bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Effects of Aminorex and Related Compounds on Brain Monoamines and Metabolites in CBA Mice
Authors: Zheng Yiwen , Russell Bruce , Schmierer David , Laverty Richard 
Published: April 2011

Abstract
Acute and long-term neurochemical effects of aminorex, an appetite-suppressing drug related to amphetamine in chemical structure, and stereoisomers of its analogues were examined and compared with those of 3,4-methylenedioxymethylarnphetamine (MDMA) and fenfluramine.
Aminorex and its analogues, with exception of 45, 5S-dimethylaminorex, did not cause the long-term neurotransmitter depletion in either the dopaminergic or 5-HT-ergic systems that was observed after MDMA or fenfluramine in CBA mice. These results are discussed in terms of possible structurally related mechanisms of neurotoxicity.
The acute neurochemical effects showed that aminorex and analogues all produced increases in 5-hydroxytryptamine (5-HT) levels, unlike fenfluramine and MDMA in the present study or in published data. This suggests that inhibition of 5-HT metabolism, rather than direct 5-HT release, may be involved in their anorectic effect. The parallel study of acute dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) changes suggest that in CBA mice MDMA may be a better dopamine releaser and this may contribute to its dopaminergic neurotoxicity. However the ability to release dopamine or 5-HT, or both, may be important, but not the only factor involved in causing the long-term neurotoxicity observed with amphetamine derivatives.
Nitric Oxide Scavenging by Curcuminoids
Authors: Sreejayan  , Rao M N A 
Published: April 2011

Abstract
Because curcumin, a compound with anti-inflammatory and anticancer activity, inhibits induction of nitric oxide synthase in activated macrophages and has been shown to be a potent scavenger of free radicals we have investigated whether it can scavenge nitric oxide directly.
Curcumin reduced the amount of nitrite formed by the reaction between oxygen and nitric oxide generated from sodium nitroprusside. Other related compounds, e.g. demethoxycurcumin, bisdemethoxycurcumin and diacetylcurcumin were as active as curcumin, indicating that the methoxy and the phenolic groups are not essential for the scavenging activity.
The results indicate curcumin to be a scavenger of nitric oxide. Because this compound is implicated in inflammation and cancer, the therapeutic properties of curcumin against these conditions might be at least partly explained by its free-radical scavenging properties, including those toward nitric oxide.
Some Effects of Cassia italica on the Central Nervous System in Mice
Authors: Ali B H , Bashir A K , Tanira M O M 
Published: April 2011

Abstract
This work examines some effects of the crude ethanolic extract of the medicinal plant Cassia italica, given at single oral doses of 0.25, 0.5 or 1 g kg−1, on the central nervous system in mice. Several models of nociception have been used to examine the analgesic effect of the extract. HPLC fingerprinting of the extract was performed to ensure uniformity of the extract material used.
In treated mice, the extract caused dose-related inhibition of acetic acid-induced abdominal constriction, and in the formalin test of antinociception the extract reduced formalin-induced pain in the second (late) but not in the first (early) phase of the pain. Treatment with the extract at doses of 0.5 and 1 g kg−1 significantly increased the reaction time in the hot-plate and warm-water tail-flick tests. Naloxone was ineffective in antagonizing the analgesic effect of C. italica on tail-flick and abdominal constriction tests, possibly indicating that the effect occurs via non-opiate pathways. The C. italica extract caused slight dose-related impairment of motor control which was significant only at a dose of 1 g kg−1. Treatment at the three doses used did not affect the rectal temperature of normothermic mice, but was effective in significantly reducing the rectal temperature of hyperthermic rats, 0.5 and 1 h (but not 6 h) after administration of the extract at doses of 0.5 and 1 g kg−1. The extract also produced progressive diminution in the ambulatory and total activity of treated mice for up to 2 h after administration.
It is concluded that the crude ethanolic extract of C. italica has CNS depressant properties, manifested as antinociception and sedation.
Characteristics of Cefdinir Uptake by Rabbit Small Intestinal Brush-border Membrane Vesicles
Authors: Kitagawa Shuji , Sugaya Yoshio , Kaseda Yoshihiko , Sato Shinji 
Published: April 2011

Abstract
Aminocephalosporins with peptide-like structures have been shown to be absorbed by the intestinal peptide carrier. We investigated the transport mechanism of cefdinir, an oral monocarboxylic acid cephalosporin, using rabbit small intestinal brush-border membrane vesicles.
Transport of cefdinir showed a slow and almost linear uptake rate for concentrations up to 30 mm with and without an inward H+ gradient. No overshoot phenomenon was observed in the presence of an inward H+ gradient. The uptake rate increased only slightly with decreasing extravesicular pH, and a protonophore had little effect on the uptake. Aminocephalosporins such as cephalexin only slightly inhibited cefdinir uptake even in the presence of an inward H+ gradient, and vice-versa. Monocarboxylic acids such as acetic acid and salicylic acid had little effect on cefdinir uptake.
These findings suggest that in contrast with other oral cephalosporins cefdinir uptake through the brush-border membrane is slow and involves a mechanism similar to passive diffusion.
Effect of a Chymotrypsin-like Inhibitor, TPCK, on Histamine Release from Cultured Human Mast Cells
Authors: Yanagida Makoto , Fukamachi Hiromi , Takei Masao , Uzumaki Hiroya , Saito Tomonobu Tokiwa Hirohisa , Iikura Yoji , Nakahata Tatsutoshi 
Published: April 2011

Abstract
The involvement of endogenous proteases in the secretory process from human mast cells remains to be clarified.
A chymotrypsin-like protease inhibitor, N-tosyl-l-phenylalanylchloromethyl ketone (TPCK), blocked both FcεRI- and A23187-mediated histamine release from cultured human mast cells at concentrations above 1 μm. At 10 μm, the concentration that completely inhibited FcεI-mediated histamine release, TPCK did not inhibit the chymase activity of the lysate or that in intact cells. The addition of TPCK to cells 30 min before challenge did not affect FcεRI- or A23187-mediated Ca2+ mobilization.
These findings suggest that a TPCK-sensitive molecule distinct from chymase is involved in a late stage of the process of histamine release from mast cells in man.
Contribution of Cytochrome P450 3A Pathway to Bromocriptine Metabolism and Effects of Ferrous Iron and Hypoxia-re-oxygenation on its Elimination in the Perfused Rat Liver
Authors: Matsubayashi Keiko , Matsumoto Hiroshi , Fukui Yuko 
Published: April 2011

Abstract
The contribution of the cytochrome P450 3A pathway to bromocriptine metabolism, and the effects of ferrous iron and hypoxia-re-oxygenation on its elimination, were evaluated with the perfused rat liver. Outflow profiles of bromocriptine after bolus administration were estimated by moment analysis and dispersion model analysis.
Kinetic parameters were not significantly changed by troleandomycin, a P450 3A inhibitor. The inhibition of bromocriptine metabolism by troleandomycin was 5.7 ± 2.4%. These findings indicate that cytochrome P450 3A does not play an important role in bromocriptine elimination with the perfused rat liver. Elimination rate constant (ke) values were significantly increased by ferrous iron perfusion or hypoxia-re-oxygenation. Free-radical generation can, therefore, affect bromocriptine elimination.
Our observations suggest that bromocriptine might be eliminated by scavenging of free radicals in the liver.
Polyhedral Non-ionic Surfactant Vesicles
Authors: Uchegbu Ijeoma F , Schätzlein Andreas , Vanlerberghe Guy , Morgatini Nicola , Florence Alexander T 
Published: April 2011

Abstract
Large polyhedral (2–10 μm) non-ionic surfactant vesicles (niosomes) formed from mixtures of a hexadecyl diglycerol ether (C16G2), a cholesteryl poly-24-oxyethylene ether (solulan C24) and a low level of cholesterol are being investigated as slow-release systems for ophthalmic, subcutaneous or intramuscular administration.
The phase-diagram of this three-component system has been constructed and these polyhedral vesicles are found to be in the gel (Lβ) phase. Confocal laser-scanning microscopy was used to confirm the complex morphology of these vesicles. The thermo-responsive nature of release of entrapped carboxyfluorescein and nicotinamide adenine dinucleotide has been studied; release is increased with increase in temperature (37°C) even though the polyhedral vesicles still maintain their polyhedral shape at this temperature.
The results indicate that the thermo-responsive features of the niosomes are a result of reversible changes in bi-layer permeability caused by temperature-mediated alteration in the membrane-packing characteristics of the polyethoxylated cholesterol ether.
Major Basic Protein from Eosinophils and Myeloperoxidase from Neutrophils Are Required for Protective Immunity to Strongyloides stercoralis in Mice
Authors: O'Connell Amy E. , Hess Jessica A. , Santiago Gilberto A. , Nolan Thomas J. , Lok James B. , Lee James J. , Abraham David 
Published: April 2011

ABSTRACTEosinophils and neutrophils contribute to larval killing during the primary immune response, and neutrophils are effector cells in the secondary response toStrongyloides stercoralisin mice. The objective of this study was to determine the molecular mechanisms used by eosinophils and neutrophils to control infections withS. stercoralis. Using mice deficient in the eosinophil granule products major basic protein (MBP) and eosinophil peroxidase (EPO), it was determined that eosinophils kill the larvae through an MBP-dependent mechanism in the primary immune response if other effector cells are absent. InfectingPHILmice, which are eosinophil deficient, withS. stercoralisresulted in development of primary and secondary immune responses that were similar to those of wild-type mice, suggesting that eosinophils are not an absolute requirement for larval killing or development of secondary immunity. TreatingPHILmice with a neutrophil-depleting antibody resulted in a significant impairment in larval killing. Naïve and immunized mice with neutrophils deficient in myeloperoxidase (MPO) infected withS. stercoralishad significantly decreased larval killing. It was concluded that there is redundancy in the primary immune response, with eosinophils killing the larvae through an MBP-dependent mechanism and neutrophils killing the worms through an MPO-dependent mechanism. Eosinophils are not required for the development or function of secondary immunity, but MPO from neutrophils is required for protective secondary immunity.
Role of Gastric Epithelial Cell-Derived Transforming Growth Factor β in Reduced CD4
+
T Cell Proliferation and Development of Regulatory T Cells during Helicobacter pylori Infection
Authors: Beswick Ellen J. , Pinchuk Iryna V. , Earley Rachel B. , Schmitt David A. , Reyes Victor E. 
Published: April 2011

ABSTRACT

Gastric epithelial cells (GECs) express the class II major histocompatibility complex (MHC) and costimulatory molecules, enabling them to act as antigen-presenting cells (APCs) and affect local T cell responses. During
Helicobacter pylori
infection, GECs respond by releasing proinflammatory cytokines and by increasing the surface expression of immunologically relevant receptors, including class II MHC. The CD4
+
T cell response during
H. pylori
infection is skewed toward a Th1 response, but these cells remain hyporesponsive. Activated T cells show decreased proliferation during
H. pylori
infection, and CD4
+
CD25
+
FoxP3
+
regulatory T cells (Tregs) are present at the site of infection. In this study, we examined the mechanisms surrounding the CD4
+
T cell responses during
H. pylori
infection and found that transforming growth factor β (TGF-β) plays a major role in these responses. GECs produced TGF-β1 and TGF-β2 in response to infection. Activated CD4
+
T cells in culture with
H. pylori
-treated GECs were decreased in proliferation but increased upon neutralization of TGF-β. Naïve CD4
+
T cell development into Tregs was also enhanced in the presence of GEC-derived TGF-β. Herein, we demonstrate a role for GEC-produced TGF-β in the inhibition of CD4
+
T cell responses seen during
H. pylori
infection.
Structural Characterization of the Erythrocyte Binding Domain of the Reticulocyte Binding Protein Homologue Family of Plasmodium yoelii
Authors: Grüber Ardina , Gunalan Karthigayan , Ramalingam Jeya Kumar , Manimekalai Malathy S. S. , Grüber Gerhard , Preiser Peter R. 
Published: April 2011

ABSTRACT

Invasion of the host cell by the malaria parasite is a key step for parasite survival and the only stage of its life cycle where the parasite is extracellular, and it is therefore a target for an antimalaria intervention strategy. Multiple members of the reticulocyte binding protein homologues (RH) family are found in all plasmodia and have been shown to bind to host red blood cells directly. In the study described here, we delineated the erythrocyte binding domain (EBD) of one member of the RH family, termed Py235, from
Plasmodium yoelii
. Moreover, we have obtained the low-resolution structure of the EBD using small-angle X-ray scattering. Comparison of the EDB structure to other characterized
Plasmodium
receptor binding domains suggests that there may be an overall structural conservation. These findings may help in developing new approaches to target receptor ligand interactions mediated by parasite proteins.
Guidelines for offshore in situ testing and interpretation in deepwater soft clays
Authors: Lunne Tom , Andersen Knut H. , Low Han Eng , Randolph Mark F. , Sjursen Morten 
Published: April 2011

Offshore developments for hydrocarbon resources have now progressed to water depths approaching 3000 m, with geotechnical design increasingly focused on soft sediments in the upper 30 m or so of the seabed. Due to the difficulties and high cost in recovering high-quality samples from deepwater sites, there is increasing dependence on in situ testing techniques for determining the geotechnical design parameters. This paper summarizes the findings from a joint industry project, undertaken by the Norwegian Geotechnical Institute and the Centre for Offshore Foundation Systems at The University of Western Australia, on the use of in situ testing for the characterization of deepwater soft soils. The project focused on theoretical and empirical studies for the interpretation of piezocone, T-bar, and ball penetration test data, linking the penetration resistance to shear strengths determined from in situ vane tests and laboratory tests on high-quality samples. Guidelines are summarized for interpreting in situ test data, particularly for estimating intact and remoulded undrained shear strengths from the penetration resistance measured by each type of penetrometer. Suggestions are also given for future development of in situ testing techniques to maximize the potential of in situ testing in characterization of deepwater soft soils.
Movement behaviour of the Little Chief Slide
Authors: Mansour Mohamed F. , Martin C. Derek , Morgenstern Norbert R. 
Published: April 2011

The Little Chief Slide has been extremely slow moving at a rate of 4–14 mm/year since the late 1960s. The 800 million m3slide lies about 3 km upstream of Mica Dam in British Columbia. The extremely slow rate was not affected by the Mica Dam reservoir filling in the 1970s. Although the Little Chief Slide is classified as a rock slide, the extremely slow movements take place on seams of soft materials composed mainly of micaceous clay gouge. The characteristics of the movement trends with time were investigated at six zones using in-place inclinometers (IPIs). The trends of the movement with the reservoir level fluctuations and pore pressure changes were investigated to quantify the contribution of steady-state creep to the total in situ movements. The creep behaviour of the clay gouge materials forming the movement zones was also investigated in the laboratory. The laboratory and field creep behaviours were then compared. The movement could be partitioned into steady-state creep and seasonally induced creep movements. This partitioning identified the locations where the seasonal movements are the highest, and, hence, where drainage measures could have the biggest impact.
Toward probabilistic real-time calculus
Authors: Santinelli Luca , Cucu-Grosjean Liliana 
Published: April 2011

A challenging research issue in analyzing probabilistic real-time systems is to model the tasks composing the system and the resource provided to the system. In this paper we propose a solution based on a probabilistic component-based model that abstracts the functional and non-functional requirements of real-time components. The obtained interfaces encode timing requirements and probability information of the component in a probabilistic version of the real-time calculus.
Besides, it has been derived probabilistic scheduling and compositional guarantees to provide real-time analyses of probabilistic real-time systems. Finally, a test case illustrates the potentialities of the proposed model and its applicability in a large variety of problems within the probabilistic real-time scenario.
Erlotinib-Mediated Inhibition of EGFR Signaling Induces Metabolic Oxidative Stress through NOX4
Authors: Orcutt Kevin P. , Parsons Arlene D. , Sibenaller Zita A. , Scarbrough Peter M. , Zhu Yueming , Sobhakumari Arya , Wilke Werner W. , Kalen Amanda L. , Goswami Prabhat , Miller Francis J. , Spitz Douglas R. , Simons Andrean L. 
Published: April 2011

Abstract
Redox regulation of epidermal growth factor receptor (EGFR) signaling helps protect cells against oxidative stress. In this study, we investigated whether the cytotoxicity of an EGFR tyrosine kinase inhibitor, erlotinib (ERL), was mediated by induction of oxidative stress in human head and neck cancer (HNSCC) cells. ERL elicited cytotoxicity in vitro and in vivo while increasing a panel of oxidative stress parameters which were all reversible by the antioxidant N-acetyl cysteine. Knockdown of EGFR by using siRNA similarly increased these oxidative stress parameters. Overexpression of mitochondrial targeted catalase but not superoxide dismutase reversed ERL-induced cytotoxicity. Consistent with a general role for NADPH oxidase (NOX) enzymes in ERL-induced oxidative stress, ERL-induced cytotoxicity was reversed by diphenylene iodonium, a NOX complex inhibitor. ERL reduced the expression of NOX1, NOX2, and NOX5 but induced the expression of NOX4. Knockdown of NOX4 by using siRNA protected HNSCC cells from ERL-induced cytotoxicity and oxidative stress. Our findings support the concept that ERL-induced cytotoxicity is based on a specific mechanism of oxidative stress mediated by hydrogen peroxide production through NOX4 signaling. Cancer Res; 71(11); 3932–40. ©2011 AACR.
Assessment of Chk1 Phosphorylation as a Pharmacodynamic Biomarker of Chk1 Inhibition
Authors: Parsels Leslie A. , Qian Yushen , Tanska Daria M. , Gross Marisa , Zhao Lili , Hassan Maria C. , Arumugarajah Sankari , Parsels Joshua D. , Hylander-Gans Linda , Simeone Diane M. , Morosini Deborah , Brown Jeffrey L. , Zabludoff Sonya D. , Maybaum Jonathan , Lawrence Theodore S. , Morgan Meredith A. 
Published: April 2011

Abstract
Purpose: Chk1 inhibitors, such as AZD7762, are in clinical development in combination with cytotoxic agents for the treatment of solid tumors, including pancreatic cancers. To maximize the likelihood of their clinical success, it is essential to optimize drug scheduling as well as pharmacodynamic biomarkers in preclinical models.
Experimental Design: We tested multiple schedules of administration of gemcitabine and AZD7762 on the survival of pancreatic cancer cells. Potential pharmacodynamic biomarkers including pChk1, pChk2, pHistone H3, and caspase-3 were evaluated in vitro, followed by assessment of promising candidate biomarkers in vivo. We then went on to determine the contributions of PP2A and DNA damage to the mechanism(s) of induction of the identified biomarker, pS345 Chk1.
Results: AZD7762 given during and after or after gemcitabine administration produced maximum chemosensitization. In vivo, AZD7762 significantly inhibited the growth of pancreatic tumor xenografts in response to gemcitabine. Of the biomarkers assessed, pS345 Chk1 was most consistently increased in response to gemcitabine and AZD7762 in tumors and normal tissues (hair follicles). pS345 Chk1 induction in response to gemcitabine and AZD7762 occurred in the presence of PP2A inhibition and in association with elevated γH2AX, suggesting that DNA damage is an underlying mechanism.
Conclusions: AZD7762 sensitizes pancreatic cancer cells and tumors to gemcitabine in association with induction of pS345 Chk1. Together these data support the clinical investigation of AZD7762 with gemcitabine in pancreatic cancer under a dosing schedule in which gemcitabine is administered concurrent with or before AZD7762 and in conjunction with skin biopsies to measure pS345 Chk1. Clin Cancer Res; 17(11); 3706–15. ©2011 AACR.
Ridaforolimus (AP23573; MK-8669), a Potent mTOR Inhibitor, Has Broad Antitumor Activity and Can Be Optimally Administered Using Intermittent Dosing Regimens
Authors: Rivera Victor M. , Squillace Rachel M. , Miller David , Berk Lori , Wardwell Scott D. , Ning Yaoyu , Pollock Roy , Narasimhan Narayana I. , Iuliucci John D. , Wang Frank , Clackson Tim 
Published: April 2011

Abstract
The mTOR pathway is hyperactivated through oncogenic transformation in many human malignancies. Ridaforolimus (AP23573; MK-8669) is a novel rapamycin analogue that selectively targets mTOR and is currently under clinical evaluation. In this study, we investigated the mechanistic basis for the antitumor activity of ridaforolimus in a range of human tumor types, exploring potential markers of response, and determining optimal dosing regimens to guide clinical studies. Administration of ridaforolimus to tumor cells in vitro elicited dose-dependent inhibition of mTOR activity with concomitant effects on cell growth and division. We showed that ridaforolimus exhibits a predominantly cytostatic mode of action, consistent with the findings for other mTOR inhibitors. Potent inhibitory effects on vascular endothelial growth factor secretion, endothelial cell growth, and glucose metabolism were also observed. Although PTEN and/or phosphorylated AKT status have been proposed as potential mTOR pathway biomarkers, neither was predictive for ridaforolimus responsiveness in the heterogeneous panel of cancer cell lines examined. In mouse models, robust antitumor activity was observed in human tumor xenografts using a series of intermittent dosing schedules, consistent with pharmacodynamic observations of mTOR pathway inhibition for at least 72 hours following dosing. Parallel skin-graft rejection studies established that intermittent dosing schedules lack the immunosuppressive effects seen with daily dosing. Overall these findings show the broad inhibitory effects of ridaforolimus on cell growth, division, metabolism, and angiogenesis, and support the use of intermittent dosing as a means to optimize antitumor activity while minimizing systemic effects. Mol Cancer Ther; 10(6); 1059–71. ©2011 AACR.