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101.
Jeffrey Y. Melamed Amy E. Zartman Nathan R. Kett Anthony L. Gotter Victor N. Uebele Duane R. Reiss Cindra L. Condra Christine Fandozzi Laura S. Lubbers Blake A. Rowe Georgia B. McGaughey Martin Henault Rino Stocco John J. Renger George D. Hartman Mark T. Bilodeau B. Wesley Trotter 《Bioorganic & medicinal chemistry letters》2010,20(15):4700-4703
Administration of Neuropeptide S (NPS) has been shown to produce arousal, that is, independent of novelty and to induce wakefulness by suppressing all stages of sleep, as demonstrated by EEG recordings in rat. Medicinal chemistry efforts have identified a quinolinone class of potent NPSR antagonists that readily cross the blood–brain barrier. We detail here optimization efforts resulting in the identification of a potent NPSR antagonist which dose-dependently and specifically inhibited 125I-NPS binding in the CNS when administered to rats. 相似文献
102.
Bisoendial RJ Kastelein JJ Peters SL Levels JH Birjmohun R Rotmans JI Hartman D Meijers JC Levi M Stroes ES 《Journal of lipid research》2007,48(4):952-960
C-reactive protein (CRP) has been suggested to exert direct adverse effects on the vasculature in experimental setups, including endothelial dysfunction and proinflammatory changes. Here, we assessed the consequences of 1.25 mg/kg highly purified recombinant human CRP, administered as an intravenous bolus, in six patients with familial hypercholesterolemia (FH) and six normocholesterolemic subjects. Endothelium-dependent and -independent vasoreactivity to serotonin and nitroprusside, respectively, were assessed using venous occlusion plethysmography before and after CRP infusion. For biochemical analyses, blood was drawn at different time points. At baseline, FH patients showed blunted endothelium-dependent vasodilation (maximum, 89.2 +/- 30.0% vs. 117.7 +/- 13.1% in normolipidemic subjects; P = 0.037). Procoagulant activity was also higher in FH patients, illustrated by increased prothrombin fragment 1+2 (F(1+2)) levels (P = 0.030) and plasminogen activator inhibitor type-1 (PAI-1) activity (P = 0.016). Upon CRP challenge, endothelium-dependent vasodilator capacity further deteriorated in FH patients (P = 0.029), whereas no change in vascular reactivity was observed in normolipidemic subjects. Additionally, coagulation activation was augmented in FH patients compared with normolipidemic subjects (P = 0.009 for F(1+2) levels; P = 0.018 and P = 0.003 for PAI-1 antigen and activity, respectively). No difference in inflammatory responses was observed between groups. In hypercholesterolemic patients, CRP aggravates endothelial dysfunction and also evokes augmented procoagulant responses. These findings suggest that particularly in hypercholesterolemia, CRP-lowering strategies should be considered in addition to LDL reduction. 相似文献
103.
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105.
Paraoxonases are associated with intestinal inflammatory diseases and intracellularly localized to the endoplasmic reticulum 总被引:2,自引:0,他引:2
Rothem L Hartman C Dahan A Lachter J Eliakim R Shamir R 《Free radical biology & medicine》2007,43(5):730-739
We demonstrated previously that the paraoxonase (PON1/2/3) genes and proteins are expressed in human intestinal biopsies and in Caco-2 cells. The current study aims were to explore whether PON1/2/3 expression is different in inflammatory bowel diseases (IBD) or celiac disease compared to healthy controls, and to explore the intracellular localization of PON1/2/3. Our results showed that significantly fewer biopsies expressed PON1 and PON3 in the duodenum of celiac patients (PON1, P<0.0001; PON3, P=0.03), in the terminal ileum of Crohn's patients (PON1, P=0.001; PON3, P=0.008), and in the colon of UC patients (PON1, P=0.02; PON3, P=0.06) compared to controls. Since all three disorders share markedly elevated inflammatory mediators we explored the PON1/2/3 mRNA expression on cytokine stimulation. No changes were observed in Caco-2 and HT29 cells. Immunofluorescence experiments localized PON1/2/3 exclusively to the endoplasmic reticulum (ER) in both CaCo-2 and HT29 cells. These results demonstrate for the first time a novel relationship between PON1 and PON3 expression and several inflammatory gastrointestinal disorders. Together with the localization of PON1/2/3 enzymes to the ER, it may be suggested that PON1/2/3 may have extracellular functions as part of the host response in IBD and celiac disease. 相似文献
106.
Hammock Bruce G. Hartman Rosemary Dahlgren Randy A. Johnston Catherine Kurobe Tomofumi Lehman Peggy W. Lewis Levi S. Van Nieuwenhuyse Erwin Ramrez-Duarte Wilson F. Schultz Andrew A. Teh Swee J. 《Hydrobiologia》2022,849(3):675-695
Hydrobiologia - Condition indices are key predictors of health and fitness in wild fish populations. Variation in body condition, therefore, can be used to identify stressful conditions that may... 相似文献
107.
Camden M. Driggers Steven J. Hartman P. Andrew Karplus 《Protein science : a publication of the Protein Society》2015,24(1):154-161
In some bacteria, cysteine is converted to cysteine sulfinic acid by cysteine dioxygenases (CDO) that are only ~15–30% identical in sequence to mammalian CDOs. Among bacterial proteins having this range of sequence similarity to mammalian CDO are some that conserve an active site Arg residue (“Arg‐type” enzymes) and some having a Gln substituted for this Arg (“Gln‐type” enzymes). Here, we describe a structure from each of these enzyme types by analyzing structures originally solved by structural genomics groups but not published: a Bacillus subtilis “Arg‐type” enzyme that has cysteine dioxygenase activity (BsCDO), and a Ralstonia eutropha “Gln‐type” CDO homolog of uncharacterized activity (ReCDOhom). The BsCDO active site is well conserved with mammalian CDO, and a cysteine complex captured in the active site confirms that the cysteine binding mode is also similar. The ReCDOhom structure reveals a new active site Arg residue that is hydrogen bonding to an iron‐bound diatomic molecule we have interpreted as dioxygen. Notably, the Arg position is not compatible with the mode of Cys binding seen in both rat CDO and BsCDO. As sequence alignments show that this newly discovered active site Arg is well conserved among “Gln‐type” CDO enzymes, we conclude that the “Gln‐type” CDO homologs are not authentic CDOs but will have substrate specificity more similar to 3‐mercaptopropionate dioxygenases. 相似文献
108.
Reger TS Yang ZQ Schlegel KA Shu Y Mattern C Cube R Rittle KE McGaughey GB Hartman GD Tang C Ballard J Kuo Y Prueksaritanont T Nuss CE Doran SM Fox SV Garson SL Li Y Kraus RL Uebele VN Renger JJ Barrow JC 《Bioorganic & medicinal chemistry letters》2011,21(6):1692-1696
A novel series of amide T-type calcium channel antagonists were prepared and evaluated using in vitro and in vivo assays. Optimization of the screening hit 3 led to identification of the potent and selective T-type antagonist 37 that displayed in vivo efficacy in rodent models of epilepsy and sleep. 相似文献
109.
Kuduk SD Di Marco CN Cofre V Ray WJ Ma L Wittmann M Seager MA Koeplinger KA Thompson CD Hartman GD Bilodeau MT 《Bioorganic & medicinal chemistry letters》2011,21(9):2769-2772
Fused aromatics such as naphthalene were identified as highly potent and CNS penetrant M1 positive allosteric modulators during an SAR study to replace the phenyl B-ring linkage. 相似文献
110.
Crossland BW Hartman JE Kilgore JL Hartman MJ Kaus JM 《Journal of strength and conditioning research / National Strength & Conditioning Association》2011,25(10):2639-2644
Start time has been shown to be a significant predictor of overall performance in the sport of luge. The starting motion in luge has been described as an explosive upper-body movement that requires significant technique and skill to perfect. This study aims to investigate upper-body factors that may relate to start time in luge. Twenty-two subjects participated in the study as part of their normal off-season training. Each subject had a minimum of 3 years' experience in the sport of luge, and at the time was a member of a U.S. Luge National Team. Subjects completed a 1 repetition maximum (1RM) in the bench press (BP), prone row (PR), and weighted pull-up (WP). Anthropometric distances were taken measuring finger-tip span (FS), biacromial breadth (BB), acromio-radial length, acromio-olecranon length (AO), hand length, and sitting cervical height. Subjects were divided into 2 groups based on which U.S. Luge National team they were currently a member of, Senior National (SN, n = 13) and Junior National (JN, n = 9). A Pearson product-moment correlation coefficient showed several significant (p ≤ 0.05) relationships between upper-body variables and start time among the groups. The BP and PR 1RM were shown to have a significant relationship in both groups. Among the anthropometric variables, AO was also significant in both groups. The WP, FS, BB, and height were all shown to have a significant relationship with start time in the SN group, but not in the JN group. These results suggest that as luge athletes become more efficient in the starting technique, outside factors such as upper-body strength and anthropometric measures play a larger role in performance. 相似文献