| Home | [11–20] << 21 22 23 24 >> |
|
Guo, G. L., Moffit, J. S., Nicol, C. J., Ward, J. M., Aleksunes, L. A., Slitt, A. L., et al. (2004). Enhanced acetaminophen toxicity by activation of the pregnane X receptor. Toxicol Sci, 82(2), 374–380.
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.
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
|
|
Nicol, C. J., Yoon, M., Ward, J. M., Yamashita, M., Fukamachi, K., Peters, J. M., et al. (2004). PPARgamma influences susceptibility to DMBA-induced mammary, ovarian and skin carcinogenesis. Carcinogenesis, 25(9), 1747–1755.
Abstract: Peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear receptor superfamily, plays a role in adipocyte differentiation, type II diabetes, macrophage response to inflammation and is suggested to influence carcinogen-induced colon cancer. Studies done in vitro and in vivo also revealed that PPARgamma ligands might promote differentiation and/or regression of mammary tumors. To directly evaluate the role of PPARgamma in mammary carcinogenesis, PPARgamma wild-type (+/+) or heterozygous (+/-) mice were administered 1 mg 7,12-dimethylbenz[a]anthracene (DMBA) by gavage once a week for 6 weeks and followed for a total of 25 weeks. Compared with congenic PPARgamma(+/+) littermate controls, PPARgamma(+/-) mice had early evidence for increased susceptibility to DMBA-mediated carcinogenesis based on a 1.6-fold increase in the percentage of mice with skin papillomas, as well as a 1.7-fold increase in the numbers of skin papillomas per mouse (P < 0.05). Similarly, PPARgamma(+/-) mice also had a 1.5-fold decreased survival rate (P = 0.059), and a 1.7-fold increased incidence of total tumors per mouse (P < 0.01). Moreover, PPARgamma(+/-) mice had an almost 3-fold increase in mammary adenocarcinomas (P < 0.05), an over 3-fold increase in ovarian granulosa cell carcinomas (P < 0.05), an over 3-fold increase in malignant tumors (P < 0.02) and a 4.6-fold increase in metastatic incidence. These results are the first to demonstrate an increased susceptibility in vivo of PPARgamma haploinsufficiency to DMBA-mediated carcinogenesis and suggest that PPARgamma may act as a tumor modifier of skin, ovarian and breast cancers. The data also support evidence suggesting a beneficial role for PPARgamma-specific ligands in the chemoprevention of mammary, ovarian and skin carcinogenesis.
Keywords: 9,10-Dimethyl-1,2-benzanthracene/*toxicity; Animals; DNA Primers/chemistry; Disease Susceptibility; Female; Heterozygote; Humans; Mammary Neoplasms, Experimental/chemically induced/*pathology; Mice; Ovarian Neoplasms/chemically induced/*pathology; RNA, Messenger/genetics/metabolism; Receptors, Cytoplasmic and Nuclear/genetics/*physiology; Reverse Transcriptase Polymerase Chain Reaction; Skin Neoplasms/chemically induced/*pathology; Survival Rate; Transcription Factors/genetics/*physiology; Zinc Fingers
|
|
Cheung, C., Akiyama, T. E., Ward, J. M., Nicol, C. J., Feigenbaum, L., Vinson, C., et al. (2004). Diminished hepatocellular proliferation in mice humanized for the nuclear receptor peroxisome proliferator-activated receptor alpha. Cancer Res, 64(11), 3849–3854.
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.
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
|
|
Beran, M. J. (2004). Long-term retention of the differential values of Arabic numerals by chimpanzees (Pan troglodytes). Anim. Cogn., 7(2), 86–92.
Abstract: As previously reported (Beran and Rumbaugh, 2001), two chimpanzees used a joystick to collect dots, one-at-a-time, on a computer monitor, and then ended a trial when the number of dots collected was equal to the Arabic numeral presented for the trial. Here, the chimpanzees were presented with the task again after an interval of 6 months and then again after an additional interval of 3.25 years. During each interval, the chimpanzees were not presented with the task, and this allowed an assessment of the extent to which both animals retained the values of each Arabic numeral. Despite lower performance at each retention interval compared to the original study, both chimpanzees performed above chance levels in collecting a quantity of dots equal to the target numeral, one chimpanzee for the numerals 1-7, and the second chimpanzee for the numerals 1-6. For the 3.25-year retention, errors were more dispersed around each target numeral than in the original study, but the chimpanzees' performances again appeared to be based on a continuous representation of magnitude rather than a discrete representation of number. These data provide an experimental demonstration of long-term retention of the differential values of Arabic numerals by chimpanzees.
|
|
Beran, M. J., Pate, J. L., Washburn, D. A., & Rumbaugh, D. M. (2004). Sequential responding and planning in chimpanzees (Pan troglodytes) and rhesus macaques (Macaca mulatta). J Exp Psychol Anim Behav Process, 30(3), 203–212.
Abstract: Chimpanzees (Pan troglodytes) and rhesus macaques (Macaca mulatta) selected either Arabic numerals or colored squares on a computer monitor in a learned sequence. On shift trials, the locations of 2 stimuli were interchanged at some point. More errors were made when this interchange occurred for the next 2 stimuli to be selected than when the interchange was for stimuli later in the sequence. On mask trials, all remaining stimuli were occluded after the 1st selection. Performance exceeded chance levels for only 1 selection after these masks were applied. There was no difference in performance for either stimulus type (numerals or colors). The data indicated that the animals planned only the next selection during these computerized tasks as opposed to planning the entire response sequence.
|
|
Zeitler-Feicht, M. H. (2004). [Critical consideration of the “Guideline for the Evaluation of Raising Horses” and keeping horses outside in the winter]. Dtsch Tierarztl Wochenschr, 111(3), 120–123.
Abstract: The guidelines of the Federal Ministry of User Protection, Nutrition and Agriculture (BMVEL) regarding “horse keeping with respect to animal welfare” are from 1995 (BMELF, 1995). Therefore, they are not suitable for modern horse keeping. The Veterinary Association for Animal Welfare (TVT) held it to be necessary to rework the guide-lines in light of 1) many subsequent investigations concerning horse keeping, and 2) the species-specific needs of horses in practice. Each chapter of the BMELF (1995) guide-lines was revised such that the literature and practical experiences were updated. Several chapters (recumbency resting behaviour, fences, underground outdoor and in stables, litter) were added in the position paper of the TVT to reflect the increasing use of boxes with paddocks, loose housing systems with open yards, pasture and winter yards as housing conditions. Keeping horses outdoors permanently during winter is possible because horses have very good thermoregulatory capabilities so that they are able to adapt themselves to cold conditions. However, in light of animal welfare, the holding system must include adequate shelter (natural or artificial). Shelters should protect against wetness, heat, cold and wind, and must be sufficiently large and high, with a dry and clean underground. In keeping horses outdoors permanently, the paths to the feeding and watering areas and to the shelter must be dry. The food must also be protected against mould and soiling. Keeping horses permanently without adequate shelter or in deep marsh without any dry places is against the Animal Protection Act.
Keywords: Animal Feed/standards; Animal Husbandry/legislation & jurisprudence/methods/*standards; *Animal Welfare/legislation & jurisprudence; Animals; Cold; Female; Germany; Guidelines/*standards; Horses/*physiology; Housing, Animal/legislation & jurisprudence/*standards; Legislation, Veterinary; Male; Seasons
|
|
Brosnan, S. F., & de Waal, F. B. M. (2004). A concept of value during experimental exchange in brown capuchin monkeys, Cebus apella. Folia Primatol (Basel), 75(5), 317–330.
Abstract: We evaluated the response of brown capuchin monkeys to two differentially valued tokens in an experimental exchange situation akin to a simple barter. Monkeys were given a series of three tests to evaluate their ability to associate tokens with food, then their responses were examined in a barter situation in which tokens were either limited or unlimited. Capuchins did not perform barter in the typical sense, returning the tokens which were associated with the reward. However, females, but not males, showed a different response, preferring the higher-value token. This may indicate that they learned to prefer one token over the other rather than to associate the tokens with their specific rewards. This sex difference parallels previous findings of greater reciprocity in female brown capuchins than in males.
|
|
Brosnan, S. F., & de Waal, F. B. M. (2004). Socially learned preferences for differentially rewarded tokens in the brown capuchin monkey (Cebus apella). J Comp Psychol, 118(2), 133–139.
Abstract: Social learning is assumed to underlie traditions, yet evidence indicating social learning in capuchin monkeys (Cebus apella), which exhibit traditions, is sparse. The authors tested capuchins for their ability to learn the value of novel tokens using a previously familiar token-exchange economy. Capuchins change their preferences in favor of a token worth a high-value food reward after watching a conspecific model exchange 2 differentially rewarded tokens, yet they fail to develop a similar preference after watching tokens paired with foods in the absence of a conspecific model. They also fail to learn that the value of familiar tokens has changed. Information about token value is available in all situations, but capuchins seem to pay more attention in a social situation involving novel tokens.
Keywords: Animals; Behavior, Animal; Cebus; *Choice Behavior; Female; *Learning; Male; *Reward; *Social Behavior
|
|
Cameron, E. Z. (2004). Facultative adjustment of mammalian sex ratios in support of the Trivers-Willard hypothesis: evidence for a mechanism. Proc Biol Sci, 271(1549), 1723–1728.
Abstract: Evolutionary theory predicts that mothers of different condition should adjust the birth sex ratio of their offspring in relation to future reproductive benefits. Published studies addressing variation in mammalian sex ratios have produced surprisingly contradictory results. Explaining the source of such variation has been a challenge for sex-ratio theory, not least because no mechanism for sex-ratio adjustment is known. I conducted a meta-analysis of previous mammalian sex-ratio studies to determine if there are any overall patterns in sex-ratio variation. The contradictory nature of previous results was confirmed. However, studies that investigated indices of condition around conception show almost unanimous support for the prediction that mothers in good condition bias their litters towards sons. Recent research on the role of glucose in reproductive functioning have shown that excess glucose favours the development of male blastocysts, providing a potential mechanism for sex-ratio variation in relation to maternal condition around conception. Furthermore, many of the conflicting results from studies on sex-ratio adjustment would be explained if glucose levels in utero during early cell division contributed to the determination of offspring sex ratios.
|
|
Liebal, K., Pika, S., & Tomasello, M. (2004). Social communication in siamangs (Symphalangus syndactylus): use of gestures and facial expressions. Primates, 45(1), 41–57.
Abstract: The current study represents the first systematic investigation of the social communication of captive siamangs (Symphalangus syndactylus). The focus was on intentional signals, including tactile and visual gestures, as well as facial expressions and actions. Fourteen individuals from different groups were observed and the signals used by individuals were recorded. Thirty-one different signals, consisting of 12 tactile gestures, 8 visual gestures, 7 actions, and 4 facial expressions, were observed, with tactile gestures and facial expressions appearing most frequently. The range of the signal repertoire increased steadily until the age of six, but declined afterwards in adults. The proportions of the different signal categories used within communicative interactions, in particular actions and facial expressions, also varied depending on age. Group differences could be traced back mainly to social factors or housing conditions. Differences in the repertoire of males and females were most obvious in the sexual context. Overall, most signals were used flexibly, with the majority performed in three or more social contexts and almost one-third of signals used in combination with other signals. Siamangs also adjusted their signals appropriately for the recipient, for example, using visual signals most often when the recipient was already attending (audience effects). These observations are discussed in the context of siamang ecology, social structure, and cognition.
|