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Author |
Cheung, C.; Akiyama, T.E.; Ward, J.M.; Nicol, C.J.; Feigenbaum, L.; Vinson, C.; Gonzalez, F.J. |
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Title |
Diminished hepatocellular proliferation in mice humanized for the nuclear receptor peroxisome proliferator-activated receptor alpha |
Type |
Journal Article |
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Year |
2004 |
Publication |
Cancer research |
Abbreviated Journal |
Cancer Res |
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Volume |
64 |
Issue |
11 |
Pages |
3849-3854 |
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Keywords |
Animals; Anticholesteremic Agents/pharmacology; Carcinogens/pharmacology; Cell Division; DNA Replication/drug effects; Fatty Acids/metabolism; Hepatocytes/cytology/drug effects/metabolism/*physiology; Humans; Mice; Mice, Transgenic; Oxidation-Reduction; Peroxisome Proliferators/pharmacology; Pyrimidines/pharmacology; Receptors, Cytoplasmic and Nuclear/genetics/*physiology; Species Specificity; Transcription Factors/genetics/*physiology |
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Abstract |
Lipid-lowering fibrate drugs function as agonists for the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha). Sustained activation of PPARalpha leads to the development of liver tumors in rats and mice. However, humans appear to be resistant to the induction of peroxisome proliferation and the development of liver cancer by fibrate drugs. The molecular basis of this species difference is not known. To examine the mechanism determining species differences in peroxisome proliferator response between mice and humans, a PPARalpha-humanized mouse line was generated in which the human PPARalpha was expressed in liver under control of the tetracycline responsive regulatory system. The PPARalpha-humanized and wild-type mice responded to treatment with the potent PPARalpha ligand Wy-14643 as revealed by induction of genes encoding peroxisomal and mitochondrial fatty acid metabolizing enzymes and resultant decrease of serum triglycerides. However, surprisingly, only the wild-type mice and not the PPARalpha-humanized mice exhibited hepatocellular proliferation as revealed by elevation of cell cycle control genes, increased incorporation of 5-bromo-2'-deoxyuridine into hepatocyte nuclei, and hepatomegaly. These studies establish that following ligand activation, the PPARalpha-mediated pathways controlling lipid metabolism are independent from those controlling the cell proliferation pathways. These findings also suggest that structural differences between human and mouse PPARalpha are responsible for the differential susceptibility to the development of hepatocarcinomas observed after treatment with fibrates. The PPARalpha-humanized mice should serve as models for use in drug development and human risk assessment and to determine the mechanism of hepatocarcinogenesis of peroxisome proliferators. |
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Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA |
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0008-5472 |
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PMID:15172993 |
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no |
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Call Number |
refbase @ user @ |
Serial |
74 |
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Author |
Tavernor, W.D.; Lees, P. |
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Title |
A pharmacological investigation of the influence of suxamethonium on cardiac function in the horse |
Type |
Journal Article |
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Year |
1968 |
Publication |
Experientia |
Abbreviated Journal |
Experientia |
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Volume |
24 |
Issue |
6 |
Pages |
582-583 |
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Keywords |
Animals; Arrhythmia/chemically induced; Consciousness; Halothane; Heart/innervation; Heart Rate/*drug effects; Horses/*physiology; Oxygen; Propranolol/pharmacology; Receptors, Sensory/drug effects; Stimulation, Chemical; Succinylcholine/antagonists & inhibitors/*pharmacology; Sympathetic Nervous System/physiology; Tachycardia/chemically induced; Thiopental |
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0014-4754 |
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PMID:5697737 |
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refbase @ user @ |
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104 |
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Touma, C.; Palme, R.; Sachser, N. |
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Title |
Analyzing corticosterone metabolites in fecal samples of mice: a noninvasive technique to monitor stress hormones |
Type |
Journal Article |
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Year |
2004 |
Publication |
Hormones and Behavior |
Abbreviated Journal |
Horm Behav |
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Volume |
45 |
Issue |
1 |
Pages |
10-22 |
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Keywords |
Adrenal Cortex/drug effects; Adrenal Cortex Function Tests; Adrenocorticotropic Hormone/pharmacology; Analysis of Variance; Animals; Circadian Rhythm; Corticosterone/*analysis/metabolism; Dexamethasone/pharmacology; Feces/*chemistry; Female; Immunoenzyme Techniques/*methods; Male; Mice; Mice, Inbred C57BL; Models, Animal; Reproducibility of Results; Stress, Psychological/*metabolism |
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Abstract |
In small animals like mice, the monitoring of endocrine functions over time is constrained seriously by the adverse effects of blood sampling. Therefore, noninvasive techniques to monitor, for example, stress hormones in these animals are highly demanded in laboratory as well as in field research. The aim of our study was to evaluate the biological relevance of a recently developed technique to monitor stress hormone metabolites in fecal samples of laboratory mice. In total, six experiments were performed using six male and six female mice each. Two adrenocorticotropic hormone (ACTH) challenge tests, two dexamethasone (Dex) suppression tests and two control experiments [investigating effects of the injection procedure itself and the diurnal variation (DV) of glucocorticoids (GCs), respectively] were conducted. The experiments clearly demonstrated that pharmacological stimulation and suppression of adrenocortical activity was reflected accurately by means of corticosterone metabolite (CM) measurements in the feces of males and females. Furthermore, the technique proved sensitive enough to detect dosage-dependent effects of the ACTH/Dex treatment and facilitated to reveal profound effects of the injection procedure itself. Even the naturally occurring DV of GCs could be monitored reliably. Thus, our results confirm that measurement of fecal CM with the recently established 5alpha-pregnane-3beta,11beta,21-triol-20-one enzyme immunoassay is a very powerful tool to monitor adrenocortical activity in laboratory mice. Since mice represent the vast majority of all rodents used for research worldwide and the number of transgenic and knockout mice utilized as animal models is still increasing, this noninvasive technique can open new perspectives in biomedical and behavioral science. |
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Department of Behavioural Biology, University of Muenster, D-48149 Muenster, Germany. touma@uni-muenster.de |
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0018-506X |
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PMID:14733887 |
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Equine Behaviour @ team @ |
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4084 |
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Author |
Tsong, T.Y. |
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Title |
Conformational relaxations of urea- and guanidine hydrochloride-unfolded ferricytochrome c |
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Journal Article |
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Year |
1977 |
Publication |
The Journal of Biological Chemistry |
Abbreviated Journal |
J Biol Chem |
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Volume |
252 |
Issue |
24 |
Pages |
8778-8780 |
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Keywords |
*Cytochrome c Group; Guanidines/*pharmacology; Protein Conformation/drug effects; Spectrometry, Fluorescence; Urea/*pharmacology |
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Abstract |
Several recent studies of protein the unfolded proteins. In urea- and guanidine HCl-unfolded ferricytochrome c (horse heart), an acid-induced spin state transformation of the heme group has been detected by the heme absorptions, Trp-59 fluorescence, and the intrinsic viscosity of protein. Kinetics of this second conformational transition, by the temperature jump and stopped flow methods, are complex. One rapid reaction (tau1), pH-independent, occurs in a 50-mus range; the second reaction (tau2), in a 1-ms range, depends linearly upon pH and is faster at the alkaline side; a third reaction (tau3), in a 1-s range, shows a sigmoidal transition at pH 5.1 and is faster at the acidic side. The results are consistent with a kinetic scheme which involves protein conformational changes in the transformation of the heme coordination state. The kinetics, along with previous equilibrium studies, indicate that ligand or charge interactions within a protein molecule are not completely prohibited even in strongly denaturing conditions, such as in high concentrations of urea and guanidine HCl. Thus, local structures of peptide chain associated with these interactions can exist in the unfolded protein. |
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0021-9258 |
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Notes |
PMID:200618 |
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no |
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Call Number |
refbase @ user @ |
Serial |
3882 |
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Author |
Pierce, M.M.; Nall, B.T. |
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Title |
Coupled kinetic traps in cytochrome c folding: His-heme misligation and proline isomerization |
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Journal Article |
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Year |
2000 |
Publication |
Journal of Molecular Biology |
Abbreviated Journal |
J Mol Biol |
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Volume |
298 |
Issue |
5 |
Pages |
955-969 |
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Keywords |
Amino Acid Sequence; Amino Acid Substitution/genetics; Binding Sites; Cytochrome c Group/*chemistry/genetics/*metabolism; *Cytochromes c; Enzyme Stability/drug effects; Fluorescence; Guanidine/pharmacology; Heme/*metabolism; Histidine/genetics/*metabolism; Hydrogen-Ion Concentration; Isomerism; Kinetics; Models, Molecular; Molecular Sequence Data; Mutation/genetics; Proline/*chemistry/metabolism; Protein Conformation/drug effects; Protein Denaturation/drug effects; *Protein Folding; Protein Renaturation; Saccharomyces cerevisiae/enzymology/genetics; Sequence Alignment; Thermodynamics |
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Abstract |
The effect of His-heme misligation on folding has been investigated for a triple mutant of yeast iso-2 cytochrome c (N26H,H33N,H39K iso-2). The variant contains a single misligating His residue at position 26, a location at which His residues are found in several cytochrome c homologues, including horse, tuna, and yeast iso-1. The amplitude for fast phase folding exhibits a strong initial pH dependence. For GdnHCl unfolded protein at an initial pH<5, the observed refolding at final pH 6 is dominated by a fast phase (tau(2f)=20 ms, alpha(2f)=90 %) that represents folding in the absence of misligation. For unfolded protein at initial pH 6, folding at final pH 6 occurs in a fast phase of reduced amplitude (alpha(2f) approximately 20 %) but the same rate (tau(2f)=20 ms), and in two slower phases (tau(m)=6-8 seconds, alpha(m) approximately 45 %; and tau(1b)=16-20 seconds, alpha(1b) approximately 35 %). Double jump experiments show that the initial pH dependence of the folding amplitudes results from a slow pH-dependent equilibrium between fast and slow folding species present in the unfolded protein. The slow equilibrium arises from coupling of the His protonation equilibrium to His-heme misligation and proline isomerization. Specifically, Pro25 is predominantly in trans in the unligated low-pH unfolded protein, but is constrained in a non-native cis isomerization state by His26-heme misligation near neutral pH. Refolding from the misligated unfolded form proceeds slowly due to the large energetic barrier required for proline isomerization and displacement of the misligated His26-heme ligand. |
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Center for Biomolecular Structure, Department of Biochemistry, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA |
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0022-2836 |
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Notes |
PMID:10801361 |
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no |
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Call Number |
refbase @ user @ |
Serial |
3853 |
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Author |
Crosby, M.B.; Svenson, J.L.; Zhang, J.; Nicol, C.J.; Gonzalez, F.J.; Gilkeson, G.S. |
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Title |
Peroxisome proliferation-activated receptor (PPAR)gamma is not necessary for synthetic PPARgamma agonist inhibition of inducible nitric-oxide synthase and nitric oxide |
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Journal Article |
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Year |
2005 |
Publication |
The Journal of pharmacology and experimental therapeutics |
Abbreviated Journal |
J Pharmacol Exp Ther |
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Volume |
312 |
Issue |
1 |
Pages |
69-76 |
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Keywords |
Animals; Cell Line; Gene Expression/drug effects; Macrophages/drug effects/metabolism; Mice; Mice, Inbred C57BL; Nitric Oxide/*metabolism; Nitric Oxide Synthase/*metabolism; Nitric Oxide Synthase Type II; PPAR delta/metabolism; PPAR gamma/*agonists/deficiency; Thiazolidinediones/pharmacology |
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Abstract |
Peroxisome proliferation-activated receptor (PPAR)gamma agonists inhibit inducible nitric-oxide synthase (iNOS), tumor necrosis factor-alpha, and interleukin-6. Because of these effects, synthetic PPARgamma agonists, including thiazolidinediones, are being studied for their impact on inflammatory disease. The anti-inflammatory concentrations of synthetic PPARgamma agonists range from 10 to 50 microM, whereas their binding affinity for PPARgamma is in the nanomolar range. The specificity of synthetic PPARgamma agonists for PPARgamma at the concentrations necessary for anti-inflammatory effects is thus in question. We report that PPARgamma is not necessary for the inhibition of iNOS by synthetic PPARgamma agonists. RAW 264.7 macrophages possess little PPARgamma, yet lipopolysaccharide (LPS)/interferon (IFN)gamma-induced iNOS was inhibited by synthetic PPARgamma agonists at 20 microM. Endogenous PPARgamma was inhibited by the transfection of a dominant-negative PPARgamma construct into murine mesangial cells. In the transfected cells, synthetic PPARgamma agonists inhibited iNOS production at 10 microM, similar to nontransfected cells. Using cells from PPARgamma Cre/lox conditional knockout mice, baseline and LPS/IFNgamma-induced nitric oxide levels were higher in macrophages lacking PPARgamma versus controls. However, synthetic PPARgamma agonists inhibited iNOS at 10 microM in the PPARgamma-deficient cells, similar to macrophages from wild-type mice. These results indicate that PPARgamma is not necessary for inhibition of iNOS expression by synthetic PPARgamma agonists at concentrations over 10 microM. Intrinsic PPARgamma function, in the absence of synthetic agonists, however, may play a role in inflammatory modulation. |
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Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA |
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0022-3565 |
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PMID:15356214 |
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no |
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Call Number |
refbase @ user @ |
Serial |
73 |
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Author |
Alexander, F. |
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Title |
A study of parotid salivation in the horse |
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Journal Article |
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Year |
1966 |
Publication |
The Journal of physiology |
Abbreviated Journal |
J Physiol |
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Volume |
184 |
Issue |
3 |
Pages |
646-656 |
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Animals; Atropine/*pharmacology; Bicarbonates/metabolism; Calcium/metabolism; Chlorides/metabolism; Horses; Mastication/*physiology; Parotid Gland/*physiology; Pilocarpine/*pharmacology; Potassium/metabolism; Salivation/*drug effects; Sodium/metabolism; Tetracaine/*pharmacology |
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0022-3751 |
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PMID:5963737 |
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refbase @ user @ |
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119 |
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Alexander, F.; Ash, R.W. |
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The effect of emotion and hormones on the concentration of glucose and eosinophils in horse blood |
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Journal Article |
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Year |
1955 |
Publication |
The Journal of physiology |
Abbreviated Journal |
J Physiol |
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Volume |
130 |
Issue |
3 |
Pages |
703-710 |
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Blood Glucose/*drug effects; Eosinophils/*drug effects; Leukocyte Count/*drug effects; *ACTH/effects; *BLOOD SUGAR/effect of drugs on; *EOSINOPHIL COUNT/effect of drugs on; *EPINEPHRINE/effects; *HISTAMINE/effects; *INSULIN/effects; *STRESS/experimental |
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0022-3751 |
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PMID:13278929 |
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no |
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Call Number |
refbase @ user @ |
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122 |
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Kirkpatrick, J.F.; Liu, I.M.; Turner, J.W.J.; Naugle, R.; Keiper, R. |
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Title |
Long-term effects of porcine zonae pellucidae immunocontraception on ovarian function in feral horses (Equus caballus) |
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Journal Article |
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Year |
1992 |
Publication |
Journal of reproduction and fertility |
Abbreviated Journal |
J Reprod Fertil |
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Volume |
94 |
Issue |
2 |
Pages |
437-444 |
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Keywords |
Animals; Contraception, Immunologic/*veterinary; *Egg Proteins; Estrogens, Conjugated (USP)/urine; Female; Glycoproteins/*pharmacology; Horses/immunology/*physiology; *Membrane Glycoproteins; Ovary/drug effects/*physiology; Progesterone/metabolism; *Receptors, Cell Surface; Swine/immunology; Time Factors; Zona Pellucida/*immunology |
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Ten feral mares free-roaming in Maryland, USA, were inoculated with porcine zonae pellucidae (PZP) protein before the breeding season for three consecutive years (1988-90). Ovarian function was monitored for 51 days during the peak of the breeding season after the third annual PZP inoculation, in seven of these mares and in four untreated control mares, by means of urinary oestrone conjugates and nonspecific progesterone metabolites. None of the ten inoculated mares became pregnant in 1990, compared with 55% of 20 control mares, which included two of the four monitored for ovarian function. Three of the untreated mares demonstrated apparent normal ovarian activity, characterized by preovulatory oestrogen peaks, concurrent progesterone nadirs at ovulation, breeding activity, and luteal-phase progesterone increases after ovulation. Two of the seven monitored PZP-treated mares demonstrated ovulatory cycles that did not result in conception. One was pregnant as a result of conception in 1989 and demonstrated a normal, late-gestation, endocrine profile. The remaining four PZP-treated mares revealed no evidence of ovulation, and urinary oestrogen concentrations were significantly depressed. The experiments indicated that (i) a third consecutive annual PZP booster inoculation is greater than 90% effective in preventing pregnancies in mares and (ii) three consecutive years of PZP treatment may interfere with normal ovarian function as shown by markedly depressed oestrogen secretion. |
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Deaconess Research Institute, Billings, MT 59102 |
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0022-4251 |
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PMID:1317449 |
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no |
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Call Number |
refbase @ user @ |
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145 |
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Author |
Jeong, S.; Han, M.; Lee, H.; Kim, M.; Kim, J.; Nicol, C.J.; Kim, B.H.; Choi, J.H.; Nam, K.-H.; Oh, G.T.; Yoon, M. |
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Title |
Effects of fenofibrate on high-fat diet-induced body weight gain and adiposity in female C57BL/6J mice |
Type |
Journal Article |
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Year |
2004 |
Publication |
Metabolism: clinical and experimental |
Abbreviated Journal |
Metabolism |
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Volume |
53 |
Issue |
10 |
Pages |
1284-1289 |
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Keywords |
Adipose Tissue/*anatomy & histology/drug effects; Animals; Antilipemic Agents/*pharmacology; Body Composition/*drug effects; Body Weight/drug effects; Dietary Fats/*pharmacology; Eating/drug effects; Fatty Acids/metabolism; Female; Gene Expression Regulation/drug effects; Leptin/metabolism; Liver/metabolism; Mice; Mice, Inbred C57BL; Ovariectomy; Procetofen/*pharmacology; RNA, Messenger/biosynthesis/genetics; Receptors, Cytoplasmic and Nuclear/biosynthesis/genetics/metabolism; Transcription Factors/biosynthesis/genetics/metabolism; Weight Gain/*drug effects |
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Our previous study suggested that fenofibrate affects obesity and lipid metabolism in a sexually dimorphic manner in part through the differential activation of hepatic peroxisome proliferator-activated receptor alpha (PPARalpha) in male and female C57BL/6J mice. To determine whether fenofibrate reduces body weight gain and adiposity in female sham-operated (Sham) and ovariectomized (OVX) C57BL/6J mice, the effects of fenofibrate on not only body weight, white adipose tissue (WAT) mass, and food intake, but also the expression of both leptin and PPARalpha target genes were measured. Compared to their respective low-fat diet-fed controls, both Sham and OVX mice exhibited increases in body weight and WAT mass when fed a high-fat diet. Fenofibrate treatment decreased body weight gain and WAT mass in OVX, but not in Sham mice. Furthermore, fenofibrate increased the mRNA levels of PPARalpha target genes encoding peroxisomal enzymes involved in fatty acid beta-oxidation, and reduced apolipoprotein C-III (apo C-III) mRNA, all of which were expressed at higher levels in OVX compared to Sham mice. However, leptin mRNA levels were found to positively correlate with WAT mass, and food intake was not changed in either OVX or Sham mice following fenofibrate treatment. These results suggest that fenofibrate differentially regulates body weight and adiposity due in part to differences in PPARalpha activation, but not to differences in leptin production, between female OVX and Sham mice. |
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Department of Life Sciences, Mokwon University, Taejon, Korea |
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Edition |
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|
| |
ISSN |
0026-0495 |
ISBN |
|
Medium |
|
|
| |
Area |
|
Expedition |
|
Conference |
|
|
| |
Notes |
PMID:15375783 |
Approved |
no |
|
| |
Call Number |
refbase @ user @ |
Serial |
72 |
|
| Permanent link to this record |
