Input: Gene expression of PPARs in tissues was analyzed by real-time reverse transcriptase polymerase chain reaction.


Input: Gestational diet (GD) did not affect PPARs gene expression in offspring at either birth or weaning.


Input: In liver, at 14 weeks postweaning, PPAR-gamma was 30% lower in the HV-RV and 30% higher in HV-Ob than in the RV-RV group [GD P =. 76, postweaning diet (PD) P =. 19, interaction P =. 02, by two-way analysis of variance].


Input: In muscle, PPAR-alpha expression was affected by GD and PD (GD P =. 05, PD P <. 01, interaction P =. 07).


Input: In adipose tissue, PPAR-alpha expression was higher in all groups compared to RV-RV (GD P =. 25, PD P =. 85, interaction P =. 03).


Input: PPAR-gamma mRNA levels correlated with abdominal fat (r = 0. 45, P <. 05) and insulin resistance index (r = 0. 39, P <. 05).


Input: In liver, PPAR-gamma expression correlated with insulin resistance index in offspring from RV (r =-0. 62, P <. 05), but not in those from HV dams (r = 0. 13, P >. 05).


Input: In conclusion, the HV diet during pregnancy interacts with postweaning diets in determining the expression of PPARs genes in a tissue-and age-dependent manner and uncouples the relationship between these genes and glucose regulation and fat mass in the rat offspring.

glucose


Input: CCAAT/Enhancer-binding protein-homologous protein sensitizes to SU5416 by modulating p21 and PI3K/Akt signal pathway in FRO anaplastic thyroid carcinoma cells.


Input: SU5416, vascular endothelial cell growth factor receptor inhibitor, suppresses hypoxia-induced angiogenesis, growth, proliferation, and metastasis in cancer cells.


Input: CCAAT/enhancer-binding protein-homologous protein (CHOP) has pivotal roles in regulation of growth and survival.


Input: In the present study, we evaluated the effects of SU5416 on cell survival, p21, and PI3K/Akt signal pathway in FRO anaplastic thyroid carcinoma (ATC) cells.


Input: Moreover, we investigated the roles of CHOP in cell survival under condition of SU5416 treatment in FRO ATC cells.


Input: After SU5416 treatment, cell viability, PARP-1, and caspase-3 protein levels were not changed.


Input: p53 and p27 protein levels decreased while p21 protein levels increased.


Input: Phospho-Akt protein levels were not altered.

Phospho


Input: In SU5416-treated situation, cell viability was not different before and after administration of either p21 siRNA or LY294002 whereas it was lessened after co-administration of p21 siRNA and LY294002.


Input: Compared to SU5416 treatment alone, cell viability was reduced with CHOP plasmid but it was unchanged with CHOP siRNA.


Input: PARP-1 and caspase-3 protein levels with CHOP plasmid were elevated whereas the protein levels with CHOP siRNA were similar.


Input: While CHOP plasmid transfection diminished p21 and phospho-Akt protein levels, CHOP siRNA transfection did not alter the protein levels.

phospho


Input: In conclusion, these results suggest that CHOP may sensitize FRO ATC cells to SU5416 thereby inhibiting cell survival by modulating p21 and PI3K/Akt signal pathway.


Input: Furthermore, these findings imply that CHOP may be a possible candidate as the chemosensitizing factor for induction of cytotoxicity in ATC cells exposed to SU5416.


Input: Functional phenotype of airway myocytes from asthmatic airways.


Input: In asthma, the airway smooth muscle (ASM) cell plays a central role in disease pathogenesis through cellular changes which may impact on its microenvironment and alter ASM response and function.


Input: The answer to the long debated question of what makes a' healthy' ASM cell become' asthmatic' still remains speculative.


Input: What is known of an' asthmatic' ASM cell, is its ability to contribute to the hallmarks of asthma such as bronchoconstriction (contractile phenotype), inflammation (synthetic phenotype) and ASM hyperplasia (proliferative phenotype).


Input: The phenotype of healthy or diseased ASM cells or tissue for the most part is determined by expression of key phenotypic markers.


Input: ASM is commonly accepted to have different phenotypes: the contractile (differentiated) state versus the synthetic (dedifferentiated) state (with the capacity to synthesize mediators, proliferate and migrate).


Input: There is now accumulating evidence that the synthetic functions of ASM in culture derived from asthmatic and non-asthmatic donors differ.


Input: Some of these differences include an altered profile and increased production of extracellular matrix proteins, pro-inflammatory mediators and adhesion receptors, collectively suggesting that ASM cells from asthmatic subjects have the capacity to alter their environment, actively participate in repair processes and functionally respond to changes in their microenvironment.


Input: Lead-induced ER calcium release and inhibitory effects of methionine choline in cultured rat hippocampal neurons.

calcium

methionine choline


Input: Lead, a ubiquitous neurotoxicant, can result in learning and memory dysfunction.


Input: Long term potentiation in the hippocampus, a potential neural substrate for learning and memory, is thought to be linked to calcium-triggered intracellular events.

calcium


Input: In this study, laser scanning confocal microscopy was used to examine the effects of Pb (2 +) on intracellular and endoplasmic reticulum free calcium concentration ([Ca (2 +)] (i) and [Ca (2 +)] (ER)) in cultured neonatal rat hippocampal neurons and their possible antagonism by methionine choline; understanding these effects would help explain the lead-induced cognitive and learning dysfunction and explore efficient safety and relief strategies.

Pb (2 +)

calcium

Ca (2 +)

Ca (2 +)

methionine choline


Input: The results showed that Pb (2 +) increased [Ca (2 +)] (i) and decreased [Ca (2 +)] (ER) linearly in a time-and concentration-dependant manner, and Pb (2 +) addition after the applying of a ryanodine receptor (RyR) antagonist and an inositol-1, 4, 5-triphosphate receptor (IP (3) R) antagonist did not increase [Ca (2 +)] (i).

Pb (2 +)

Ca (2 +)

Ca (2 +)

Pb (2 +)

ryanodine

inositol-1, 4, 5-triphosphate

Ca (2 +)


Input: The addition of 10, 20, or 40 mmol/L methionine choline simultaneously with addition of 10 mu mol/L Pb (2 +) decreased [Ca (2 +)] (i) in Ca (2 +)-free culture medium by 39. 0%, 66. 0%, and 61. 6%, respectively, in a concentration-dependant manner in a certain dose range.

methionine choline

Pb (2 +)

Ca (2 +)

Ca (2 +)


Input: Our results suggest that Pb (2 +) induces ER calcium release to increase the resting [Ca (2 +)] (i); and methionine choline inhibit this increase in [Ca (2 +)] (i).

Pb (2 +)

calcium

Ca (2 +)

methionine choline

Ca (2 +)


Input: Interactions between bufadienolides derived from toad venom and verapamil in langendorff-perfused guinea-pig hearts.

bufadienolides

verapamil


Input: Drug toxicity may occur due to dangerous drug combination.


Input: We aimed to investigate the influence of verapamil (a P-gp inhibitor)--bufadienolides interaction on cardiotoxicity and bufadienolide uptake by the isolated heart.

verapamil

bufadienolides

bufadienolide


Input: The study was performed in Langendorff isolated perfused guinea-pig hearts by bufadienolides infusion in the absence and presence of verapamil (250, 500ng/ml).

bufadienolides

verapamil


Input: Arrhythmia parameters were evaluated by ECG and the content of bufadienolides in heart were measured by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS).

bufadienolides


Input: In the present of verapamil, the wide QRS duration and lightly rapid heart rate (HR) were markedly reduced in the early stage of bufadienolide intoxication.

verapamil

bufadienolide


Input: However, the ECG changes characterized by prolonged P-R interval, and slow heart rate and low QRS amplitude in the late stage of bufadienolide intoxication were significantly enhanced.

bufadienolide


Input: Furthermore, the contents of a variety of bufadienolide compounds in the verapamil + bufadienolide group were significantly higher when cardiac arrest occurred.

bufadienolide

verapamil

bufadienolide


Input: Although verapamil reduced the bufadienolide-induced ventricular arrhythmias, verapamil worsened heart block and lethal bradycardia of bufadienolides partly via increasing the uptake of bufadienolides in heart tissue, which could compromise the protective effects of verapamil against bufadienolide intoxication.

verapamil

bufadienolide

verapamil

bufadienolides

bufadienolides

verapamil

bufadienolide


Input: These results suggested that the verapamil may produce dangerous interactions with drugs containing bufadienolides.

verapamil

bufadienolides


Input: Synthesis of NaP zeolite at room temperature and short crystallization time by sonochemical method.

NaP zeolite


Input: NaP zeolite nano crystals were synthesized by sonochemical method at room temperature with crystallization time of 3h.

NaP zeolite


Input: For comparison, to insure the effect of sonochemical method, the hydrothermal method at conventional synthesis condition, with same initial sol composition was studied.


Input: NaP zeolites are directly formed by ultrasonic treatment without the application of autogenous pressure and also hydrothermal treatment.

NaP zeolites


Input: The effect of ultrasonic energy and irradiation time showed that with increasing sonication energy, the crystallinity of the powders decreased but phase purity remain unchanged.


Input: The synthesized powders were characterized by XRD, IR, DTA TGA, FESEM, and TEM analysis.


Input: FESEM images revealed that 50 nm zeolite crystals were formed at room temperature by using sonochemical method.


Input: However, agglomerated particles having cactus/cabbage like structure was obtained by sonochemical method followed by hydrothermal treatment.


Input: In sonochemical process, formation of cavitation and the collapsing of bubbles produced huge energy which is sufficient for crystallization of zeolite compared to that supplied by hydrothermal process for conventional synthesis.


Input: With increasing irradiation energy and time, the crystallinity of the synthesized zeolite samples increased slightly.


Input: The value of selected in vitro and in silico methods to predict acute oral toxicity in a regulatory context: Results from the European Project ACuteTox.


Input: ACuteTox is a project within the 6th European Framework Programme which had as one of its goals to develop, optimise and prevalidate a non-animal testing strategy for predicting human acute oral toxicity.


Input: In its last 6months, a challenging exercise was conducted to assess the predictive capacity of the developed testing strategies and final identification of the most promising ones.


Input: Thirty-two chemicals were tested blind in the battery of in vitro and in silico methods selected during the first phase of the project.


Input: This paper describes the classification approaches studied: single step procedures and two step tiered testing strategies.


Input: In summary, four in vitro testing strategies were proposed as best performing in terms of predictive capacity with respect to the European acute oral toxicity classification.


Input: In addition, a heuristic testing strategy is suggested that combines the prediction results gained from the neutral red uptake assay performed in 3T3 cells, with information on neurotoxicity alerts identified by the primary rat brain aggregates test method.


Input: Octanol-water partition coefficients and in silico prediction of intestinal absorption and blood-brain barrier passage are also considered.

Octanol


Input: This approach allows to reduce the number of chemicals wrongly predicted as not classified (LD50 > 2000mg/kg b. w.).


Input: Amino acid sequence of the ligand-binding domain of the aryl hydrocarbon receptor 1 predicts sensitivity of wild birds to effects of dioxin-like compounds.

Amino acid

aryl hydrocarbon

dioxin


Input: The sensitivity of avian species to the toxic effects of dioxin-like compounds (DLCs) varies up to 1000-fold among species, and this variability has been associated with interspecies differences in aryl hydrocarbon receptor 1 ligand-binding domain (AHR1 LBD) sequence.

dioxin

aryl hydrocarbon


Input: We previously showed that LD (50) values, based on in ovo exposures to DLCs, were significantly correlated with in vitro EC (50) values obtained with a luciferase reporter gene (LRG) assay that measures AHR1-mediated induction of cytochrome P4501A in COS-7 cells transfected with avian AHR1 constructs.


Input: Those findings suggest that the AHR1 LBD sequence and the LRG assay can be used to predict avian species sensitivity to DLCs.


Input: In the present study, the AHR1 LBD sequences of 86 avian species were studied, and differences at amino acid sites 256, 257, 297, 324, 337, and 380 were identified.

amino acid


Input: Site-directed mutagenesis, the LRG assay, and homology modeling highlighted the importance of each amino acid site in AHR1 sensitivity to 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin and other DLCs.

amino acid

2, 3, 7, 8-tetrachlorodibenzo-p-dioxin


Input: The results of the study revealed that (1) only amino acids at sites 324 and 380 affect the sensitivity of AHR1 expression constructs of the 86 avian species to DLCs and (2) in vitro luciferase activity of AHR1 constructs containing only the LBD of the species of interest is significantly correlated (r (2) = 0. 93, p < 0. 0001) with in ovo toxicity data for those species.

amino acids


Input: These results indicate promise for the use of AHR1 LBD amino acid sequences independently, or combined with the LRG assay, to predict avian species sensitivity to DLCs.

amino acid


Input: Acid-induced gelation behavior of soybean protein isolate with high intensity ultrasonic pre-treatments.


Input: High intensity ultrasonic (HUS, 20 kHz, 400 W) pre-treatments of soybean protein isolate (SPI) improved the water holding capacity (WHC), gel strength and gel firmness (final elastic moduli) of glucono-delta-lactone induced SPI gels (GISG).

glucono-delta-lactone


Input: Sonication time (0, 5, 20, and 40 min) had a significant effect on the above three properties.


Input: 20 min HUS-GISG had the highest WHC (95. 53 +/- 0. 25%), gel strength (60. 90 +/- 2. 87 g) and gel firmness (96340Pa), compared with other samples.


Input: Moreover, SH groups and non-covalent interactions of GISG also changed after HUS pre-treatments.

SH


Input: The HUS GISG had denser and more uniform microstructures than the untreated GISG.


Input: Rheological investments showed that the cooling step (reduce the temperature from 95 to 25 degrees C at a speed of 2 degrees C/min) was more important for the HUS GISG network formation while the heat preservation step (keep temperature at 95 for 20 min) was more important for the untreated GISG.


Input: HUS reduced the particle size of SPI and Pearson correlation test showed that the particle size of SPI dispersions was negatively correlated with WHC, gel strength and gel firmness.


Input: Proteomic allergen-peptide/protein interaction assay for the identification of human skin sensitizers.


Input: Modification of proteins by skin sensitizers is a pivotal step in T cell mediated allergic contact dermatitis (ACD).


Input: In this process small reactive chemicals interact covalently or non-covalently with cellular or extracellular skin self-proteins or self-peptides to become recognized by the human immune system.


Input: Aiming to develop a novel non-animal in vitro test system for predicting sensitization potential of small reactive chemicals in human skin the allergen-peptide/protein interaction assay (APIA) has been developed.


Input: By applying modern proteomic technologies together with a target peptide containing all amino acids, the assay permits the profiling of all amino acid specific allergen-peptide interactions.

amino acids

amino acid


Input: Moreover, potentially crucial allergen-specific Cys-modifications are qualitatively monitored by mass spectrometry and confirmed by a dual peptide approach.

Cys


Input: Assay conditions chosen mimic the distinct human epidermal reactivity compartments of the skin surface (pH 5. 5), stratum basale (pH 6. 8), and typical physiological conditions (pH 7. 4).


Input: An extreme as well as a moderate human contact sensitizer produced Cys-specific mass shifts, whereas a skin irritant did not.

Cys


Input: Our data indicate that MALDI-MS based and skin-related in vitro technology platforms-like the APIA-are promising tools in developing alternative non-animal allergen assays.


Input: This will assist in chemical classification and next generation risk assessment strategies, including REACH and experimental immunotoxicology.


Input: An overview of transcriptional regulation in response to toxicological insult.


Input: The completion of the human genome project and the subsequent advent of DNA microarray and high-throughput sequencing technologies have led to a renaissance in molecular toxicology.


Input: Toxicogenomic data sets, from both in vivo and in vitro studies, are growing exponentially, providing a wealth of information on regulation of stress pathways at the transcriptome level.


Input: Through such studies, we are now beginning to appreciate the diversity and complexity of biological responses to xenobiotics.


Input: In this review, we aim to consolidate and summarise the major toxicologically relevant transcription factor-governed molecular pathways.


Input: It is becoming clear that different chemical entities can cause oxidative, genotoxic and proteotoxic stress, which induce cellular responses in an effort to restore homoeostasis.


Input: Primary among the response pathways involved are NFE2L2 (Nrf2), NFE2L1 (Nrf1), p53, heat shock factor and the unfolded protein response.


Input: Additionally, more specific mechanisms exist where xenobiotics act as ligands, including the aryl hydrocarbon receptor, metal-responsive transcription factor-1 and the nuclear receptor family of transcription factors.

aryl hydrocarbon


Input: Other pathways including the immunomodulatory transcription factors NF-kappa B and STAT together with the hypoxia-inducible transcription factor HIF are also implicated in cellular responses to xenobiotic exposure.


Input: A less specific but equally important aspect to cellular injury controlled by transcriptional activity is loss of tissue-specific gene expression, resulting in dedifferentiation of target cells and compromise of tissue function.


Input: Here, we review these pathways and the genes they regulate in order to provide an overview of this growing field of molecular toxicology.


Input: Creaming enhancement in a liter scale ultrasonic reactor at selected transducer configurations and frequencies.


Input: Recent research has shown that high frequency ultrasound (0. 4-3 MHz), can enhance milkfat separation in small scale systems able to treat only a few milliliters of sample.


Input: In this work, the effect of ultrasonic standing waves on milkfat creaming was studied in a 6L reactor and the influence of different frequencies and transducer configurations in direct contact with the fluid was investigated.


Input: A recombined coarse milk emulsion with fat globules stained with oil-red-O dye was selected for the separation trials.

oil-red-O


Input: Runs were performed with one or two transducers placed in vertical (parallel or perpendicular) and horizontal positions (at the reactor base) at 0. 4, 1 and/or 2 MHz (specific energy 8. 5 +/- 0. 6 kJ/kg per transducer).


Input: Creaming behavior was assessed by measuring the thickness of the separated cream layer.


Input: Other methods supporting this assessment included the measurement of fat content, backscattering, particle size distribution, and microscopy of samples taken at the bottom and top of the reactor.


Input: Most efficient creaming was found after treatment at 0. 4 MHz in single and double vertical transducer configurations.


Input: Among these configurations, a higher separation rate was obtained when sonicating at 0. 4 MHz in a vertical perpendicular double transducer setup.


Input: The horizontal transducer configuration promoted creaming at 2 MHz only.


Input: Fat globule size increase was observed when creaming occurred.


Input: This research highlights the potential for enhanced separation of milkfat in larger scale systems from selected transducer configurations in contact with a dairy emulsion, or emulsion splitting in general.


Input: Variations in the nature of behavioral experience can differentially alter the consequences of developmental exposures to lead, prenatal stress, and the combination.


Input: Behavioral experience (BE) can critically influence later behavior and brain function, but the central nervous system (CNS) consequences of most developmental neurotoxicants are examined in the absence of any such context.


Input: We previously demonstrated marked differences in neurotransmitter changes produced by developmental lead (Pb) exposure +/- prenatal stress (PS) depending upon whether or not rats had been given BE (Cory-Slechta, D.

Pb


Input: A., Virgolini, M.


Input: B., Rossi-George, A., Weston, D., and Thiruchelvam, M.


Input: The current study examined the hypothesis that the nature of the BE itself would be a critical determinant of outcome in mice that had been continually exposed to 0 or 100 ppm Pb acetate in drinking water alone or in combination with prenatal restraint stress.

Pb acetate


Input: Half of the offspring in each of the four resulting groups/gender were exposed to positively reinforced (food-rewarded Fixed Interval schedule-controlled behavior) or negatively reinforced (inescapable forced swim) BE.


Input: Brain monoamines and amino acids differed significantly in relation to BE, even in control animals, as did the trajectory of effects of Pb +/- PS, particularly in frontal cortex, hippocampus (both genders), and midbrain (males).

monoamines

amino acids

Pb


Input: In males, Pb +/- PS-related changes in neurotransmitters correlated with behavioral performance.

Pb


Input: These findings suggest that CNS consequences of developmental toxicants studied in the absence of a broader spectrum of BEs may not necessarily be predictive of human outcomes.


Input: Evaluating the role of specific BEs as a modulator of neurodevelopmental insults offers the opportunity to determine what specific BEs may ameliorate the associated impacts and can assist in establishing underlying neurobiological mechanisms.


Input: alpha-Amino-alpha'-Halomethylketones: Synthetic Methodologies and Pharmaceutical Applications as Serine and Cysteine Protease Inhibitors.

alpha-Amino-alpha'-Halomethylketones

Serine

Cysteine


Input: alpha-Amino-alpha'-halomethylketones are interesting scaffolds bearing (at least) two sequential electrophilic carbons that by interacting with the nucleophilic moieties of several enzymes, represent the ideal candidates for in vivo and in vitro inhibition studies.

alpha-Amino-alpha'-halomethylketones

carbons


Input: In this work a summary of their use as optimal inhibitors of physiologically relevant serine and cysteine proteases is given with a particular emphasis on recently established SAR studies.

serine

cysteine


Input: A brief survey of the most relevant synthetic processes for their obtainment and the importance they possess in synthetic medicinal chemistry is reported.


Input: Cholinergic modulation by opioid receptor ligands: potential application to Alzheimer' s disease.


Input: Morphinans have a storied history in medicinal chemistry as pain management drugs but have received attention as modulators of cholinergic signaling for the treatment of Alzheimer' s Disease (AD).

Morphinans


Input: Galantamine is a reversible, competitive acetylcholinesterase (AChE) inhibitor and allosteric potentiating ligand of nicotinic acetylcholine receptors (nAChR-APL) that shares many common structural elements with morphinan-based opioids.

Galantamine

acetylcholinesterase

morphinan


Input: The structurally diverse opioids codeine and eseroline, like galantamine, are also nAChR-APL that have greatly diminished affinity for AChE, representing potential lead compounds for selective nAChR-APL development.

codeine

eseroline

galantamine


Input: In accordance with the emerging repurposing trend of evaluating known compounds for novel pharmacological activity, ongoing research on augmentation of cholinergic signaling that has been aided by the use of opioids will be reviewed.


Input: Adhesion of osteoblasts to a vertically aligned TiO2 nanotube surface.


Input: The adhesion of cells to vertically aligned TiO2 nanotubes is reviewed.


Input: The attraction between a negatively charged nanotube surface and a negatively charged osteoblast is facilitated by charged protein-mediators like proteins with a quadrupolar internal charge distribution, fibronectin and vitronectin.


Input: It is shown that adhesion and spreading of osteoblasts on vertically aligned TiO2 nanotube surfaces depend on the diameter of the nanotubes.


Input: Apparently, a small diameter nanotube surface has on average more sharp convex edges per unit area than a large one, leading to stronger binding affinity on its surface.


Input: Manganese-enhanced magnetic resonance imaging detects declining pancreatic beta-cell mass in a cyclophosphamide-accelerated mouse model of type 1 diabetes.

Manganese

cyclophosphamide


Input: Currently, there is no ideal noninvasive method to quantify the progressive loss of pancreatic beta-cell mass (BCM) that occurs in type 1 diabetes.


Input: Magnetic resonance imaging has detected gross differences in BCM between healthy and diabetic mice using the contrast agent manganese, which labels functional beta-cells and increases the water proton relaxation rate (R1), but its ability to measure gradations in BCM during disease progression is unknown.

manganese


Input: Our objective was to test the hypothesis that measurements of the manganese-enhanced pancreatic R1 could detect decreasing BCM in a mouse model of type 1 diabetes.

manganese


Input: We used cyclophosphamide-accelerated BDC2. 5 T-cell receptor transgenic nonobese diabetic mice, which experience development of type 1 diabetes during a 7-day time period after cyclophosphamide injection, whereas transgene-negative mice do not.

cyclophosphamide

cyclophosphamide


Input: We measured the manganese-enhanced pancreatic R1 before cyclophosphamide injection (day 0) and on days 3, 4, 5, and 7 afterward.

manganese

cyclophosphamide


Input: Pancreatic R1 remained constant in transgene-negative mice and decreased stepwise day-to-day in transgene-positive mice, mirroring their loss of BCM, confirmed by pancreatic insulin measurements and histology.


Input: Changes in R1 in transgene-positive mice occurred before elevations in blood glucose, a clinical indicator of diabetes, suggesting potential for early noninvasive detection of changes in functional BCM.

glucose


Input: Bcl-2 and Bcl-xL suppress glucose signaling in pancreatic beta-cells.

glucose


Input: B-cell lymphoma 2 (Bcl-2) family proteins are established regulators of cell survival, but their involvement in the normal function of primary cells has only recently begun to receive attention.


Input: In this study, we demonstrate that chemical and genetic loss-of-function of antiapoptotic Bcl-2 and Bcl-x (L) significantly augments glucose-dependent metabolic and Ca (2 +) signals in primary pancreatic beta-cells.

glucose

Ca (2 +)


Input: Antagonism of Bcl-2/Bcl-x (L) by two distinct small-molecule compounds rapidly hyperpolarized beta-cell mitochondria, increased cytosolic Ca (2 +), and stimulated insulin release via the ATP-dependent pathway in beta-cell under substimulatory glucose conditions.

Ca (2 +)

ATP

glucose


Input: Experiments with single and double Bax-Bak knockout beta-cells established that this occurred independently of these proapoptotic binding partners.


Input: Pancreatic beta-cells from Bcl-2 (-/-) mice responded to glucose with significantly increased NAD (P) H levels and cytosolic Ca (2 +) signals, as well as significantly augmented insulin secretion.

glucose

NAD (P) H

Ca (2 +)


Input: Inducible deletion of Bcl-x (L) in adult mouse beta-cells also increased glucose-stimulated NAD (P) H and Ca (2 +) responses and resulted in an improvement of in vivo glucose tolerance in the conditional Bcl-x (L) knockout animals.

glucose

NAD (P) H

Ca (2 +)

glucose


Input: Our work suggests that prosurvival Bcl proteins normally dampen the beta-cell response to glucose and thus reveals these core apoptosis proteins as integrators of cell death and physiology in pancreatic beta-cells.

glucose


Input: Dual-responsive nanoparticles and their self-assembly.


Input: Dual-responsive nanoparticles are designed by functionalizing magnetic cores with light-responsive ligands.


Input: These materials respond to both light and magnetic fields and can be assembled into various higher-order structures, depending on the relative contributions of these two stimuli.


Input: Pharmacokinetics, pharmacodynamics and clinical use of valganciclovir in newborns with symptomatic congenital cytomegalovirus infection.

valganciclovir


Input: Congenital cytomegalovirus infection is the most common cause of nonhereditary sensorineural hearing loss and an important cause of psychomotor retardation.


Input: Newborns suffering from symptomatic congenital cytomegalovirus infection have been typically treated with i. v. ganciclovir (GCV).

ganciclovir

GCV


Input: Nowadays valganciclovir (V-GCV), a mono-valyl ester pro-drug of GCV, is available as an oral syrup.

valganciclovir

V-GCV

mono-valyl ester

GCV


Input: The existing literature demonstrated that V-GCV is well absorbed from the gastrointestinal tract and is rapidly converted into GCV in the intestinal wall and liver.

V-GCV

GCV


Input: The mechanism of antiviral action is the same that has been described for GCV.

GCV


Input: All these characteristics make this formulation particularly suitable for the symptomatic congenitally infected newborns.


Input: In neonates, V-GCV oral formulation proved stable and constant GVC plasma concentrations, in the suggested therapeutic range.

V-GCV


Input: The syrup demonstrated to be clinically effective and well tolerated and to be appropriate for a prolonged post-discharge therapy avoiding the discomfort of hospitalization, reducing the risk for nosocomial infections and decreasing the cost for the National Health Service.


Input: This article reviews all the available literature about V-GCV syrup in the treatment of newborns and infants with congenital CMV infection with the regard to pharmacokinetics, pharmacodynamic properties and clinical use, focussing on new data and on our experience.

V-GCV


Input: Noncanonical control of C. elegans germline apoptosis by the insulin/IGF-1 and Ras/MAPK signaling pathways.


Input: The insulin/IGF-1 pathway controls a number of physiological processes in the nematode worm Caenorhabditis elegans, including development, aging and stress response.


Input: We previously found that the Akt/PKB ortholog AKT-1 dampens the apoptotic response to genotoxic stress in the germline by negatively regulating the p53-like transcription factor CEP-1.


Input: Here, we report unexpected rearrangements to the insulin/IGF-1 pathway, whereby the insulin-like receptor DAF-2 and 3-phosphoinositide-dependent protein kinase PDK-1 oppose AKT-1 to promote DNA damage-induced apoptosis.

phosphoinositide


Input: While DNA damage does not affect phosphorylation at the PDK-1 site Thr350/Thr308 of AKT-1, it increased phosphorylation at Ser517/Ser473.


Input: Although ablation of daf-2 or pdk-1 completely suppressed akt-1-dependent apoptosis, the transcriptional activation of CEP-1 was unaffected, suggesting that daf-2 and pdk-1 act independently or downstream of cep-1 and akt-1.


Input: Ablation of the akt-1 paralog akt-2 or the downstream target of the insulin/IGF-1 pathway daf-16 (a FOXO transcription factor) restored sensitivity to damage-induced apoptosis in daf-2 and pdk-1 mutants.


Input: In addition, daf-2 and pdk-1 mutants have reduced levels of phospho-MPK-1/ERK in their germ cells, indicating that the insulin/IGF-1 pathway promotes Ras signaling in the germline.

phospho


Input: Ablation of the Ras effector gla-3, a negative regulator of mpk-1, restored sensitivity to apoptosis in daf-2 mutants, suggesting that gla-3 acts downstream of daf-2.


Input: In addition, the hypersensitivity of let-60/Ras gain-of-function mutants to damage-induced apoptosis was suppressed to wild-type levels by ablation of daf-2.


Input: Thus, insulin/IGF-1 signaling selectively engages AKT-2/DAF-16 to promote DNA damage-induced germ cell apoptosis downstream of CEP-1 through the Ras pathway.


Input: Inactivation of anoctamin-6/Tmem16f, a regulator of phosphatidylserine scrambling in osteoblasts, leads to decreased mineral deposition in skeletal tissues.

phosphatidylserine


Input: During vertebrate skeletal development, osteoblasts produce a mineralized bone matrix by deposition of hydroxyapatite crystals in the extracellular matrix.

hydroxyapatite


Input: Anoctamin6/Tmem16F (Ano6) belongs to a conserved family of transmembrane proteins with chloride channel properties.

chloride


Input: In addition, Ano6 has been linked to phosphatidylserine (PS) scrambling in the plasma membrane.

phosphatidylserine


Input: During skeletogenesis, Ano6 mRNA is expressed in differentiating and mature osteoblasts.


Input: Deletion of Ano6 in mice results in reduced skeleton size and skeletal deformities.


Input: Molecular analysis revealed that chondrocyte and osteoblast differentiation are not disturbed.


Input: However, mutant mice display increased regions of nonmineralized, Ibsp-expressing osteoblasts in the periosteum during embryonic development and increased areas of uncalcified osteoid postnatally.


Input: In primary Ano6 (-/-) osteoblasts, mineralization is delayed, indicating a cell autonomous function of Ano6.


Input: Furthermore, we demonstrate that calcium-dependent PS scrambling is impaired in osteoblasts.

calcium


Input: Our study is the first to our knowledge to reveal the requirement of Ano6 in PS scrambling in osteoblasts, supporting a function of PS exposure in the deposition of hydroxyapatite.

hydroxyapatite


Input: Fragrance chemicals lyral and lilial decrease viability of HaCat cells' by increasing free radical production and lowering intracellular ATP level: protection by antioxidants.

lyral

lilial

ATP


Input: We investigate in this study the biochemical effects on cells in culture of two commonly used fragrance chemicals: lyral and lilial.

lyral

lilial


Input: Whereas both chemicals exerted a significant effect on primary keratinocyte (s), HaCat cells, no effect was obtained with any of HepG2, Hek293, Caco2, NIH3T3, and MCF7 cells.


Input: Lyral and lilial: (a) decreased the viability of HaCat cells with a 50% cell death at 100 and 60 nM respectively; (b) decreased significantly in a dose dependant manner the intracellular ATP level following 12-h of treatment; (c) inhibited complexes I and II of electron transport chain in liver sub-mitochondrial particles; and (d) increased reactive oxygen species generation that was reversed by N-acetyl cysteine and trolox and the natural antioxidant lipoic acid, without influencing the level of free and/or oxidized glutathione.

Lyral

lilial

ATP

oxygen

N-acetyl cysteine

trolox

lipoic acid

glutathione


Input: Lipoic acid protected HaCat cells against the decrease in viability induced by either compound.

Lipoic acid


Input: Dehydrogenation of lyral and lilial produce alpha, beta-unsaturated aldehydes, that reacts with lipoic acid requiring proteins resulting in their inhibition.

lyral

lilial

alpha, beta-unsaturated aldehydes

lipoic acid


Input: We propose lyral and lilial as toxic to mitochondria that have a direct effect on electron transport chain, increase ROS production, derange mitochondrial membrane potential, and decrease cellular ATP level, leading thus to cell death.

lyral

lilial

ATP


Input: Silver nanoparticles induce toxicity in A549 cells via ROS-dependent and ROS-independent pathways.

Silver


Input: Silver nanoparticles (AgNPs) are incorporated into a large number of consumer and medical products.

Silver


Input: Several experiments have demonstrated that AgNPs can be toxic to the vital organs of humans and especially to the lung.


Input: The present study evaluated the in vitro mechanisms of AgNP (< 100 nm) toxicity in relationship to the generation of reactive oxygen species (ROS) in A549 cells.

oxygen


Input: AgNPs caused ROS formation in the cells, a reduction in their cell viability and mitochondrial membrane potential (MMP), an increase in the proportion of cells in the sub-G1 (apoptosis) population, S phase arrest and down-regulation of the cell cycle associated proliferating cell nuclear antigen (PCNA) protein, in a concentration-and time-dependent manner.


Input: Pretreatment of the A549 cells with N-acetyl-cysteine (NAC), an antioxidant, decreased the effects of AgNPs on the reduced cell viability, change in the MMP and proportion of cells in the sub-G1population, but had no effect on the AgNP-mediated S phase arrest or down-regulation of PCNA.

N-acetyl-cysteine

NAC


Input: These observations allow us to propose that the in vitro toxic effects of AgNPs on A549 cells are mediated via both ROS-dependent (cytotoxicity) and ROS-independent (cell cycle arrest) pathways.


Input: In silico structural and functional analysis of the human TOPK protein by structure modeling and molecular dynamics studies.


Input: Over expression of T-lymphokine-activated killer cell-originated protein kinase (TOPK) has been associated with leukemia, myeloma tumors and various other cancers.


Input: The function and regulatory mechanism of TOPK in tumor cells remains unclear.


Input: Structural studies that could reveal the regulatory mechanism have been a challenge because of the unavailabity of TOPK' s crystal structure.


Input: Hence, in this study, the 3D structure of TOPK protein has been constructed by using multiple templates.


Input: The quality and reliability of the generated model was checked and the molecular dynamics method was utilized to refine the model.


Input: APBS method was employed to know the electrostatic potential surface of the modeled protein and it was found that the optimum pH for protein stability is 3. 4 which will further help in mechanistic hypothesis of TOPK protein.


Input: Active site of TOPK was identified from available literature and HTVS was employed to identify the lead molecules.


Input: The expected binding modes of protein-ligand complexes were reproduced in the MD simulation which indicates that the complex is relatively stable.


Input: The pharmacokinetic properties of the lead molecules are also under acceptable range.


Input: TOPK act as a substrate for CDK1 and the protein-protein docking and dynamics studies were carried out to analyze the effect of Thr9Ala mutation of TOPK in the two protein complex formation.


Input: It shows that the wild type complex is more stable when compared with the mutant type.


Input: Such structural information at atomic level not only exhibits the action modes of TOPK inhibitors but also furnishes a novel starting point for structure based drug design of TOPK inhibitors.


Input: Low calorie and carbohydrate diet: to improve the cardiovascular risk indicators in overweight or obese adults with prediabetes.

carbohydrate


Input: Our objective was to evaluate the effects of a moderate calorie and carbohydrate-restricted diet on cardiovascular risk indicators in overweight or obese patients with prediabetes.

carbohydrate


Input: A clinical trial was conducted in which 86 subjects presenting with overweight or obesity and prediabetes received a personalized diet of 1, 200 to 1, 700 calories with a distribution of 50% carbohydrates, 20% proteins, and 30% fat.

carbohydrates


Input: Body weight, fat mass, and lean mass were measured through bioimpedance.


Input: Glucose, total cholesterol, high density lipoprotein cholesterol and low density cholesterol, and triglycerides were measured.

Glucose

cholesterol

cholesterol

cholesterol

triglycerides


Input: The measurements were taken at the beginning of, and at, 6 and 12 months during the intervention, and the differences were compared by paired Student' s t and chi (2) tests.


Input: At 12 months, a significant reduction was noticed in body weight in patients with overweight and obesity (72. 4 +/- 7. 8-69. 6 +/- 7. 5 kg) (85. 7 +/- 14. 8-80. 2 +/- 12. 7 kg) with body mass index (28. 2 +/- 0. 8-27. 2 +/- 2. 1 kg/m (2)) (34. 3 +/- 3. 5-32. 1 +/- 3. 2 kg/m (2)), systolic (120. 9 +/- 14. 2-112. 4 +/- 11. 5 mmHg) (124. 1 +/- 11. 9-115. 7 +/- 14. 0 mmHg), diastolic blood pressures (79. 0 +/- 9. 3-71. 8 +/- 8. 3 mmHg) (80. 4 +/- 9. 0-73. 7 +/- 13. 1 mmHg), glucose (106. 0 +/- 8. 9-95. 9 +/- 7. 5 mg/dL) (107. 3 +/- 7. 0-97. 0 +/- 8. 2 mg/dL), and significant improvement on lipid profile (p < 0. 05).

glucose


Input: The restrictions in the calorie and carbohydrate diet decrease the cardiovascular risk indicators in overweight or obese adults with prediabetes.

carbohydrate


Input: Quantitation of UGT1A1 in human liver microsomes using stable isotope-labelled peptides and mass spectrometry based proteomic approaches.


Input: 1. UDP-glucuronosyltransferases (UGTs) are a group of drug-metabolizing enzymes that catalyse the conjugation of endogeonous compounds and xenobiotics to yield hydrophilic glucuronides which subsequently undergo excretion.

UDP


Input: This report describes an approach for the identification and accurate quantitation of human UGT1A1 in complex biological matrices using liquid chromatography/mass spectrometry/mass spectrometry (LC-MS/MS) analysis of protein digests.


Input: 2. A stable isotope-labelled (SIL) peptide of a unique peptide spanning residues 54-69 in exon 1 of the human UGT1A1 protein with the sequence RIYLSADPALVVIEHG was synthesized.


Input: The peptide sequence synthesized was in the reverse order of the human peptide with the stable isotope-labels in the amino acid arginine ((13) C6 (15) N4) resulting in an increase in the mass of the SIL peptide of 10 amu, from 1753 to 1763.

amino acid arginine

(13) C6 (15) N4


Input: The SIL peptide was quantitated by injecting increasing concentrations of the peptide into the LC-MS to obtain a standard curve.


Input: 3. The labelled peptide along with precursor ion monitoring was used to quantify the levels of UGT1A1 in commercial recombinant preparations (supersomes) and individual human liver microsomal samples and pooled human liver micrsomes obtained from BD Biosciences.


Input: 4. Glucuronidation activity studies were performed, which demonstrated a positive correlation between enzyme activity levels and the UGT1A1 content in the liver microsomes obtained from individual human donors.


Input: A dose response study to assess effects after dietary administration of diisononyl phthalate (DINP) in gestation and lactation on male rat sexual development.

diisononyl phthalate

DINP


Input: Male rat sexual development was evaluated after dietary administration of 0, 760, 3800, 11, 400 ppm diisononyl phthalate (DiNP) and 7600 ppm dibutyl phthalate (DBP) from gestation day (GD) 12 to postnatal day (PND) 14.

diisononyl phthalate

DiNP

dibutyl phthalate

DBP


Input: Maternal weight was reduced on GD 20, PND 2 and 14 at 11, 400 ppm DiNP.

DiNP


Input: Pup weight was reduced on PND 2 and 14 at 11, 400 and 3800 ppm DiNP.

DiNP


Input: DBP induced multinucleated germ cells (MNGs) and Leydig cell aggregates (LCAs) in PND 2 testes.

DBP


Input: 7600 ppm DBP reduced anogenital distance (AGD) on PND 2 and 14, and increased nipple retention and reproductive tract malformations on PND 49.

DBP


Input: DiNP induced MNGs (3800 ppm) and LCAs (11, 400 ppm) on PND 2, and reduced AGD (11, 400 ppm) on PND 14.

DiNP


Input: DiNP did not alter AGD, nipple retention or reproductive tract malformations on PND 49.

DiNP


Input: Global endpoint analysis showed no evidence of a rat " phthalate syndrome " on PND 49 with DiNP administration.

phthalate

DiNP


Input: Suppression of collagen Q expression in the extrajunctional regions of rat fast muscles is encoded in their stem cells (satellite cells).


Input: In rat fast muscles, collagen Q (ColQ) expression is restricted to the neuromuscular junctions.


Input: In contrast, it is high also extrajunctionally in the slow soleus muscles.


Input: Fast muscles activated by chronic low-frequency electrical stimulation, similar to neural activation of the soleus muscles, did not increase their extrajunctional expression of ColQ.


Input: We assumed that the myogenic stem cells (satellite cells) in fast and slow muscles were intrinsically different in regard to the capacity that they convey to their respective muscle fibers to increase the extrajunctional ColQ expression upon innervation.


Input: ColQ mRNA levels were determined by quantitative real-time PCR.


Input: Extensive neural suppression of the extrajunctional ColQ expression in regenerating fast muscles during maturation is a very slow process requiring 30-60days.


Input: If the immature regenerating fast EDL muscles were indirectly or directly electrically stimulated immediately after innervation by chronic low-frequency impulse pattern for 8days, no significant increase of the extrajunctional ColQ mRNA levels was observed in stimulated regenerates in comparison to non-stimulated ones.


Input: In contrast, the extrajunctional ColQ mRNA levels in the regenerates of the soleus muscles, trans-innervated by the EDL nerve at the time of muscle injury, increased 4-to 5-fold after 8days of the same chronic low-frequency electrical stimulation in comparison to those in the stimulated EDL regenerates.


Input: Since both fast and slow muscles completely regenerated only from their own myogenic stem cells and were innervated by the same nerve and later activated by the same tonic pattern of impulses, these results demonstrated that the mechanism causing incapacity of regenerating fast muscles to increase their extrajunctional ColQ expression upon tonic activation is encoded in their satellite cells, which in this respect differ from those in the slow muscles.


Input: Lithium treatment induces proteasomal degradation of over-expressed acetylcholinesterase (AChE-S) and inhibit GSK3 beta.

Lithium


Input: Lithium is one of the most widely used mood-stabilizing agents for the treatment of bipolar disorder.

Lithium


Input: Lithium is also a potent inhibitor of glycogen synthase kinase-3 beta (GSK3 beta) activity, which is linked to Alzheimer' s disease (AD).

Lithium


Input: In experiments with cultured HEK293T cells, we show here that GSK3 beta stabilizes synaptic acetylcholinesterase (AChE-S), a critical component of AD development.


Input: Cells treated with lithium exhibited rapid proteasomal degradation of AChE-S.

lithium


Input: Furthermore treatment of the cells with MG132, an inhibitor of the 26S proteasome, prevented the destabilizing effect of lithium on AChE-S.

lithium


Input: Taken together, these findings suggest that regulation of AChE-S protein stability may be an important biological target of lithium therapy.

lithium


Input: Toxicity of terpenes on fibroblast cells compared to their hemolytic potential and increase in erythrocyte membrane fluidity.

terpenes


Input: Terpenes are considered potent skin permeation enhancers with low toxicity.

Terpenes


Input: Electron paramagnetic resonance (EPR) spectroscopy of the spin label 5-doxyl stearic acid (5-DSA) was used to monitor the effect of sesquiterpene nerolidol and various monoterpenes on membrane fluidity in erythrocyte and fibroblast cells.

5-doxyl stearic acid

sesquiterpene nerolidol

monoterpenes


Input: In addition, the hemolytic levels and cytotoxic effects on cultured fibroblast cells were also measured to investigate possible relationships between the cellular irritation potentials of terpenes and the ability to modify membrane fluidity.

terpenes


Input: All terpenes increased cell membrane fluidity with no significant differences between the monoterpenes, but the effect of sesquiterpene was significantly greater than that of the monoterpenes.

terpenes

monoterpenes

sesquiterpene

monoterpenes


Input: The IC (50) values for the terpenes in the cytotoxicity assay indicated that 1, 8-cineole showed lower cytotoxicity and alpha-terpineol and nerolidol showed higher cytotoxicity.

terpenes

1, 8-cineole

alpha-terpineol

nerolidol


Input: The correlation between the hemolytic effect and the IC (50) values for fibroblast viability was low (R = 0. 61); however, in both tests, nerolidol was among the most aggressive of terpenes and 1, 8-cineole was among the least aggressive.

nerolidol

terpenes

1, 8-cineole


Input: Obtaining information concerning the toxicity and potency of terpenes could aid in the design of topical formulations optimized to facilitate drug absorption for the treatment of many skin diseases.

terpenes


Input: A probable clinically significant interaction between warfarin and cloxacillin: three case reports.

warfarin

cloxacillin


Input: CASES: Three patients were admitted to the Imam Hospital, Tehran, Iran with a diagnosis of bacterial endocarditis.


Input: The patients had indications for valve replacement surgery and anticoagulant therapy.


Input: The administration of cloxacillin reduced the effect of warfarin, and subsequent increases in warfarin doses were unable to overcome this effect.

cloxacillin

warfarin

warfarin


Input: CONCLUSION: A decrease in warfarin anticoagulation effects was detected in our three patients following cloxacillin therapy for infective endocarditis.

warfarin

cloxacillin


Input: Penicillinase-resistant penicillins remain essential antibiotics in the treatment of severe infections caused by Staphylococcus aureus due to their bactericidal activity, safety, and cost.

penicillins


Input: Thus, in situations where anticoagulants are indicated in patients with infective endocarditis, it would be better to replace warfarin with low-molecular-weight or unfractionated heparin.

warfarin


Input: Abnormal uterine bleeding and dysfunctional uterine bleeding in pediatric and adolescent gynecology.


Input: Abnormal uterine bleeding (AUB), which is defined as excessively heavy, prolonged and/or frequent bleeding of uterine origin, is a frequent cause of visits to the Emergency Department and/or health care provider.


Input: While there are many etiologies of AUB, the one most likely among otherwise healthy adolescents is dysfunctional uterine bleeding (DUB), which is characterizing any AUB when all possible underlying pathologic causes have been previously excluded.


Input: The most common cause of DUB in adolescence is anovulation, which is very frequent in the first 2-3 post-menarchal years and is associated with immaturity of the hypothalamic-pituitary-ovarian axis.


Input: Management of AUB is based on the underlying etiology and the severity of the bleeding and primary goals are prevention of complications, such as anemia and reestablishment of regular cyclical bleeding, while the management of DUB can in part be directed by the amount of flow, the degree of associated anemia, as well as patient and family comfort with different treatment modalities.


Input: Treatment options for DUB are: combined oral contraceptives (COCs), progestogens, non steroidal anti inflammatory drugs (NSAIDs), tranexamic acid (anti-fibrinolytic), GnRH analogues, Danazol and Levonorgestrel releasing intra uterine system (LNG IUS).

progestogens

tranexamic acid

GnRH

Danazol

Levonorgestrel


Input: An assessment of pure, hybrid, meta, and hybrid-meta GGA density functional theory methods for open-shell systems: the case of the nonheme iron enzyme 8R-LOX.

iron


Input: The performance of a range density functional theory functionals combined in a quantum mechanical (QM)/molecular mechanical (MM) approach was investigated in their ability to reliably provide geometries, electronic distributions, and relative energies of a multicentered open-shell mechanistic intermediate in the mechanism 8R-Lipoxygenase.


Input: With the use of large QM/MM active site chemical models, the smallest average differences in geometries between the catalytically relevant quartet and sextet complexes were obtained with the B3LYP (*) functional.


Input: Moreover, in the case of the relative energies between (4) II and (6) II, the use of the B3LYP (*) functional provided a difference of 0. 0 kcal mol (-1).


Input: However, B3LYP (+/-) and B3LYP also predicted differences in energies of less than 1 kcal mol (-1).


Input: In the case of describing the electronic distribution (i. e., spin density), the B3LYP (*), B3LYP, or M06-L functionals appeared to be the most suitable.


Input: Overall, the results obtained suggest that for systems with multiple centers having unpaired electrons, the B3LYP (*) appears most well rounded to provide reliable geometries, electronic structures, and relative energies.


Input: Design of a testing strategy using non-animal based test methods: Lessons learnt from the ACuteTox project.


Input: In the framework of toxicology, a testing strategy can be viewed as a series of steps which are taken to come to a final prediction about a characteristic of a compound under study.


Input: The testing strategy is performed as a single-step procedure, usually called a test battery, using simultaneously all information collected on different endpoints, or as tiered approach in which a decision tree is followed.


Input: Design of a testing strategy involves statistical considerations, such as the development of a statistical prediction model.


Input: During the EU FP6 ACuteTox project, several prediction models were proposed on the basis of statistical classification algorithms which we illustrate here.


Input: The final choice of testing strategies was not based on statistical considerations alone.


Input: However, without thorough statistical evaluations a testing strategy cannot be identified.


Input: We present here a number of observations made from the statistical viewpoint which relate to the development of testing strategies.


Input: The points we make were derived from problems we had to deal with during the evaluation of this large research project.


Input: A central issue during the development of a prediction model is the danger of overfitting.


Input: Procedures are presented to deal with this challenge.


Input: Role of TNF-alpha in renal damage in mice showing hepatic steatosis induced by high fat diet.


Input: The present study was designed to investigate the role of TNF-alpha in renal damage observed in mice with hepatic steatosis.


Input: We induced hepatic steatosis in mice using high fat diet and treated mice with ectanercept at the dose sufficient to block TNF-alpha receptors or vehicle for 1 month.


Input: Plasma TNF-alpha, total cholesterol (TC), triglyceride (TG), LDL-cholesterol (LDL-C), and HDL-cholesterol (HDL-C) were determined at the end of this treatment.

cholesterol

triglyceride

cholesterol

cholesterol


Input: Renal damage was identified by histologic observation and the higher of serum blood urea nitrogen (BUN) and creatinine.

urea nitrogen

creatinine


Input: Also, changes of PPAR-delta in kidney and renal mesangial cell (RMC) were analyzed using Western blot.


Input: Plasma TNF-alpha was markedly raised in mice showing hepatic steatosis.


Input: However, the levels of blood lipids (TC, TG, HDL-C, and LDL-C) and TNF-alpha were not modified by the treatment of etanercept although the hepatic steatosis has been improved.


Input: Etanercept shows renal protection from histological identification and recovery of serum BUN and creatinine levels.

creatinine


Input: Moreover, restoration of PPAR-delta expression by etanercept was observed in mice kidney.


Input: Direct effect of TNF-alpha on PPAR-delta expression was also characterized in RMC cell.


Input: We suggest that renal damage in mice with hepatic steatosis is mainly induced by increase of TNF-alpha through the decrease of renal PPAR-delta.


Input: Etanercept could block TNF-alpha receptors to restore PPAR-delta and improve renal function in mice with hepatic steatosis.


Input: Loss of A (1) adenosine receptor attenuates alpha-naphthylisothiocyanate-induced cholestatic liver injury in mice.

adenosine

alpha-naphthylisothiocyanate


Input: Cholestasis has limited therapeutic options and is associated with high morbidity and mortality.


Input: The A (1) adenosine receptor (A (1) AR) was postulated to participate in the pathogenesis of hepatic fibrosis induced by experimental extrahepatic cholestasis; however, the contribution of A (1) AR to intrahepatic cholestatic liver injury remains unknown.

adenosine


Input: Here, we found that mice lacking A (1) AR were resistant to alpha-naphthyl isothiocyanate (ANIT)-induced liver injury, as evidenced by lower serum liver enzyme levels and reduced extent of histological necrosis.

alpha-naphthyl isothiocyanate

ANIT


Input: Bile acid accumulation in liver and serum was markedly diminished in A (1) AR (-/-) mice compared with wild-type (WT) mice.

Bile acid


Input: However, biliary and urinary outputs of bile acids were significantly enhanced in A (1) AR (-/-) mice.

bile acids


Input: In the liver, mRNA expression of genes related to bile acid transport (Bsep and Mdr2) and hydroxylation (Cyp3a11) was increased in A (1) AR (-/-) mice.

bile acid


Input: In the kidney, A (1) AR deficiency prevented the decrease of glomerular filtration rate caused by ANIT.

ANIT


Input: Treatment of WT mice with A (1) AR antagonist DPCPX also protected against ANIT hepatotoxicity.

DPCPX

ANIT


Input: Our results indicated that lack of A (1) AR gene protects mice from ANIT-induced cholestasis by enhancing toxic biliary constituents efflux through biliary excretory route and renal elimination system and suggested a potential role of A (1) AR as therapeutic target for the treatment of intrahepatic cholestasis.

ANIT


Input: Methamphetamine-induced nitric oxide promotes vesicular transport in blood-brain barrier endothelial cells.

Methamphetamine

nitric oxide


Input: Methamphetamine' s (METH) neurotoxicity is thought to be in part due to its ability to induce blood-brain barrier (BBB) dysfunction.

Methamphetamine

METH


Input: Here, we investigated the effect of METH on barrier properties of cultured rat primary brain microvascular endothelial cells (BMVECs).

METH


Input: Transendothelial flux doubled in response to METH, irrespective of the size of tracer used.

METH


Input: At the same time, transendothelial electrical resistance was unchanged as was the ultrastructural appearance of inter-endothelial junctions and the distribution of key junction proteins, suggesting that METH promoted vesicular but not junctional transport.

METH


Input: Indeed, METH significantly increased uptake of horseradish peroxidase into vesicular structures.

METH


Input: METH also enhanced transendothelial migration of lymphocytes indicating that the endothelial barrier against both molecules and cells was compromised.

METH


Input: Barrier breakdown was only observed in response to METH at low micromolar concentrations, with enhanced vesicular uptake peaking at 1 mu M METH.

METH

METH


Input: The BMVEC response to METH also involved rapid activation of endothelial nitric oxide synthase and its inhibition abrogated METH-induced permeability and lymphocyte migration, indicating that nitric oxide was a key mediator of BBB disruption in response to METH.

METH

nitric oxide

METH

nitric oxide

METH


Input: This study underlines the key role of nitric oxide in BBB function and describes a novel mechanism of drug-induced fluid-phase transcytosis at the BBB.

nitric oxide


Input: Centrally acting oximes in reactivation of tabun-phosphoramidated AChE.

oximes

tabun


Input: Organophosphates (OP) inhibit acetylcholinesterase (AChE, EC 3. 1. 1. 7), both in peripheral tissues and central nervous system (CNS), causing adverse and sometimes fatal effects due to the accumulation of neurotransmitter acetylcholine (ACh).

Organophosphates

acetylcholinesterase

AChE


Input: The currently used therapy, focusing on the reactivation of inhibited AChE, is limited to peripheral tissues because commonly used quaternary pyridinium oxime reactivators do not cross the blood brain barrier (BBB) at therapeutically relevant levels.

quaternary pyridinium oxime


Input: A directed library of thirty uncharged oximes that contain tertiary amine or imidazole protonable functional groups that should cross the BBB as unionized species was tested as tabun-hAChE conjugate reactivators along with three reference oximes: DAM (diacetylmonoxime), MINA (monoisonitrosoacetone), and 2-PAM.

oximes

tertiary amine

imidazole

tabun

oximes

DAM

diacetylmonoxime

MINA

monoisonitrosoacetone


Input: The oxime RS150D [N-((1-(3-(2-((hydroxyimino) methyl)-1H-imidazol-1-yl) propyl)-1H-1, 2, 3-triazol-4-yl) methyl) benzamide] was highlighted as the most promising reactivator of the tabun-hAChE conjugate.

oxime RS150D

N-((1-(3-(2-((hydroxyimino) methyl)-1H-imidazol-1-yl) propyl)-1H-1, 2, 3-triazol-4-yl) methyl) benzamide

tabun


Input: We also observed that oximes RS194B [N-(2-(azepan-1-yl) ethyl)-2-(hydroxyimino) acetamide] and RS41A [2-(hydroxyimino)-N-(2-(pyrrolidin-1-yl) ethyl) acetamide], which emerged as lead uncharged reactivators of phosphylated hAChE with other OPs (sarin, cyclosarin and VX), exhibited only moderate reactivation potency for tabun inhibited hAChE.

oximes RS194B

N-(2-(azepan-1-yl) ethyl)-2-(hydroxyimino) acetamide

2-(hydroxyimino)-N-(2-(pyrrolidin-1-yl) ethyl) acetamide

sarin

cyclosarin

tabun


Input: This implies that geometry of oxime access to the phosphorus atom conjugated to the active serine is an important criterion for efficient reactivation, along with the chemical nature of the conjugated moiety: phosphorate, phosphonate, or phosphoramidate.

oxime

phosphorus

serine

phosphorate

phosphonate

phosphoramidate


Input: Moreover, modification of the active center through mutagenesis enhances the rates of reactivation.


Input: The phosphoramidated-hAChE choline-binding site mutant Y337A showed three-times enhanced reactivation capacity with non-triazole imidazole containing aldoximes (RS113B, RS113A and RS115A) and acetamide derivative (RS194B) than with 2PAM.

choline

triazole imidazole

aldoximes

acetamide


Input: Increased nuclear thioredoxin-1 potentiates cadmium-induced cytotoxicity.

cadmium


Input: Cadmium (Cd) is a widely dispersed environmental agent that causes oxidative toxicity through mechanisms that are sensitive to thioredoxin-1 (Trx1).

Cadmium

Cd


Input: Trx1 is a cytoplasmic protein that translocates to nuclei during oxidative stress.


Input: Recent research shows that interaction of Trx1 with actin plays a critical role in cell survival and that increased nuclear Trx-1 potentiates proinflammatory signaling and death in cell and mouse models.


Input: These observations indicate that oxidative toxicity caused by low-dose Cd could involve disruption of actin-Trx1 interaction, nuclear Trx1 translocation, and potentiation of proinflammatory cell death mechanisms.

Cd


Input: In this study, we investigated the role of nuclei-localized Trx1 in Cd-induced inflammation and cytotoxicity using in vitro and in vivo models.

Cd


Input: The results show that Cd stimulated nuclear translocation of Trx1 and p65 of NF-kappa B.

Cd


Input: Elevation of Trx1 in nuclei in in vitro cells and kidney of transgenic mice potentiated Cd-stimulated NF-kappa B activation and cell death.

Cd


Input: Cd-stimulated Trx1 nuclear translocation and NF-kappa B activation were inhibited by cytochalasin D, an inhibitor of actin polymerization, suggesting that actin regulates Trx1 nuclear translocation and NF-kappa B activation by Cd.

Cd

cytochalasin D

Cd


Input: A nuclear-targeted dominant negative form of Trx1 blocked Cd-stimulated NF-kappa B activation and decreased cell death.

Cd


Input: Addition of zinc, known to antagonize Cd toxicity by increasing metallothionein, had no effect on Cd-stimulated nuclear translocation of Trx1 and NF-kappa B activation.

zinc

Cd

Cd


Input: Taken together, the results show that nuclear translocation and accumulation of redox-active Trx1 in nuclei play an important role in Cd-induced inflammation and cell death.

Cd


Input: The influence of pH on phosphatidylethanolamine monolayer at the air/aqueous solution interface.

phosphatidylethanolamine


Input: The dependence of the interfacial tension of a phosphatidylethanolamine (PE) monolayer on the pH of the aqueous solution has been studied.

phosphatidylethanolamine


Input: A theoretical equation is derived to describe this dependence.


Input: A simple model of the influence of pH on the phosphatidylethanolamine monolayer at the air/hydrophobic chains of PE is presented.

phosphatidylethanolamine


Input: The contributions of additive phosphatidylethanolamine forms (both interfacial tension values and molecular area values) depend on pH.

phosphatidylethanolamine


Input: The interfacial tension values and the molecular area values for PEH (+) and PEOH (-) forms of phosphatidylethanolamine were calculated.

PEH (+)

PEOH (-)

phosphatidylethanolamine


Input: The assumed model was verified experimentally.


Input: The experimental results agreed with those derived from the theoretical equation in a whole range of pH values.


Input: A new flavonoid and other polar compounds from Galeopsis angustifolia Ehrh.

flavonoid


Input: ex Hoffm.


Input: The analysis of the polar fraction of Galeopsis angustifolia Ehrh.


Input: ex Hoffm. indicates that the main components are iridoids and flavonoids.

iridoids

flavonoids


Input: Six compounds were identified: a new flavonoid, 3'-hydroxy-isoscutellarein 7-O-[6''' acetyl-beta-D-glucopyranosyl-(1 --> 2)-beta-D-glucopyranoside]; three iridoid glucosides: harpagide, acetyl harpagide and for the first time in this species, 8-epi-loganin; two known acetylated flavonoid glycosides: 3'-hydroxy-4'-O-methylisoscutellarein 7-O-[6''' acetyl-beta-D-allopyranosyl-(1 --> 2)-6''-acetyl-beta-D-glucopyranoside], 3'-hydroxy-4'-O-methylisoscutellarein 7-O-[6''' acetyl-beta-D-allopyranosyl-(1 --> 2)-beta-D-glucopyranoside].

flavonoid

3'-hydroxy-isoscutellarein 7-O-[6''' acetyl-beta-D-glucopyranosyl-(1 --> 2)-beta-D-glucopyranoside]

iridoid glucosides

harpagide

acetyl harpagide

acetylated flavonoid glycosides

3'-hydroxy-4'-O-methylisoscutellarein 7-O-[6''' acetyl-beta-D-allopyranosyl-(1 --> 2)-6''-acetyl-beta-D-glucopyranoside]

3'-hydroxy-4'-O-methylisoscutellarein 7-O-[6''' acetyl-beta-D-allopyranosyl-(1 --> 2)-beta-D-glucopyranoside]


Input: Both flavonoids and iridoids are present in high amount; respectively, 16. 7% and 4. 5% of the crude extract.

flavonoids

iridoids


Input: Pharmacological and dietary antioxidant therapies for chronic obstructive pulmonary disease.


Input: The progression and exacerbations of chronic obstructive pulmonary disease (COPD) are intimately associated with tobacco smoke/biomass fuel-induced oxidative and aldehyde/carbonyl stress.

aldehyde

carbonyl


Input: Alterations in redox signaling proinflammatory kinases and transcription factors, steroid resistance, unfolded protein response, mucus hypersecretion, extracellular matrix remodeling, autophagy/apoptosis, epigenetic changes, cellular senescence/aging, endothelial dysfunction, autoimmunity, and skeletal muscle dysfunction are some of the pathological hallmarks of COPD.

steroid


Input: In light of the above it would be prudent to target systemic and local oxidative stress with agents that can modulate the antioxidants/redox system or by boosting the endogenous levels of antioxidants for the treatment and management of COPD.


Input: Identification of various antioxidant agents, such as thiol molecules (glutathione and mucolytic drugs, such as N-acetyl-Lcysteine, N-acystelyn, erdosteine, fudosteine, ergothioneine, and carbocysteine lysine salt), dietary natural productderived polyphenols and other compounds (curcumin, resveratrol, green tea catechins, quercetin sulforaphane, lycopene, acai, alpha-lipoic acid, tocotrienols, and apocynin) have made it possible to modulate various biochemical aspects of COPD.

thiol

glutathione

N-acetyl-Lcysteine

N-acystelyn

erdosteine

fudosteine

ergothioneine

carbocysteine lysine

polyphenols

curcumin

resveratrol

catechins

quercetin sulforaphane

lycopene

alpha-lipoic acid

tocotrienols

apocynin


Input: Various researches and clinical trials have revealed that these antioxidants can detoxify free radicals and oxidants, control expression of redox and glutathione biosynthesis genes, chromatin remodeling, and ultimately inflammatory gene expression.

glutathione


Input: In addition, modulation of cigarette smoke-induced oxidative stress and related cellular changes have also been reported to be effected by synthetic molecules.


Input: This includes specific spin traps like alpha-phenyl-N-tert-butyl nitrone, a catalytic antioxidant (ECSOD mimetic), porphyrins (AEOL 10150 and AEOL 10113), and a superoxide dismutase mimetic M40419, lipid peroxidation and protein carbonylation blockers/inhibitors, such as edaravone and lazaroids/tirilazad, myeloperoxidase inhibitors, as well as specialized pro-resolving mediators/inflammatory resolving lipid mediators, omega-3 fatty acids, vitamin D, and hydrogen sulfide.

alpha-phenyl-N-tert-butyl nitrone

porphyrins

AEOL 10150

AEOL 10113

superoxide

edaravone

lazaroids

tirilazad

omega-3 fatty acids

vitamin D

hydrogen sulfide


Input: According to various studies it appears that the administration of multiple antioxidants could be a more effective mode used in the treatment of COPD.


Input: In this review, various pharmacological and dietary approaches to enhance lung antioxidant levels and beneficial effects of antioxidant therapeutics in treating or intervening the progression of COPD have been discussed.


Input: A photochemical mechanism for homochirogenesis.


Input: Part 2.


Input: A theoretical investigation of the photochemistry of racemic compounds with circularly polarized light was undertaken.


Input: The exact solutions of the differential equations by numerical integration to the approximate solutions used in an earlier article were compared.


Input: The exact solutions showed that sequential reactions yield enhanced optical activities in the products.


Input: For irreversible reactions, all enantiomeric excesses are lost if the reactions are carried to completion, but appreciable resolution occurs in many cases for partial conversion.


Input: For reversible reactions, significant enantiomeric excesses are found at the photostationary state.


Input: Clear evidence of carcinogenic activity by a whole-leaf extract of Aloe barbadensis miller (aloe vera) in F344/N rats.


Input: Aloe barbadensis Miller (Aloe vera) is an herbal remedy promoted to treat a variety of illnesses; however, only limited data are available on the safety of this dietary supplement.


Input: Drinking water exposure of F344/N rats and B6C3F1 mice to an Aloe vera whole-leaf extract (1, 2, and 3%) for 13 weeks resulted in goblet cell hyperplasia of the large intestine in both species.


Input: Based upon this observation, 2-year drinking water studies were conducted to assess the carcinogenic potential of an Aloe vera whole-leaf extract when administered to F344/N rats (48 per sex per group) at 0. 5, 1, and 1. 5%, and B6C3F1 mice (48 per sex per group) at 1, 2, and 3%.


Input: Compared with controls, survival was decreased in the 1. 5% dose group of female rats.


Input: Treatment-related neoplasms and nonneoplastic lesions in both species were confined primarily to the large intestine.


Input: Incidences of adenomas and/or carcinomas of the ileo-cecal and cecal-colic junction, cecum, and ascending and transverse colon were significantly higher than controls in male and female rats in the 1 and 1. 5% dose groups.


Input: There were no neoplasms of the large intestine in mice or in the 0 or 0. 5% dose groups of rats.


Input: Increased incidences of mucosa hyperplasia of the large intestine were observed in F344/N rats, and increased incidences of goblet cell hyperplasia of the large intestine occurred in B6C3F1 mice.


Input: These results indicate that Aloe vera whole-leaf extract is an intestinal irritant in F344/N rats and B6C3F1 mice and a carcinogen of the large intestine in F344/N rats.


Input: Advances in supramolecular electronics-from randomly self-assembled nanostructures to addressable self-organized interconnects.


Input: Supramolecular organic electronics rests on the use of bottom-up chemical self-assembly processes in order to design conducting components on the 5-100 nm scale.


Input: The challenges in this field are both the construction of 1D-nanostructures displaying optimized transport properties and their precise connections to electrodes.


Input: The present Research News highlights important advances in such materials regarding their electrical performances, from semiconductors to organic metals, but also regarding their processability.


Input: In particular, by externally controlling light-responsive supramolecular polymerization processes, and by using appropriate methods of casting with an applied electric field, it becomes possible to pre-determine the accurate positioning of organic interconnects within patterned nano-circuitry.


Input: These strategies using external stimuli to obtain addressability, thus hold promising alternatives to other conducting materials such as carbon nanotubes for further technological applications in nanosciences.

carbon


Input: Recent developments in antimalarial natural products isolated from medicinal plants.


Input: Malaria is an infectious disease causing almost one million deaths each year.


Input: There is an urgent need for discovery of new antimalarial compounds.


Input: Natural products have been the single most productive source of leads for the development of drugs, because of their great variety of chemical structures.


Input: This review covers studies on antimalarial natural products isolated from plants, published from January 2010 until April 2012.


Input: A total of 171 structures comprising alkaloids, terpenoids, phenolics and other metabolites are listed in this review, including information on their antiplasmodial and cytotoxic activity.

terpenoids

phenolics


Input: Four new coumarinolignoids from seeds of Solanum indicum.

coumarinolignoids


Input: Activity-guided fractionation of seeds of Solanum indicum for anti-HBV activity led to the isolation of two novel coumarinolignoid alkaloids (indicumines A-B, 1-2) and two new coumarinolignoids (indicumines C-D, 3-4), together with four known coumarins (5-8).

coumarinolignoid alkaloids

indicumines A-B

coumarinolignoids

indicumines C-D

coumarins


Input: Their structures were established on the basis of spectroscopic data.


Input: The two novel coumarinolignoid alkaloids shows anti-HBV activities through specifically inhibiting the secretion of HBsAg in HepG2. 2. 15.

coumarinolignoid alkaloids


Input: Relevance of non-guideline studies for risk assessment: the coverage model based on most frequent targets in repeated dose toxicity studies.


Input: A common challenge for human risk assessment is the quality of the available animal studies.


Input: Non-guideline studies are often limited for different aspects of study design and documentation.


Input: Within this publication the relevance of a limited scope of examination is discussed.


Input: Preliminary analyses of the RepDose database have shown that liver, body weight, kidney and clinical symptoms are frequently affected in oral repeated dose toxicity in rats and mice (Bitsch et al., 2006), while many other targets are seldom affected.


Input: As most of these targets are investigated frequently also in non-guideline studies, it is likely that they provide a reliable NOEL, although the full spectrum of endpoints has not been covered.


Input: Based on RepDose data we investigate the relevance of individual targets for determining the LOEL and the consequences for risk assessment.


Input: The resulting coverage model for subchronic oral rat studies includes up to six targets and an additional assessment factor for LOEL extrapolation.


Input: It can be applied to assess the reliability of non-guideline studies with respect to the scope of examination.


Input: Furthermore the application of the coverage model to other databases will increase and/or specify the chemical domain and reveal respective targets as well as effects.


Input: Molecular characterization of 355 mucopolysaccharidosis patients reveals 104 novel mutations.


Input: Mucopolysaccharidosis (MPS) disorders are heterogeneous and caused by deficient lysosomal degradation of glycosaminoglycans, resulting in distinct but sometimes overlapping phenotypes.


Input: Molecular analysis was performed for a total of 355 MPS patients with MPSI (n = 15), MPSII (n = 218), MPSIIIA (n = 86), MPSIIIB (n = 20), MPSIVA (n = 6) or MPSVI (n = 10).


Input: This analysis revealed 104 previously unreported mutations: seven in IDUA (MPSI), 61 in IDS (MPSII), 19 in SGSH (MPSIIIA), 11 in NAGLU (MPSIIIB), two in GALNS (MPSIVA) and four in ARSB (MPSVI).


Input: The intergenic comparison of the mutation data for these disorders has revealed interesting differences.


Input: Whereas IDUA, IDS, NAGLU and ARSB demonstrate similar levels of mutation heterogeneity (0. 6-0. 675 different mutations per total alleles), SGSH and GALNS have lower levels of mutation heterogeneity (0. 282 and 0. 455, respectively), due to more recurrent mutations.


Input: The type of mutation also varies significantly by gene.


Input: SGSH, GALNS and ARSB mutations are usually missense (76. 5%, 81. 8% and 85%), while IDUA has many more nonsense mutations (56%) than the other genes (<= 20%).


Input: The mutation spectrum is most diverse for IDS, including intergenic inversions and multi-exon deletions.


Input: By testing 102 mothers of MPSII patients, we determined that 22. 5% of IDS mutations are de novo.


Input: We report the allele frequency of common mutations for each gene in our patient cohort and the exonic distribution of coding sequence alterations in the IDS, SGSH and NAGLU genes, which reveals several potential " hot-spots ".


Input: This further molecular characterization of these MPS disorders is expected to assist in the diagnosis and counseling of future patients.


Input: The role of residues T248, Y249 and T422 in the function of human pregnane X receptor.

pregnane


Input: The pregnane X receptor (PXR) is a key xenobiotic receptor that regulates the expression of numerous drug-metabolizing enzymes.

pregnane


Input: Some posttranslational mechanisms modulate its transcriptional activity.


Input: Although several kinases have been shown to directly phosphorylate this receptor, little is known about phosphorylation sites of PXR.


Input: In the present work, we examined T248, Y249 and T422 putative phosphorylation sites determined based on in silico consensus kinase site prediction analysis.


Input: T248 and T422 residues are critical for the interaction of the PXR ligand-binding domain and the activation function-2 (AF2) domain.


Input: Site-directed mutagenesis analysis was performed to generate phospho-deficient and phospho-mimetic mutants.

phospho

phospho


Input: We examined transactivation activity of the PXR mutants in gene reporter assays, formation of PXRmutant/RXR alpha heterodimer, binding of PXR mutants to the CYP3A4 gene response element DR3 and CYP3A4 expression in HepG2 cells after expression of the mutants.


Input: We found that T248D mutant activated CYP3A4 transactivation constitutively regardless of the presence or absence of a ligand.


Input: Contrary, T248V mutant exhibited low basal and ligand-inducible transactivation capacity as compared to wild-type PXR.


Input: Dose-response analysis revealed reduced ligand-dependent transactivation potency of PXR Y249D mutant.


Input: Transactivation of the CYP3A4 promoter was abolished with T422A/D mutants.


Input: All PXR mutants formed heterodimer with RXR alpha at a similar level to that observed with wild-type PXR.


Input: The ability to bind to DNA in vitro was substantially decreased in case of T248D, T422D and T248V mutants.


Input: Our data thus indicate that phosphorylation of T248, Y249 and T422 residues may be critical for the both basal and ligand-activated function of PXR.


Input: Circadian rhythm of salivary cortisol in infants with congenital heart disease.

cortisol


Input: Children with congenital heart disease (CHD) have associated extracardiac co-morbidities at the time of surgery and during ongoing growth and development.


Input: Perioperative events include disrupted glucose homeostasis, capillary leak, and fluid retention.

glucose


Input: The hypothalamic-pituitary-adrenal (HPA) axis has an important role in homeostasis in that the secretion of cortisol contributes to the response to stress, glucose regulation, blood volume control, and immune regulation.

cortisol

glucose


Input: We investigated the diurnal rhythm of the HPA axis in infants with CHD by measuring salivary cortisol in the morning (0600-0900 h-circadian peak) and evening (2100-2400 h-circadian nadir).

cortisol


Input: Twenty-nine infants aged 12 weeks to 1 year were included: 16 with acyanotic disease (SpO (2) >= 90%) and 13 with cyanotic disease (SpO2 < 90%).


Input: Morning salivary cortisol was similar between the two groups [acyanotic 7. 0 nmol/L (1. 8-23. 1); cyanotic 9. 7 nmol/L (0. 9-15. 6); p = 0. 68].

cortisol


Input: Evening salivary cortisol was similar between the two groups [acyanotic 0. 9 nmol/L (0. 2-8. 5); cyanotic 1. 4 nmol/L (0. 5-14. 9); p = 0. 32].

cortisol


Input: Both cyanotic and acyanotic groups demonstrated an intact diurnal rhythm.


Input: In conclusion, chronic hypoxia secondary to cyanotic CHD does not affect the circadian rhythm of the HPA axis.


Input: By 12 weeks of age, infants with hypoxia secondary to cyanotic CHD have a normal cortisol diurnal rhythm.

cortisol


Input: Brain involvement in glaucoma: advanced neuroimaging for understanding and monitoring a new target for therapy.


Input: On the basis of a large body of experimental data the notion that glaucoma damages retinal ganglion cells and central areas of the visual system has been put forward.


Input: The mechanisms underlying glaucomatous involvement of the central areas are not known: the most likely hypothesis is that this event is the result of an anterograde transynaptic neurodegeneration triggered by ganglion cells' death.


Input: However, it is possible that in some cases it may be the consequence of a neurodegenerative disease of the central nervous system.


Input: In any event, novel mechanisms leading to cell demise might be implicated.


Input: The development of powerful neuroimaging techniques in conjunction with sophisticated analysis has recently provided compelling support to the involvement of central stations of the visual pathway in patients suffering of glaucoma.


Input: Diffusion Tensor-MRI allows the central damage associated with glaucoma to be assessed and therapeutic efficacy of novel neuroprotective interventions to be quantified.


Input: Peptide reactivity assay using spectrophotometric method for high-throughput screening of skin sensitization potential of chemical haptens.


Input: Haptens must react with cellular proteins to be recognized by antigen presenting cells.


Input: Therefore, monitoring reactivity of chemicals with peptide/protein has been considered an in vitro skin sensitization testing method.


Input: The reactivity of peptides with chemicals (peptide reactivity) has usually been monitored by chromatographic methods like HPLC or LC/MS, which are robust tools for monitoring common chemical reactions but are rather expensive and time consuming.


Input: Here, we examined the possibility of using spectrophotometric methods to monitor peptide reactivity.


Input: Two synthetic peptides, Ac-RWAACAA and Ac-RWAAKAA, were reacted with 48 chemicals (34 sensitizers and 14 non-sensitizers).


Input: Peptide reactivity was measured by monitoring unreacted peptides with UV-Vis spectrophotometer using 5, 5'-dithiobis-2-nitrobenzoic acid as a detection reagent for the free thiol group of cysteine-containing peptide or fluorometer using fluorescamine (TM) as a detection reagent for the free amine group of lysine-containing peptide.

5, 5'-dithiobis-2-nitrobenzoic acid

thiol

cysteine

fluorescamine

lysine


Input: Chemicals were categorized as sensitizers when they induced more than 10% depletion of cysteine-containing peptide or 20% depletion of lysine-containing peptide.

cysteine

lysine


Input: The sensitivity, specificity, and accuracy of this method were 82. 4%, 85. 7%, and 83. 3%, respectively.


Input: These results demonstrate that spectrophotometric methods can be easy, fast, and high-throughput screening tools for the prediction of the skin sensitization potential of chemical haptens.


Input: Biomarkers of Parkinson' s disease: current status and future perspectives.


Input: This review summarizes major advances in biomarker discovery for diagnosis, differential diagnosis and progression of Parkinson' s disease (PD), with emphasis on neuroimaging and biochemical markers.


Input: Potential strategies to develop biomarkers capable of predicting PD in the prodromal stage before the appearance of motor symptoms or correlating with nonmotor symptoms, an active area of research, are also discussed.


Input: Leukotriene D4 induces cognitive impairment through enhancement of CysLT 1 R-mediated amyloid-beta generation in mice.

Leukotriene D4


Input: Amyloid plaques in the extracellular parenchyma mainly consist of amyloid-beta peptides (A beta), one of the pathological hallmarks in Alzheimer' s disease (AD).


Input: In the present study, we examined neuroinflammation, amyloidogenesis, and memory performance following intracerebral infusions of leukotriene D4 (LTD4) in mice.

leukotriene D4


Input: The results demonstrated that intracerebral infusions of LTD4 (1 ng/mouse) produced memory impairment as determined by Morris water maze test and Y-maze test in mice, and caused the accumulation of A beta 1-40 and A beta 1-42 in the hippocampus and cortex through increased activity of beta-and gamma-secretases accompanied with increased expression of amyloid precursor protein (APP).


Input: LTD4 also induced expression of cysteinyl leukotriene receptor 1 (CysLT (1) R) and NF-kappa B p65 in the hippocampus and cortex.

cysteinyl leukotriene


Input: Pretreatment with pranlukast (1. 5 ng/mouse, intracerebroventricularly), a CysLT (1) R antagonist, blocked LTD4-induced amyloidogenesis, memory deficits.

pranlukast


Input: Pranlukast (0. 6 mu M) also prevented LTD4 (20 nM)-induced amyloidogenesis in the cultured neurons in vitro.

Pranlukast


Input: Moreover, LTD4-induced increases in CysLT (1) R and NF-kappa B p65 in the brain were also attenuated by pranlukast.

pranlukast


Input: These results suggest that LTD4 increases A beta peptide burden via activation of CysLT (1) R, which further affects APP levels and activity of beta-and gamma-secretases via the NF-kappa B pathway.


Input: Our findings identify CysLT (1) R signaling as a novel proinflammatory and proamyloidogenic pathway, and suggest a rationale for development of therapeutics targeting the CysLT (1) R in neuroinflammatory diseases such as AD.


Input: Comparative gene expression profiling in human-induced pluripotent stem cell--derived cardiocytes and human and cynomolgus heart tissue.


Input: Cardiotoxicity is one of the leading causes of drug attrition.


Input: Current in vitro models insufficiently predict cardiotoxicity, and there is a need for alternative physiologically relevant models.


Input: Here we describe the gene expression profile of human-induced pluripotent stem cell-derived cardiocytes (iCC) postthaw over a period of 42 days in culture and compare this profile to human fetal and adult as well as adult cynomolgus nonhuman primate (NHP, Macaca fascicularis) heart tissue.


Input: Our results indicate that iCC express relevant cardiac markers such as ion channels (SCN5A, KCNJ2, CACNA1C, KCNQ1, and KCNH2), tissue-specific structural markers (MYH6, MYLPF, MYBPC3, DES, TNNT2, and TNNI3), and transcription factors (NKX2. 5, GATA4, and GATA6) and lack the expression of stem cell markers (FOXD3, GBX2, NANOG, POU5F1, SOX2, and ZFP42).


Input: Furthermore, we performed a functional evaluation of contractility of the iCC and showed functional and pharmacological correlations with myocytes isolated from adult NHP hearts.


Input: These results suggest that stem cell-derived cardiocytes may represent a novel in vitro model to study human cardiac toxicity with potential ex vivo and in vivo translation.


Input: A modern in vivo pharmacokinetic paradigm: combining snapshot, rapid and full PK approaches to optimize and expedite early drug discovery.


Input: Successful drug discovery relies on the selection of drug candidates with good in vivo pharmacokinetic (PK) properties as well as appropriate preclinical efficacy and safety profiles.


Input: In vivo PK profiling is often a bottleneck in the discovery process.


Input: In this review, we focus on the tiered in vivo PK approaches implemented at the Genomics Institute of the Novartis Research Foundation (GNF), which includes snapshot PK, rapid PK and full PK studies.


Input: These in vivo PK approaches are well integrated within discovery research, allow tremendous flexibility and are highly efficient in supporting the diverse needs and increasing demand for in vivo profiling.


Input: The tiered in vivo PK studies expedite compound profiling and help guide the selection of more desirable compounds into efficacy models and for progression into development.


Input: Enhancement of social novelty discrimination by positive allosteric modulators at metabotropic glutamate 5 receptors: adolescent administration prevents adult-onset deficits induced by neonatal treatment with phencyclidine.

glutamate

phencyclidine


Input: Metabotropic glutamate-5 receptors (mGluR5), which physically and functionally interact with N-methyl-D-Aspartate (NMDA) receptors, likewise control cognitive processes and have been proposed as targets for novel classes of antipsychotic agent.

glutamate

N-methyl-D-Aspartate

NMDA


Input: Since social cognition is impaired in schizophrenia and disrupted by NMDA receptor antagonists like dizocilpine, we evaluated its potential modulation by mGluR5.

NMDA

dizocilpine


Input: Acute administration (0. 63-40 mg/kg) of the mGluR5 positive allosteric modulators (PAMs), 3-cyano-N-(1, 3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB) and ADX47273, reversed a delay-induced impairment in social novelty discrimination (SND) in adult rats.

3-cyano-N-(1, 3-diphenyl-1H-pyrazol-5-yl) benzamide

CDPPB


Input: The action of CDPPB was blocked by the mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (2. 5-10 mg/kg), and was also expressed upon microinjection into frontal cortex (0. 63-10 mu g/side), but not striatum.

CDPPB


Input: Supporting an interrelationship between mGluR5 and NMDA receptors, enhancement of SND by CDPPB was blocked by dizocilpine (0. 08 mg/kg) while, reciprocally, dizocilpine-induced impairment in SND was attenuated by CDPPB (10 mg/kg).

NMDA

CDPPB

dizocilpine

dizocilpine

CDPPB


Input: The SND deficit elicited by post-natal administration of phencyclidine (10 mg/kg, days 7-11) was reversed by CDPPB or ADX47273 in adults at week 8.

phencyclidine

CDPPB


Input: This phencyclidine-induced impairment in cognition emerged in adult rats from week 7 on, and chronic, pre-symptomatic treatment of adolescent rats with CDPPB over weeks 5-6 (10 mg/kg per day) prevented the appearance of SND deficits in adults until at least week 13.

phencyclidine

CDPPB


Input: In conclusion, as evaluated by a SND procedure, mGluR5 PAMs promote social cognition via actions expressed in interaction with NMDA receptors and exerted in frontal cortex.

NMDA


Input: MGluR5 PAMs not only reverse but also (when given during adolescence) prevent the emergence of cognitive impairment associated with a developmental model of schizophrenia.


Input: Swim training of monosodium L-glutamate-obese mice improves the impaired insulin receptor tyrosine phosphorylation in pancreatic islets.

monosodium L-glutamate

tyrosine


Input: The goal of the present study was to investigate changes on glucose homoeostasis and of the insulin receptor (IR) and insulin receptor substrate-1 (IRS-1) signalling in pancreatic islets from MSG-obese mice submitted to or not submitted to swim training.

glucose

MSG


Input: Swim training of 90-day-old MSG mice was used to evaluate whether signalling pathways of the IR and IRS-1 in islets are involved with the insulin resistance and glucose intolerance observed in this obese animal model.

MSG

glucose


Input: The results showed that IR tyrosine phosphorylation (pIR) was reduced by 42% in MSG-obese mice (MSG, 6. 7 +/- 0. 2 arbitrary units (a. u.); control, 11. 5 +/- 0. 4 a. u.); on the other hand, exercise training increased pIR by 76% in MSG mice without affecting control mice (MSG, 11. 8 +/- 0. 3; control, 12. 8 +/- 0. 2 a. u.).

tyrosine

MSG

MSG

MSG

MSG


Input: Although the treatment with MSG increased IRS-1 tyrosine phosphorylation (pIRS-1) by 96% (MSG, 17. 02 +/- 0. 6; control, 8. 7 +/- 0. 2 a. u.), exercise training also increased it in both groups (control, 13. 6 +/- 0. 1; MSG, 22. 2 +/- 1. 1 a. u.).

MSG

tyrosine

MSG

MSG


Input: Current research shows that the practice of swim training increases the tyrosine phosphorylation of IRS-1 which can modulate the effect caused by obesity in insulin receptors.

tyrosine


Input: Juvenile hormone levels reflect social opportunities in the facultatively eusocial sweat bee Megalopta genalis (Hymenoptera: Halictidae).

Juvenile hormone


Input: The evolution of eusociality is hypothesized to have involved de-coupling parental care from reproduction mediated by changes in endocrine regulation.


Input: While data for obligately eusocial insects are consistent with this hypothesis, we lack information from species representative of the transition from solitary reproduction to eusociality.


Input: Here we report the first evidence for a link between endocrine processes and social behavior in a facultatively eusocial bee, Megalopta genalis (Halictidae).


Input: Using females that varied in social, reproductive, and ecological context, we measured juvenile hormone (JH), a major regulator of colony caste dynamics in other eusocial species.

juvenile hormone


Input: JH was low at adult emergence, but elevated after 10 days in all nesting females.


Input: Females reared in cages with ad lib nutrition, however, did not elevate JH levels after 10 days.


Input: All reproductive females had significantly more JH than all age-matched non-reproductive females, suggesting a gonadotropic function.


Input: Among females in established nests, JH was higher in queens than workers and solitary reproductives, suggesting a role for JH in social dominance.


Input: A lack of significant differences in JH between solitary reproductives and non-reproductive workers suggests that JH content reflects more than reproductive status.


Input: Our data support the hypothesis that endocrine modifications are involved in the evolutionary decoupling of reproductive and somatic effort in social insects.


Input: These are the first measurements of JH in a solitary-nesting hymenopteran, and the first to compare eusocial and solitary nesting individuals of the same species.


Input: Friedelin and lanosterol from Garcinia prainiana stimulated glucose uptake and adipocytes differentiation in 3T3-L1 adipocytes.

Friedelin

lanosterol

glucose


Input: Friedelin and lanosterol have been isolated from twigs of Garcinia prainiana.

Friedelin

lanosterol


Input: Their structures were elucidated by spectroscopic methods.


Input: The compounds were examined for their effects on 3T3-L1 adipocytes.


Input: In the MTT assay, it was found that the compounds had no cytotoxic effects up to 25 micro M.

MTT


Input: Adipocyte differentiation analysis was carried out by Oil Red O staining method.

Oil Red O


Input: In the presence of adipogenic cocktail (MDI), it was found that friedelin and lanosterol enhanced intracellular fat accumulation by 2. 02 and 2. 18-fold, respectively, compared with the vehicle-treated cells.

friedelin

lanosterol


Input: Deoxyglucose uptake assay was used to examine the insulin sensitivity of adipocytes in the presence of the compounds.

Deoxyglucose


Input: It was found that friedelin was able to stimulate glucose uptake up to 1. 8-fold compared with insulin-treated cells.

friedelin

glucose


Input: It was suggested that friedelin and lanosterol may be beneficial to mimic insulin action that would be useful in the treatment of diabetes type 2 patients.

friedelin

lanosterol


Input: Airway contractility and remodeling: links to asthma symptoms.


Input: Respiratory symptoms are largely caused by obstruction of the airways.


Input: In asthma, airway narrowing mediated by airway smooth muscle (ASM) contraction contributes significantly to obstruction.


Input: The spasmogens produced following exposure to environmental triggers, such as viruses or allergens, are initially responsible for ASM activation.


Input: However, the extent of narrowing of the airway lumen due to ASM shortening can be influenced by many factors and it remains a real challenge to decipher the exact role of ASM in causing asthmatic symptoms.


Input: Innovative tools, such as the forced oscillation technique, continue to develop and have been proven useful to assess some features of ASM function in vivo.


Input: Despite these technologic advances, it is still not clear whether excessive narrowing in asthma is driven by ASM abnormalities, by other alterations in non-muscle factors or simply because of the overexpression of spasmogens.


Input: This is because a multitude of forces are acting on the airway wall, and because not only are these forces constantly changing but they are also intricately interconnected.


Input: To counteract these limitations, investigators have utilized in vitro and ex vivo systems to assess and compare asthmatic and non-asthmatic ASM contractility.