, non-glucidic nutrients such as SAD and/or palmitate failed to display a more efficient insulinotropic action, relative to basal insulin output, in diabetic than control rats. These results indicate that both formycin A and non-glucidic nutrients are unable, through their immediate insulinotropic action, to restore a normal output of insulin in islets of animals with inherited or acquired non-insulin-dependent diabetes.

Animals↗
PubMed1996

Nitric oxide donors decrease the function and survival of human pancreatic islets.

Nitric oxide (NO) has been proposed as a possible mediator of beta-cell damage in human IDDM. This hypothesis is based on in vitro studies with rodent pancreatic islets. In the present study we examined whether human beta-cells are affected by NO. In view of species differences in beta-cell sensitivity to damaging agents, rat islets were investigated in parallel. Isolated islets were exposed for 90 min to different concentrations of three chemically unrelated NO donors, SIN-1, GSNO or RBS. At the end of this incubation, human insulin release was mostly similar in control and NO-treated islets but, 48 h later, islet retrieval, islet DNA and insulin content, and glucose-induced insulin release were markedly lower in islets exposed to NO donors. Rat islets were already inhibited during the initial 90 min; 48 h later their loss in beta-cell function was similar to that in human islets. Nicotinamide or succinic acid monomethyl ester partially protected against SIN-1 induced islet cell loss, but not against the functional inhibition of human pancreatic islets. Exposure of human or rat islets to RBS was associated with significant DNA strand breakage, as judged by the comet assay (single cell gel electrophoresis) and by ultrastructural signs of cell damage. DNA damage was more severe in rat islet cells exposed to similar amounts of RBS. It is concluded that NO donors can damage human pancreatic islets, an effect paralleled by induction of nuclear DNA strand breaks.

Adolescent↗
PubMed1994

Insulinotropic action of meglitinide analogs: concentration-response relationship and nutrient dependency.

The insulinotropic action of meglitinide was compared to that of its analogs S 3075, A-4166, KAD-1229 and repaglinide. None of these hypoglycemic agents significantly enhanced insulin output from rat pancreatic islets incubated for 90 min in the absence of exogenous nutrient. However, all these agents, when tested at a 10 microM concentration, augmented insulin release evoked by either 7 mM D-glucose or 10 microM succinic acid monomethyl ester (SAM). In this respect, meglitinide was a less efficient secretagogue than the other non-sulfonylurea hypoglycemic agents. Moreover, in the presence of 7 mM D-glucose, the lowest concentration of the drug required to cause a significant increase in insulin output decreased from about 1.0 microM for meglitinide to 0.1 microM with A-4166, KAD-1229 or repaglinide and even close to 10 nM in the case of S 3075. The concentration-response relationship thus yielded the following hierarchy, S 3075 > KAD-1229 = repaglinide > A-4166 > meglitinide, there being a difference of more than two orders of magnitude between the weakest and most potent agent.

Animals↗
PubMed1994

Imaging of exocrine pancreatic function. Investigation of the bioavailability of weak organic acids as potential pancreatic contrast agents for computed tomography.

RATIONALE AND OBJECTIVES: The feasibility of targeting iodinated contrast agents to the exocrine pancreas was investigated. Iodinated weak organic acids including succinic acid-mono-3-amino-2,4,6-triiodo- N-ethylanilide (compound I), the ethanolamine salt of N-ethylsuccinic acid-(2,4,6-triiodo-3-methylamino anilide) (compound II), and the sodium salt of 2,4,6-triiodo-3-N-ethylacetylamino-phenylpropionic acid (compound III) were studied as potential contrast agents for computed tomography (CT) of the pancreas. METHODS: An ex vivo perfusion system was used to compare pancreatic uptake of the three compounds. In vivo CT studies were conducted using domestic pigs to study potential enhancement of the pancreas after intravenous injection of the compound. RESULTS: Ex vivo perfusion studies with isolated rat pancreas demonstrated nearly identical extraction ratios of approximately 0.6 for all three compounds tested. Average iodine concentrations measured in pancreas at the end of the perfusion studies was 0.27 mg/g +/- 0.20 for compound I, 0.18 mg/g +/- 0.06 for compound II, and 0.16 mg/g +/- 0.09 for compound III. Differences in iodine concentrations retained were not statistically significant. Computed tomography studies in domestic pigs demonstrated up to 30% enhancement of the pancreas after intravenous injection of 75 and 150 mg/kg of compound II at 45 minutes. Whereas ex vivo perfusion studies indicated increasing extraction of the three compounds with increasing doses/concentrations in the perfusate, no improved contrast enhancement was observed at the higher dose level compared with the lower dose in CT. CONCLUSION: Both ex vivo perfusion studies and dose-independent enhancement levels achieved seem to indicate a transport maximum in the pancreas for the iodinated weak organic acids studied.

Anilides↗
PubMed1997

Insulinotropic action of 1,2,3-Tri(methylsuccinyl)glycerol ester.

A novel ester of succinic acid, 1,2,3-tri(methylsuccinyl)glycerol ester (3SMG), was found to stimulate insulin release from rat pancreatic islets. In the presence of 7 mM d-glucose, a 10 microM concentration of 3SMG was sufficient to cause a significant increase in insulin output. The ester mimicked the effect of other nutrient secretagogues in enhancing the synthesis of islet peptides, with a preferential action on proinsulin as distinct from nonhormonal peptides, in decreasing 86Rb outflow from prelabeled islets, and in stimulating Ca2+ inflow into the islet cells. It is proposed, therefore, that 3SMG displays the attributes suitable for stimulation or potentiation of insulin release in noninsulin-dependent diabetes, without requiring administration in large amounts and, hence, without the risk of excessive hepatic gluconeogenesis.

Animals↗
PubMed1982

Brain damage after deep hypothermia in dogs.

Histopathological and succinic acid dehydrogenase (SAD) activity changes, and the electron spin resonance (ESR) were examined in the brains of dogs exposed to various hypothermic conditions. A simple hypothermic cardiac arrest of 5 min duration occurred in the group subjected to 28 degrees C, and normal SAD activity was noted in dogs exposed 1-hour extracorporeal circulation under normothermia. In cases of a hypothermia below 28 degrees C, a decrease in enzyme activity, marked histopathological changes and the disappearance of the ESR signal were observed. In dogs killed immediately after induction of 20 degrees C hypothermia, the histopathological changes were primarily ischemic in nature, while in dogs killed at 1-12 month intervals after the experiments, irreversible gliosis was dominant. Our findings suggest that, to avoid brain damage under conditions of deep hypothermic circulatory arrest, the critical range is between 26-28 degrees C for rectal, and approximately 28-30 degrees C for brain temperature.

Animals↗
PubMed1974

The effects of arginine deficiency on lymphoma cells.

When L5178Y and L1210 mouse lymphosarcoma cells were incubated with rat or beef liver arginase there was up to 100% cell destruction in 24 hours. This was reversed specifically with arginine and partially with arginino-succinic acid, citrulline and ornithine. The concentration of arginine was critical; at 8 μmol/l the cells remained viable and reversible inhibition could be shown; below this level cells died. L5178Y cells were grown in medium containing from 0 to 80 μmol/l arginine for 24 hours then transferred to fresh medium for 24 hours. Viable cell counts and mitotic indices were determined, and cells were pulsed with (3)H-thymidine, (3)H-uridine, (14)C-leucine and (14)C-arginine at various times. Thymidine uptake was affected most and preceded parallel changes in viable cell numbers. It was concluded that arginine is required by these cells even in a "resting" state and despite some evidence for their capacity to utilize precursors, the tumour cells underwent rapid and extensive destruction when available arginine was severely depleted.

Animals↗
PubMed1977

Effect of diphenylhydantoin on gamma aminobutyric acid (GABA) and succinate activity in rat Purkinje cells.

A study has been made of the effect of diphenylhydantoin (DPH) upon the levels of gamma aminobutyric acid (GABA) and succinic dehydrogenase in rat Purkinje cells. DPH was administered over 26 days in chronic experiments using controls receiving the same injection vehicle without DPH. Animals in this group received daily 1.25 mg/kg body weight, 12.5 mg/kg body weight, and 50 mg/kg body weight DPH. Acute experiments were carried out over the course of not more than four days, three groups of animals receiving 75 mg/kg body weight, 87.5 mg/kg body weight, and 100 mg/kg body weight DPH. No effect upon succinic dehydrogenase could be demonstrated at any dose level. There was a significant progressive loss of GABA with increasing dosage of DPH.

Aminobutyrates↗
PubMed1985

Isolation and characterization of a succinylated polysaccharide from the cell wall of Micrococcus agilis.

A polysaccharide consisting of rhamnose, galactose, glucosamine and ester-linked succinic acid was extracted from the isolated cell walls of Micrococcus agilis by the hot water-phenol and 5% trichloroacetic acid (TCA) extraction methods. The hot water-phenol extractable polysaccharide accounted for 30% of the weight of the wall, with 23% by the TCA method. Phosphorus contents were less than 0.01% of the polysaccharide. Succinyl residues released by alkali treatment (0.1 N NaOH, 30 min, 37 degrees C) were identified by gas-liquid chromatography, and accounted for 6.3% and 5.1% of the polysaccharide purified from the hot water-phenol and TCA extracts, respectively. The polysaccharide was not bound when chromatography on Concanavalin A-Sepharose 4B (Con A/Sepharose 4B) columns was performed and it could thus be separated from any residual membrane lipomannan. The purified polysaccharide behaved as a negatively-charged polymer on electrophoresis in 1% agarose (at pH 8.6). A strong cross-reaction, unaffected by removal of the succinyl groups, was observed with type XXIII pneumococcal polysaccharide antiserum indicating the presence of L-rhamnose, linked through non-reducing, lateral end groups.

Antigen-Antibody Complex↗
PubMed2000

Effects of D-mannoheptulose and its hexaacetate ester on hormonal secretion from the perfused pancreas.

D-mannoheptulose was recently proposed to be transported into cells by GLUT2, whereas its hexaacetate ester may cross the plasma membrane without requiring the intervention of a specific carrier system. In the light of these proposals, the effects of unesterified D-mannoheptulose and D-mannoheptulose hexaacetate upon hormonal secretion by the perfused rat pancreas were now investigated. Unesterified D-mannoheptulose (1.7 mM) inhibited insulin release and, in most cases, somatostatin output, whereas it augmented glucagon secretion by pancreases exposed to D-glucose (3.3 mM) in the presence of the dimethyl ester of succinic acid (SAD, 10.0 mM). The heptose failed, however, to affect hormonal secretion in the sole presence of SAD. D-mannoheptulose hexaacetate (also 1.7 mM) reproduced, within limits, the effects of unesterified D-mannoheptulose in pancreases exposed to both D-glucose and SAD. In addition, however, the ester displayed a positive effect upon the secretion of the three hormones, even in the sole presence of SAD. These findings support the view that monosaccharide esters may affect the secretion of pancreatic hormones in a dual manner, linked to both the metabolic response to their glucidic moiety and a direct effect of the ester itself. Moreover, they reveal that unesterified D-mannoheptulose is able to antagonize the effect of D-glucose upon hormonal secretion even in cells claimed not to contain GLUT2. The modality by which D-mannoheptulose apparently gains access to the cytosol of these cells remains to be elucidated.

Analysis of Variance↗
PubMed1981

Affinity chromatography with 25-hydroxycholecalciferol ester in the isolation of the binding protein for vitamin D and its metabolites from human serum.

The 3 beta-hemisuccinate ester of 25-hydroxycholecalciferol was prepared by incubating the sterol with succinic acid anhydride in the presence of 4-dimethylaminopyridine at 4 degrees. The ester was isolated by silica gel column chromatography, and its hydrolysis in ethanolic sodium hydroxide yielded 25-hydroxycholecalciferol. The ester was covalently linked to aminoagarose in the presence of isobutylchloroformate, yielding 16 to 60 micrograms of sterol per packed ml of gel. Normal human serum was applied to the 3 beta-hemisuccinate-25-OH-D3 aminoagarose gel and elutions with buffer of increasing molarity were carried out. Total protein and DBP content of the 6M guanidine elution fractions revealed a 12 to 134-fold purification of human serum DBP by this technique. Best purifications were achieved by incubating serum with the gel at pH 8.3 and rinsing the gel with 0.3 M KCl prior to its elution with the guanidine. Our results indicate that affinity chromatography with this ligand, or possibly other vitamin D sterol esters, is a practical and useful technique in the analysis and preparative isolation of vitamin D sterol-binding proteins.

4-Aminopyridine↗