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81.
82.
Landgren S Simms JA Thelle DS Strandhagen E Bartlett SE Engel JA Jerlhag E 《PloS one》2011,6(3):e18170
The gastric-derived orexigenic peptide ghrelin affects brain circuits involved in energy balance as well as in reward. Indeed, ghrelin activates an important reward circuit involved in natural- as well as drug-induced reward, the cholinergic-dopaminergic reward link. It has been hypothesized that there is a common reward mechanism for alcohol and sweet substances in both animals and humans. Alcohol dependent individuals have higher craving for sweets than do healthy controls and the hedonic response to sweet taste may, at least in part, depend on genetic factors. Rat selectively bred for high sucrose intake have higher alcohol consumption than non-sucrose preferring rats and vice versa. In the present study a group of alcohol-consuming individuals selected from a population cohort was investigated for genetic variants of the ghrelin signalling system in relation to both their alcohol and sucrose consumption. Moreover, the effects of GHS-R1A antagonism on voluntary sucrose-intake and operant self-administration, as well as saccharin intake were investigated in preclinical studies using rodents. The effects of peripheral grelin administration on sucrose intake were also examined. Here we found associations with the ghrelin gene haplotypes and increased sucrose consumption, and a trend for the same association was seen in the high alcohol consumers. The preclinical data show that a GHS-R1A antagonist reduces the intake and self-administration of sucrose in rats as well as saccharin intake in mice. Further, ghrelin increases the intake of sucrose in rats. Collectively, our data provide a clear indication that the GHS-R1A antagonists reduces and ghrelin increases the intake of rewarding substances and hence, the central ghrelin signalling system provides a novel target for the development of drug strategies to treat addictive behaviours. 相似文献
83.
Abhold EL Kiang A Rahimy E Kuo SZ Wang-Rodriguez J Lopez JP Blair KJ Yu MA Haas M Brumund KT Altuna X Patel A Weisman RA Ongkeko WM 《PloS one》2012,7(2):e32459
Members of the EGFR/ErbB family of tyrosine kinases are found to be highly expressed and deregulated in many cancers, including head and neck squamous cell carcinoma (HNSCC). The ErbB family, including EGFR, has been demonstrated to play key roles in metastasis, tumorigenesis, cell proliferation, and drug resistance. Recently, these characteristics have been linked to a small subpopulation of cells classified as cancer stem cells (CSCs) which are believed to be responsible for tumor initiation and maintenance. In this study, we investigated the possible role of EGFR as a regulator of "stemness" in HNSCC cells. Activation of EGFR by the addition of EGF ligand or ectopic expression of EGFR in two established HNSCC cell lines (UMSCC-22B and HN-1) resulted in the induction of CD44, BMI-1, Oct-4, NANOG, CXCR4, and SDF-1. Activation of EGFR also resulted in increased tumorsphere formation, a characteristic ability of cancer stem cells. Conversely, treatment with the EGFR kinase inhibitor, Gefinitib (Iressa), resulted in decreased expression of the aforementioned genes, and loss of tumorsphere-forming ability. Similar trends were observed in a 99.9% CD44 positive stem cell culture derived from a fresh HNSCC tumor, confirming our findings for the cell lines. Additionally, we found that these putative cancer stem cells, when treated with Gefitinib, possessed a lower capacity to invade and became more sensitive to cisplatin-induced death in vitro. These results suggest that EGFR plays critical roles in the survival, maintenance, and function of cancer stem cells. Drugs that target EGFR, perhaps administered in combination with conventional chemotherapy, might be an effective treatment for HNSCC. 相似文献
84.
Marybel Soto Gomez Qianshi Lin Eduardo da Silva Leal Timothy J. Gallaher David Scherberich Constantijn B. Mennes Selena Y. Smith Sean W. Graham 《Cladistics : the international journal of the Willi Hennig Society》2020,36(5):481-504
We used a bi-organellar phylogenomic approach to address higher-order relationships in Pandanales, including the first molecular phylogenetic study of the panama-hat family, Cyclanthaceae. Our genus-level study of plastid and mitochondrial gene sets includes a comprehensive sampling of photosynthetic lineages across the order, and provides a framework for investigating clade ages, biogeographic hypotheses and organellar molecular evolution. Using multiple inference methods and both organellar genomes, we recovered mostly congruent and strongly supported relationships within and between families, including the placement of fully mycoheterotrophic Triuridaceae. Cyclanthaceae and Pandanaceae plastomes have slow substitution rates, contributing to weakly supported plastid-based relationships in Cyclanthaceae. While generally slowly evolving, mitochondrial genomes exhibit sporadic rate elevation across the order. However, we infer well-supported relationships even for slower evolving mitochondrial lineages in Cyclanthaceae. Clade age estimates across photosynthetic lineages are largely consistent with previous studies, are well correlated between the two organellar genomes (with slightly younger inferences from mitochondrial data), and support several biogeographic hypotheses. We show that rapidly evolving non-photosynthetic lineages may bias age estimates upwards at neighbouring photosynthetic nodes, even using a relaxed clock model. Finally, we uncovered new genome structural variants in photosynthetic taxa at plastid inverted repeat boundaries that show promise as interfamilial phylogenetic markers. 相似文献
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86.
Influence of glutathione S-transferase polymorphisms on genotoxic effects induced by tobacco smoke 总被引:1,自引:0,他引:1
Genotoxicity of tobacco smoke has long been investigated and tobacco smoke is considered to be one of the principal human carcinogens. Although its role in DNA-damage induction and cancer development has been documented, the mechanisms by which this happens are not well understood. Many chemical constituents of tobacco smoke are enzymatically metabolized by phase-I and phase-II enzymes, but modifications in coding and regulating sequences of these genes could influence their ability to detoxify these compounds. In this work, we studied several enzymes involved in the metabolism of xenobiotics, viz. the glutathione S-transferases (GST) M1, T1, P1 and A1, with respect to their influence on the genotoxic effects induced by cigarette smoking. We assessed the genotoxic effects of tobacco smoke on peripheral blood lymphocytes of 72 healthy caucasians by use of the chromosomal aberration (CA) assay and the micronucleus (MN) test. Genotypes of GST M1, T1, P1 and A1 were determined by means of the polymerase chain reaction and methods based on restriction fragment length polymorphism (RFLP). We found that smoke and gender are the two variables that most influence the DNA damage. In particular, we observed that female smokers seem to be more sensitive than male smokers, having a significantly higher frequency of CAs. Moreover, a significant increase in frequency of micronuclei in bi-nucleated cells (BNMN) was found in smokers, but not in non-smokers. This increase seems to be influenced not only by age and gender, but also by genetic constitution. Subjects carrying GSTM1-null genotype seemed to have an higher susceptibility to DNA damage induced by tobacco smoke than GSTM1-positive ones. When considering a combination of GST genotypes, we found a lower BNMN frequency in subjects with GSTP1 variant allele plus GSTM1-positive genotypes, while the most damaged cells are found in subjects bearing GSTM1-null plus GSTP1-wild type. Our results suggest that investigation of the association between several gene polymorphisms and important endpoints of DNA damage could contribute to better understanding the role of gene-gene interaction. 相似文献
87.
Tombusviruses use a 19 kDa protein (p19) as a suppressor of the RNA silencing pathway during infection. The p19 protein binds to short-interfering RNA (siRNA) as a dimer and shows a high selectivity for short duplex RNAs over other RNA species. Since p19 can bind to synthetic and RNA silencing generated small RNAs with little sequence dependence and with size selectivity, this protein has utility as a tool for studying RNA silencing pathways in eukaryotes. However, the ability of p19 to serve as a tool for studying RNA silencing pathways may be complicated by the presence of other endogenous small RNAs such as micro-RNAs (miRNAs). To understand the importance of endogenous small RNA components with respect to p19's ability to bind to siRNAs, we examined the interactions of p19 with human miR-122, a 23-nucleotide duplex miRNA containing several mismatched base pairs that is highly abundant in the liver. The binding characteristics were compared with those of an siRNA optimized against the human kinase CSK. The binding studies were performed using fluorescence polarization experiments on duplex oligonucleotides containing Cy3 dye labels at the 5'-end of one of the strands of RNA as well as electrophoretic gel mobility shift assays. Both methods indicate that the synthetic siRNA with no mismatches in base pairing bound with >3-fold selectivity over that of miR-122. Our results suggest that p19 can distinguish between siRNAs and miRNA species, although the difference in binding constants is not so large that interactions with endogenous miRNAs can be totally ignored. 相似文献
88.
89.
Kim JA Bartlett S He L Nielsen CK Chang AM Kharazia V Waldhoer M Ou CJ Taylor S Ferwerda M Cado D Whistler JL 《Current biology : CB》2008,18(2):129-135
Opioid drugs, such as morphine, are among the most effective analgesics available. However, their utility for the treatment of chronic pain is limited by side effects including tolerance and dependence. Morphine acts primarily through the mu-opioid receptor (MOP-R) , which is also a target of endogenous opioids. However, unlike endogenous ligands, morphine fails to promote substantial receptor endocytosis both in vitro, and in vivo. Receptor endocytosis serves at least two important functions in signal transduction. First, desensitization and endocytosis act as an "off" switch by uncoupling receptors from G protein. Second, endocytosis functions as an "on" switch, resensitizing receptors by recycling them to the plasma membrane. Thus, both the off and on function of the MOP-R are altered in response to morphine compared to endogenous ligands. To examine whether the low degree of endocytosis induced by morphine contributes to tolerance and dependence, we generated a knockin mouse that expresses a mutant MOP-R that undergoes morphine-induced endocytosis. Morphine remains an excellent antinociceptive agent in these mice. Importantly, these mice display substantially reduced antinociceptive tolerance and physical dependence. These data suggest that opioid drugs with a pharmacological profile similar to morphine but the ability to promote endocytosis could provide analgesia while having a reduced liability for promoting tolerance and dependence. 相似文献
90.
The vanilloid receptor (VR1)-mediated effects of anandamide are potently enhanced by the cAMP-dependent protein kinase 总被引:13,自引:0,他引:13
Luciano De Petrocellis Selena Harrison † Tiziana Bisogno Michele Tognetto † Ines Brandi Graham D. Smith ‡ Cristophe Creminon § John B. Davis ‡ Pierangelo Geppetti† Vincenzo Di Marzo 《Journal of neurochemistry》2001,77(6):1660-1663
The endogenous cannabinoid receptor ligand, anandamide (AEA), is a full agonist of the vanilloid receptor type 1 (VR1) for capsaicin. Here, we demonstrate that the potency and efficacy of AEA at VR1 receptors can be significantly increased by the concomitant activation of protein kinase A (PKA). In human embryonic kidney (HEK) cells over-expressing human VR1, AEA induces a rise in cytosolic Ca(2+) concentration that is mediated by this receptor. The EC(50) for this effect was decreased five-fold in the presence of forskolin (FRSK, 1-5 microM) or the cAMP analogue, 8-Br-cAMP (10-100 microM). The effects of 8-Br-cAMP and FRSK were blocked by a selective PKA inhibitor. The FRSK (10 nM) also potently enhanced the sensory neurone- and VR1-mediated constriction by AEA of isolated guinea-pig bronchi, and this effect was abolished by a PKA inhibitor. In rat dorsal root ganglia slices, AEA-induced release of substance P, an effect mediated by VR1 activation, was enhanced three-fold by FRSK (10 nM). Thus, the ability of AEA to stimulate sensory VR1, with subsequent neuropeptide release, appears to be regulated by the state of activation of PKA. This observation supports the hypothesis that endogenous AEA might stimulate VR1 under certain pathophysiological conditions. 相似文献