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PubMed1981

The lack of a "pleiotypic response' in hepatocyte proliferation induced in the rat by 3,5,3'-triiodothyronine.

Early morphological and biochemical alterations in proliferatively stimulated liver tissue obtained from 3,5,3'-triiodo-L-thyronine-treated rats were compared to those occurring in the liver remnant of 70% hepatectomized animals, and to controls. Subjecting photographic enlargements of histological slides prepared from these liver tissues to computer-assisted analyses, hepatocyte nuclear and nucleolar volumes were shown to be virtually identical in control and hormone-treated preparations through the first 24 hours after treatment, but significantly different from tissues obtained from partially hepatectomized animals, In vitro estimations of hepatic nuclear RNA polymerase activities early after treatment were also shown to be similar when comparing the hormone- and the saline-treated rats. Estimated by either 3H-orotic acid or 3H-leucine incorporation, the early accumulation of hepatic RNA and liver and serum proteins, significantly enhanced by 70% hepatectomy, were found similar in triiodothyronine-injected and control animals at least through the first 6 h after treatment; hormone administration appeared to cause slight enhancements in these parameters at later prereplicative times. While pharmacological doses (200 micrograms/100g) of the thyroid hormone induce a strong proliferative response in rat liver tissue, only minor prereplicative alterations appear to be elicited in the hepatocytes. This hepatic model offers an important potential tool to investigations aimed at understanding proliferative controls in mammalian liver cells.

Animals↗
PubMed1981

Studies on the structure of rat liver messenger ribonucleoprotein. II. Non-poly(A) RNase resistant fragments and electron microscopic appearance of mRNP.

Partially fragmented 12-21S rat liver messenger ribonucleoprotein (mRNP), labelled either with [3H]-orotic acid or [3H]-adenine was treated with 5 (micrograms/ml or 0.1 microgram/ml pancreatic ribonuclease (EC 3.1.27.5) and the resistant fragments were separated by sucrose gradient centrifugation. Two types of fragments were obtained. Digestion of mRNP with ribonuclease at a concentration of 5 micrograms/ml resulted in 9S poly(A)-protein particles of mRNP as evidenced by their characteristic sedimentation, electrophoretic mobility of the RNA moiety and protein composition. In contrast, ribonuclease at a concentration of 0.1 microgram/ml produced 2-5S pyrimidine labelled fragments carrying polynucleotide sequences consisting of approximately 16-50 residues. Two polypeptides of rat liver mRNP with molecular weights of 38 000 (P38) and 44 000 (P44) were found to be attached to these sequences. The data demonstrate that RNA sequences other than poly(A) interact with protein in mRNP. Electron microscopic studies revealed that the liberation of mRNP from the polysomes by EDTA changes its surface properties since EDTA releases the mRNP mainly in the form of globular particles. However, a small proportion of the mRNP remains in fibril-like form. Among the fibrils several blobs could be seen which were probably the proteins attached to the mRNA. From the available data a model for the structure of an "average" mRNP molecule is proposed.

Animals↗
PubMed1995

Inhibitory activity of the anti-malarial atovaquone (566C80) against ookinetes, oocysts, and sporozoites of Plasmodium berghei.

Ookinete formation from mature Plasmodium berghei gametocytes in vitro was partially inhibited by 0.05-0.1 microM atovaquone and almost totally blocked at a concentration of 0.25 microM. Microgametocyte exflagellation was not affected by atovaquone at concentrations up to 300 microM. Ookinete formation was also inhibited in culture when addition of 0.20 microM atovaquone was delayed by 4 hr, by which time DNA replication was likely to have been completed. Inhibition of ookinete formation by atovaquone was not reversed by orotic acid. Plasmodium berghei-infected Anopheles stephensi mosquitoes were fed a second blood meal 4, 7, 14, and 20 days postinfection (p.i.) from mice that had been treated with atovaquone or control diluent 8 hr previously. Atovaquone blood feeds on day 4 reduced oocyst numbers on days 6-12, although sporozoite numbers in the thorax and abdomen on day 20 were not significantly reduced. Blood feeds on day 7 slowed oocyst growth, blood feeds on day 14 did not significantly reduce sporozoite numbers, and feeds to mosquitoes on day 20 p.i. had no effect on transmission to naive mice. Sporozoite invasion of human hepatoma cells was unaffected by the presence of atovaquone.

Animals↗
PubMed1997

The immunosuppressive metabolite of leflunomide, A77 1726, affects murine T cells through two biochemical mechanisms.

The immunosuppressive metabolite of leflunomide, A77 1726, inhibits the enzymatic activity of protein tyrosine kinases and of dihydro-orotic acid dehydrogenase, an enzyme involved in pyrimidine biosynthesis. Here murine CTLL cell lines were studied to determine which of the biochemical targets of A77 1726 was responsible for the observed inhibition of proliferation and cytotoxic activity. At low concentrations of A77 1726, pyrimidine biosynthesis is the target, since inhibition of proliferation correlates with a reduction in pyrimidine NTP levels and is reversed by uridine. At higher concentrations of A77 1726, uridine no longer reverses the inhibition of proliferation even though pyrimidine NTP levels are restored. This second mechanism for inhibiting proliferation is probably inhibition of protein tyrosine kinases, since these higher concentrations of A77 1726 inhibit IL-2-induced tyrosine phosphorylation of Jak1 and Jak3, the protein tyrosine kinases initiating signaling by the IL-2R. Tyrosine phosphorylation of the beta-chain of the IL-2R, which is required for IL-2-driven proliferation, is also inhibited by A77 1726. Cytotoxicity of a CTLL line that overexpresses the Lck protein tyrosine kinase is inhibited by A77 1726; this inhibition is not affected by uridine, but does correlate with inhibition of an Lck in vitro kinase reaction. These studies establish that inhibition of pyrimidine biosynthesis and that of protein tyrosine kinase both contribute to the effects of A77 1726 on CTLL cell lines.

Aniline Compounds↗
PubMed1997

Identification of a new P-glycoprotein-like ATP-binding cassette transporter gene that is overexpressed during hepatocarcinogenesis.

The liver is remarkably insensitive to a variety of cytotoxins and expresses a number of known drug resistance genes. To isolate new P-glycoprotein (Pgp)-related genes, we screened a normal rat liver cDNA library at low stringency with a MDR1 cDNA fragment containing the P-loop and ATP binding site. We isolated a novel cDNA closely related to the Pgps that is dramatically increased in hepatic neoplasia and refer to it as P-glycoprotein-related protein (PRP). The predicted protein shows PRP to be a member of the ATP-Binding Cassette (ABC) family of proteins, and a multisequence comparison of the nucleotide binding domain and the ABC family signature sequences reveals that PRP sequences are highly conserved with the greatest similarity to the yeast heavy metal transporter encoded by hmtl. However, the hydropathy plot analysis suggests that PRP does not have any prominent membrane-spanning domains and thus is not typical of ABC transporters. The PRP transcript is detected in many normal tissues. In the H35 hepatoma cell line, PRP was overexpressed compared to normal liver. Southern blot analysis of DNA from the H35 rat hepatoma cells reveals that the PRP gene was amplified compared to normal liver. The orotic acid model of hepatocarcinogenesis was used to determine if during stepwise progression to liver cancer, PRP changed with hepatocarcinogenesis. At the hyperplastic nodule stage, PRP expression was increased over its expression in normal surrounding liver. More dramatic increases in PRP expression were found in frank hepatic carcinomas. Cumulatively, these studies are the first to link a novel ABC family member to the hepatic neoplastic process, a role that may be recapitulated in other cells, considering the ubiquitous expression of PRP.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

[Application of polymeric endoprostheses in surgery of external ear].

Biocompatible polymeric endoprostheses EFOS are offered for endoprosthetic reconstruction of the external acoustic meatus in atresia. Such endoprostheses are safe for the adjacent tissues. Moreover, such prostheses contain antibacterial drugs (quinoxidine, dioxidin) and substances promoting tissue regeneration (orotic acid derivatives). This provides good epithelization of the walls of the newly established external acoustic meatus and sufficient lumen of the organ. The removal of the endoprosthesis is recommended on the postoperative day 90-120 in the outpatient setting.

Adolescent↗
PubMed2000

Synergistic potentiating effect of D(+)-mannose, orotic, and hippuric acid sodium salt on selective toxicity of a mixture of 13 substances of the circulatory system in culture for various tumor cell lines.

Despite global immune system abnormalities in the autoimmune deficiency syndrome, the incidence of only a few tumor types increases, and the degree of immunosuppression does not seem to be critical in the development of these tumors, indicating that the immune system does not prevent tumor development. Consequently, because tumors do not develop in most individuals, other defense systems may exist. We demonstrated previously that 13 substances in the circulatory system acting synergistically induced apoptosis in vitro and in vivo in different tumor cell lines, but not in normal cells and animals. We investigated another 17 compounds and five ions in the circulatory system to determine their participation in the defense provided by the 13 substances. Three of the 17 substances but no ions had a potentiating effect on the mixture of substances used previously. The new 16-component mixture suppressed in vitro growth of six human and murine tumor cell lines, including multidrug-resistant tumor cells, without cytotoxic effects in two normal cell lines. The selectivity also was demonstrated by investigating the mixture's effect over time on tumor and normal cell growth.

Animals↗
PubMed2006

Influence of calcium and phosphorus, lactose, and salt-to-moisture ratio on Cheddar cheese quality: changes in residual sugars and water-soluble organic acids during ripening.

Cheddar cheese ripening involves the conversion of lactose to glucose and galactose or galactose-6-phosphate by starter and nonstarter lactic acid bacteria. Under ideal conditions (i.e., where bacteria grow under no stress of pH, water activity, and salt), these sugars are mainly converted to lactic acid. However, during ripening of cheese, survival and growth of bacteria occurs under the stressed condition of low pH, low water activity, and high salt content. This forces bacteria to use alternate biochemical pathways resulting in production of other organic acids. The objective of this study was to determine if the level and type of organic acids produced during ripening was influenced by calcium (Ca) and phosphorus (P), residual lactose, and salt-to-moisture ratio (S/M) of cheese. Eight cheeses with 2 levels of Ca and P (0.67 and 0.47% vs. 0.53 and 0.39%, respectively), lactose at pressing (2.4 vs. 0.78%), and S/M (6.4 vs. 4.8%) were manufactured. The cheeses were analyzed for organic acids (citric, orotic, pyruvic, lactic, formic, uric, acetic, propanoic, and butyric acids) and residual sugars (lactose, galactose) during 48 wk of ripening using an HPLC-based method. Different factors influenced changes in concentration of residual sugars and organic acids during ripening and are discussed in detail. Our results indicated that the largest decrease in lactose and the largest increase in lactic acid occurred between salting and d 1 of ripening. It was interesting to observe that although the lactose content in cheese was influenced by several factors (Ca and P, residual lactose, and S/M), the concentration of lactic acid was influenced only by S/M. More lactic acid was produced in low S/M treatments compared with high S/M treatments. Although surprising for Cheddar cheese, a substantial amount (0.2 to 0.4%) of galactose was observed throughout ripening in all treatments. Minor changes in the levels of citric, uric, butyric, and propanoic acids were observed during early ripening, whereas during later ripening, a substantial increase was observed. A gradual decrease in orotic acid and a gradual increase in pyruvic acid content of the cheeses were observed during 12 mo of ripening. In contrast, acetic acid did not show a particular trend, indicating its role as an intermediate in a biochemical pathway, rather than a final product.

Acetic Acid↗
PubMed1993

DNA precursors are channelled to nuclear matrix DNA replication sites.

Studies of replicative DNA synthesis using DNA precursors have shown that the DNA that was replicated most recently is that associated with the nuclear matrix. Consequently, precursors arising via the salvage and the de novo metabolic pathways are first incorporated into a small percentage of the total nuclear DNA that is termed nuclear matrix-associated DNA. These results have been substantiated in cell culture, as well as in intact mammalian systems. Furthermore, when DNA precursors were injected intravenously into regenerating rat liver, a significant lag in the incorporation of orotic acid-derived nucleotides (de novo pathway precursors) into nuclear DNA was observed, when compared with deoxythymidine-derived nucleotides (salvage pathway precursors). This lag in incorporation kinetics was also evident at the nuclear matrix level, although, once incorporated into nuclear matrix-associated DNA, the distribution patterns of both precursors into extra-matrix nuclear DNA fractions were identical. To determine the basis for this kinetic lag, we compared the incorporation kinetics of orotic acid and of deoxythymidine into dTTP and into nuclear matrix-associated DNA, respectively. Orotic acid-derived nucleotides entered the cytosolic dTTP pool before being incorporated into nuclear matrix-associated DNA, that is, traversing the classical metabolic route of DNA precursors. Conversely, deoxythymidine-derived nucleotides by-passed the soluble dTTP cellular pool and engaged directly in DNA synthesis at the nuclear matrix. Not only is this the first evidence for nucleotide channelling in an intact mammalian system, but it also forms direct evidence that salvage pathway DNA precursors are channelled to nuclear matrix-associated sites of DNA replication.

Animals↗
PubMed1992

Changes in liver microsome lipids and plasma fatty acids induced by dietary orotate in the weanling rat.

1. Dietary orotate produced a decrease in total plasma fatty acids which was reflected in low values of saturated, monounsaturated and polyunsaturated fatty acids longer than 18 carbon atoms of the n-6 series. The relative content of saturated fatty acids in microsomes of animals fed orotate was also decreased. 2. Rat liver delta-9 desaturase activity was lower in the group fed orotate. However, delta-6 desaturase activity did not show significant differences between the groups. 3. Microsomal cholesterol content was lower in rats fed orotate than in controls but phospholipid phosphorus contents were similar. These results suggest a direct effect of dietary orotate on the key enzymes which regulates cholesterol liver metabolism.

Animals↗
PubMed1995

Changes in activity levels and isozyme patterns of isoleucine aminotransferase in response to experimentally induced hepatic lesion.

Branched-chain amino acid aminotransferase activities were measured in rats in which hepatic lesions were induced experimentally, that is, fatty liver produced by an orotic acid-containing diet and acute hepatic lesion induced by D-galactosamine injection into the abdominal cavity. The levels of the enzyme activities, using L-isoleucine as substrate, were elevated in both cases. Among the isozymes (enzymes I, II and III) of the enzyme, the activity of enzyme I was elevated by orotic acid treatment. However, with D-galactosamine treatment, another isoleucine aminotransferase activity was chromatographically separated from that of enzyme I and is considered to be enzyme III, and not enzyme II, based on its substrate specificity.

Animals↗