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Biomedical subjects

M Gannon

Publications and source records attributed to M Gannon.

16 recordsLinked to original sources
PubMed1992

Beta-naphthoflavone induction of a cytochrome P-450 arachidonic acid epoxygenase in chick embryo liver distinct from the aryl hydrocarbon hydroxylase and from phenobarbital-induced arachidonate epoxygenase.

Cytochrome P-450-mediated arachidonic acid metabolism in chick embryo liver microsomes was increased by both Ah receptor-dependent (2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and beta-naphthoflavone) and independent (phenobarbital) P-450 inducers. Arachidonic acid epoxides and monohydroxyeicosatetraenoic acids were increased 9-12-fold. omega-1-OH arachidonic acid was also significantly increased by TCDD and beta-naphthoflavone while omega-OH arachidonic acid, the main metabolite in uninduced livers, was decreased by all three agents. The P-450s catalyzing the enhanced arachidonate metabolism in beta-naphthoflavone- and phenobarbital-treated liver were investigated in reconstituted systems containing wholly or partially purified P-450s. beta-Naphthoflavone induced formation of a 55-kDa P-450 selective for arachidonate metabolism and for epoxygenation in particular. This P-450 was purified (beta NFAA). It was found to be distinct from a 54.5-kDa beta-naphthoflavone-induced P-450 catalyzing aryl hydrocarbon hydroxylase and 7-ethoxyresorufin deethylase (designated NF1). Mean turnover numbers for arachidonate epoxygenase, aryl hydrocarbon hydroxylase, and 7-ethoxyresorufin deethylase were 11.2, 0.56, and 0.04, respectively, for reconstituted beta NFAA and 0.33, 11.8, and 2.4 for NF1. beta NFAA and NF1 also differed in chromatography elution characteristics and N-terminal amino acid sequences. Both were low spin, with carbon monoxide binding peaks at 448 nm. The phenobarbital-induced arachidonate epoxygenation was catalyzed by P-450 fractions containing the main 48- and 49-kDa phenobarbital-induced P-450s; fractions in which the 49-kDa P-450 predominated were the most active. Turnover numbers for arachidonic acid epoxygenation were not correlated with those for aminopyrine demethylation or 7-ethoxycoumarin deethylation for P-450s from phenobarbital-treated livers or with aryl hydrocarbon hydroxylase, 7-ethoxyresorufin deethylase, or 7-ethoxycoumarin deethylase for P-450s from beta-naphthoflavone-treated livers. Also, different P-450s catalyzed the epoxygenation and the omega-hydroxylation of arachidonic acid in both beta-naphthoflavone- and phenobarbital-treated livers. The findings support a physiologic role for P-450-induced arachidonate metabolism and provide a basis for a possible link between TCDD's induction of P-450 and alterations of cellular homeostasis.

Amino Acid Sequence↗
PubMed1992

Interactions of trimethyl tin (TMT) with rat primary astrocyte cultures: altered uptake and efflux of rubidium, L-glutamate and D-aspartate.

Studies were undertaken to assess the effects of trimethyl tin (TMT) on metabolic functions in primary neonatal rat cultured astrocytes. Concentrations as low as 10(-5) M TMT significantly inhibited the initial rate (1 min) of uptake of 86RbCl, used as a tracer for K+. TMT also markedly inhibited the initial rate (1 min) of Na(+)-dependent uptake of L-[3H]glutamate and D-[3H]aspartate, and stimulated the release of intracellular 86Rb+, -[3H]glutamate and D-[3H]aspartate in a dose-dependent fashion. These observations support the hypothesis that the astrocyte plasma membrane is potentially an important target for TMT's toxic effect and specifically that small concentrations of this organometal can inhibit the ability of astrocytes to maintain a transmembrane K+ gradient. This would be expected to compromise the ability of astrocytes to control extracellular K+ either by spatial buffering or active uptake, and exacerbate on-going swelling. Increased levels of glutamate and aspartate in the extracellular fluid upon release from astrocytes may play an important role in TMT neurotoxicity.

Animals↗
PubMed1992

Transforming growth factor-beta 1 acts cooperatively with sodium n-butyrate to induce differentiation of normal human keratinocytes.

Growth factors with established biological activity toward cultured normal human epidermal keratinocytes (NHEKs) (e.g., transforming growth factor-beta, TGF-beta; retinoic acid, RA) initiate programmed changes in cellular maturation which differ with regard to the specific differentiation pathway (normal or abnormal) analyzed. Sodium butyrate (NaB) initiates one form of epidermal differentiation leading to enhanced cornified envelope (CE) formation which involves abrogation of the normally inhibitory effect of RA on NHEK maturation. NaB also induces TGF-beta mRNA in the maturing suprabasal compartment, suggesting that TGF-beta may play a role in NaB-initiated NHEK differentiation. Treatment with TGF-beta 1 alone, however, only marginally increased (by twofold) the number of detergent-resistant CEs compared to control NHEKs and did not alter the prevalence of fully mature enucleated CEs. TGF-beta 1 was quite effective in inducing significant levels of CE expression when used simultaneously with suboptimal concentrations of NaB. The cooperative action of suboptimal NaB and TGF-beta 1 generated numbers of CEs which, in fact, exceeded the incidence of mature CEs formed in response to optimal levels of NaB alone. Neutralizing antibodies to TGF-beta, moreover, effectively reduced the incidence of CE formation in cultures treated with optimal NaB concentrations, further implicating endogenous TGF-beta activity in the NaB-initiated NHEK differentiation model. It is suggested, therefore, that within the NaB-induced pathway of NHEK differentiation, TGF-beta can positively modulate expression of the differentiated phenotype but alone is insufficient for generation of mature CEs.

Butyrates↗
PubMed1992

Manganese uptake and efflux in cultured rat astrocytes.

Astrocytes play a central role in manganese (Mn) regulation in the CNS. Using primary astrocyte cultures from neonatal rat brains, these studies demonstrate a specific high-affinity transport system for Mn2+. Saturation kinetics are clearly indicated by both 1/v versus 1/s plots (Km = 0.30 +/- 0.03 microM; Vmax = 0.30 +/- 0.02 nmol/mg of protein/min) and plots of v versus [s]. Several divalent cations (Co2+, Zn2+, and Pb2+) failed to inhibit the initial rate of 54Mn2+ uptake. In contrast, extracellular Ca2+ at 10 microM decreased 54Mn2+ uptake. Exchange with extracellular Mn2+ was not obligatory for the efflux of 54Mn2+ into extracellular medium because efflux occurred into Mn(2+)-free extracellular medium, but efflux of 54Mn2+ was enhanced when astrocytes were equilibrated in the presence of unlabeled Mn2+. Efflux of 54Mn2+ was biphasic with both a rapid and a slow component. Efflux was most rapid during the first 10 min of incubation, with 27.5 +/- 2.2% of 54Mn2+ transported extracellularly, and 37.2 +/- 1.2% of preloaded 54Mn2+ was retained by the astrocytes at 120 min. These studies show, for the first time, that mammalian astrocytes can transport Mn via a specific transport system.

Animals↗
PubMed1990

Arachidonic acid metabolism by dioxin-induced cytochrome P-450: a new hypothesis on the role of P-450 in dioxin toxicity.

Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) is a highly potent inducer of cytochrome P-450. The role of the induced P-450 in TCDD toxicity has been obscure as P-450 neither detoxifies TCDD nor activates it to genotoxic or cytotoxic metabolites. We show, using a chick embryo model, that TCDD causes major increases in the NADPH dependent metabolism of arachidonic acid (AA), a predominant cell membrane fatty acid, that it does so with extremely high potency (ED50, 6.3 pmol per egg) and that this metabolism is catalyzed by TCDD-induced cytochrome P-450 species. Thus, TCDD treatment increased by six to ten fold the P-450 mediated hepatic microsomal metabolism of AA to epoxides and monohydroxyeicosatetraenoic acids, products whose diverse biological activities suggest links to TCDD's toxic effects. In contrast only x and x-1 hydroxy AA, inactive products, were significantly formed by the controls. These findings open a new perspective on how P-450 induction could be related to the diverse toxic effects of TCDD. They lead to the novel hypothesis that TCDD-induced cytochrome P-450 metabolizes an endogenous fatty acid to reactive products that in turn mediate or modulate varied manifestations of TCDD toxicity.

Animals↗
PubMed1987

High-dose naltrexone therapy and dietary counseling for obesity.

There is considerable evidence that antagonism of the endogenous opioids will suppress food intake in a variety of animal species. The authors report a double-blind, placebo-controlled trial of the long-acting, orally active narcotic antagonist naltrexone in the promotion of weight loss in obese male subjects who were also undergoing dietary counseling for weight reduction. Subjects received medication (naltrexone, 300 mg/day or placebo) for 8 weeks following an initial 2-week single-blind placebo phase. The results failed to demonstrate an advantage for the active drug. However, the naltrexone was associated with hepatotoxicity when used at this dosage in this population.

Adult↗
PubMed1987

The effect of naloxone on nocturnal food intake in female and male rats.

Previous studies have shown that estradiol and progesterone can alter the response of female rats to naloxone. For example, ovariectomized rats receiving estradiol were found to be less sensitive to the anorexic effect of naloxone than ovariectomized rats receiving oil (vehicle) or progesterone. In the present paper, we evaluated the effect of naloxone on nocturnal food intake in female rats during each stage of the estrous cycle to determine whether changing levels of gonadal hormones in intact female rats would affect their response to naloxone. To evaluate the role testosterone might play in modulating the male rat's feeding response to naloxone we studied the effect of peripherally administered naloxone (0.1, 1.0 and 10 mg/kg) on nocturnal food intake of intact, castrate and castrate + testosterone propionate male rats. During late metestrus, diestrus and proestrus, female rats decreased nocturnal food intake following the administration of naloxone (1.0 and 10 mg/kg) SC (p less than 0.05). During estrus, female rats failed to decrease food intake following any of the doses of naloxone administered. The male rat's response to naloxone does not appear to be altered by the presence or absence of testosterone. Thus, the level of estradiol and progesterone at different stages of the estrous cycle may affect the female rat's response to the satiety effect of naloxone.

Animals↗
PubMed1987

The effect of cholecystokinin on food intake in gonadectomized and intact rats: the influence of sex hormones.

Cholecystokinin (CCK) suppresses food intake in a number of animal models, but appears to be less effective in females [5,23]. We studied the effect of CCK on food intake in female rats on each day of the estrous cycle. In addition, we evaluated the effect of sex hormones on food intake in intact and castrate male rats which had been injected daily with oil or testosterone propionate + oil and ovariectomized female rats injected daily with oil, estradiol, progesterone or estradiol + progesterone. Food intake in intact, castrate and castrate + testosterone replaced male rats was decreased by CCK (5, 10 and 20 micrograms/kg) IP (p less than 0.05). Food intake was decreased by CCK (20 micrograms/kg) only during diestrous and metestrus in cycling female rats. During metestrus, a period of low estradiol in the presence of progesterone, food intake was also suppressed by CCK (5 and 10 micrograms/kg). CCK failed to decrease food intake in ovariectomized females receiving oil, estradiol and estradiol + progesterone. However, animals receiving progesterone alone responded to the high dose of CCK (20 micrograms/kg). Our data suggest that the effect of CCK on food intake in female rats may be dependent on the presence of progesterone. The lack of sensitivity to CCK during proestrus and estrus suggests that estradiol may be modulating the "permissive" action of progesterone on CCK's satiety effect.

Animals↗
PubMedDate not supplied

Expression of atrial natriuretic factor gene in heart ventricular tissue.

A novel peptide hormone, atrial natriuretic factor (ANF), was recently isolated and characterized in mammalian atria. This hormone has potent natriuretic diuretic and vasorelaxant activities. Since ANF bioactivity was initially found in atria but not in ventricles, it was assumed that the ANF gene is specifically expressed in atria. We now report that ANF mRNA is present in ventricular tissue as well as in atria. This is clearly demonstrated by in situ hybridization and by Northern blot analysis. Rat ventricular ANF mRNA concentration is a hundred-fold lower than in atria. As in atria, the 126 amino acids precursor form of ANF is predominant in ventricles and it is present at a thousand-fold lower concentration. The ten-fold discrepancy in the ratio of ANF mRNA to immunoreactivity between atria and ventricles could reflect a higher rate of peptide release in the latter. Thus, ventricular ANF production may be physiologically significant in view of the much larger ventricular mass.

Animals↗
PubMedDate not supplied

Psychiatric disorders in Parkinson's disease.

Parkinson's disease is associated with a wide variety of psychiatric syndromes. Advances in the neuropathology and neuropharmacology have not been applied to the associated psychiatric disorders due to complex interactions between social, psychological and pathological variables.

Adult↗