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PubMed1991

Transformation system for an asporogenous methylotrophic yeast, Candida boidinii: cloning of the orotidine-5'-phosphate decarboxylase gene (URA3), isolation of uracil auxotrophic mutants, and use of the mutants for integrative transformation.

An integrative transformation system was established for an asporogenous methylotrophic yeast, Candida boidinii. This system uses a uracil auxotrophic mutant of C. boidinii as the host strain in combination with its URA3 gene as the selectable marker. First, the C. boidinii URA3 gene coding for orotidine-5'-phosphate decarboxylase (ODCase) was cloned by using complementation of the pyrF mutation of Escherichia coli. Next, the host ODCase-negative mutant strains (ura3 strains) were isolated by mutagenesis and selection for 5-fluro-orotic acid (5-FOA) resistance. Five ura3 host strains that exhibited both a low reversion rate and good methylotrophic growth were obtained. All of these strains could be transformed to Ura+ phenotype with a C. boidinii URA3-harboring plasmid linearized within the Candida DNA. The transformants had a stable Ura+ phenotype after nonselective growth for 10 generations. These results and extensive Southern analysis indicated that the linearized plasmid was integrated into the host chromosomal DNA by homologous recombination at the URA3 locus in C. boidinii.

Blotting, Southern↗
PubMed1987

Directed mutagenesis in Candida albicans: one-step gene disruption to isolate ura3 mutants.

A method for introducing specific mutations into the diploid Candida albicans by one-step gene disruption and subsequent UV-induced recombination was developed. The cloned C. albicans URA3 gene was disrupted with the C. albicans ADE2 gene, and the linearized DNA was used for transformation of two ade2 mutants, SGY-129 and A81-Pu. Both an insertional inactivation of the URA3 gene and a disruption which results in a 4.0-kilobase deletion were made. Southern hybridization analyses demonstrated that the URA3 gene was disrupted on one of the chromosomal homologs in 15 of the 18 transformants analyzed. These analyses also revealed restriction site dimorphism of EcoRI at the URA3 locus which provides a unique marker to distinguish between chromosomal homologs. This enabled us to show that either homolog could be disrupted and that disrupted transformants of SGY-129 contained more than two copies of the URA3 locus. The A81-Pu transformants heterozygous for the ura3 mutations were rendered homozygous and Ura- by UV-induced recombination. The homozygosity of a deletion mutant and an insertion mutant was confirmed by Southern hybridization. Both mutants were transformed to Ura+ with plasmids containing the URA3 gene and in addition, were resistant to 5-fluoro-orotic acid, a characteristic of Saccharomyces cerevisiae ura3 mutants as well as of orotidine-5'-phosphate decarboxylase mutants of other organisms.

Candida albicans↗
PubMed1982

On the contribution of the mitochondrial genome to the growth of Chinese hamster embryo cells in culture.

The present results demonstrate that Chinese hamster embryo cell populations in culture can be adapted to grow in the presence of chloramphenicol. It is shown that tryptose phosphate broth and uridine, one of its components, prevent the growth inhibitory effect of the drug. Study of some respiratory parameters (cytochrome c oxidase, cytochrome spectra, oxygen consumption) indicated that neither the broth nor uridine prevented the inhibitory effect of chloramphenicol on mitoribosomal protein synthesis. The cells grew with mitochondria devoid of a functional respiratory chain. Auxotrophy for pyrimidines appeared to result from the absence of dihydroorotate dehydrogenase, a respiratory chain-linked enzyme that catalyzes the fourth step of de novo pyrimidine biosynthesis. These and other results suggest that the synthesis of orotic acid may be considered as one of the main contributions of mitochondria to the growth of animal cells in culture.

Animals↗
PubMed1980

Effects of infection and endotoxin on rat hepatic RNA production and distribution.

Rat liver was quantitatively subfractionated into free ribosomal, bound ribosomal, nuclear, and soluble fractions to determine the effects of infection and endotoxin treatment on hepatic RNA production and distribution. A 4-h pulse label of [14C]orotic acid was used to monitor newly transcribed RNA; distribution was determined by measuring RNA content at various times after infection or endotoxin treatment. A significant increase in the rate of RNA synthesis was seen by 12 h and continued through 20 h in response to Streptococcus pneumoniae infection. During the peak hours of the RNA response, redistribution of RNA into the bound ribosomal fraction takes place at the expense of the free ribosomes. However, in Salmonella typhimurium and its endotoxin, more involvement of the free ribosoma fraction during the early stages of the infection was apparent. These data suggest that the hepatic RNA response takes place in two stages, an early "endotoxin" response, resulting in redistribution of cytoplasmic RNA into free ribosomes, and a later "infection" response, involving the mobilization of the bound ribosomes.

Animals↗
PubMed1979

Noncoordinate regulation of cytoplasmic RNA in compensatory renal hypertrophy.

To examine the regulatory role of mRNA in compensatory renal hypertrophy, the accumulation and decay of [3H]orotic acid in poly(A)-containing mRNA in mouse kidney was analyzed after unilateral nephrectomy during the period of maximal rRNA accretion. The distribution of radioactivity between newly synthesized poly(A)-containing and poly(A)-lacing polysomal RNA was altered, but no differences in mRNA half-life were observed in growth compared with effects of sham nephrectomy. Radioactivity in polysomal polyadenylated RNA was diminished by approximately 25% during growth where mice were labeled after nephrectomy, but if mice were labeled 18 h before operation, no difference was noted. Thus, accumulation of newly synthesized poly(A)-containing mRNA relative to RNAs that lack poly(A) is changed early in the course of renal hypertrophy. This noncoordinate regulation may represent a control mechanism effective early in induced cell growth involving mRNAs that lack poly(A).

Animals↗
PubMed1991

Functional and morphological changes of the exocrine pancreas in ciclosporin-treated rats.

We have examined whether or not ciclosporin A (CsA) affects structure and function of the exocrine pancreas. Male Wistar rats were treated once a day for 7 days with intraperitoneal injections of vehicle or 5, 15, 30, or 50 mg/kg of CsA. Following the CsA treatment, incorporations of [3H]thymidine into DNA and [3H]orotic acid into RNA were found to be significantly reduced in a dose-dependent manner up to 30 and 15 mg/kg, respectively, at which doses the incorporations reached a plateau. The incorporation of [3H]-L-leucine into protein also decreased by 36% at the dose of 5 and by 53% at the dose of 50 mg/kg of CsA. The activities of amylase and lipase in the pancreas also decreased in the CsA-treated rats. Furthermore, a significant reduction in the specific binding of [3H]N-methylscopolamine to muscarinic receptor was observed following the administration of CsA. The Scatchard analysis for the [3H]N-methylscopolamine binding to the pancreatic membrane revealed a significant decrease in Bmax, but not in Kd values in the CsA-treated animals. In addition, it was found histologically that administration of CsA induced cellular atrophy, cytoplasmic vacuolization, and cellular necrosis in the exocrine pancreas. These results strongly suggest that prolonged treatment with CsA may induce the suppression of pancreatic exocrine functions by decreasing the contents of amylase and lipase as well as the number of muscarinic receptors, possibly by the inhibition of the syntheses of protein and DNA in the exocrine pancreas.

Amylases↗
PubMed1984

Random X inactivation resulting in mosaic nullisomy of region Xp21.1----p21.3 associated with heterozygosity for ornithine transcarbamylase deficiency and for chronic granulomatous disease.

A young woman with normal gonadal development and mild mental retardation was found to have a small de novo interstitial deletion of most of band Xp21, karyotype designation 46,X,del(X) (pter----p21.3:: p21.1----qter). Replication studies on lymphocytes and skin fibroblasts revealed that in 45% of cells the normal X was late replicating. Somatic cell hybrids between her fibroblasts and HPRT-deficient Chinese hamster cells were obtained and selected for and against retention of the active human X chromosome. In several independent hybrids the deleted X was retained in the active state. Partial ornithine transcarbamylase (ornithine carbamoyltransferase EC 2.1.3.3) (OTC) deficiency was documented by elevated urinary orotic acid excretion and increased serum glutamine after a protein load. This confirms the mapping of the structural gene for OTC to this deletion. Testing of neutrophil function revealed heterozygosity for chronic granulomatous disease (CGD) suggesting that a gene for CGD maps within the deletion. Thus, X inactivation mosaicism is also present in hepatocytes and neutrophilic granulocytes. Random X inactivation in a female with an Xp deletion has not been previously reported. The cells from this patient and the somatic cell hybrids containing her deleted X chromosome in the absence of the normal X provide material for the precise mapping of X linked genes and DNA sequences on the short arm of the human X chromosome.

Adult↗
PubMed1995

Brain lipofuscinolysis and ceroidolysis--to be or not to be.

Lipofuscin pigment (LP) accumulations and ceroid pigment (CP) storages were demonstrated by multiple consensus studies. On the contrary, fewer researches, sometimes with opposite conclusions were made on brain LP and CP decrease, dissolution and elimination. Neuroactive agents (such as Meclofenoxate, Orotic acid, Antagonic-Stress, Piracetam, L-Deprenyl, Geriforte) generate LP and CP decrease and dissolution by cytoplasm rehydration, optimization of the brain cellular recycling system activities, by neuronal, glial and capillary LP lysis and CP lysis, by neurono-glio-endothelial transfer of highly processed LP and CP, with final capillary elimination. Therefore, these nootropic drugs may become therapeutical solutions in brain aging deceleration, in CP inductive circumstances and in age-associated diseases.

Aging↗
PubMed1983

Binding sites for glucocorticoids in cytosols from the ventral prostate and seminal vesicle of rats.

Binding sites for 3H-dexamethasone (Dex) were demonstrated in cytosols from the ventral prostate and seminal vesicle of rats only if dithiothreitol (DTT) was present in the incubation mixture. The binding observed in the presence of DTT was high affinity (Kd=1-5 nM) and low capacity (Bmax=approx. 0.1 p mole/mg protein) and exhibited a binding specificity for glucocorticoids. The addition of molybdate (Mo) to the incubation mixture enforced the effect of DTT on the binding but the extent of the effect of Mo in cytosols of the ventral prostate differed from that in the seminal vesicle. The binding sites in the cytosols of these tissues were depleted after administration of Dex to animals. The depletion observed was not due to occupation of the binding sites by injected Dex and this was confirmed by the exchange assay. Addition of the cytosol from the seminal vesicle inhibited the 3H-Dex binding in the liver cytosol but the cytosol from the ventral prostate did not show an inhibitory effect. The binding sites in neither of these male accessory sex organs were modified markedly after the animals were castrated. Although the 3H-Dex binding sites observed in the cytoplasm of male accessory sex organs fit the definition proposed for the steroid hormone receptors, it is not clear whether these tissues are under the influence of glucocorticoid or not; the rate of incorporation of 3H-leucine and 3H-orotic acid into the acid-insoluble fraction from the ventral prostate is not influenced by the administration of Dex to animals.

Animals↗
PubMed1975

Elevated serum growth hormone in protein-deprived rats, and decreased liver RNA after hypophysectomy.

Serum growth hormone was significantly higher in rats fed on a non-protein than on a 25% casein diet. In both dietary groups, hypophysectomy provoked a decrease in the RNA/DNA ratio of the liver, and, especially in the protein-deprived rats, a decrease in the RNA synthesis per liver cell, measured as the product of the RNA/DNA ratio, and the ratio of specific RNA activity to specific nucleotide activity, two hours after administration of [3H]orotic acid. In the protein-deprived rats, full reconstitution of these figures was obtained with a combination of growth hormone, hydrocortisone and triiodothyronine, but not quite with growth hormone alone. The possible role of growth hormone in protein deprivation is discussed.

Animals↗
PubMed1986

Biochemical changes in liver and blood during liver fattening in rats.

Excessive fat accumulation in the liver is a common metabolic disorder seen in humans and animals. Fatty liver was induced in the rat by feeding the animals with a sucrose rich diet containing 1% orotic acid for 2-3 weeks. In the sera from fatty liver rats there were significant changes in the level of alanine aminotransferase (+ 68.7%), malic dehydrogenase (+ 77.8%), gamma-glutamyl transpeptidase (- 53.4%) and total lipids (+ 26.6%). There were small to no changes in the levels of aspartate aminotransferase, glucose-6-phosphate dehydrogenase, lactic dehydrogenase, aldolase, malic enzyme, 6-phosphogluconic acid dehydrogenase, alkaline phosphatase and albumin. In fatty liver, significant differences were seen in the levels of glucose 6-phosphate dehydrogenase (+ 235%), malic enzyme (+ 170%), gamma-glutamyl transpeptidase (+ 113%), 6-phosphogluconate dehydrogenase (+ 63%), aspartate aminotransferase (+ 35.6%), malic dehydrogenase (+ 38%), lactic dehydrogenase (+ 37%), and alanine aminotransferase (- 23%). Comparison of the non-fatty part with the fatty part of the fatty liver showed larger changes in the non-fatty part of the liver, suggesting that during the fattening process, there is an induction of enzymes in the liver reaching a peak prior to lipid accumulation, declining thereafter during liver fattening. The increase in NADPH-generating lipogenic enzymes suggests that accumulated fat in the liver is at least partially from de-novo increased synthesis in the liver.

Animals↗
PubMed2000

Ornithine aminotransferase, a potential target for the treatment of hyperammonemias.

Ornithine-delta-aminotransferase (OAT) (EC 2.6.1.13) is a pyridoxal-5' phosphate dependent mitochondrial matrix enzyme. It controls the L-ornithine (Orn) level in tissues by catalysing the transfer of the delta-amino group of Orn to 2-oxoglutarate. The products of this reaction are L-glutamate-gamma-semialdehyde and L-glutamate. Among the compounds known to inhibit (or inactivate) OAT, only L-canaline and (SS)-5-(fluoromethyl)ornithine [(SS)-5FMOrn] are selective for OAT. Treatment of laboratory animals with 5FMOrn causes a dramatic accumulation of Orn in most tissues and organs, and the enhanced formation of urea due to saturation of ornithine:carbamoyltransferase with its substrate. The enhancement of urea formation by increased endogenous levels of Orn is comparable with that produced by large doses of Orn and arginine, a treatment known to enhance the detoxification of ammonia. However, protection to lethal doses of ammonium salts by exogenous Orn is rapidly fading. In contrast, inactivation of OAT by a small dose of 5FMOrn renders a long-lasting protective effect against various forms of hyperammonemic states. Among these the reduction of ammonia concentrations in blood and tissues, and the reduction of the pathologic excretion of orotic acid to normal levels in mice with hereditary defects of the urea cycle, were most impressive. In human hereditary OAT deficiency the elevated intraocular concentrations of Orn are considered to be a cause of gyrate atrophy. This is presumably the reason, why OAT has not been considered as a therapeutically useful target. Chronic inactivation of OAT by repeated administration of 5FMOrn, caused elevated intraocular Orn concentrations, but this treatment had no effect on the function and histology of the visual system, or the behaviour of adult mice. The confirmation of this and related observations in higher species will show, whether OAT inactivation has potentials in the treatment of hyperammonemic states.

Ammonia↗
PubMed1981

Subcellular localization of pyrimidine synthesis enzymes in bovine mammary tissue.

Subcellular localization of enzymes of the pyrimidine biosynthetic pathway was determined in lactating bovine mammary tissue. Aspartate transcarbamylase was associated with a membrane portion of the microsomal cell fraction. Dihydroorotate dehydrogenase w3as in the mitochondrial fraction with no evidence for a cytosolic enzyme requiring pyridine nucleotides. Orotate phosphoribosyltransferase was in the cytosol of the cell. The significance of these findings to other mammalian cells and orotic acid accumulation in bovine milk is discussed.

Animals↗
PubMed1978

Effect of dietary methionine level on anserine and carnosine contents in the gastrocnemius muscle of rat.

Anserine and carnosine in the muscle of growing rats were measured to explore the effect of dietary methionine. Carnosine was reduced in the gastrocnemius muscle of rats fed on a methionine-free diet. After refeeding on methionine for one week, carnosine in the muscle approached to the normal level. In contrast, anserine increased in the muscle of rats fed on a methionine-free diet. Anserine also increased in the gastrocnemius muscle of rats fed on a methionine-excess diet, whereas carnosine did not vary. Npi-Methylhistidine was detected in the muscle of rats fed on a methionine-excess diet. Moreover, Npi-methylhistindine and Ntau-methylhistine in the urine increased in the rats fed on both methionine-excess and methionine-free diets. Carnosine in the gastrocnemius muscle was not affected by a ethionine diet nor by a orotic acid diet which induced fatty liver. However, anserine increased in the muscle of rats fed on a ethionine diet.

Amino Acids↗
PubMedDate not supplied

[Use of a novel hepato-protective preparation "phospholiv" for inhibition of development of chronic hepatitis in rats].

Protective influence of a new phospholipid preparation "Phospholiv" was studied using a model of chronic hepatitis. Animals were treated 45 days intraperitoneay with CCl4 with parallel intragastral administration of Phospholiv or--(for comparison)--the of other phospholipid hepatoprotector, Essential. Morphologic changes of liver, as well as protein and RNA biosynthesis were evaluated in the end of experiment--by means of measuring C14-leucine and C14-orotic acid incorporation into hepatocyte subcellular fractions. Both phospholipid preparations attenuated dystrophic liver changes, Phospholiv effect being more pronounced. They both prevented CCl4 induced inhibition of label incorporation into subcellular fraction proteins, but only Phospholiv, promoted the maintaining normal level of radioactivity incorporation into cytosol proteins and hepatocyte RNA. The results, confirming certain protective effect of Essential, show more pronounced hepatoprotective action of the new preparation Phospholiv (developed on the basis of polyunsaturated phosphatidylcholine and glycyrrhizinic acid salt). Data show also on possible fit hepatitis treatment.

Animals↗
PubMedDate not supplied

[The creatine effect on RNA and protein synthesis in growing culture of chick embryo myoblasts].

4hr incubation of the growing culture of chick embrio myoblasts in the presence of 5 mM creatine resulted, regardless of a well-defined lowering of cell membrane permeability to labelled precursors, in: (1) the 1.5-fold induction of 14C-orotic acid incorporation into total cellular RNA; (2) the 1.9-fold stimulation of DNA-dependent RNA-polymerase activity and (3) the preferable, in comparison with total proteins, 14C-leucine incorporation in the myosin heavy chain. The stimulating effect of creatine on RNA-poly-merase deals with a definite enzyme fraction and it is caused by the augmentation of the transcriptional complex enzyme activity. Polyacrilamide gel electrophoresis of total 14C-RNA revealed a relative increase of radioactivity after creatine treatment in both high-molecular pike and the fraction corresponding to 26S RNA, the relative proportion of mRNA containing Poly-A in the composition of total cellular RNA being invariable. The data obtained show that, though creatine as a positive regulator manifestates its effect at different stages of the sucessive chain of reactions leading to muscular protein synthesis, the direct realization of creatine regulatory function is connected with nucleus and is fullfilled at the transcription level.

Animals↗
PubMed1975

Increased synthesis of nuclear RNA in regenerating rat liver after gamma-irradiation.

Nine hours after partial hepatectomy rats were whole-body, 60Co-gamma-irradiated with exposures of 50, 100, 200, 500, 1000 and 2000 R, respectively. RNA was prepared from isolated nuclei of rat liver 12 hours after partial hepatectomy. Animals were injected with 14C-orotic acid 20 minutes before killing. The isolated labelled nuclear RNA was fractionated by sucrose density gradient centrifugation. The specific radioactivity of RNA was correlated with that of the specific radioactivity of nucleotide pool of the liver homogenates. RNA synthesis was found to increase after each dose applied as compared to the rate of RNA synthesis in 12 hours regenerating liver. The increment depended on the dose delivered: 10% at 50 R, 50% at 500 R and 30% at 2000 R. Nuclear RNA synthesis also increased in the liver of non-hepatectomized rats 3 hours after 500 R gamma-irradiation, but the increment was only 20-30% above the non-hepatectomized and unirradiated control.

Animals↗
PubMed1992

A binding profile of manganese to the nucleus of rat liver cells, and manganese-induced aberrations in thyroid hormone content and RNA synthesis in the nucleus.

Manganese (Mn) is accumulated in the nuclear and mitochondrial fractions when excess Mn is administered. However, little is known with respect to the behaviors of Mn in nuclei. In the present study, rats were given excess Mn and the nuclei were purified from liver cells by differential and sucrose gradient centrifugations. Being subjected to equilibrium dialysis with a radioactive 54Mn, the binding capacity of Mn in nuclei from the control rat was five-fold higher than BSA, which was used as a reference protein; and the capacity of 54Mn-binding rose in the nuclei from the Mn-treated animals in comparison with those from the control. On the analyses of nuclear materials with partial solubilization, sepharose column chromatography and HPLC, there were two major fractions which associated with a lot of Mn; one fraction was of large molecules of DNA, and the other fraction seemed to be peptides with small molecular weights. Therefore, Mn may open up a superhelical structure of DNA to provide more negatively charged phosphate moiety as a binding-site for a positively charged Mn. The results also disclosed a possible aberration in biological functions due to excess Mn in nuclei; the apparent association constant of triiodothyronine, a physiologically active thyroid hormone, to the nucleus was reduced by 75% and the uptake of 14C-labelled orotic acid to a newly synthesized RNA in the liver was severely inhibited.

Animals↗