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61.
Fowler CJ Tiger G Ligresti A López-Rodríguez ML Di Marzo V 《European journal of pharmacology》2004,492(1):1-11
There is considerable debate at present as to whether the uptake of anandamide (AEA) into cells is by a facilitated transport process or by passive diffusion driven by fatty acid amide hydrolase (FAAH). The possibility that both processes occur, but to different extents depending upon the cell type used, has been difficult to investigate pharmacologically since available compounds show little selectivity between inhibition of AEA uptake and inhibition of FAAH. Recently, three compounds, UCM707 [N-(Fur-3-ylmethyl)arachidonamide], OMDM-1 and OMDM-2 [the 1'-(S)- and 1'-(R)-enantiomers of the 1'-4-hydroxybenzoyl analogue of oleoylethanolamide], selective for the uptake process, have been described and we have used these compounds, together with AM404 [(N-(4-hydroxyphenyl) arachidonoyl amide)] and VDM11 [(5Z,8Z,11Z,14Z)-N-(4-Hydroxy-2-methylphenyl)-5,8,11,14-eicosatetraenamide]), with the initial aim of determining which mechanism of uptake predominates in C6 glioma and RBL-2H3 cells. AM404 and VDM11 were both found to decrease the uptake of 2 microM AEA into cells (IC50 values 6-11 microM), but they also inhibited rat brain FAAH (IC50 values 1-6 microM). However, when using a different FAAH assay protocol, VDM11 was a much less potent FAAH inhibitor (IC50>50 microM) regardless of the cell type and animal species used. In contrast, we confirmed that UCM707, OMDM-1 and OMDM-2 were weak inhibitors of FAAH (IC50 values >50 microM) under all conditions used. However, their potency as inhibitors of AEA cellular accumulation appears to be largely dependent on the cell type and assay conditions used. In particular, the potency of UCM707 (IC50 value > or =25 microM) was considerably lower than the submicromolar potency previously reported for U937 cells. It is concluded that the cause/effect relationship between AEA uptake and hydrolysis cannot be investigated uniquely by using supposedly selective inhibitors of each process. 相似文献
62.
Piesse C Cadel S Gouzy-Darmon C Jeanny JC Carrière V Goidin D Jonet L Gourdji D Cohen P Foulon T 《Experimental eye research》2004,79(5):639-648
Aminopeptidase B (Ap-B), a ubiquitous enzyme, catalyses the amino-terminal cleavage of basic residues of peptide or protein substrates, indicating a role in precursor processing. The physiological function of Ap-B still remains an open question, even though its activity suggests that it could be involved in inflammatory processes and proliferation of tumor cells. This study was conducted to determine the expression of Ap-B in the developing and adult retina as a path to envisage physiological roles of Ap-B. RT-PCR and in situ hybridization were used to detect expression of Ap-B mRNA and activity tests, Western blotting and immunofluorescence microscopy were performed to identify and localize the enzyme in the rat retina. These biochemical and morphological methods show that Ap-B is expressed in the retina from embryo to adult. Expression level is restricted to specific layers (pigmented epithelium, outer and inner plexiform layers and ganglion cell layer) and is developmentally regulated. Moreover, a preliminary analysis indicates that Ap-B, the glucose transporter GLUT3 and choline acetyltransferase (ChAT) share a similar expression pattern in retina. Altogether, Ap-B appears predominantly expressed in neuronal cells lying in retinal layers containing neuritic extensions and synaptic junctions. Such expression is up-regulated during ontogenesis allowing to hypothesized that Ap-B participates in processes accompanying retinal neuronal cell differentiation. 相似文献
63.
An Ile93Met substitution in the UCH-L1 gene is not a disease-causing mutation for idiopathic Parkinson’s disease 总被引:1,自引:0,他引:1
Objective To ascertain whether a coding mutation(Ⅱe93Met) in ubiquitin carboxy-terminal hydrolase(UCH-L1) gene plays a role in idiopathic Parkinson‘s disease(IPD).Methods Polymerase chain reaction-restriction fragment length polymorphism assay(PCR-RFLP) was used to distingusih the wild-type(two DNA fagments of 34 and 126bp)from the variant allele(three fragments of 34,60 and 66bp)because the mutation created a new site for restriction engonuclease Bsm F1.DNA was isolated from various blood samples using a phenolchlorofom extraction. 相似文献
64.
环氧化合物[Ⅱ]在氯化亚铜存在下的无水四氢呋喃溶液中,用对一二甲胺基溴化苯基镁处理得到化合物[Ⅲ]。它是合成RU486[Ⅰ]的重要中间体。11β-芳胺基的引入,是导致RU486分子和黄体酮受体之间产生相对亲和力的主要基团之一。因此,它具有良好的抗孕酮的作用。化合物[Ⅲ]的结构经红外光谱、核磁共振光谱和比旋度得到确定。 相似文献
65.
Dysregulation of the Endocannabinoid System in Obesity 总被引:1,自引:0,他引:1
S. Engeli 《Journal of neuroendocrinology》2008,20(S1):110-115
An activation of the endocannabinoid system (ECS) in obesity with increased concentrations of endocannabinoids in several tissues and in the circulation is described in this review. This increased availability of endocannabinoids might stimulate cannabinoid receptors in a pathophysiological manner. The successful use of the cannabinoid receptor CB1 inverse agonists rimonabant and taranabant for weight loss and the treatment of obesity-associated metabolic disorders might well be through blocking this overstimulation of cannabinoid receptors. At present, no single mechanism has been identified that explains the increased bioavailability of endocannabinoids in obesity. Both increased synthesis and decreased degradation appear to operate in a species- and tissue-dependent manner, but many pieces of the puzzle still need to be collected. For example, most data show decreased fatty acid amide hydrolase (FAAH) expression and/or activity as a result of obesity or high-fat intake, but the endocannabinoid predominantly increased in tissues is 2-arachidonoylglycerol (2-AG), which is not degraded by FAAH in vivo . Furthermore, the influence of dietary fatty acids on the synthesis of endocannabinoids needs to be studied in much more detail. Although weight loss does not seem to influence activation of the endocannabinoid system (ECS) in human obesity, suggesting an underlying mechanisms independent of body weight, no such mechanism at the genetic level has yet been identified either. Thus, activation of the ECS is a hallmark of abdominal obesity, and explains the success of pharmacological CB1 blockade, but serious attempts have to be made to clarify the underlying mechanisms of this activation. 相似文献
66.
Andrea M Dlugos Ajna Hamidovic Colin A Hodgkinson David Goldman Abraham A Palmer Harriet de Wit 《Neuropsychopharmacology》2010,35(3):613-622
Amphetamine is a stimulant drug that enhances attention and feelings of alertness. Amphetamine''s effects are known to be modulated by endogenous cannabinoids, which are degraded by the enzyme fatty acid amide hydrolase (FAAH). In this study we investigated inter-individual differences in mood response to amphetamine in relation to four polymorphisms in the FAAH gene, including the FAAH missense variant rs324420C → A (Pro129Thr), which was previously found to be associated with street drug use and addictive traits. One hundred and fifty-nine healthy Caucasian volunteers participated in a three-session, double-blind crossover study receiving either placebo or oral d-amphetamine (10 and 20 mg). Associations between individual genotypes and levels of self-reported Arousal (Profile of Mood States) after d-amphetamine ingestion were investigated using two-way ANOVAs/ANCOVAs. Association analyses for haplotypes were performed using the adaptive permutation approach implemented in PLINK. Genotypes at rs3766246 and rs2295633 were significantly associated with increased ratings of Arousal (p<0.05) and Fatigue (p<0.01) after the 10-mg dose. Fatigue levels were also found to be associated with the haplotypes CCC and TAT formed from rs3766246, rs324420, and rs2295633 (p<0.05). These data suggest that the endocannabinoid system influences variation in subjective response to amphetamine. This has important implications for understanding the role of endogenous cannabinoids in response to amphetamine, studies of poly-substance abuse, and understanding the genetic determinants of inter-individual differences in stimulant effects and risk of abuse. 相似文献
67.
S. VanHook Harris D. Marin Thompson R. J. Linderman M. D. Tomalski R. M. Roe 《Insect molecular biology》1999,8(1):85-96
A full-length cDNA encoding for a microsomal juvenile hormone (JH)-metabolizing epoxide hydrolase (TmEH-1) was isolated from a cDNA library constructed from fat body of last stadium (wandering) cabbage loopers, Trichoplusia ni, at the exact developmental time of maximum JH epoxide hydrolase activity. TmEH-1 was 1887 base pairs in lenght with a 1389 base pair open reading frame encoding 463 amino acids. Amino acid sequence analysis showed that TmEH-1 was most similar to and contained the exact catalytic triad (Asp-226, Glu-403 and His-430) found in microsomal epoxide hydrolases. TmEH-1-specific message was present along with JH III epoxide hydrolase activity in fat body in feeding (days 1 and 2) and wandering (day 3) larvae with the peak in message level preceding the peak in JH epoxide hydrolase activity by 1 day. When TmEH-1 was expressed in baculovirus-infected Spodoptera frugiperda cells, a 46,000 molecular weight protein appeared on SDS-PAGE which corresponded to the predicted size coded by the TmEH-1 message and which was positively correlated with increases in JH III epoxide hydrolase activity above that of wild-type controls. In subcellular distribution studies, 58% of the juvenile hormone III epoxide hydrolase activity was in the insoluble fractions. Baculovirus expressed TmEH-1 demonstrated a higher specific activity for JH III as compared to the general EH substrates, cis- and trans-stibene oxide. Southern blot analyses suggested that multiple epoxide hydrolase genes are present in T. ni. 相似文献
68.
69.
70.
Ellen A Cannady Cheryl A Dyer Patricia J Christian I Glenn Sipes Patricia B Hoyer 《Toxicological sciences》2002,68(1):24-31
Microsomal epoxide hydrolase (mEH) is involved in the detoxification of xenobiotics that are or can form epoxide metabolites, including the ovotoxicant, 4-vinylcyclohexene (VCH). This industrial chemical is bioactivated by hepatic CYP450 to the diepoxide metabolite, VCD, which destroys mouse small preantral follicles (F1). Since ovarian mEH may play a role in VCD detoxification, these studies investigated the expression and activity of mEH in isolated ovarian fractions. Mice were given 1 or 15 daily doses (ip) of VCH (7.4 mmol/kg/day) or VCD (0.57 mmol/kg/day); 4 h following the final dose, ovaries were removed, distinct populations of intact follicles (F1, 25-100 microm; F2, 100-250 microm; F3, > 250 microm) and interstitial cells (Int) were isolated, and total RNA and protein were extracted. Real-time polymerase chain reaction and the substrate cis-stilbene oxide (CSO; 12.5 microM) were used to evaluate expression and specific activity of mEH, respectively. Confocal microscopy evaluated ovarian distribution of mEH protein. Expression of mRNA encoding mEH was increased in F1 (410 +/- 5% VCH; 292 +/- 5% VCD) and F2 (1379 +/- 4% VCH; 381 +/- 11% VCD) follicles following repeated dosing with VCH or VCD. Catalytic activity of mEH increased in F1 follicles following repeated dosing with VCH/VCD (381 +/- 11% VCH; 384 +/- 27% VCD). Visualized by confocal microscopy, mEH protein was distributed throughout the ovary with the greatest staining intensity in the interstitial cells and staining in the theca cells that was increased by dosing (56 +/- 0.8% VCH; 29 +/- 0.9% VCD). We conclude that mEH is expressed and is functional in mouse ovarian follicles. Additionally,in vivo dosing with VCH and VCD affects these parameters. 相似文献