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991.
Claudio Erratico Noelia Negreira Helia Norouzizadeh Adrian Covaci Hugo Neels Kristof Maudens Alexander L.N. van Nuijs 《Drug testing and analysis》2015,7(10):866-876
N‐[(1S)‐1‐(aminocarbonyl)‐2‐methylpropyl]‐1‐(cyclohexylmethyl)‐1H‐indazole‐3‐carboxamide (AB‐CHMINACA) is a recently introduced synthetic cannabinoid. At present, no information is available about in vitro or in vivo human metabolism of AB‐CHMINACA. Therefore, biomonitoring studies to screen AB‐CHMINACA consumption lack any information about the potential biomarkers (e.g. metabolites) to target. To bridge this gap, we investigated the in vitro metabolism of AB‐CHMINACA using human liver microsomes (HLMs). Formation of AB‐CHMINACA metabolites was monitored using liquid chromatography coupled to time‐of‐flight mass spectrometry. Twenty‐six metabolites of AB‐CHMINACA were detected including seven mono‐hydroxylated and six di‐hydroxylated metabolites and a metabolite resulting from N‐dealkylation of AB‐CHMINACA, all produced by cytochrome P450 (CYP) enzymes. Two carboxylated metabolites, likely produced by amidase enzymes, and five glucuronidated metabolites were also formed. Five mono‐hydroxylated and one carboxylated metabolite were likely the major metabolites detected. The involvement of individual CYPs in the formation of AB‐CHMINACA metabolites was tested using a panel of seven human recombinant CYPs (rCYPs). All the hydroxylated AB‐CHMINACA metabolites produced by HLMs were also produced by the rCYPs tested, among which rCYP3A4 was the most active enzyme. Most of the in vitro metabolites of AB‐CHMINACA were also present in urine obtained from an AB‐CHMINACA user, therefore showing the reliability of the results obtained using the in vitro metabolism experiments conducted to predict AB‐CHMINACA in vivo metabolism. The AB‐CHMINACA metabolites to target in biomonitoring studies using urine samples are now reliably identified and can be used for routine analysis. Copyright © 2015 John Wiley & Sons, Ltd. 相似文献
992.
Angelo DAlessandro Davide Stefanoni Sherrill J. Slichter Xiaoyun Fu James C. Zimring 《Trasfusione del sangue》2021,19(3):216
BackgroundThe impact of donor biology on blood component storability is increasingly appreciated as a determinant of the storage lesion and post-transfusion performances. Platelet metabolism is affected by age and it is critical to platelet responses to activating stimuli in an age-dependent manner. Sex has been previously highlighted as a contributing factor to the platelet proteomics lesion. However, little is known about the impact of donor sex and age on stored platelet metabolism and post-transfusion capacity to circulate.Materials and methodsApheresis platelets were donated via apheresis by 21 healthy volunteers (12 males and 9 females; ages 20 to 59). Metabolomics analyses were performed at day 0 and after 5 days of storage at 22+2 °C, along with autologous post-transfusion recovery and survival studies with 51Cr and 111In.ResultsSex and age significantly impacted platelet metabolism at baseline and upon storage. Platelets from older, male donors were characterised by higher levels of Krebs cycle metabolites, pentose phosphate pathway intermediates and byproducts, deaminated purines and long chain fatty acids. These metabolites ranked amongst the top significant correlates to post-transfusion recoveries. Glutathione homeostasis and sphingosine 1-phosphate were the top positive correlates to long term survival, which was lower in platelets from older, male donors – without reaching statistical significance.DiscussionIn this study we report that donor sex and age have a significant impact on platelet metabolism. Novel metabolic correlates to platelet post-transfusion performances (24 h recovery and long-term survival) were identified through high-resolution, stable isotope-labeled internal standard-assisted metabolomics approach. 相似文献
993.
Giuliano Enzi Giuliano Cagnoni Aldo Baritussio Flora De Biasi Laura Favaretto Emine M. Inelmen Gaetano Crepaldi 《Acta diabetologica》1979,16(2):147-156
Summary The interrelation of enlarged body fat mass (BFM) with reduced carbohydrate tolerance and hyperinsulinemia was studied in
obese subjects with chemical diabetes. These patients were subjected to lipectomy following weight loss induced by a low-calorie,
low-carbohydrate diet. An improvement in glucose tolerance and in insulin sensitivity and a reduction in insulin release during
OGTT was observed after a diet-induced BFM loss of 9.9 ± 1.2 kg. Subsequent surgical reduction of BFM by 6.0 ± 0.5 kg had
no further effect upon carbohydrate tolerance, insulin release or insulin sensitivity though a marked decrease in basal plasma
FFA values was observed. These findings suggest that fat mass enlargementper se has no effect on blood glucose homeostasis after oral or i.v. loading. The improvement in carbohydrate tolerance and in insulin
resistance usually observed following diet-induced loss of BFM seems to be due to the reduction in calorie and carbohydrate
intake rather than to decrease of BFM.
Preliminary results of this study were presented at the 9th Congress of the International Diabetes Federation, held in New
Delhi in 1976 (abstract ≠ 333). 相似文献
994.
Huang N Agrawal V Giacomini KM Miller WL 《Proceedings of the National Academy of Sciences of the United States of America》2008,105(5):1733-1738
P450 oxidoreductase (POR) is an electron-donating flavoprotein required for the activity of all microsomal cytochrome P450 enzymes. We sequenced 5,655 bp of the POR gene in a representative population of 842 healthy unrelated individuals in four ethnic groups: 218 African Americans, 260 Caucasian Americans, 179 Chinese Americans, and 185 Mexican Americans. One hundred forty SNPs were detected, of which 43 were found in >/=1% of alleles. Twelve SNPs were in the POR promoter region. Fifteen of 32 exonic variations altered the POR amino acid sequence; 13 of these 15 are previously undescribed missense variations. We found eight indels, only one of which was in the coding region. A previously described variant, A503V, was found on 27.9% of all alleles with some ethnic predilection (19.1% in African Americans, 26.4% in Caucasian Americans, 36.7% Chinese Americans, and 31.0% in Mexican Americans). We built cDNA expression vectors for the 13 previously undescribed missense variants, expressed each protein lacking 27 N-terminal residues in Escherichia coli, and assayed the apparent K(m) and V(max) of each in four assays: reduction of cytochrome c, oxidation of NADPH, 17alpha-hydroxylase activity of P450c17, and 17,20 lyase activity of P450c17. The catalytic activities of several missense mutants differed substantially in these assays, indicating that each POR mutant must be assayed separately with each potential target P450 enzyme. The activity of A503V was reduced to a modest but statistically significant degree in all four assays, suggesting that it may play an important role in interindividual variation in drug response. 相似文献
995.
Mesenteric adipose tissue was removed from adult goldfish, Carassius auratus, and incubated in vitro with (1alpha,2alpha)-3[H]testosterone (T). Total radioactivity in the medium decreased and tissue total radioactivity increased in a time-dependent fashion between 1 and 6 h of incubation with maximum uptake occurring between 4 and 6 h. After ether extraction and thin layer chromatography the amount of radioactivity comigrating with authentic T standard decreased over time in both medium and tissue samples. Radioactivity in the aqueous fraction remaining after ether extraction increased in a time-dependent manner, suggesting the presence of water-soluble conjugated steroids. Acid hydrolysis of the aqueous fraction yielded radioactivity that principally comigrated with T standard following a second ether extraction and TLC, along with a small, unidentified peak of poorly migrating radioactivity. Aromatization of T was assessed after charcoal stripping samples and measuring radioactivity remaining in the form of 3H(2)O. Small but significant amounts of 3H(2)O were present in both incubation medium and tissue samples. Incubation with the aromatase inhibitor 4-androsten-4-ol-3,17-dione acetate (ATD) decreased the formation of 3H(2)O in a dose-dependent manner. These results suggest that goldfish mesenteric adipose tissue is capable of converting T to several metabolites including water-soluble conjugates and estrogen. 相似文献
996.
997.
Summary Menadione and NH4Cl were reported to lower the islet content of reduced pyridine nucleotides. They were used to investigate the possible significance
of NAD(P)H in the regulation of glucagon release by glucose and arginine. Menadione (10–25 μmol/l) enhanced arginine-stimulated
glucagon release at a low glucose concentration (3.3 mmol/l), but failed both to affect glucagon secretion in the sole presence
of glucose (3.3 mmol/l) and to suppress the inhibitory action of glucose 11.1 mmol/l upon glucagon output. In contrast to
menadione, NH4Cl inhibited arginine-stimulated glucagon release at the low glucose concentration. The inhibitory action of glucose in high
concentration upon glucagon release was not suppressed by NH4Cl. These findings do not permit to extrapolate to the A2-cell the concept that reduced pyridine nucleotides represent a major coupling factor in the nutritional regulation of hormonal
release. 相似文献
998.
Eric J. Koch Clotilde Bongrand Brittany D. Bennett Susannah Lawhorn Silvia Moriano-Gutierrez Marko Pende Karim Vadiwala Hans-Ulrich Dodt Florian Raible William Goldman Edward G. Ruby Margaret McFall-Ngai 《Proceedings of the National Academy of Sciences of the United States of America》2020,117(44):27578
999.
1000.
M. WORWOOD 《International journal of laboratory hematology》1998,20(2):65-75
Genetic haemochromatosis (GH) is the most common, autosomal recessive disorder in Northern Europe. The studies which led to the identification of the HFE gene are described. In the UK over 90% of patients with GH are homozygous for the C282Y mutation of this gene. This mutation is confined to populations of European origin. The significance of another mutation, H63D, in causing iron overload is less certain. Preliminary studies on the localization of the protein and the effects of the mutations are described. Genetic testing and the measurement of iron status now provide the means to allow for widespread testing for the prevention of iron overload and its consequences. However, questions remain about the clinical penetrance of GH. 相似文献