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Biomedical subjects

C A Jones

Publications and source records attributed to C A Jones.

At least 163 records · Page 9Linked to original sources
PubMed1990

Expression of murine renin genes in subcutaneous connective tissue.

A renin promoter-large tumor antigen (T antigen) fusion gene was constructed to provide a reporter function for renin expression in transgenic mice. These transgenic mice gave rise to tumors in subcutaneous soft tissue, which was attributed to transgene expression at this site. An immunohistochemical analysis of transgenic fetuses from several independent lines revealed scattered T-antigen-containing mesenchymal cells and fibroblasts in the subcutaneous layer of the skin between the panniculus carnosus muscle of the skin and the skeletal muscle of the body wall. This localization is consistent with the location of overt tumorigenesis in adult mice. This pattern was specific for the renin-T antigen fusion gene as no immunohistochemical staining was observed in transgenic fetuses containing a heterologous promoter-T antigen fusion gene. Northern blot analysis of tumor RNA indicated that most of the tumors expressed both T antigen and the endogenous renin gene Ren-1c. In addition, when multiple renin genes were introduced by crossing transgenic mice with nontransgenic DBA/2J mice, which contain another allele of the Ren-1 locus as well as the duplicated locus Ren-2, the resultant tumors expressed the Ren-2 gene. Northern blots were then used to analyze renin expression in the subcutaneous tissue of normal mice. Fully processed renin mRNA was detected in eviscerated 15.5-day postcoitus fetal and newborn carcasses and in newborn skin. Our data indicate that there is a renin-expressing cell population in fetal and newborn subcutaneous tissue.

Animals↗
PubMed1990

Fission-neutron-induced expression of a tumour-associated antigen in human cell hybrids (HeLa x skin fibroblasts): evidence for increased expression at low dose rate.

The induction of a tumour-associated antigen in a human cell hybrid line (HeLa x skin fibroblast) following exposure to fission neutrons of average energy 0.85 MeV (Janus reactor, Argonne National Laboratory) at two dose rates, 0.086 and 10.3 cGy/min, has been examined. The dose-response data obtained indicate the lower dose rate to be 2.9-fold more effective than the higher in inducing expression of the tumour-associated antigen, while there was no significant dose-rate effect in terms of cell killing. These results are qualitatively in agreement with previous observations using neutrons from the Janus reactor for the neoplastic transformation of C3H10T1/2 cells and Syrian hamster embryo cells.

Antigens, Neoplasm↗
PubMed1990

Expression of murine renin genes during fetal development.

Fetuses were examined to produce a developmental profile of renin expression in the kidneys and adrenal glands in single renin gene and two renin gene strains of mice. Sites of renin expression were detected by in situ hybridization using an 35S-labeled antisense RNA probe complimentary to the renin cDNA. Accumulation of renin transcripts in the adrenal gland reached a maximum at 15.5 days post coitum for all strains examined, but declined to undetectable levels by birth in one gene strains, while in two gene strains, the levels of renin transcripts lessened and by birth became limited to the developing inner cortex. Kidney renin transcripts were first detected at 14.5 days post coitum in the newly developing arteries in fetuses of both genotypes of mice. As the renal arterial tree developed, renin mRNA containing cells were progressively localized to more distal blood vessels and finally to the specialized cells of the afferent arteriole (juxtaglomerular cells). These results were confirmed by examining the localization of immunoreactive T antigen in transgenic fetuses. These mice carried a transgene which placed the SV40 T antigen structural gene under control of renin regulatory elements. Expression of T antigen occurred at the same sites in the kidneys and adrenal glands as renin mRNA. Furthermore, in strains with two renin genes, primer extension analysis indicated transcripts from both genes were present in equal proportion in combined kidney and adrenal gland extracts of total RNA. These transcripts were full length in size. The transient localization of renin mRNA in cells of the fetal intrarenal arteries is consistent with the notion that renin may be a useful marker for the developing renal vasculature.

Adrenal Glands↗
PubMed1990

Evidence that hydrogen peroxide generated by 365-nm UVA radiation is not important in mammalian cell killing.

We compared measurements of cell survival and DNA single-strand breaks (SSBs) caused by hydrogen peroxide (H2O2) and UVA radiation (365-nm) in both a parental and a H2O2-resistant variant of the Chinese hamster ovary HA1 line derived by culturing cells in progressively higher concentrations of H2O2. Both RNA slot blot analysis and enzyme analysis confirmed that the variant possesses high levels of both catalase activity and mRNA. The variant was completely resistant to the lethal effects of H2O2 over the concentration range tested (up to 480 microM), whereas the parental strain showed less than 1% survival at this concentration. Similarly, the H2O2-resistant strain exhibited far fewer SSBs after exposure to H2O2 than the parental strain. Addition of o-phenanthroline to the parental cells during H2O2 exposure almost completely inhibited SSB induction, evidence that these SSBs are produced via the Fenton pathway of Haber-Weiss reactions. Very little difference was found between the variant and the parent after exposure to 365-nm radiation: only a minor difference in survival kinetics and no difference is SSB induction were observed between the two cell lines. These results are consistent with a hypothesis that most lethal events caused in cells by UVA occur by pathways that do not involve the H2O2 that is produced by sensitized reactions within the cells.

Animals↗
PubMed1989

Relation between dopaminergic control of pituitary lactotroph function and deceleration of age-related changes in serum prolactin of diet-restricted rats.

Pituitary lactotroph function has been examined in diet-restricted (6 hr/day) male and female rats and compared with that in animals fed ad lib. After 12 months the age-related increase in serum prolactin concentration was significantly attenuated in diet-restricted female rats. Similar effects were not observed in male rats. Isolated superfused anterior pituitary glands removed from rats on both feeding regimens at 12 or 18 months and challenged with dopamine in vitro (5 microM) did not show differential prolactin secretion. No significant differences were observed in serum prolactin secretion in vivo after administration of bromocriptine (3 mg/kg body weight, sc) or haloperidol (1.75 mg/kg body weight, ip). These results do not support an altered dopamine receptor function in the anterior pituitary lactotrophs. In contrast, central dopamine receptor function in rats 12 months of age was altered by dietary restriction, since the frequency of cataleptic responses to haloperidol injection (2 mg/kg body weight, ip) was significantly depressed in the test animals.

Aging↗
PubMed1989

The effects of desipramine (DMI) and electroconvulsive shock (ECS) on the function of the hypothalamo-pituitary-thyroid axis in the rat.

Monoaminergic systems influence the hypothalamo-pituitary-thyroid (HPT) axis. Since two different antidepressant treatments, desipramine (DMI) and electroconvulsive shock (ECS), are known to alter monoaminergic function in the rat central nervous system (CNS), the effects of DMI and ECS on the function of the HPT axis in the rat were examined. Animals were treated with either DMI (5 mg/kg) twice daily for 14 days (DMI x 14) or once only (DMI x 1) or ECS five times in 10 days (ECS x 5) or once only (ECS x 1). Three and 24 hours after the final treatment, blood samples were taken for measurement of plasma total thyroxine (TT4), total tri-iodothyronine (TT3), free thyroxine (FT4), free tri-iodothyronine (FT3) and thyroid stimulating hormone (TSH). Plasma TSH concentrations were decreased by the DMI x 14 and increased by the ECS x 5 regimen. Small decreases in thyroid hormones (T3 and T4) occurred after DMI x 14. No other consistent changes were observed in the animals treated with ECS. The effect of DMI or ECS treatment on the responsiveness of pituitary thyrotrophs was assessed in vitro. Isolated superfused pituitary glands from rats treated in vivo with either DMI x 14 or ECS x 5 were exposed to a pulse of thyrotropin releasing hormone (TRH; 1 ng/ml). No significant change in TSH secretion was observed in response to TRH in either case. Therefore, the changes observed in circulating plasma TSH levels are unlikely to have resulted from either direct or indirect effects on pituitary thyrotroph TRH receptor sensitivity.

Animals↗
PubMed1989

Beta-adrenergic responsiveness in stress-sensitive and stress-resistant pigs.

This study investigated whether enhanced metabolic responsiveness to beta-adrenergic stimulation might explain the liability of the stress-sensitive pig to develop an acidosis during stressful situations. Blood lactate, pH, PCO2 and heart rate response to an intravenous infusion of isoprenaline were examined in three lines of pentobarbitone anaesthetized, atropinized pigs. The lines were Pietrain X Hampshire which had been selected over eight generations for a positive reaction to the halothane test (stress-sensitive); Pietrain X Hampshire which had been selected over eight generations for no reaction to the halothane test (stress-resistant) and British Landrace which had been selected over four generations for a positive halothane reaction (stress-sensitive). The metabolic responses to isoprenaline were greater in the stress-sensitive Pietrain X Hampshire line than the stress-resistant line. The stress-sensitive Landrace pigs, however, had smaller changes in pH and PCO2 in response to isoprenaline than the stress-resistant Pietrain X Hampshire pigs. This inconsistent trend across the three lines led to the conclusion that enhanced beta-adrenergic responsiveness was not the likely cause of stress sensitivity.

Animals↗
PubMed1989

SK&F 93574, a histamine H2-receptor antagonist, releases histamine in the dog.

This study was designed to establish whether SK&F 93574 releases histamine in dogs. Three female beagle dogs each received single infusions (on separate days) of each of SK&F 93574 (2.5 mg kg-1), polyvinylpyrrolidone (PVP, 20 mg kg-1) and sterile saline. The treatments were given at 14 day intervals by rapid intravenous infusion at 0.5 mL kg-1 min-1 for 2 minutes. Dogs showed clinical signs of histamine release such as vasodilation, licking lips, head drooping and increased gut movement after treatment with the known histamine releaser PVP or the test compound SK&F 93574. These signs were of similar severity and duration for the two compounds. No such changes were observed when the dogs received vehicle alone. Treatment with PVP or SK&F 93574 also resulted in markedly elevated plasma histamine concentrations (greater than 10-fold increase over control). It is concluded that intravenous administration of SK&F 93574 to dogs is associated with histamine release.

Animals↗
PubMed1989

Studies on the effects of omeprazole on thyroid function in the rat.

The effects of omeprazole (an H+, K+ -ATPase inhibitor) on thyroid parameters in rats have been examined. SK&F Wistar rats were dosed orally with omeprazole (up to 500 mg kg-1) or vehicle. Treatment for 7 or 14 days resulted in generally decreased plasma T3 concentrations in males (with little change or slight increases in females) and increased serum TSH concentrations (22%-68% increases). No changes were detected in thyroid 125I uptake or organification. Liver 5'-deiodinase activity was decreased in male rats after 7 days treatment. Thyroxine clearance was not altered after a single dose of omeprazole. In-vitro studies showed omeprazole to be only a weak inhibitor of TSH-stimulated 125I organification in cultured porcine thyrocytes. It is concluded that omeprazole has weak effects on the pituitary-thyroid-liver axis, its main action being to inhibit the peripheral deiodination of thyroid hormones.

Animals↗
PubMed1989

Differential effects of prostaglandin E2 on contractions of airway smooth muscle.

In an in vitro muscle bath, the active tension generated by strips of canine tracheal smooth muscle responding to cumulative additions of either histamine (10(-8) to 10(-3) M) or acetylcholine (10(-9) to 10(-3) M) was measured in the absence and presence of prostaglandin E2 (PGE2) (10(-6) to 10(-5) M). When contractile responses of equal magnitude were compared, the contractions elicited by acetylcholine were resistant to the inhibitory effects of PGE2, relative to comparable contractions elicited by histamine. To assess the role of adenylate cyclase in determining the different responses to histamine and acetylcholine in the presence of PGE2, we assayed adenylate cyclase activity in membranes prepared from canine tracheal smooth muscle and found that acetylcholine, but not histamine, decreased PGE2-stimulated adenylate cyclase activity by 48 +/- 2% (mean +/- SE; n = 5). However, in other experiments, we found that even large pharmacological increases in tissue adenosine 3',5'-cyclic monophosphate (cAMP) content only partially inhibited muscarinic tone. Also, exogenously applied analogues of cyclic AMP inhibited contractions induced by histamine more effectively than comparable contractions induced by acetylcholine. We concluded that acetylcholine decreased adenylate cyclase activity in membranes prepared from canine tracheal smooth muscle and that this effect may have contributed to, but did not completely account for, the relative resistance of muscarinic contractions to the inhibitory effects of PGE2.

1-Methyl-3-isobutylxanthine↗
PubMed1988

Comparison of the toxicity of orally administered L-triiodothyronine (T3) in rat and cynomolgus monkey.

Oral administration of L-triiodothyronine (L-T3) (0.015-1 mg/kg) for 30 days to mature rats or cynomolgus monkeys resulted in both species in a high mortality at 1 mg/kg (after 2 weeks of treatment) and a progressive loss in body weight. Dose-related elevations in plasma marker enzymes occurred, mainly after 1-2 weeks of treatment. The approximate no-effect dose for these changes was around 0.015-0.020 mg/kg for both rat and primate. The large elevations of leucine aminopeptidase (LAP) at 1 mg/kg L-T3 in monkey indicated hepatocellular toxicity although in the rat such large increases in alanine aminotransferase (ALT) and glutamate dehydrogenase (GLDH) were not seen. L-T3 also showed little toxicity to rat hepatocytes in vitro. High concentrations of L-T3 (7 x 10(-9) to 7 x 10(-7) M) had minimal effects on parameters of cell viability such as lactate dehydrogenase (LDH) leakage, chromium-51 release and [3H]leucine incorporation. Urinary enzymes in the rat showed a similar profile to those in plasma. Large rises in alkaline phosphatase (AKP) and N-acetyl glucosaminidase (NAG) at 1 mg/kg indicated possible proximal tubular damage although this was not supported histologically. Clinically, in both species L-T3 appeared more toxic to males than females but this was not supported histologically. The histological lesions observed were different in the 2 species. In the monkeys there was extensive lipid vacuolation of hepatocytes and changes in thyroid and adrenal cortex. In the rat there was fine, non-lipid vacuolation of hepatocytes and thyroid changes. In the rat, 2 previously unreported lesions were also noted. There were multinucleated cells in the renal distal tubular epithelium, and focal fibroplasia of serosal surfaces of abdominal viscera.

Acetylglucosaminidase↗
PubMed1988

Differential effects of D- and L-isomers of triiodothyronine on pituitary TSH secretion and peripheral deiodinase activity in the rat.

The effects of D- and L-T3 were compared in male SK & F Wistar rats to define overall effects on the 'pituitary-thyroid-liver axis' at high doses. After in vivo administration of L-T3 (up to 1 mg/kg orally, or up to 0.1 mg/kg subcutaneously) serum TSH and T4 were decreased in a dose-related manner. Similarly, following in vivo exposure to L-T3, both basal and TRH-stimulated TSH output from isolated superfused pituitary glands was decreased, but only the latter was affected by direct in vitro exposure to L-T3.D-T3 had between 1% and 10% the activity of L-T3 in decreasing these parameters both in vivo and in vitro. In contrast, both enantiomers increased liver and kidney deiodinase activity to approximately the same extent, presumably as a compensatory response to clear hormone from the body. These observations indicate that, following treatment with L- or D-T3 by oral gavage for 14 days, the 'no effect' dose (i.e. the dose which did not significantly decrease serum TSH concentrations as compared with controls) for L-T3 was below 0.01 mg/kg whereas that for D-T3 was 0.1 mg/kg.

Animals↗
PubMed1988

Sodium fluoride promotes morphological transformation of Syrian hamster embryo cells.

Sequential treatment of Syrian hamster embryo (SHE) cells with a chemical carcinogen followed by sodium fluoride (NaF) resulted in a higher yield of morphologically transformed cell colonies than treatment of the cells with carcinogen alone. For example, cells treated with benzo[a]pyrene (B[a]P; 3 micrograms/ml) for 3 days, then with NaF (25 micrograms/ml) for 4 days, exhibited a transformation frequency more than six times greater than that obtained by summing the transformation frequencies from cells treated with either B[a]P or NaF alone. This enhancement/promotion of cell transformation by NaF was only expressed after the cells had been pretreated with either direct-acting carcinogens or procarcinogens. Pretreatment of the cells with noncarcinogens or weakly-acting carcinogens or administration of NaF prior to treatment with the carcinogen failed to enhance the yield of transformation. Transformation was enhanced even when the NaF treatment was delayed for several days after the carcinogen treatment. However, the continued presence of NaF was necessary for maintenance of the increased level of transformation. Removal of NaF prior to termination of the assay resulted in a reversal of the transformed clonal morphologies to a normal phenotype such that the final yield of transformants was decreased, but was still greater than that observed after carcinogen treatment alone. A similar pattern for reversibility of the transformation enhancement also occurs for the widely recognized tumor promoter phorbol 12-myristate 13-acetate (PMA). Seven different SHE cell pools were tested for sensitivity to NaF promotion following carcinogen treatment. Although the response was heterogeneous, no carcinogen-treated cell pool was refractory to the NaF-induced enhancement. A second fluorocompound, sodium monofluorophosphate (NaMFP), was also found to enhance carcinogen-induced cell transformation in a manner resembling that of NaF.

Animals↗
PubMed1988

Muscarinic cholinergic inhibition of cyclic AMP accumulation in airway smooth muscle. Role of a pertussis toxin-sensitive protein.

Muscarinic agonists are potent constrictors of airway smooth muscle. In many tissues, muscarinic agonists also reduce intracellular cyclic AMP by inhibiting its synthesis. In airway smooth muscle, the role muscarinic agonists have in the regulation of cyclic AMP content is not established. The hypothesis of our study was that muscarinic agonists reduce cyclic AMP accumulation in dog tracheal smooth muscle, and that this reduction involves a pertussis toxin-sensitive regulatory protein (Gi) that couples occupancy of the muscarinic receptor by the agonist to inhibition of adenylate cyclase. We measured cyclic AMP accumulation in tracheal smooth muscle from 4 dogs, and found that acetylcholine (10(-4) M) diminished basal and isoproterenol-stimulated cyclic AMP accumulation by 37.6 +/- 12.1% and 39.4 +/- 1.9%, respectively (mean +/- SEM, p less than 0.05). This reduction of cyclic AMP was dose-dependent and inhibited by atropine (10(-5) M). Incubation of dog tracheal smooth muscle with pertussis toxin (12.5 micrograms/ml) for 21 h catalyzed covalent modification of a membrane protein with an approximate Mr of 40,000. In control strips, acetylcholine decreased isoproterenol-stimulated cyclic AMP content by 33.7 +/- 5.6% (p less than 0.05). However, in strips treated with pertussis toxin (10 micrograms/ml), acetylcholine decreased cyclic AMP by only 7.9 +/- 4.8%; this change was not significant. Thus, pertussis toxin (10 micrograms/ml) attenuated muscarinic cholinergic regulation of cyclic AMP. These findings are consistent with muscarinic cholinergic regulation of adenylate cyclase via Gi in dog tracheal smooth muscle. In addition, the techniques we employed should permit the evaluation of other functions of pertussis toxin-sensitive G proteins in airway smooth muscle.

Acetylcholine↗
PubMed1987

Dual regulation of the yeast CDC28-p40 protein kinase complex: cell cycle, pheromone, and nutrient limitation effects.

A 40 kd polypeptide that coprecipitates with the CDC28 gene product in immune complexes is specifically phosphorylated by the CDC28 protein kinase. Using this reaction, we detect activity only in extracts from dividing G1 phase cells. Exit from G1 by entry into S phase or the preconjugatory state induced by mating pheromone correlates with loss of p40 phosphorylation activity. Inactive extracts from cdc28 mutants complement extracts from cells arrested in S or M phase, suggesting that non-G1 cells are deficient in an exchangeable activating factor. Stationary and pheromone-treated cultures are rich in this exchangeable factor, but possess an inactive kinase that is not activated by complementation. cAMP-deficient mutants resemble stationary cells.

Adenylyl Cyclases↗
PubMed1987

Morphologic characterization of cultured smooth muscle cells isolated from the tracheas of adult dogs.

The goals of our study were to isolate smooth muscle cells from the trachealis muscle of adult dogs and to characterize the cells morphologically when they were maintained in primary culture. Enzymatic digestion of the muscle yielded 4.8 +/- 1.8 X 10(6) viable smooth muscle cells per gram of tissue. When placed in culture, these cells rapidly proliferated until confluence was reached. The proliferating cells in culture differed from the cells in the intact tissue in that they stained less intensely for smooth muscle myosin, developed immunofluorescent staining for the intermediate filament protein vimentin, and lost many of the ultrastructural properties of the intact muscle. Only within nodules of cells in the confluent cultures were these ultrastructural properties preserved. Cultures of canine tracheal fibroblasts differed from these smooth muscle cell cultures in that the fibroblasts did not stain for smooth muscle myosin and did not form nodules at confluence. We concluded that adult canine airway smooth muscle cells may be maintained in primary culture, that the confluent cultures contain nodules of cells with many morphologic characteristics of the intact muscle, and that these preparations may be distinguished from cultured canine tracheal fibroblasts on specific morphologic grounds.

Animals↗