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Author |
Crosby, M.B.; Zhang, J.; Nowling, T.M.; Svenson, J.L.; Nicol, C.J.; Gonzalez, F.J.; Gilkeson, G.S. |
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Title |
Inflammatory modulation of PPAR gamma expression and activity |
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Journal Article |
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Year |
2006 |
Publication |
Clinical immunology |
Abbreviated Journal |
Clin Immunol |
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Volume |
118 |
Issue |
2-3 |
Pages |
276-283 |
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Age Factors; Animals; Cell Line, Transformed; Cells, Cultured; Female; Inflammation Mediators/*physiology; Kidney/metabolism; Mesangial Cells/metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred MRL lpr; Mice, Knockout; Nitric Oxide/biosynthesis; Nitric Oxide Synthase Type II/biosynthesis/genetics; PPAR gamma/*biosynthesis/*genetics/metabolism; Up-Regulation/immunology |
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Nitric oxide (NO) production increases with age in the lupus-prone MRL/lpr mouse, paralleling disease activity. One mechanism for excess NO production in MRL/lpr mice may be a defect in down-regulatory mechanisms of the iNOS pathway. A potential modulator of NO is the nuclear hormone receptor peroxisome proliferation activated receptor gamma (PPARgamma). We demonstrate that renal PPARgamma protein expression was altered as disease progressed in MRL/lpr mice, which paralleled increased iNOS protein expression. Additionally, MRL/lpr-derived primary mesangial cells expressed less PPARgamma than BALB/c mesangial cells and produced more NO in response to LPS and IFNgamma. Furthermore, PPARgamma activity was reduced in mesangial cells following exposure to inflammatory mediators. This activity was restored with the addition of a NOS enzyme inhibitor. These results indicate that the activation of inflammatory pathways may lead to reduced activity and expression of PPARgamma, further exacerbating the disease state. |
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Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA |
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1521-6616 |
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PMID:16303334 |
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Call Number |
refbase @ user @ |
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67 |
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Nicol, C.J.; Badnell-Waters, A.J.; Bice, R.; Kelland, A.; Wilson, A.D.; Harris, P.A. |
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The effects of diet and weaning method on the behaviour of young horses |
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Journal Article |
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Year |
2005 |
Publication |
Applied Animal Behaviour Science |
Abbreviated Journal |
Appl. Anim. Behav. Sci. |
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Volume |
95 |
Issue |
3-4 |
Pages |
205-221 |
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Keywords |
Horse; Diet; Weaning; Temperament test |
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The effects of diet on horse behaviour have not previously been quantified in detail. In this study, we examined the behaviour of 17 foals from the age of 2 to 40 weeks. Each foal received either a starch and sugar (SS) diet or a fat and fibre (FF) diet. The two diets contained similar digestible energy, crude protein and micronutrients, but differed in the fat and non-structural carbohydrate balance. The baseline behaviour of the foals was observed every 2 weeks by focal animal sampling. Additional behavioural observations were conducted when the foals were weaned by one of two methods. Approximately 2 months after weaning, the temperament and tractability of the young horses was assessed using standardised tests. Responses to a novel object, to a novel person, and during a handling test were observed and quantified. Horses grew well on both diets with no apparent effects of diet on growth rate or baseline behaviour. Immediately after weaning, horses receiving the FF diet cantered less frequently (F = 5.10; p < 0.05), for a shorter duration (F = 7.23; p < 0.05) and appeared to be more settled. Foals that were barn-weaned appeared more stressed than foals that were paddock-weaned. In the temperament tests, horses receiving the FF diet spent significantly more time investigating (F = 6.78; p < 0.05), and less time looking at (F = 7.93; p < 0.05), the novel object than horses receiving the SS diet. They also spent less time walking away from the novel person (F = 5.16; p < 0.05) and their time taken to complete the handling test was significantly lower (F = 8.72; p = 0.01). Overall, the horses that received the FF diet appeared less distressed immediately after weaning and seemed calmer and more inquisitive during a range of temperament tests. |
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Equine Behaviour @ team @ |
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3642 |
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Nicol, C.J.; Badnell-Waters, A.J. |
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Title |
Suckling behaviour in domestic foals and the development of abnormal oral behaviour |
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Journal Article |
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Year |
2005 |
Publication |
Animal Behaviour. |
Abbreviated Journal |
Anim. Behav. |
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70 |
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1 |
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21-29 |
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We investigated how the behaviour of domestic foals, Equus caballus, living at pasture with their dams was associated with foal gender, mare rank and the development of abnormal oral behaviour, both during the preweaning period, and over a period of up to 4 years postweaning. A population of 186 foals belonging to private owners and commercial studs was studied. The behaviour of male and female foals hardly differed, but mare rank affected patterns of foal social interaction and suckling behaviour, with foals of subordinate mares involved in more affiliative interactions. These foals also spent more time in perisuckling activities such as teat nuzzling than foals of other mares. During the study, 18 foals developed abnormal oral behaviour before weaning and 42 foals developed abnormal oral behaviour after weaning. The development of abnormal oral behaviour was associated with suckling behaviour in a variety of ways. Foals that had already developed abnormal oral behaviour at the time of the preweaning observations were involved in more suckling terminations within bouts than normal foals or foals that developed future abnormal behaviour, and pushing the udder with the muzzle was most frequent in these foals. Foals that had no current abnormal oral behaviour, but that would develop this in the future, spent more time suckling and twice as much time teat nuzzling as other foals. The results add to the growing evidence of associations between digestive function and abnormal oral behaviour in horses. |
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Equine Behaviour @ team @ |
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3631 |
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Hothersall, B.; Gale, E.; Harris, P.; Nicol, C. |
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Title |
Cue use by foals (Equus caballus) in a discrimination learning task |
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2010 |
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Animal Cognition |
Abbreviated Journal |
Anim. Cogn. |
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13 |
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1 |
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63-74 |
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Abstract Discrimination learning studies suggest that horses learn more easily using spatial than visible object-specific (OS) cues. However, spatial cues have generally confounded intra-array, distal and/or egocentric spatial information. It is also unclear whether conflicting cues compete for association or are redundantly encoded, and furthermore, the influence of prior experiences or training has not been quantified so far. We examined the effect of cue modality on unweaned foals’ performance in a discrimination learning task. After a pilot study confirmed that horses could perform the required OS cue discrimination, nine foals learnt to find food in one of three covered buckets, in any of four positions within a test arena. In Stage 1 the rewarded bucket was signified both by OS cues (pattern) and by relative spatial cues (position). On reaching criterion, cues were separated and foals had to ignore the inappropriate cue (Stage 2). Foals assigned to follow spatial cues (n = 5) completed Stage 2 faster than foals for whom OS cues remained consistent (n = 4). Spatial group foals all reached criterion without delay; no foal in the OS group reached criterion within the testing period. OS group foals initially persisted in responding to the previously correct position, adopting spatially-based strategies when this proved unsuccessful. The findings show for the first time that, even in the absence of distal spatial information, intra-array spatial cues were more salient than OS cues for foals in a food-finding task and learning appeared rather inflexible. |
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Equine Behaviour @ team @ |
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5082 |
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Nicol, C.J.; Davidson, H.P.D.; Harris, P.A.; Waters, A.J.; Wilson, A.D. |
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Title |
Study of crib-biting and gastric inflammation and ulceration in young horses |
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Journal Article |
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2002 |
Publication |
The Veterinary record |
Abbreviated Journal |
Vet. Rec. |
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151 |
Issue |
22 |
Pages |
658-662 |
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Animal Husbandry/methods; Animals; Antacids/therapeutic use; *Behavior, Animal; Diet/veterinary; Endoscopy, Gastrointestinal/veterinary; Feces/chemistry; Female; Gastritis/diet therapy/physiopathology/*veterinary; Horse Diseases/diet therapy/*physiopathology/psychology; Horses; Hydrogen-Ion Concentration; Male; Random Allocation; Stereotyped Behavior/*physiology; Stomach Ulcer/diet therapy/physiopathology/*veterinary; Treatment Outcome; Weaning |
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Nineteen young horses that had recently started to perform the stereotypy of crib-biting were compared with 16 non-stereotypic horses for 14 weeks. After initial observations of their behaviour and an endoscopic examination of the condition of their stomachs, the horses were randomly allocated to a control or an antacid diet At the start of the trial, the stomachs of the crib-biting foals were significantly more ulcerated and inflamed than the stomachs of the normal foals. In addition, the faecal pH of the crib-biting foals (6.05) was significantly lower than that of the normal foals (6.58). The antacid diet resulted in a significant improvement in the condition of the horses' stomachs. The crib-biting behaviour declined in most of the foals, regardless of their diet, but tended to decline to a greater extent in the foals on the antacid diet. |
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Department of Clinical Veterinary Science, University of Bristol, Langford House, Bristol BS40 5DU |
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0042-4900 |
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PMID:12498408 |
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refbase @ user @ |
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83 |
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Waters, A.J.; Nicol, C.J.; French, N.P. |
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Factors influencing the development of stereotypic and redirected behaviours in young horses: findings of a four year prospective epidemiological study |
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Journal Article |
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2002 |
Publication |
Equine veterinary journal |
Abbreviated Journal |
Equine Vet J |
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34 |
Issue |
6 |
Pages |
572-579 |
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Age Factors; Animal Husbandry/*methods; Animal Welfare; Animals; *Behavior, Animal; Female; Horse Diseases/epidemiology/prevention & control/*psychology; Horses; Housing, Animal; Longitudinal Studies; Male; Prevalence; Prospective Studies; Risk Factors; *Stereotyped Behavior; Weaning |
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Stereotypies are invariant and repetitive behaviour patterns that seemingly have no function, which tend to develop in captive animals faced with insoluble problems and may be indicative of reduced welfare. A 4 year prospective study of the factors influencing the development of stereotypic and redirected behaviours (abnormal behaviour) in a population of 225 young Thoroughbred and part-Thoroughbred horses was conducted between 1995 and 1999. Abnormal behaviour affected 34.7% of the population. Multivariable analysis showed that foals of low- or middle-ranking mares were less likely to develop abnormal behaviour than foals of dominant mares (rate ratio (RR) 0.23, P<0.01; RR 0.48, P<0.01, respectively). Weaning by confinement in a stable or barn was associated with an increased rate of development of abnormal behaviour, compared with paddock-weaning (RR 2.19, P<0.05), and housing in barns, rather than at grass after weaning, was associated with a further increase (RR 2.54, P<0.01). Specific stereotypic and redirected behaviours were then considered as separate outcomes. Crib-biting was initiated by 10.5% of horses at median age 20 weeks, weaving by 4.6% of horses at median age 60 weeks, box-walking by 2.3% of horses at median age 64 weeks and wood-chewing by 30.3% of horses at median age 30 weeks. Wood-chewing developed at a lower rate in horses born to subordinate or mid-ranking mares than in horses born to dominant mares (RR 0.29, P<0.01; RR 0.41, P<0.01, respectively), and at a higher rate in horses kept in barns or stables rather than at grass after weaning (RR 4.49, P<0.001; RR 1A6, P<0.001, respectively). Feeding concentrates after weaning was associated with a 4-fold increase in the rate of development of crib-biting (RR 4.12, P = 0.02). The results of this study support the idea that simple changes in feeding, housing and weaning practices could substantially lower the incidence of abnormal behaviour in young horses. |
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University of Bristol, Department of Clinical Veterinary Science, Langford, Bristol, UK |
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0425-1644 |
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PMID:12357996 |
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refbase @ user @ |
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84 |
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Dixon, G.; Green, L.E.; Nicol, C.J. |
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Title |
Effect of diet change on the behavior of chicks of an egg-laying strain |
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Journal Article |
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2006 |
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Journal of applied animal welfare science : JAAWS |
Abbreviated Journal |
J Appl Anim Welf Sci |
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9 |
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1 |
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41-58 |
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*Animal Feed; *Animal Nutrition Physiology; Animals; Behavior, Animal/*physiology; Chickens/*physiology; Crowding; Feeding Behavior/*physiology; Female; Food Preferences/physiology; Oviposition; Random Allocation; Taste |
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Injurious pecking has serious welfare consequences in flocks of hens kept for egg laying, especially when loose-housed. Frequent diet change is a significant risk for injurious pecking; how the mechanics of diet change influence pecking behavior is unknown. This study investigated the effect of diet change on the behavior of chicks from a laying strain. The study included a 3-week familiarity phase: 18 chick pairs received unflavored feed (Experiment 1); 18 pairs received orange oil-flavored (Experiment 2). All chicks participated in a dietary preference test (P); a diet change (DC); or a control group (C), 6 scenarios. All P chicks preferred unflavored feed. In Experiment 1, DC involved change from unflavored to orange-flavored; Experiment 2, orange- flavored to unflavored. Compared with controls, Experiment 2 DC chicks exhibited few behavioral differences; Experiment 1 DC chicks exhibited increased behavioral event rates on Days 1 and 7. They pecked significantly longer at their environment; by Day 7, they showed significantly more beak activity. There was little evidence of dietary neophobia. Change from more preferred to less preferred feed led to increased activity and redirected pecking behavior. |
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School of Veterinary Science, University of Bristol, England |
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1088-8705 |
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PMID:16649950 |
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refbase @ user @ |
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64 |
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Cheung, C.; Akiyama, T.E.; Ward, J.M.; Nicol, C.J.; Feigenbaum, L.; Vinson, C.; Gonzalez, F.J. |
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Diminished hepatocellular proliferation in mice humanized for the nuclear receptor peroxisome proliferator-activated receptor alpha |
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Journal Article |
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2004 |
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Cancer research |
Abbreviated Journal |
Cancer Res |
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64 |
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11 |
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3849-3854 |
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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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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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refbase @ user @ |
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74 |
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Crosby, M.B.; Svenson, J.L.; Zhang, J.; Nicol, C.J.; Gonzalez, F.J.; Gilkeson, G.S. |
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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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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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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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refbase @ user @ |
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73 |
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Guo, G.L.; Moffit, J.S.; Nicol, C.J.; Ward, J.M.; Aleksunes, L.A.; Slitt, A.L.; Kliewer, S.A.; Manautou, J.E.; Gonzalez, F.J. |
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Title |
Enhanced acetaminophen toxicity by activation of the pregnane X receptor |
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Journal Article |
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Year |
2004 |
Publication |
Toxicological sciences : an official journal of the Society of Toxicology |
Abbreviated Journal |
Toxicol Sci |
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Volume |
82 |
Issue |
2 |
Pages |
374-380 |
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Keywords |
Acetaminophen/pharmacokinetics/*toxicity; Analgesics, Non-Narcotic/pharmacokinetics/*toxicity; Animals; Aryl Hydrocarbon Hydroxylases/biosynthesis; Biotransformation; Blotting, Northern; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP3A; Membrane Proteins; Mice; Mice, Knockout; Oxidoreductases, N-Demethylating/biosynthesis; Pregnenolone Carbonitrile/pharmacology; Receptors, Cytoplasmic and Nuclear/*drug effects; Receptors, Steroid/*drug effects; Sulfhydryl Compounds/metabolism |
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Abstract |
The pregnane X receptor (PXR) is a ligand-activated transcription factor and member of the nuclear receptor superfamily. Activation of PXR represents an important mechanism for the induction of cytochrome P450 3A (CYP3A) enzymes that can convert acetaminophen (APAP) to its toxic intermediate metabolite, N-acetyl-p-benzoquinone imine (NAPQI). Therefore, it was hypothesized that activation of PXR plays a major role in APAP-induced hepatotoxicity. Pretreatment with the PXR activator, pregnenolone 16alpha-carbonitrile (PCN), markedly enhanced APAP-induced hepatic injury, as revealed by increased serum ALT levels and hepatic centrilobular necrosis, in wild-type but not in PXR-null mice. Further analysis showed that following PCN treatment, PXR-null mice had lower CYP3A11 expression, decreased NAPQI formation, and increased maintenance of hepatic glutathione content compared to wild-type mice. Thus, these results suggest that PXR plays a critical role in APAP-induced hepatic toxicity, probably by inducing CYP3A11 expression and hence increasing bioactivation. |
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Address |
Laboratory of Metabolism, CCR, NCI, NIH, Bethesda, Maryland 20892, USA |
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English |
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1096-6080 |
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PMID:15456926 |
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refbase @ user @ |
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71 |
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