Input: Selective fluorescence detection of small-molecule-binding proteins by using a dual photoaffinity labeling system.


Input: PHOTO OPPORTUNITY: We have developed a dual photoaffinity labeling system in which an active and an inactive probe bearing orthogonal detection groups are co-reacted in a single photoreaction.


Input: The approach allowed selective fluorescent detection of a model binding protein in cell lysate by either 1D or 2D electrophoresis.


Input: Selective fluorogenic chemosensors for distinct classes of nucleases.


Input: NUCLEASE SENSOR TRIO: Fluorogenic DNA sensors were developed for distinct classes of nucleases: 3'-exonucleases, 5'-exonucleases, and endonucleases.


Input: The highly selective sensors, built from very small modified DNA oligomers containing the unnatural fluorescent base pyrene, and employing thymine as a quencher, were found to function in a variety of complex biological media.

pyrene

thymine


Input: Role of autophagy in the progression from obesity to diabetes and in the control of energy balance.


Input: Autophagy plays a crucial role in cellular homeostasis through the degradation and recycling of organelles such as mitochondria or endoplasmic reticulum (ER) that are closely related to the pathogenesis of diabetes.


Input: In pancreatic beta-cells producing insulin, autophagy helps maintain beta-cell mass, structure and function.


Input: In mice with beta-cell-specific deletion of Atg7 (autophagy-related 7), a critical autophagy gene, reduction of beta-cell mass and pancreatic insulin content were observed together with impaired insulin secretory function.


Input: Because of such structural and functional defects, beta-cell-specific Atg7-null mice showed hypoinsulinemia and hyperglycemia.


Input: However, those mice never developed diabetes.


Input: Obesity and lipids are physiological ER stressors that can precipitate beta-cell dysfunction and insulin resistance.


Input: Recent studies showed that beta-cell-specific Atg7-null mice, when bred with ob/ob mice, developed severe diabetes, suggesting that autophagy-deficient beta-cells can handle basal metabolic stress but have problems dealing with increased metabolic stress.


Input: Thus, autophagy deficiency in beta-cells could be a factor in the progression from obesity to diabetes due to an inappropriate response to obesity-induced ER stress.


Input: Autophagy also appears to play a role in the hypothalamic control of energy expenditure, appetite and body weight.


Input: Thus, autophagy is important to body and nutrient metabolism in many ways, and its dysregulation could contribute to the pathogenesis of metabolic disorders and diabetes.


Input: Manganese supplementation protects against diet-induced diabetes in wild type mice by enhancing insulin secretion.

Manganese


Input: Mitochondrial dysfunction is both a contributing mechanism and complication of diabetes, and oxidative stress contributes to that dysfunction.


Input: Mitochondrial manganese-superoxide dismutase (MnSOD) is a metalloenzyme that provides antioxidant protection.

manganese

superoxide


Input: We have previously shown in a mouse model of hereditary iron overload that cytosolic iron levels affected mitochondrial manganese availability, MnSOD activity, and insulin secretion.

iron

manganese

MnSOD


Input: We therefore sought to determine the metallation status of MnSOD in wild-type mice and whether altering that status affected beta-cell function.

MnSOD


Input: 129/SvEVTac mice given supplemental manganese exhibited a 73% increase in hepatic MnSOD activity and increased metallation of MnSOD.

MnSOD

MnSOD


Input: To determine whether manganese supplementation offered glucose homeostasis under a situation of beta-cell stress, we challenged C57BL/6J mice, which are more susceptible to diet-induced diabetes, with a high-fat diet for 12 weeks.

glucose


Input: Manganese was supplemented or not for the final 8 weeks on that diet, after which we examined glucose tolerance and the function of isolated islets.

Manganese

glucose


Input: Liver mitochondria from manganese-injected C57BL/6J mice had similar increases in MnSOD activity (81%) and metallation as were seen in 129/SvEVTac mice.

manganese

MnSOD


Input: The manganese-treated group fed high fat had improved glucose tolerance (24% decrease in fasting glucose and 41% decrease in area under the glucose curve), comparable with mice on normal chow and increased serum insulin levels.

manganese

glucose

glucose

glucose


Input: Isolated islets from the manganese-treated group exhibited improved insulin secretion, decreased lipid peroxidation, and improved mitochondrial function.

manganese


Input: In conclusion, MnSOD metallation and activity can be augmented with manganese supplementation in normal mice on normal chow, and manganese treatment can increase insulin secretion to improve glucose tolerance under conditions of dietary stress.

MnSOD

manganese

manganese

glucose


Input: A simple and sensitive method for determination of vitamins D (3) and K (1) in rat plasma: application for an in vivo pharmacokinetic study.

vitamins D (3) and K (1)


Input: Abstract Purpose: To develop and to validate a simple but sensitive method for determination of vitamins D (3) and K (1) in rat plasma.

vitamins D (3) and K (1)


Input: Methods: The sample treatment included protein precipitation by cold acetonitrile, evaporation, reconstitution with methanol and filtration.

acetonitrile

methanol


Input: The chromatography conditions included Xterra RP18 3. 5 micro m 4. 6 x 100 mm column at ambient temperature and mobile phase consisting of methanol/water (93/7, v/v) at 0. 5 mL/min flow rate.

methanol


Input: Vitamin D (3) and probucol were detected at 265 nm and vitamin K (1) at 239 nm.

Vitamin D (3)

probucol

vitamin K (1)


Input: Rats were administered intravenously by 0. 1 mg/kg of vitamin D (3) or K (1) and the blood samples were withdrawn pre-administration and at pre-determined time points post-administration.

vitamin D (3) or K (1)


Input: The pharmacokinetic analysis was performed using a non-compartmental approach.


Input: Results: The calibration curves in rat plasma were linear up to 5000 ng/mL for both vitamins.

vitamins


Input: The limit of quantification (LOQ) was 20 ng/mL for vitamin D (3) and 40 ng/mL for K (1).

vitamin D (3)


Input: Inter-and intra-day precision and accuracy were below 15%.


Input: The pharmacokinetic parameters of vitamin D (3) following intravenous administration were: AUC (0-infinity) = 11323 +/- 1081 h x ng/mL, V (d) = 218 +/- 80 mL/kg, CL = 8. 9 +/- 0. 8 mL/h/kg, t (1/2) = 16. 8 +/- 5 h; and of vitamin K (1): AUC (0-infinity) = 2495 +/- 297 h x ng/mL, V (d) = 60 +/- 24 mL/kg, CL = 40. 5 +/- 5. 1 mL/h/kg, t (1/2) = 1. 1 +/- 0. 5 h.

vitamin D (3)

vitamin K (1)


Input: Conclusion: The developed HPLC-UV assay is a simple and sensitive method for the determination of vitamins D (3) and K (1) in rat plasma.

vitamins D (3) and K (1)


Input: A higher dose of vitamin K (1) should be used in future studies for accurate estimation of pharmacokinetic parameters.

vitamin K (1)


Input: The data show the suitability of the assay for pharmacokinetic studies in rats.


Input: Synthesis of superparamagnetic particles with tunable morphologies: the role of nanoparticle-nanoparticle interactions.


Input: Superparamagnetic microparticles are extensively used in the purification of biomolecules due to the speed and ease of magnetic separation.


Input: It is desirable that the microparticles used in biological affinity separations have both high surface area and high magnetic mobility to facilitate a high binding capacity of target biomolecules and their rapid removal from solution, respectively.


Input: Scaling laws for conventional spherical superparamagnetic microparticles are such that increasing the microparticle specific surface area results in a significant decrease in the magnetic mobility.


Input: More favorable combinations of these key parameters can be found if alternative microparticle morphologies are developed for use in affinity separations.


Input: Emulsion-templated self-assembly of iron oxide nanoparticles into microparticles using oil-in-water emulsions was carried out using a modified Couette shear mixer with separate inlet ports for the oil and aqueous phases, enabling high throughput microparticle synthesis.

iron oxide


Input: By controlling the dissolved nanoparticle concentration and nanoparticle surface activity at the droplet interfaces, the resulting microparticles were tuned to spherical, dimpled, or crumpled morphologies.


Input: The specific binding capacity and magnetic mobility of each type of microparticle were measured by a peroxidase-based colorimetric assay and by their magnetic field-induced motion in a viscous fluid, respectively.


Input: Superparamagnetic microparticles with dimpled and crumpled morphologies were found to have higher specific binding capacities compared to spherical microparticles, while maintaining high magnetic field velocities due to their high iron oxide content.

iron oxide


Input: Superparamagnetic microparticles with these novel morphologies would make excellent tools for affinity-based bioseparations where binding capacity and magnetic mobility are key factors.


Input: Investigation of astatine (III) hydrolyzed species: experiments and relativistic calculations.

astatine (III)


Input: This work aims to resolve some controversies about astatine (III) hydroxide species present in oxidant aqueous solution.

astatine (III) hydroxide


Input: AtO (+) is the dominant species existing under oxidizing and acidic pH conditions.

AtO (+)


Input: This is consistent with high-performance ion-exchange chromatography data showing the existence of one species holding one positive charge.


Input: A change in speciation occurs as the pH changes from 1 to 4, while remaining under oxidizing conditions.


Input: Dynamic experiments with ion-exchange resins evidence the existence of a neutral species witnessed by its elution in the void volume.


Input: Batch-experiments using a competition method show the exchange of one proton indicating the formation of the AtO (OH) species.

AtO (OH)


Input: The hydrolysis thermodynamic constant, extrapolated to zero ionic strength, was determined to be 10 (-1. 9).


Input: This value is supported by two-component relativistic quantum calculations and therefore allows disclosing unambiguously the structure of the formed species.


Input: Polymer therapeutics with a coiled coil motif targeted against murine bcl1 leukemia.


Input: The specificity of polymer conjugates based on N-(2-hydroxypropyl) methacrylamide (HPMA) bearing cytostatic drugs for cancer cells could be significantly increased by the incorporation of a suitable targeting ligand, such as a monoclonal antibody (mAb).

N-(2-hydroxypropyl) methacrylamide

HPMA


Input: However, direct binding of the protein to the polymer carrier could cause considerable problems, such as decreasing the binding capacity of mAb to its target.


Input: Here, we introduce a novel strategy of joining a targeting moiety to a polymeric conjugate with cytostatic drug.


Input: The scFv of B1 mAb (specific for BCL1 leukemia cells) was tagged with peptide K ((VAALKEK) 4).


Input: Peptide E ((VAALEKE) 4), which forms a stable coiled coil structure heterodimer with peptide K, was assembled with the HPMA copolymers bearing doxorubicin.

HPMA

doxorubicin


Input: Such targeted polymeric conjugates possess very selective and high binding activity toward BCL1 cells.


Input: Similarly, targeted polymeric conjugates exert approximately 100 times higher cytostatic activity toward BCL1 cells in comparison to nontargeted conjugates in vitro.


Input: At the same time, the conjugates have comparable and rather low cytostatic activity for 38C13 cells, which are used as a negative control, in vitro.


Input: Dopamine D2 receptor activation leads to an up-regulation of glial cell line-derived neurotrophic factor via G beta gamma-Erk1/2-dependent induction of Zif268.

Dopamine


Input: Glial cell line-derived neurotrophic factor (GDNF) is a potent growth factor essential to the development, survival, and function of dopaminergic neurons (Airaksinen and Saarma 2002).


Input: The molecular mechanisms underlying GDNF expression remain elusive; thus, we set out to identify a signaling pathway that governs GDNF levels.


Input: We found that treatment of both differentiated dopaminergic-like SH-SY5Y cells and rat midbrain slices with the dopamine D2 receptor (D2R) agonist, quinpirole, triggered an increase in the expression of GDNF that was temporally preceded by an increase in the levels of zinc-finger protein 268 (Zif268), a DNA-binding transcription factor encoded by an immediate-early gene.

dopaminergic

quinpirole

zinc


Input: Moreover, the D2R inhibitor raclopride blocked the increase of both GDNF and Zif268 expression following potassium-evoked dopamine release in SH-SY5Y cells.

raclopride

potassium

dopamine


Input: We used adenoviral delivery of small hairpin RNA (shRNA) targeting Zif268 to down-regulate its expression and found that Zif268 is specifically required for the D2R-mediated up-regulation of GDNF.


Input: Furthermore, the D2R-mediated induction of GDNF and Zif268 expression was dependent on G beta gamma-mediated signaling and activation of extracellular signal-regulated kinase 1/2.


Input: Importantly, using chromatin immunoprecipitation assay, we identified a direct association of Zif268 with the GDNF promoter.


Input: These results suggest that D2R activation induces a G beta gamma-and extracellular signal-regulated kinase 1/2-dependent increase in the level of Zif268, which functions to directly up-regulate the expression of GDNF.


Input: Fast protein motions are coupled to enzyme H-transfer reactions.

H


Input: Coupling of fast protein dynamics to enzyme chemistry is controversial and has ignited considerable debate, especially over the past 15 years in relation to enzyme-catalyzed H-transfer.

H


Input: H-transfer can occur by quantum tunneling, and the temperature dependence of kinetic isotope effects (KIEs) has emerged as the " gold standard " descriptor of these reactions.

H


Input: The anomalous temperature dependence of KIEs is often rationalized by invoking fast motions to facilitate H-transfer, yet crucially, direct evidence for coupled motions is lacking.

H


Input: The fast motions hypothesis underpinning the temperature dependence of KIEs is based on inference.


Input: Here, we have perturbed vibrational motions in pentaerythritol tetranitrate reductase (PETNR) by isotopic substitution where all non-exchangeable atoms were replaced with the corresponding heavy isotope ((13) C, (15) N, and (2) H).

pentaerythritol tetranitrate

(13) C

(15) N

(2) H


Input: The KIE temperature dependence is perturbed by heavy isotope labeling, demonstrating a direct link between (promoting) vibrations in the protein and the observed KIE.


Input: Further we show that temperature-independent KIEs do not necessarily rule out a role for fast dynamics coupled to reaction chemistry.


Input: We show causality between fast motions and enzyme chemistry and demonstrate how this impacts on experimental KIEs for enzyme reactions.


Input: Cis-trans isomerizations of proline residues are key to bradykinin conformations.

proline

bradykinin


Input: A recent ion mobility-mass spectrometry (IM-MS) study of the nonapeptide bradykinin (BK, amino acid sequence Arg (1)-Pro (2)-Pro (3)-Gly (4)-Phe (5)-Ser (6)-Pro (7)-Phe (8)-Arg (9)) found evidence for 10 populations of conformations that depend upon the solution composition [J. Am. Chem. Soc. 2011, 133, 13810].

bradykinin

amino acid

Arg

Pro

Pro

Gly

Phe

Ser

Pro

Phe

Arg


Input: Here, the role of the three proline residues (Pro (2), Pro (3), and Pro (7)) in establishing these conformations is investigated using a series of seven analogue peptides in which combinations of alanine residues are substituted for prolines.

proline

Pro

Pro

Pro

alanine

prolines


Input: IM-MS distributions of the analogue peptides, when compared to the distribution for BK, indicate the multiple structures are associated with different combinations of cis and trans forms of the three proline residues.

proline


Input: These data are used to assign the structures to different peptide populations that are observed under various solution conditions.


Input: The assignments also show the connectivity between structures when collisional activation is used to convert one state into another.


Input: REMNANT UPTAKE AS A POSTOPERATIVE ONCOLOGIC QUALITY INDICATOR.


Input: BACKGROUND: The purpose of this study was to examine the utility of remnant uptake on postoperative radioiodine scans as an oncologic indicator after thyroidectomy for differentiated thyroid cancer (DTC).

radioiodine


Input: METHODS: We conducted a retrospective review of patients undergoing total thyroidectomy for DTC and subsequent radioactive iodine (RAI) treatment.

iodine


Input: Of the eight surgeons included, three were considered high volume, performing at least 20 thyroidectomies per year.


Input: Patients with distant metastases at diagnosis or poorly differentiated variants were excluded.


Input: To control for the effect of varying RAI doses, the remnant uptake was analyzed as a ratio of the percentage uptake to the dose received (uptake to dose ratio, UDR).


Input: Multivariate logistic regression was used to determine the influence of UDR on recurrence.


Input: RESULTS: Of the 223 patients who met inclusion criteria, 21 patients (9. 42%) experienced a recurrence.


Input: Those who recurred had a ten-fold higher UDR compared to those who did not recur (0. 030 vs. 0. 003, p = 0. 001).


Input: Similarly, patients with increasing postoperative thyroglobulin measurements (0. 339 vs. 0. 003, p < 0. 001) also had significantly greater UDRs compared to those with stable thyroglobulin.


Input: The UDRs of high volume surgeons were significantly smaller than low volume surgeons (0. 003 vs. 0. 025, p = 0. 002).


Input: When combined with other known predictors for recurrence, UDR (OR 3. 71, C. I 1. 05-13. 10, p = 0. 041) was significantly associated with recurrence.


Input: High volume surgeons maintained a low level of permanent complications across all UDRs whereas low volume surgeons had greater permanent complications associated with higher uptake.


Input: Mdm2 and MdmX inhibitors for the treatment of cancer: a patent review (2011-present).


Input: INTRODUCTION: One of the hallmarks of cancer cells is the inactivation of the p53 pathway either due to mutations in the p53 gene or over-expression of negative regulators, Mdm2 and/or MdmX.


Input: Pharmacological disruption of the Mdm2/X-p53 interaction to restore p53 activity is an attractive concept, aiming at a targeted and non-toxic cancer treatment.


Input: AREAS COVERED: The introduction covers the biological role of p53 pathway and its regulation by Mdm2 and MdmX in normal and cancer cells and the current repertoire and development status of inhibitors of the Mdm2/X-p53 interaction for the treatment of cancer.


Input: The main part of the article covers patents and patent applications describing small molecule inhibitors of the Mdm2/X-p53 interaction published from 2011 until 2012.


Input: EXPERT OPINION: The area of small molecule Mdm2/X-p53 interaction inhibitor development is progressing fast.


Input: Several Phase I clinical studies and preclinical programs are now in progress, however, the clinical proof concept has yet to be demonstrated.


Input: Multiple available compounds inhibit Mdm2-p53 interaction with nanomolar affinities, but MdmX is still missing such potent binders.


Input: Since research points to a complementary mode of Mdm2 and MdmX action, the future compound classes will possibly want to include dual actions versus Mdm2 and MdmX.


Input: Enter the matrix: shape, signal and superhighway.


Input: Mammalian skeletal muscle is notable for both its highly ordered biophysical structure and its regenerative capacity following trauma.


Input: Critical to both of these features is the specialized muscle extracellular matrix, comprising both the multiple concentric sheaths of connective tissue surrounding structural units from single myofibers to whole muscles and the dense interstitial matrix that occupies the space between them.


Input: Extracellular matrix-dependent interactions affect all activities of the resident muscle stem cell population (the satellite cells), from maintenance of quiescence and stem cell potential to the regulation of proliferation and differentiation.


Input: This review focuses on the role of the extracellular matrix in muscle regeneration, with a particular emphasis on regulation of satellite-cell activity.


Input: Synthesis and biological evaluation of 5-nitropyrimidine analogs with azabicyclic substituents as GPR119 agonists.

azabicyclic


Input: 5-Nitropyrimidine analogs substituted with conformationally restricted azabicyclic amines and alcohols were prepared and evaluated their agonistic activity against human GPR119.

azabicyclic amines and alcohols


Input: The analogs bearing endo-azabicyclic amines and alcohols (7, 8, 11, and 12) exhibited full agonistic activities while the analogs with exo-azabicyclic amines and alcohols were proved as partial agonists (9, 10, 13, and 14) regardless of their EC (50) values.

endo-azabicyclic amines and alcohols

exo-azabicyclic amines and alcohols


Input: 5-Nitropyrimidine analogs with (2-fluoro-4-methylsulfonyl) phenylamino group (8, 10, 12, 14) showed more potent GPR119 activation activities than the analogs without fluorine in all cases (7, 9, 11, 13).

(2-fluoro-4-methylsulfonyl) phenylamino

fluorine


Input: 2', 4'-BNA/LNA aptamers: CE-SELEX using a DNA-based library of full-length 2'-O, 4'-C-methylene-bridged/linked bicyclic ribonucleotides.

2'-O, 4'-C-methylene-bridged/linked bicyclic ribonucleotides


Input: DNA-based aptamers that contain 2'-O, 4'-C-methylene-bridged/linked bicyclic ribonucleotides (B/L nucleotides) over the entire length were successfully obtained using a capillary electrophoresis systematic evolution of ligands by exponential enrichment (CE-SELEX) method.

2'-O, 4'-C-methylene-bridged/linked bicyclic ribonucleotides

nucleotides


Input: A modified DNA library was prepared with an enzyme mix of KOD Dash and KOD mutant DNA polymerases.


Input: Forty 2'-O, 4'-C-methylene bridged/locked nucleic acid (2', 4'-BNA/LNA) aptamers were isolated from an enriched pool and classified into six groups according to their sequence.

methylene


Input: 2', 4'-BNA/LNA aptamers of groups V and VI bound human thrombin with K (d) values in the range of several 10 nanomolar levels.


Input: Discovery and structure-activity relationships of small molecules that block the human immunoglobulin G-human neonatal Fc receptor (hIgG-hFcRn) protein-protein interaction.


Input: The neonatal Fc receptor, FcRn, prolongs the half-life of IgG in the serum and represents a potential therapeutic target for the treatment of autoimmune disease.


Input: Small molecules that block the protein-protein interactions of human IgG-human FcRn may lower pathogenic autoantibodies and provide effective treatment.


Input: A novel class of quinoxalines has been discovered as antagonists of the IgG: FcRn protein-protein interaction through optimization of a hit derived from a virtual ligand-based screen.

quinoxalines


Input: 3'-R/S-Hydroxyvoacamine, a potent acetylcholinesterase inhibitor from Tabernaemontana divaricata.


Input: Guided by the acetylcholinesterase inhibiting activity, the bisindole alkaloid 3'-R/S-hydroxyvoacamine was isolated from a stem extract of Tabernaemontana divaricata, a plant used in Thailand in traditional rejuvenation remedies for improving the memory.

bisindole alkaloid 3'-R/S-hydroxyvoacamine


Input: The structure of the alkaloid was elucidated by extensive use of NMR spectroscopy and the complete assignment of the (1) H and (13) C NMR spectra is reported.

(1) H

(13) C


Input: The alkaloid acted as a non-competitive inhibitor against AChE with an IC50 value of 7. 00 +/- 1. 99 mu M.


Input: An HPLC method was developed for the quantitative analysis of the AChE inhibitor.


Input: It suggested that there was 12. 4% (w/w) of 3'-R/S-hydroxyvoacamine in the alkaloid enriched fraction of T. divaricata stem.


Input: Of marsupials and men: " Backdoor " dihydrotestosterone synthesis in male sexual differentiation.

dihydrotestosterone


Input: Following development of the fetal bipotential gonad into a testis, male genital differentiation requires testicular androgens.

androgens


Input: Fetal Leydig cells produce testosterone that is converted to dihydrotestosterone in genital skin, resulting in labio-scrotal fusion.

testosterone

dihydrotestosterone


Input: An alternative' backdoor' pathway of dihydrotestosterone synthesis that bypasses testosterone has been described in marsupials, but its relevance to human biology has been uncertain.

dihydrotestosterone

testosterone


Input: The classic and backdoor pathways share many enzymes, but a 3 alpha-reductase, AKR1C2, is unique to the backdoor pathway.


Input: Human AKR1C2 mutations cause disordered sexual differentiation, lending weight to the idea that both pathways are required for normal human male genital development.


Input: These observations indicate that fetal dihydrotestosterone acts both as a hormone and as a paracrine factor, substantially revising the classic paradigm for fetal male sexual development.

dihydrotestosterone


Input: Long-range interactions in the alpha subunit of tryptophan synthase help to coordinate ligand binding, catalysis, and substrate channeling.

tryptophan


Input: The alpha-subunit of tryptophan synthase (alpha TS) catalyzes the conversion of indole-3-glycerol phosphate to d-glyceraldehyde-3-phosphate and indole.

tryptophan

indole-3-glycerol phosphate

indole


Input: We propose that allosteric networks intrinsic to alpha TS are modulated by the binding of the beta-subunit to regulate alpha TS function.


Input: Understanding these long-range amino acid networks in alpha TS thus gives insight into the coordination of the two active sites within TS.

amino acid


Input: In this study, we have used Ala residues as probes for structural and dynamic changes of alpha TS throughout its catalytic cycle, in the absence of the beta-subunit.

Ala


Input: Projection analysis of the chemical shift changes by site-specific amino acid substitutions and ligand titrations indicates that alpha TS has three important conformational states: ligand-free, glyceraldehyde-3-phosphate-bound (like), and the active states.

amino acid


Input: The amino acid networks within these conformations are different, as suggested by chemical shift correlation analysis.

amino acid


Input: In particular, there are long-range connections, only in the active state, between Ala47, which reports on structural and dynamic changes associated with the general acid/base Glu49, and residues within the beta 2 alpha 2 loop, which contains the catalytically important Asp60 residue.


Input: These long-range interactions are likely important for coordinating chemical catalysis.


Input: In the free state, but not in the active state, there are connections between the beta 2 alpha 2 and beta 6 alpha 6 loops that likely help to coordinate substrate binding.


Input: Changes in the allosteric networks are also accompanied by protein dynamic changes.


Input: During catalytic turnover, the protein becomes more rigid on the millisecond timescale and the active-site dynamics are driven to a faster nanosecond timescale.


Input: Fibroblast-mediated drug resistance in cancer.


Input: Tumor progression relies upon the dynamic interaction of cancer cells with host fibroblasts, endothelial cells, immune cells and components of the extracellular matrix, collectively known as the tumor microenvironment.


Input: Despite this, relatively little is known about how normal host cells dictate the response of tumors to anti-cancer therapies.


Input: Emerging data suggests that host factors play a critical role in determining risks for tumor progression and decreased therapeutic responses.


Input: In particular, recent findings have provided evidence that the tumor microenvironment provides a protective niche that allows minor populations of cancer cells to escape from the cytotoxic effects of radiation, chemotherapy and targeted therapies.


Input: In this review we will outline the mechanisms by which tumor cells and host fibroblasts co-operate to drive tumor initiation and progression.


Input: In particular, we will focus upon the mechanisms by which tumor cells exposed to targeted therapies co-opt the host leading to therapeutic escape and resistance.


Input: We will end by discussing the idea that long-term responses to targeted anticancer therapies will only be achieved through strategies that target both the tumor and host.


Input: Characterization of the mouse promoter region of the acyl-CoA synthetase 4 gene: role of Sp1 and CREB.

acyl-CoA


Input: Acyl-CoA synthetase 4 (Acsl4) is involved in several cellular functions including steroidogenesis, synaptic development and cancer metastasis.

Acyl-CoA


Input: Although the expression of Acsl4 seems to be regulated by tissue-and cell-specific factors as well as pituitary hormones and growth factors, the transcriptional mechanisms involved remain unknown.


Input: We demonstrated hCG and cAMP regulation of Acsl4 mRNA in mouse steroidogenic MA-10 Leydig cells.

cAMP


Input: We characterized the transcription initiation site and promoter of the Acsl4 mouse gene and identified three alternative splice variants present in MA-10 cells.


Input: Sequence analysis of a 1. 5-kb fragment of the Acsl4 promoter revealed the absence of a TATA box and the presence of many putative binding sites for transcription factors including Sp1 and CREB.


Input: Functional characterization revealed that the specificity protein/Kr u ppel-like factor Sp1 binding site in the proximal promoter is involved in basal activity and that the cAMP response element-binding site is involved in cAMP stimulation of Acsl4 transcription.

cAMP

cAMP


Input: Synthesis and biological evaluation of thieno [2', 3': 4, 5] pyrimido [1, 2-b] [1, 2, 4] triazines and thieno [2, 3-d] [1, 2, 4] triazolo [1, 5-a] pyrimidines as anti-inflammatory and analgesic agents.

thieno [2', 3': 4, 5] pyrimido [1, 2-b] [1, 2, 4] triazines

thieno [2, 3-d] [1, 2, 4] triazolo [1, 5-a] pyrimidines


Input: A new series of thieno [2', 3': 4, 5] pyrimido [1, 2-b] [1, 2, 4] triazines and thieno [2, 3-d] [1, 2, 4] triazolo [1, 5-a] pyrimidines was synthesized.

thieno [2', 3': 4, 5] pyrimido [1, 2-b] [1, 2, 4] triazines

thieno [2, 3-d] [1, 2, 4] triazolo [1, 5-a] pyrimidines


Input: The newly synthesized compounds were evaluated for their anti-inflammatory and analgesic activity using diclofenac Na as a reference standard.

diclofenac Na


Input: Additionally, the ulcerogenic effects and acute toxicity (ALD50) values of the active compounds were also determined.


Input: In general, the thieno [2, 3-d] [1, 2, 4] triazolo [1, 5-a] pyrimidine derivatives exhibited better biological activities than the thieno [2', 3': 4, 5] pyrimido [1, 2-b] [1, 2, 4] triazines.

thieno [2, 3-d] [1, 2, 4] triazolo [1, 5-a] pyrimidine

thieno [2', 3': 4, 5] pyrimido [1, 2-b] [1, 2, 4] triazines


Input: Collectively, the thienotriazolopyrimidine derivatives 9, 13 and 14a were proved to display distinctive anti-inflammatory activity at the acute and subacute models as well as good analgesic profile with a delayed onset of action.

thienotriazolopyrimidine


Input: Moreover, they revealed good gastrointestinal safety profile and are well tolerated by experimental animals with high safety margin (ALD50 > 0. 3 g/kg).


Input: Molecular insight into the inhibition mechanism of cyrtominetin to alpha-hemolysin by molecular dynamics simulation.

cyrtominetin


Input: The protein alpha-hemolysin (alpha-HL) is a self-assembling exotoxin that binds to the membrane of a susceptible host cell.


Input: In this paper, experimental studies show that cyrtominetin (CTM) can inhibit the hemolytic activity of alpha-HL.

cyrtominetin

CTM


Input: To understand how CTM can affect hemolytic activity, molecular dynamics simulations were carried out for alpha-HL-CTM complex and these results were compared with the crystal structure of monomeric alpha-HL.

CTM

CTM


Input: With this approach, the analysis revealed that the inhibition of CTM involves CTM directly binding to alpha-HL.

CTM

CTM


Input: Due to the binding of CTM, the conformation of the critical " Loop " region was restrained.

CTM


Input: This mechanism was confirmed by the experimental data.


Input: These findings indicate that CTM hinders the lysis activity of alpha-HL through a novel mechanism.

CTM


Input: Influence of environmentally relevant concentrations of vinclozolin on quality, DNA integrity, and antioxidant responses of sterlet Acipenser ruthenus spermatozoa.

vinclozolin


Input: The effects of vinclozolin (VIN), an anti-androgenic fungicide, on quality, oxidative stress, DNA integrity, and ATP level of sterlet (Acipenser ruthenus) spermatozoa were investigated in vitro.

vinclozolin

VIN

ATP


Input: Fish spermatozoa were incubated with different concentrations of vinclozolin (0. 5, 2, 10, 15, 20 and 50 mu g/l) for 2h.

vinclozolin


Input: A dose-dependent reduction in spermatozoa motility and velocity was observed at concentrations of 2-50 mu g/l.


Input: A dramatic increase in DNA fragmentation was recorded at concentrations 10 mu g/l and above.


Input: After 2h exposure at higher test concentrations (10-50 mu g/l), oxidative stress was apparent, as reflected by significantly higher levels of protein and lipid oxidation and significantly greater superoxide dismutase activity.

superoxide


Input: Intracellular ATP content of spermatozoa decreased with increasing concentrations of VIN.

ATP

VIN


Input: The results demonstrated that VIN can induce reactive oxygen species stress in fish spermatozoa, which could impair the sperm quality, DNA integrity, ATP content, and the antioxidant defense system.

VIN

oxygen

ATP


Input: Elimination and utilization of oxidized guanine nucleotides in the synthesis of RNA and its precursors.

guanine nucleotides


Input: Reactive oxygen species are produced as side products of oxygen utilization and can lead to the oxidation of nucleic acids and their precursor nucleotides.

oxygen

oxygen

nucleotides


Input: Among the various oxidized bases, 8-oxo-7, 8-dihydroguanine seems to be the most critical during the transfer of genetic information because it can pair with both cytosine and adenine.

8-oxo-7, 8-dihydroguanine

cytosine

adenine


Input: During the de novo synthesis of guanine nucleotides, GMP is formed first, and it is converted to GDP by guanylate kinase.

guanine nucleotides

GMP

GDP

guanylate


Input: This enzyme hardly acts on an oxidized form of GMP (8-oxo-GMP) formed by the oxidation of GMP or by the cleavage of 8-oxo-GDP and 8-oxo-GTP by MutT protein.

GMP

GMP


Input: Although the formation of 8-oxo-GDP from 8-oxo-GMP is thus prevented, 8-oxo-GDP itself may be produced by the oxidation of GDP by reactive oxygen species.

GDP

oxygen


Input: The 8-oxo-GDP thus formed can be converted to 8-oxo-GTP because nucleoside-diphosphate kinase and adenylate kinase, both of which catalyze the conversion of GDP to GTP, do not discriminate 8-oxo-GDP from normal GDP.

nucleoside-diphosphate

adenylate

GDP

GTP

GDP


Input: The 8-oxo-GTP produced in this way and by the oxidation of GTP can be used for RNA synthesis.

GTP


Input: This misincorporation is prevented by MutT protein, which has the potential to cleave 8-oxo-GTP as well as 8-oxo-GDP to 8-oxo-GMP.


Input: When (14) C-labeled 8-oxo-GTP was applied to CaCl2-permeabilized cells of a mutT (-) mutant strain, it could be incorporated into RNA at 4% of the rate for GTP.

(14) C-labeled 8-oxo-GTP

GTP


Input: Escherichia coli cells appear to possess mechanisms to prevent misincorporation of 8-oxo-7, 8-dihydroguanine into RNA.

8-oxo-7, 8-dihydroguanine


Input: Bradykinin modulates spontaneous nerve growth factor production and stretch-induced ATP release in human urothelium.

Bradykinin

ATP


Input: The urothelium plays a crucial role in integrating urinary bladder sensory outputs, responding to mechanical stress and chemical stimulation by producing several diffusible mediators, including ATP and, possibly, neurotrophin nerve growth factor (NGF).

ATP


Input: Such urothelial mediators activate underlying afferents and thus may contribute to normal bladder sensation and possibly to the development of bladder overactivity.


Input: The muscle-contracting and pain-inducing peptide bradykinin is produced in various inflammatory and non-inflammatory pathologies associated with bladder overactivity, but the effect of bradykinin on human urothelial function has not yet been characterized.

bradykinin

bradykinin


Input: The human urothelial cell line UROtsa expresses mRNA for both B1 and B2 subtypes of bradykinin receptors, as determined by real-time PCR.

bradykinin


Input: Bradykinin concentration-dependently (pEC50 = 8. 3, Emax 4434 +/- 277nM) increased urothelial intracellular calcium levels and induced phosphorylation of the mitogen-activated protein kinase (MAPK) ERK1/2.

Bradykinin


Input: Activation of both bradykinin-induced signaling pathways was completely abolished by the B2 antagonist icatibant (1 mu M), but not the B1 antagonist R715 (1 mu M).

bradykinin


Input: Bradykinin-induced (100nM) B2 receptor activation markedly increased (192 +/- 13% of control levels) stretch-induced ATP release from UROtsa in hypotonic medium, the effect being dependent on intracellular calcium elevations.

Bradykinin

ATP


Input: UROtsa cells also expressed mRNA and protein for NGF and spontaneously released NGF to the medium in the course of hours (11. 5 +/- 1. 4pgNGF/mgprotein/h).


Input: Bradykinin increased NGF mRNA expression and accelerated urothelial NGF release to 127 +/- 5% in a protein kinase C-and ERK1/2-dependent manner.

Bradykinin


Input: Finally, bradykinin up-regulated mRNA for transient-receptor potential vanilloid (TRPV1) sensory ion channel in UROtsa.

bradykinin


Input: In conclusion, we show that bradykinin represents a versatile modulator of human urothelial phenotype, accelerating stretch-induced ATP release, spontaneous release of NGF, as well as expression of sensory ion channel TRPV1.

bradykinin

ATP


Input: Bradykinin-induced changes in urothelial sensory function might contribute to the development of bladder dysfunction.

Bradykinin


Input: 3, 3'-Diindolymethane ameliorates adriamycin-induced cardiac fibrosis via activation of a BRCA1-dependent anti-oxidant pathway.

3, 3'-Diindolymethane

adriamycin


Input: The cardiotoxicity of adriamycin greatly limits its application in the treatment of cancer.

adriamycin


Input: Heart failure that is caused by adriamycin-treatment induced cardiac fibrosis is a major cause of death in patients who are treated with this medication.

adriamycin


Input: The severe oxidative stress that is induced by adriamycin is considered to be one of the primary mechanisms by which fibrogenesis of cardiac tissue occurs.

adriamycin


Input: In the present study, we demonstrate that 3, 3'-diindolymethane (DIM) exhibits a significant anti-fibrosis effect on cardiac tissue in an animal model of adriamycin-induced cardiac fibrosis (AICF).

3, 3'-diindolymethane

DIM

adriamycin


Input: Further studies demonstrated that DIM is able to dramatically up-regulate the expression of breast cancer type 1 susceptibility protein (BRCA1) in cardiac tissue and fibroblast, which subsequently activate the transcription factor Nuclear factor (erythroid-derived 2)-like 2 (Nrf2).

DIM


Input: The upregulation of this transcription factor resulted in the expression of several anti-oxidant genes in the cell.


Input: Because DIM is a safe food additive that has been used for decades, our findings suggest that there is a great potential for this chemical to be developed into a clinical medication for the treatment of adriamycin-induced heart failure during cancer therapy.

DIM

adriamycin


Input: PI3 k/akt inhibition induces apoptosis through p38 activation in neurons.


Input: Accumulating evidence suggests that the PI3K/AKT pathway is a pro-survival signalling system in neurons.


Input: Therefore, the inhibition of this pathway may be implicated in the degeneration of neurons in Parkinson' s disease (PD), Alzheimer' s disease (AD), and other neurological disorders.


Input: Here we study the participation of the mitogen-activated protein kinase (MAPK) pathway on apoptosis induced by PI3K/AKT inhibition in cultured cerebellar granule cells (CGCs).


Input: LY294002, a specific PI3K/AKT inhibitor, selectively activated the p38 MAPK kinase pathway and enhanced c-Jun phosphorylation, but did not activate JNK.


Input: The pharmacological inhibitors SB203580 (p38 inhibitor) and SP600125 (a JNK inhibitor) protected primary cultures of rat CGCs from LY294002-induced apoptosis.


Input: Furthermore, both compounds decreased the phosphorylation of c-Jun and lowered mRNA levels of the pro-apoptotic gene dp5, a direct target of c-Jun.


Input: Taken together, our data demonstrate that PI3K/AKT inhibition induces neuronal apoptosis, a process that is mediated by the activation of p38 MAPK/c-Jun/dp5.


Input: Gender and strain contributions to the variability of buprenorphine-related respiratory toxicity in mice.

buprenorphine


Input: While most deaths from asphyxia related to buprenorphine (BUP) overdose have been reported in males, higher plasma concentrations of BUP and its toxic metabolite norbuprenorphine (NBUP) have been observed in females.

buprenorphine

BUP

BUP

norbuprenorphine

NBUP


Input: We previously demonstrated that P-glycoprotein (P-gp) modulation at the blood-brain barrier (BBB) contributes highly to BUP-related respiratory toxicity, by limiting NBUP entrance into the brain.

BUP

NBUP


Input: In this work, we sought to investigate the role of P-gp-mediated transport at the BBB in gender and strain-related variability of BUP and NBUP-induced respiratory effects in mice.

BUP

NBUP


Input: Ventilation was studied using plethysmography, P-gp expression using western blot, and transport at the BBB using in situ cerebral perfusion.


Input: In male Fvb and Swiss mice, BUP was responsible for ceiling respiratory effects.

BUP


Input: NBUP-related reduction in minute volume was dose-dependent but more marked in Fvb (p < 0. 01 at 1mg/kg NBUP and p < 0. 001 at 3 and 9mg/kg NBUP) than in Swiss mice (p < 0. 001 at 9mg/kg NBUP).

NBUP

NBUP

NBUP

NBUP


Input: Female Fvb mice were more susceptible to BUP than males with significantly increased inspiratory time (p < 0. 05) and to NBUP with significantly increased expiratory time (p < 0. 01).

BUP

NBUP


Input: Following BUP administration, plasma BUP concentrations were significantly higher (p < 0. 01) and plasma NBUP concentrations significantly lower (p < 0. 001) in Fvb mice compared to Swiss mice.

BUP

BUP

NBUP


Input: Plasma BUP concentrations were significantly higher (p < 0. 05) and plasma NBUP concentrations significantly lower (p < 0. 01) in male compared to female Fvb mice.

BUP

NBUP


Input: In contrast, following NBUP administration, comparable plasma NBUP concentrations were observed in both genders and strains.

NBUP

NBUP


Input: No differences in P-gp expression or BUP and NBUP transport across the BBB were observed between male and female Fvb mice as well as between Swiss and Fvb mice.

BUP

NBUP


Input: Our results suggest that P-gp-mediated transport across the BBB does not play a key-role in gender and strain-related variability in BUP and NBUP-induced respiratory toxicity in mice.

BUP

NBUP


Input: Both gender-and strain-related differences in respiratory effects of BUP could be attributed to BUP itself rather than to its metabolite, NBUP.

BUP

BUP

NBUP


Input: Absence of CC chemokine receptors 2a and 2b from human adipose lineage cells.


Input: Previous results have suggested the existence of receptors for monocyte chemoattractant protein-1 (MCP-1), CC chemokine receptors 2 (CCR2), in human adipocytes and their involvement in mediating effects of MCP-1 on adipocyte functions.


Input: However, the presence of CCR2 present on non-adipose-lineage cells of adipose tissue has not been excluded.


Input: We have used human Simpson-Golabi-Behmel-Syndrome (SGBS) preadipocytes and in-vitro-differentiated mature adipocytes to investigate the expression of CCR2 in human (pre) adipocytes.


Input: We found that the cells are devoid of CCR2 receptor protein and mRNA expression and fail to respond to treatment with all known CCR2 chemokine agonists.


Input: CCR2 is also absent from (pre) adipocytes prepared in vitro from human multipotent adipose-derived stem cells, bone-marrow-derived mesenchymal stem cells, or from primary (pre) adipocytes.


Input: Conditions mimicking proinflammatory changes in adipose tissue did not induce CCR2 receptor expression.


Input: We conclude that CCR2 is absent from human adipose lineage cells.


Input: Functional effects previously described for MCP-1 in human adipose tissue may be mediated indirectly through paracrine effects on non-adipose-lineage cells or by a (pre) adipocyte receptor for MCP-1 distinct from CCR2.


Input: FGF signalling through Fgfr2 isoform IIIb regulates adrenal cortex development.


Input: Developmental signalling pathways are implicated in the formation and maintenance of the adrenal gland, but their roles are currently not well defined.


Input: In recent years it has emerged that Sonic hedgehog (Shh) and Wnt/beta catenin signalling are crucial for the growth and development of the adrenal cortex.


Input: Here we demonstrate that Fibroblast growth factor receptor (Fgfr) 2 isoforms IIIb and IIIc are expressed mainly in the adrenal subcapsule during embryogenesis and that specific deletion of the Fgfr2 IIIb isoform impairs adrenal development, causing reduced adrenal growth and impaired expression of SF1 and steroidogenic enzymes.


Input: The hypoplastic adrenals also have thicker, disorganised capsules which retain Gli1 expression but no longer express Dlk1.


Input: Fgfr2 ligands were detected in both the capsule and the cortex, suggesting the importance of signalling between the capsule and the cortex in adrenal development.


Input: Changes in skeletal muscle proteolytic gene expression after prophylactic supplementation of EGCG and NAC and eccentric damage.

EGCG

NAC


Input: PURPOSE: The impact of prophylactic supplementation of N-acetyl-cysteine (NAC) and epigallocatechin gallate (EGCG) on intramuscular expression of proteolytic genes after unaccustomed eccentric muscle contractions was investigated.

N-acetyl-cysteine

NAC

epigallocatechin gallate

EGCG


Input: METHODS: Thirty apparently healthy males (mean +/- SD: 20. 0 +/- 1. 8years, 175 +/- 7. 1cm, 76. 1 +/- 16. 9kg) ingested daily either 1800mg of NAC or 1800mg of EGCG (98% total polyphenols, 80% total catechins, and 50% EGCG), or 1000mg of a glucomannan placebo (PLA) in a double blind, prophylactic fashion for 14days.

NAC

EGCG

polyphenols

catechins

EGCG


Input: Subjects then completed an unaccustomed eccentric exercise bout (100 repetitions at 30 degrees s (-1)) using the dominant knee extensors.


Input: Skeletal muscle biopsies were collected from the vastus lateralis at baseline and both 6 and 24h after exercise.


Input: The expression of proteolytic genes [i. e., muscle ring-finger 1 (MuRF1), atrogin-1, alpha-type 20S subunit C2 (HC2), alpha-type 20S subunit C3 (HC3), ubiquitin protein ligase 3B (UBE3B), mu-calpain, and m-calpain] was quantified using real-time RT-PCR.


Input: Separate 3 x 3 (group x time) repeated measures ANOVAs were used to analyze changes in gene expression over time between groups.


Input: RESULTS: No significant group x time interactions were detected between groups for the expression of any of the atrogenes or calpains (p > 0. 05).


Input: Significant main effects for time identified increases in MuRF1 (6h: 5. 3 +/- 10. 8 fold; p = 0. 046), UBE3B (6h: 5. 3 +/- 7. 7 fold; p = 0. 006; 24h: 3. 3 +/- 4. 5 fold; p = 0. 005), and m-calpain expression (6h: 2. 7 +/- 4. 4 fold; p = 0. 045) in all participants following exercise.


Input: Increases approached significance in HC2 (6h: 1. 9 +/- 2. 4 fold; p = 0. 079; 24h: 1. 6 +/- 1. 9 fold; p = 0. 084) and m-calpain expression (24h: 1. 8 +/- 2. 3 fold; p = 0. 084) following exercise.


Input: CONCLUSIONS: Prophylactic supplementation of NAC and EGCG did not impact acute changes in skeletal muscle proteolytic gene expression following eccentric exercise.

NAC

EGCG


Input: Eccentric muscle contractions elevated MuRF1 and UBE3B, while m-calpain and HC2 mRNA tended to increase.


Input: Lead at 2. 5 and 5. 0 mu M induced aberrant MH-II surface expression through increased MII exocytosis and increased autophagosome formation in Raw 267. 4 cells.


Input: Aberrant major histocompatibility complex class II (MHC-II) surface expression on antigen presenting cells (APCs) is associated with dysregulated immune homeostasis.


Input: Lead (Pb) is known to increase MHC-II surface expression on murine peritoneal macrophages ex vivo at concentrations exceeding 25 mu M.

Pb


Input: Little data exist examining this effect at physiologically relevant concentrations.


Input: To address this deficit, we examined the effects of Pb on MHC-II surface expression, secondary T-cell activation markers (CD80, CD86, CD40), cell viability, cellular metabolic activity, and beta-hexosaminidase activity in RAW 267. 4 macrophage cell lines, with changes in cell ultrastructure evaluated by electron and confocal microscopy.

Pb


Input: Pb induced an increase in MHC-II, CD86, and lysosome-associated LAMP-1 and LAMP-2 surface mean expression during one doubling cycle (17 h), which was mirrored by increased beta-hexosaminidase activity.

Pb


Input: Although cell viability was unaffected, cellular metabolism was inhibited.


Input: Electron microscopy revealed evidence of lipid vacuolization, macroautophagy and myelin figure formation in cells cultured with either Pb or LPS.

Pb


Input: Confocal microscopy with antibodies against LC3B showed a punctate pattern consistent with the presence of mature autophagosomes.


Input: Collectively, these data suggest that 2. 5-5. 0 mu M Pb increased MHC-II surface expression by inhibiting metabolic activity, inducing autophagy, and increasing MHC-II trafficking in a macrophage cell line.

Pb


Input: Prenatal developmental toxicity studies on diundecyl and ditridecyl phthalates in Sprague-Dawley rats.

diundecyl and ditridecyl phthalates


Input: This study evaluates the developmental toxicity of two high molecular weight dialkyl phthalate esters, diundecyl phthalate (DUDP) and ditridecyl phthalate (DTDP).

dialkyl phthalate esters

diundecyl phthalate

DUDP

ditridecyl phthalate

DTDP


Input: Sprague-Dawley rats were administered 0, 0. 25, 0. 50, or 1g/kg/day of DUDP or DTDP, by gavage, on gestation days 6-20.

DUDP

DTDP


Input: DUDP and DTDP had no adverse effects on maternal body weight and food consumption.

DUDP

DTDP


Input: The number of live fetuses, percent of post-implantation loss and of resorptions, fetal sex, and fetal body weights were not affected by either phthalate.

phthalate


Input: There was no evidence of teratogenicity, whatever treatment.


Input: Small decreases in the anogenital distance of male fetuses were noted at 0. 5 and 1g DUDP/kg/day.

DUDP


Input: The incidence of fetuses with supernumerary lumbar ribs was significantly higher than control at 0. 5 and 1g DUDP/kg/day.

DUDP


Input: Thus, DTDP was not developmentally toxic up to 1g/kg/day and there were signs of DUDP-induced fetal effects at 0. 5 and 1g/kg/day.

DTDP

DUDP


Input: Optimal dosing of warfarin and other coumarin anticoagulants: the role of genetic polymorphisms.

warfarin

coumarin


Input: Coumarin anticoagulants, which include warfarin, acenocoumarol and phenprocoumon, are among the most widely prescribed drugs worldwide.

Coumarin

warfarin

acenocoumarol

phenprocoumon


Input: There is now a large body of published data showing that genotype for certain common polymorphisms in the genes encoding the target vitamin K epoxide reductase (G-1639A/C1173T) and the main metabolizing enzyme CYP2C9 (CYP2C9 * 2 and * 3 alleles) are important determinants of the individual coumarin anticoagulant dose requirement.

vitamin K epoxide

coumarin


Input: Additional less common polymorphisms in these genes together with polymorphisms in other genes relevant to blood coagulation such as the cytochrome P450 CYP4F2, gamma-glutamyl carboxylase, calumenin and cytochrome P450 oxidoreductase may also be significant predictors of dose, especially in ethnic groups such as Africans where there have been fewer genetic studies compared with European populations.

gamma-glutamyl


Input: Using relevant genotypes to calculate starting dose may improve safety during the initiation period.


Input: Various algorithms for dose calculation, which also take patient age and other characteristics into consideration, have been developed for all three widely used coumarin anticoagulants and are now being tested in ongoing large randomised clinical trials.

coumarin


Input: One recently completed study has provided encouraging results suggesting that calculation of warfarin dose on the basis of individual patient genotype leads to few adverse events and a higher proportion of time within the therapeutic coagulation rate window, but these findings still need confirmation.

warfarin


Input: Effects of caffeine and alcohol on mood and performance changes following consumption of lager.

caffeine

alcohol


Input: RATIONALE: The present study examined whether caffeine would modify the behavioural effects of alcohol.

caffeine

alcohol


Input: OBJECTIVES: The aim of the study was to determine whether caffeine modifies the effects of alcohol on mood and psychomotor performance and to identify possible dose-response and temporal relationships.

caffeine

alcohol


Input: METHODS: A double-blind study examined the effects of three successive lager drinks (330 ml each) in the early afternoon on mood and psychomotor performance assessed at 30-min intervals over a 2-h period.


Input: Participants carried out a baseline session and were then randomly assigned to one of six conditions formed by combining three different doses of caffeine (0, 62. 5 and 125 mg per drink) with either no alcohol or 4. 3% alcohol.

caffeine

alcohol

alcohol


Input: One hundred and forty-six young adults (65 male, 81 female; age range 18-30 years) participated in the study.


Input: Mood (alertness, hedonic tone and anxiety) was assessed before and after performing simple reaction time and choice reaction time tasks.


Input: RESULTS: Alcohol was associated with higher hedonic tone (p < 0. 005), reduced anxiety (p < 0. 05) and reduced alertness (p < 0. 005).

Alcohol


Input: Caffeine had no modifying effect on hedonic tone or anxiety.

Caffeine


Input: However, the highest dose of caffeine did remove the effect of alcohol on alertness (p < 0. 05).

caffeine

alcohol


Input: Effects of alcohol and caffeine were found on the performance tasks (all p values < 0. 05) but these were independent effects.

alcohol

caffeine


Input: CONCLUSIONS: The results from the present study confirm that caffeine does not remove the negative effects of alcohol on performance although high doses counteract the drop in subjective alertness produced by alcohol.

caffeine

alcohol

alcohol


Input: 3D Organotypic Cultures of Human HepaRG Cells: A Tool for In Vitro Toxicity Studies.


Input: Drug-induced human hepatotoxicity is difficult to predict using the current in vitro systems.


Input: In this study, long-term 3D organotypic cultures of the human hepatoma HepaRG cell line were prepared using a high-throughput hanging drop method.


Input: The organotypic cultures were maintained for 3 weeks and assessed for (1) liver specific functions, including phase I enzyme and transporter activities, (2) expression of liver-specific proteins, and (3) responses to three drugs (acetaminophen, troglitazone, and rosiglitazone).

acetaminophen

troglitazone

rosiglitazone


Input: Our results show that the organotypic cultures maintain high liver-specific functionality during 3 weeks of culture.


Input: The immunohistochemistry analyses illustrate that the organotypic cultures express liver-specific markers such as albumin, CYP3A4, CYP2E1, and MRP-2 throughout the cultivation period.


Input: Accordingly, the production rates of albumin and glucose, as well as CYP2E1 activity, were significantly higher in the 3D versus the 2D cultures.

glucose


Input: Toxicity studies show that the organotypic cultures are more sensitive to acetaminophen-and rosiglitazone-induced toxicity but less sensitive to troglitazone-induced toxicity than the 2D cultures.

acetaminophen

rosiglitazone

troglitazone


Input: Furthermore, the EC50 value (2. 7mM) for acetaminophen on the 3D cultures was similar to in vivo toxicity.

acetaminophen


Input: In summary, the results from our study suggest that the 3D organotypic HepaRG culture is a promising in vitro tool for more accurate assessment of acute and also possibly for chronic drug-induced hepatotoxicity.


Input: Mending leaky blood vessels: the angiopoietin-Tie2 pathway in sepsis.


Input: Sepsis is a systemic inflammatory response to infection.


Input: A common end-feature, these patients regularly suffer from is the so-called multiple organ dysfunction syndrome, an often fatal consequence of organ hypoperfusion, coagulopathy, immune dysregulation, and mitochondrial dysfunction.


Input: Microvascular dysfunction critically contributes to the morbidity and mortality of this disease.


Input: The angiopoietin (Angpt)/Tie2 system consists of the transmembrane endothelial tyrosine kinase Tie2 and its circulating ligands (Angpt-1,-2, and-3/4).

tyrosine


Input: The balance between the canonical agonist Angpt-1 and its competitive inhibitor, Angpt-2, regulates basal endothelial barrier function and the leakage and vascular inflammation that develop in response to pathogens and cytokines.


Input: Here we summarize recent work in mice and men to highlight the therapeutic potential in this pathway to prevent or even reverse microvascular dysfunction in this deadly disease.


Input: Implications of lipid moiety in oligomerization and immunoreactivities of GPI-anchored proteins.


Input: Glycosylphosphatidylinositol (GPI) enriches GPI-anchored proteins (GPI-AP) in lipid rafts by intimate interaction of its lipid moiety with sphingolipids and cholesterol.

sphingolipids

cholesterol


Input: In addition to such lipid-lipid interactions, it has been reported that GPI may interact with protein moiety linked to GPI and affect protein conformations because GPI delipidation reduced immunoreactivities of protein.


Input: Here, we report that GPI-APs that have not undergone fatty acid remodeling exhibit reduced immunoreactivities in Western blotting, similar to delipidated proteins, compared with normal remodeled GPI-APs.

fatty acid


Input: In contrast, immunostaining in flow cytometry and immunoprecipitation did not show significant differences between remodeled and unremodeled GPI-APs.


Input: Moreover, detection with premixed primary/secondary antibody complexes or Fab fragments eliminated this difference in Western blotting.


Input: These results indicate that normally remodeled GPI enhanced oligomerization of GPI-APs and that inefficient oligomerization of unremodeled GPI-APs was responsible for reduced immunoreactivities.


Input: Moreover, the reduction in immunoreactivities of delipidated GPI-APs was most likely caused by the same effect.


Input: Finally, by chemical cross-linking of surface proteins in living cells and cell killing assay using a pore-forming bacterial toxin, we showed that enhanced oligomerization by GPI-remodeling occurs under a physiological membrane environment.


Input: Thus, this study clarifies the significance of GPI fatty acid remodeling in oligomerization of GPI-APs and provides useful information for technical studies of these cell components.

fatty acid


Input: Structural Modifications to Tetrahydropyridine-3-carboxylate Esters en Route to the Discovery of M (5)-Preferring Muscarinic Receptor Orthosteric Antagonists.

Tetrahydropyridine-3-carboxylate Esters


Input: The M (5) muscarinic acetylcholine receptor is suggested to be a potential pharmacotherapeutic target for the treatment of drug abuse.

acetylcholine


Input: We describe herein the discovery of a series of M (5)-preferring orthosteric antagonists based on the scaffold of 1, 2, 5, 6-tetrahydropyridine-3-carboxylic acid.

1, 2, 5, 6-tetrahydropyridine-3-carboxylic acid


Input: Compound 56, the most selective compound in this series, possesses an 11-fold selectivity for the M (5) over M (1) receptor and shows little activity at M (2)-M (4).


Input: This compound, although exhibiting modest affinity (K (i) = 2. 24 mu M) for the [(3) H] N-methylscopolamine binding site on the M (5) receptor, is potent (IC (50) = 0. 45 nM) in inhibiting oxotremorine-evoked [(3) H] DA release from rat striatal slices.

[(3) H] N-methylscopolamine

oxotremorine

[(3) H] DA


Input: Further, a homology model of human M (5) receptor based on the crystal structure of the rat M (3) receptor was constructed, and docking studies of compounds 28 and 56 were performed in an attempt to understand the possible binding mode of these novel analogues to the receptor.


Input: Small molecule antivirulents targeting the iron-regulated heme oxygenase (HemO) of P. aeruginosa.

iron

heme


Input: Bacteria require iron for survival and virulence and employ several mechanisms including utilization of the host heme containing proteins.

iron

heme


Input: The final step in releasing iron is the oxidative cleavage of heme by HemO.

iron

heme


Input: A recent computer aided drug design (CADD) study identified several inhibitors of the bacterial HemOs.


Input: Herein we report the near complete HN, N, CO, C alpha, and C beta chemical shift assignment of the P. aeruginosa HemO in the absence and presence of inhibitors (E)-3-(4-(phenylamino) phenylcarbamoyl) acrylic acid (3) and (E)-N'-(4-(dimethylamino) benzylidene) diazenecarboximidhydrazide (5).

HN

N

CO

(E)-3-(4-(phenylamino) phenylcarbamoyl) acrylic acid

(E)-N'-(4-(dimethylamino) benzylidene) diazenecarboximidhydrazide


Input: The NMR data confirm that the inhibitors bind within the heme pocket of HemO consistent with in silico molecular dynamic simulations.

heme


Input: Both inhibitors and the phenoxy derivative of 3 have activity against P. aeruginosa clinical isolates.

phenoxy


Input: Furthermore, 5 showed antimicrobial activity in the in vivo C. elegans curing assay.


Input: Thus, targeting virulence mechanisms required within the host is a viable antimicrobial strategy for the development of novel antivirulants.


Input: Landscape heterogeneity shapes host-parasite interactions and results in apparent plant-virus codivergence.


Input: Knowledge on how landscape heterogeneity shapes host-parasite interactions is central to understand the emergence, dynamics and evolution of infectious diseases.


Input: However, this is an underexplored subject, particularly for plant-virus systems.


Input: Here, we analyse how landscape heterogeneity influences the prevalence, spatial genetic structure, and temporal dynamics of Pepper golden mosaic and Pepper huasteco yellow vein begomoviruses infecting populations of the wild pepper Capsicum annuum glabriusculum (chiltepin) in Mexico.


Input: Environmental heterogeneity occurred at different nested spatial scales (host populations within biogeographical provinces), with levels of human management varying among host population within a province.


Input: Results indicate that landscape heterogeneity affects the epidemiology and genetic structure of chiltepin-infecting begomoviruses in a scale-specific manner, probably related to conditions favouring the viruses' whitefly vector and its dispersion.


Input: Increased levels of human management of the host populations were associated with higher virus prevalence and erased the spatial genetic structure of the virus populations.


Input: Also, environmental heterogeneity similarly shaped the spatial genetic structures of host and viruses.


Input: This resulted in the congruence between host and virus phylogenies, which does not seem to be due to host-virus co-evolution.


Input: Thus, results provide evidence of the key role of landscape heterogeneity in determining plant-virus interactions.


Input: Bifunctional inhibition of HIV-1 reverse transcriptase: a first step in designing a bifunctional triphosphate.

triphosphate


Input: The onset of resistance to approved anti-AIDS drugs by HIV necessitates the search for novel inhibitors of HIV-1 reverse transcriptase (RT).


Input: Developing single molecular agents concurrently occupying the nucleoside and nonnucleoside binding sites in RT is an intriguing idea but the proof of concept has so far been elusive.

nucleoside


Input: As a first step, we describe molecular modeling to guide focused chemical syntheses of conjugates having nucleoside (d4T) and nonnucleoside (TIBO) moieties tethered by a flexible polyethylene glycol (PEG) linker.

nucleoside

TIBO

polyethylene glycol

PEG


Input: A triphosphate of d4T-6PEG-TIBO conjugate was successfully synthesized that is recognized as a substrate by HIV-1 RT and incorporated into a double-stranded DNA.

triphosphate


Input: Association of serum proprotein convertase subtilisin/kexin type 9 with carotid intima media thickness in hypertensive subjects.


Input: OBJECTIVE: The clinical significance of the measurement of serum PCSK9 (proprotein subtilisin kexin type 9) is not well defined.


Input: This study investigated the association between serum PCSK9 levels and atherosclerosis assessed by carotid intima media thickness (IMT) in hypertensive patients.


Input: METHODS: A total of 126 hypertensive patients over the age of 45 were enrolled.


Input: The maximum carotid IMT (max-IMT) and the mean carotid IMT (mean-IMT) were measured at the time of enrollment.


Input: Clinical and laboratory parameters including serum PCSK9 were analyzed.


Input: RESULTS: Patients were divided into tertiles based on serum PCSK9 levels.


Input: After adjusting for age, sex, total cholesterol, HDL-cholesterol and triglyceride, max-IMT was significantly increased in the highest tertile of serum PCSK9 (0. 969 +/- 0. 033 vs 0. 959 +/- 0. 033 vs 1. 077 +/- 0. 033mm, respectively; P = 0. 026).

cholesterol

triglyceride


Input: Mean-IMT showed a tendency to increase across the tertile groups (0. 773 +/- 0. 025 vs 0. 790 +/- 0. 026 vs 0. 856 +/- 0. 025mm, respectively; P = 0. 059).


Input: Multivariate regression analysis revealed that serum PCSK9 was independently associated with carotid IMT (max-IMT: beta = 0. 212, P = 0. 016; mean-IMT: beta = 0. 184, P = 0. 04).


Input: CONCLUSION: The present study is the first to report the association between serum PCSK9 levels and carotid IMT in hypertensive patients.


Input: These results suggest that serum PCSK9 may have a certain role in early pathogenesis of atherosclerosis.


Input: Impairing effect of amphetamine and concomitant ionotropic glutamate receptors blockade in the ventral striatum on spatial learning in mice.

amphetamine

glutamate


Input: RATIONALE: Accumulating evidence supports the involvement of the ventral striatum (VS) in spatial information processing.


Input: The multiple cortical glutamatergic and mesolimbic dopaminergic (DAergic) afferences on the same neurons in the ventral striatum provide the neuroanatomical substrate for glutamate and dopamine functional interaction.

glutamatergic

dopaminergic


Input: However, there is little evidence in the literature on how this interaction affects the ability to encode spatial information.


Input: OBJECTIVE: First, we evaluated the effect of intra-VS bilateral infusion of different doses of amphetamine (0. 3, 0. 75, and 1. 5 mu g/side) on the ability to detect spatial novelty in mice.

amphetamine


Input: Next, we examined the impact produced on the same abilities by intra-VS infusion of ineffective doses of amphetamine (0. 3 mu g/side) in association with N-methyl-D-aspartate (NMDA) (3. 125 ng/side) or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) (0. 25 ng/side) receptor antagonist.

amphetamine

N-methyl-D-aspartate

NMDA

alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid

AMPA


Input: RESULTS: The results show that infusion of amphetamine impairs detection of spatial novelty, affecting also exploratory activity and marginally the detection of nonspatial novelty.

amphetamine


Input: In contrast, an association of subthreshold doses of amphetamine with NMDA or AMPA receptor antagonists exerted a selective effect on reactivity to a spatial change.

amphetamine

NMDA

AMPA


Input: CONCLUSIONS: These findings demonstrate that enhanced DAergic activity in the VS enhances glutamate receptor antagonist-induced impairment in learning and memory.

glutamate


Input: Differential autophagic cell death under stress with ectopic cytoplasmic and mitochondrial-specific PPP2R2B in human neuroblastoma cells.


Input: Protein phosphatase 2A is one of four major classes of serine/threonine phosphatases.

serine

threonine


Input: Overexpression of brain-specific regulatory subunit PPP2R2 in neuron cells is implicated in pathogenesis.


Input: The alternative splicing of PPP2R2B encodes two isoforms.


Input: They are subunit of cytoplasmic specific B beta 1 and mitochondria-targeted B beta 2.


Input: The two constructs were transfected into human neuroblastoma cells, SK-N-SH, respectively, and the stable clones overexpressing either B beta 1 or B beta 2 established.


Input: We have reported that B beta 2 clones are sensitive to reactive oxygen species (ROS) treatment by inducing autophagic cell death.

oxygen


Input: To study more on the onset of neuropathogenesis under strain, both clones were exposed to different environmental stress, e. g. starvation and endoplasmic reticulum (ER) stress.


Input: To learn how PPP2R2B overexpression responds to starvation, cells were incubated in Hank' s buffered salt solution of deprived nutrient.


Input: Cell death was induced in B beta 1 clones after 6 h starvation, but not in B beta 2 clones.


Input: The pharmacological inhibitor, Bafilomycin A1, rescued the cell death while suppressing autophagy.

Bafilomycin A1


Input: On the other hand, to assess how cells respond to ER stress, the cells were treated with 0. 1 mu M of N-glycosylation inhibitor, tunicamycin (TM).

N

tunicamycin


Input: In contrast with B beta 1, the apoptotic cell death appeared in B beta 2 after 48 h treatment.


Input: The formation of autophagolysosome was detected in B beta 2 following 12 h treatment with TM as evidenced by lysotracker and GFP-LC3 staining for fluorescence microscopy analysis.


Input: The autophagy inhibitor, 3-methyladenine, salvaged the final apoptosis.


Input: The stable cell lines with ectopically transfected PPP2R2B genes encoding isoforms of brain-specific regulatory subunit exhibit distinct apoptosis under different stressors.


Input: The induced autophagic apoptotic cell death is related to mitochondrial membrane potential drop and ROS generation.


Input: Disturbance of autophagy alleviates the induced cell death.


Input: The results promised a good model for understanding the onset in pathogenesis under stress in neuron cells with aberrant PPP2R2B expression.


Input: A review of fabrication and applications of carbon nanotube film-based flexible electronics.

carbon


Input: Flexible electronics offer a wide-variety of applications such as flexible circuits, flexible displays, flexible solar cells, skin-like pressure sensors, and conformable RFID tags.


Input: Carbon nanotubes (CNTs) are a promising material for flexible electronics, both as the channel material in field-effect transistors (FETs) and as transparent electrodes, due to their high intrinsic carrier mobility, conductivity, and mechanical flexibility.

Carbon


Input: In this feature article, we review the recent progress of CNTs in flexible electronics by describing both the processing and the applications of CNT-based flexible devices.


Input: To employ CNTs as the channel material in FETs, single-walled carbon nanotubes (SWNTs) are used.

carbon


Input: There are generally two methods of depositing SWNTs on flexible substrates-transferring CVD-grown SWNTs or solution-depositing SWNTs.


Input: Since CVD-grown SWNTs can be highly aligned, they often outperform solution-processed SWNT films that are typically in the form of random network.


Input: However, solution-based SWNTs can be printed at a large-scale and at low-cost, rendering them more appropriate for manufacturing.


Input: In either case, the removal of metallic SWNTs in an effective and a scalable manner is critical, which must still be developed and optimized.


Input: Nevertheless, promising results demonstrating SWNT-based flexible circuits, displays, RF-devices, and biochemical sensors have been reported by various research groups, proving insight into the exciting possibilities of SWNT-based FETs.


Input: In using carbon nanotubes as transparent electrodes (TEs), two main strategies have been implemented to fabricate highly conductive, transparent, and mechanically compliant films-superaligned films of CNTs drawn from vertically grown CNT forests using the " dry-drawing " technique and the deposition or embedding of CNTs onto flexible or stretchable substrates.

carbon


Input: The main challenge for CNT based TEs is to fabricate films that are both highly conductive and transparent.


Input: These CNT based TEs have been used in stretchable and flexible pressure, strain, and chemical and biological sensors.


Input: In addition, they have also been used as the anode and cathode in flexible light emitting diodes, solar cells, and supercapacitors.


Input: In summary, there are a number of challenges yet to overcome to optimize the processing and performance of CNT-based flexible electronics; nonetheless, CNTs remain a highly suitable candidate for various flexible electronic applications in the near future.


Input: A Serum-Resistant Low-Generation Polyamidoamine with PEI 423 Outer Layer for Gene Delivery Vector.

Polyamidoamine

PEI 423


Input: A new derivative of polyamidoamine and polyethylenimine, G2. 5-PEI 423 or G1. 5-PEI 423, is prepared by an amidation reaction of PAMAM G2. 5 or PAMAM G1. 5 using PEI 423.

polyamidoamine

polyethylenimine

PEI 423

PEI 423

PAMAM

PAMAM

PEI 423


Input: The polycations show a great ability to combine with pDNA to form complexes, which protect the pDNA from nuclease degradation.


Input: The polymers display stronger buffer capacity and lower cytotoxicity.


Input: The complexes have particle sizes of 120-180 nm and zeta potentials of 20-40 mV.


Input: The G2. 5-PEI 423 complexes display much higher transfection efficiencies than PAMAM G5 and Lipo-2k, and the G1. 5-PEI 423 complexes display higher transfection efficiencies than PAMAM G4 and PEI-25k.

PEI 423

PAMAM

PEI 423

PAMAM

PEI


Input: The complexes possess better serum-resistant capacity.


Input: The G2. 5-PEI 423 has a great potential to be used as a serum-resistant gene vector.

PEI 423


Input: The influence of bypass procedures and other anatomical changes in the gastrointestinal tract on the oral bioavailability of drugs.


Input: The gastrointestinal (GI) tract plays an important role in the absorption of orally administered drugs.


Input: However, in some cases the anatomy of the GI tract is changed due to GI surgery, which has the potential of influencing drug bioavailability.


Input: In this review, we aim to compile, review, and comment the existing but sometimes fragmented scientific data regarding the impact of GI surgery on the oral bioavailability of drugs.


Input: Relevant reports were gathered through the PubMed database from database inception through January 2012.


Input: Drugs for which at least one trial or case report suggested a change in oral bioavailability or absorption caused by GI surgery are discussed in detail.


Input: Major methodological differences, such as study design, number of subjects and choice of reference group, were observed in the reported studies.


Input: Predicting the impact of GI surgery on the oral bioavailability was therefore difficult to perform, even the most sophisticated classification systems could not be used for predicting purposes.


Input: Population pharmacokinetics of atorvastatin and its active metabolites in children and adolescents with heterozygous familial hypercholesterolemia: selective use of informative prior distributions from adults.

atorvastatin


Input: The population pharmacokinetics (PPK) of atorvastatin and its principal active metabolite, o-hydroxyatorvastatin, were described in 6-17 years old pediatric hypercholesterolemia patients with a 2-compartment model for both parent and metabolite.

atorvastatin

o-hydroxyatorvastatin


Input: Informative prior distributions on selected parameters, based on adult data, were required to stabilize the model and were implemented using a Bayesian penalty term on the likelihood function in the nonlinear mixed effects model (NONMEM VI with PRIOR).


Input: Concentrations below the limit of quantitation were treated as censored data using a conditional likelihood function.


Input: Atorvastatin apparent oral clearance (CL/F) was described as a function of body weight using an allometric equation.

Atorvastatin


Input: Based on the final model, the typical CL/F estimates for a Tanner Stage 1 patient (35 kg weight) and Tanner Stage >= 2 (50 kg weight), would be 553 and 543 L/hour, respectively.


Input: When scaled allometrically, CL/F was similar to values reported for adults.


Input: Variability in atorvastatin PK was primarily affected by weight.

atorvastatin


Input: Different effects of clopidogrel and clarithromycin on the enantioselective pharmacokinetics of sibutramine and its active metabolites in healthy subjects.

clopidogrel

clarithromycin

sibutramine


Input: In this study, we assessed the effects of clopidogrel and clarithromycin, known CYP2B6 and CYP3A inhibitors, respectively, on the enantioselective disposition of racemic sibutramine in conjunction with CYP2B6 polymorphisms in humans.

clopidogrel

clarithromycin

racemic sibutramine


Input: Sibutramine showed enantioselective plasma profiles with consistently higher concentrations of R-enantiomers.

Sibutramine


Input: Clopidogrel and clarithromycin significantly increased the sibutramine plasma concentration, but their effects differed between enantiomers; a 2. 2-fold versus 4. 1-fold increase in the AUC in S-enantiomer and 1. 8-fold versus 2. 0-fold for the R-enantiomer, respectively.

Clopidogrel

clarithromycin

sibutramine


Input: The AUCs of S-and R-desmethyl metabolites changed significantly during the clopidogrel phase (P <. 001 and P <. 001, respectively) but not during the clarithromycin phase (P =. 099 and P =. 090, respectively).

clopidogrel

clarithromycin


Input: Exposure to sibutramine was higher in subjects with the CYP2B6 * 6/* 6 genotype, but no statistical difference was observed among the CYP2B6 genotypes.

sibutramine


Input: These results suggest that the enantioselective disposition of sibutramine and its active metabolites are influenced by the altered genetic and environmental factors of CYP2B6 and CYP3A activity in vivo.

sibutramine


Input: Absence of edge States in covalently bonded zigzag edges of graphene on ir (111).

graphene

ir (111)


Input: The zigzag edges of graphene on Ir (111) are studied by ab initio simulations and low-temperature scanning tunneling spectroscopy, providing information about their structural, electronic, and magnetic properties.

graphene

Ir (111)


Input: No edge state is found to exist, which is explained in terms of the interplay between a strong geometrical relaxation at the edge and a hybridization of the d orbitals of Ir atoms with the graphene orbitals at the edge.

graphene


Input: Characterization of efflux transporters involved in distribution and disposition of apixaban.

apixaban


Input: The studies reported here were conducted to investigate the transport characteristics of apixaban (1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl) phenyl)-4, 5, 6, 7-tetrahydro-1H-pyrazolo [3, 4-c] pyridine-3-carboxamide) and to understand the impact of transporters on apixaban distribution and disposition.

apixaban

1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl) phenyl)-4, 5, 6, 7-tetrahydro-1H-pyrazolo [3, 4-c] pyridine-3-carboxamide


Input: In human permeability glycoprotein (P-gp)-and breast cancer resistance protein (BCRP)-cDNA-transfected cell monolayers as well as Caco-2 cell monolayers, the apparent efflux ratio of basolateral-to-apical (PcB-A) versus apical-to-basolateral permeability (PcA-B) of apixaban was > 10.

apixaban


Input: The P-gp-and BCRP-facilitated transport of apixaban was concentration-and time-dependent and did not show saturation over a wide range of concentrations (1-100 mu M).

apixaban


Input: The efflux transport of apixaban was also demonstrated by the lower mucosal-to-serosal permeability than that of the serosal-to-mucosal direction in isolated rat jejunum segments.

apixaban


Input: Apixaban did not inhibit digoxin transport in Caco-2 cells.

Apixaban

digoxin


Input: Ketoconazole decreased the P-gp-mediated apixaban efflux in Caco-2 and the P-gp-cDNA-transfected cell monolayers, but did not affect the apixaban efflux to a meaningful extent in the BCRP-cDNA-transfected cell monolayers.

Ketoconazole

apixaban


Input: Coincubation of a P-gp inhibitor (ketoconazole or cyclosporin A) and a BCRP inhibitor (Ko134) provided more complete inhibition of apixaban efflux in Caco-2 cells than separate inhibition by individual inhibitors.

ketoconazole

cyclosporin A


Input: Naproxen inhibited apixaban efflux in Caco-2 cells but showed only a minimal effect on apixaban transport in the BCRP-transfected cells.

Naproxen

apixaban

apixaban


Input: Naproxen was the first nonsteroidal antiinflammatory drug that was demonstrated as a weak P-gp inhibitor.

Naproxen


Input: These results demonstrate that apixaban is a substrate for efflux transporters P-gp and BCRP, which can help explain its low brain penetration, and low fetal exposures and high milk excretion in rats.

apixaban


Input: A large-scale zebrafish gene knockout resource for the genome-wide study of gene function.


Input: With the completion of the zebrafish genome sequencing project, it becomes possible to analyze the function of zebrafish genes in a systematic way.


Input: The first step in such an analysis is to inactivate each protein-coding gene by targeted or random mutation.


Input: Here we describe a streamlined pipeline using proviral insertions coupled with high-throughput sequencing and mapping technologies to widely mutagenize genes in the zebrafish genome.


Input: We also report the first 6144 mutagenized and archived F1' s predicted to carry up to 3776 mutations in annotated genes.


Input: Using in vitro fertilization, we have rescued and characterized ~ 0. 5% of the predicted mutations, showing mutation efficacy and a variety of phenotypes relevant to both developmental processes and human genetic diseases.


Input: Mutagenized fish lines are being made freely available to the public through the Zebrafish International Resource Center.


Input: These fish lines establish an important milestone for zebrafish genetics research and should greatly facilitate systematic functional studies of the vertebrate genome.


Input: High-relaxivity and luminescent silica nanoparticles as multimodal agents for molecular imaging.

silica


Input: The design and synthesis of a new bimodal contrast agent for magnetic resonance imaging and optical imaging is reported.


Input: Tunable-sized silica nanoparticles were synthesized by a microemulsion-mediated pathway and used as carriers for paramagnetic and luminescent probes.

silica


Input: The near-infrared luminescent agent was a ruthenium complex that was directly entrapped in the silica shell to provide photoluminescence enhancement and to make it highly photostable as it was protected from the surrounding environment.

ruthenium

silica


Input: The paramagnetic activity came from a Gd-DTPA derivative that was grafted on the silica surface.

Gd-DTPA

silica


Input: NMRD profiles showed a strong relaxivity enhancement (increase of 432% in the r1 value at 20 MHz) when the paramagnetic complex was grafted at the nanoparticle surface, because of a reduction of its mobility.


Input: Polyethylene glycol was also grafted at the nanoparticle surface to enhance the nanoparticle residence time in the bloodstream.

Polyethylene glycol


Input: A thorough characterization of the material confirmed its potential as a very effective bimodal contrast agent.


Input: Effectiveness of preoperative plasmapheresis in a pregnancy complicated by hyperthyroidism and anti-thyroid drug-associated angioedema.


Input: Abstract Hyperthyroidism is not a rare entity in pregnancy and 85% of these cases attributed to Graves' disease (GD).


Input: There is no therapeutic modality for GD considered as totally safe in pregnancy.


Input: Fetal and neonatal risks of maternal hyperthyroid disease are related to the hyperthyroidism itself and/or to the medical treatment of the disease.


Input: There are no data supporting an association between congenital anomalies in the fetus and propylthiouracil (PTU).

propylthiouracil

PTU


Input: Hepatotoxicity, cytopenias-especially agranulocytosis and quite rarely, angioedema, may be seen as side effects of PTU.

PTU


Input: In this case report, we examine an instance of Graves' hyperthyroidism diagnosed during pregnancy.


Input: In this case, a serious side effect during anti-thyroid drug usage was encountered, eventually resulting in surgery in the second trimester.


Input: This intervention was assisted by the use of plasmapheresis to obtain rapid normalization of serum thyroid hormone levels.

thyroid hormone


Input: Frequency and intensity of pain related to thyroid nodule fine needle aspiration cytology.


Input: Background: Quality of life is an important issue in endocrine tumors because of the high prevalence of benign tumors and the indolent course of most malignant tumors.


Input: Objective: To evaluate the frequency and the intensity of pain and anxiety in patients undergoing thyroid nodule fine needle aspiration cytology (FNAC), and to identify factors associated with pain.


Input: Method: Single center prospective study in the setting of a one-stop outpatient diagnostic clinic for thyroid nodules.


Input: Pain was evaluated using a 100-mm visual analogue scale (VAS) immediately following (VAS1) and 30 minutes after (VAS2) FNAC and was considered significant if >= 30.


Input: Anxiety symptoms were assessed prior to FNAC using a self-report measure questionnaire: the state form of Spielberger State-Trait Anxiety Inventory (STAI, form Y-A).


Input: FNAC was performed with a 25-Gauge needle and a moderate aspiration and two passes for each nodule.


Input: Results: 218 consecutive patients (163 females, 55 males; mean age 53 years, range 12-84) undergoing FNAC of 1 to 3 nodules were included.


Input: VAS1 was >= 30 in 24% of the patients and VAS2 was <F0B3> 30 in 13% of the patients.


Input: Independent significant factors correlated to a VAS1 <F0B3> 30 were age under 25 and the number of nodules being biopsied.


Input: Independent significant factors correlated to a VAS2 <F0B3> 30 were VAS1 <F0B3> 30 and female gender.


Input: No correlation was found between pain and nodule size or nodule depth, nor the duration of application of the Eutectic Mixture of Local Anesthetics (EMLA patch) prior to FNAC.


Input: The mean STAI score for anxiety was 37 <F0B1> 12.


Input: The average STAI score was significantly higher in women (39) than in men (33) (p = 0. 01).


Input: There was no significant correlation between STAI score and age under 25, previous FNAC, number of nodules biopsied or acetaminophen administration, but the STAI score was significantly correlated to VAS1 and VAS2 Conclusions: FNAC-related pain is frequent and correlates with the number of nodules biopsied, age under 25, female gender and anxiety.


Input: Maximal Raman optical activity in hybrid single molecule-plasmonic nanostructures with multiple dipolar resonances.


Input: We show that a hybrid system built of a plasmonic nanoparticle cluster and a single molecule can attain maximal Raman optical activity (ROA), converting linearly polarized light into purely circularly polarized light at the Raman-scattered frequency.


Input: In contrast to standard molecular ROA, the effect described here does not involve magnetic modes and is attributed to off-resonance excitation of electric-dipole plasmon modes of the nanoparticle cluster.


Input: A model based on a combination of harmonic oscillators excited at the frequency of the Raman-scattered light is shown to successfully capture the physics of the effect.


Input: Acitretin affects bioenergetics of liver mitochondria and promotes mitochondrial permeability transition: Potential mechanisms of hepatotoxicity.

Acitretin


Input: Acitretin is a synthetic retinoid used for severe extensive psoriasis and it has been shown to be an effective and a safe therapeutic drug for other diseases including cancer when used in combination with other agents.

Acitretin


Input: However, cases of acitretin-associated liver injury have been documented, but the possible mechanisms of acitretin-associated hepatotoxicity and apoptosis are not entirely clarified.

acitretin

acitretin


Input: This study reports that mitochondrial dysfunctions may play an important role in liver injury and apoptosis induced by this retinoid.

retinoid


Input: Acitretin (5-20 mu M) impaired mitochondrial phosphorylation efficiency as demonstrated by the decrease in the state 3 respiration and ATP levels, and by the increase in the lag phase of ADP phosphorylation cycle, without affecting the membrane potential.

Acitretin

ATP

ADP


Input: Acitretin induced Ca (2 +)-mediated mitochondrial permeability transition (MPT) and decreased the adenine nucleotide translocase (ANT) content.

Acitretin

Ca (2 +)

adenine nucleotide


Input: Acitretin-induced MPT was not prevented by thiol group protecting and antioxidant agents, excluding the involvement of oxidative stress mechanisms.

Acitretin

thiol


Input: However, MPT was prevented by ANT ligands ATP, ADP, tamoxifen and 4-hydroxytamoxifen, implying that the MPT induction by acitretin is mediated by the ANT.

ATP

ADP

tamoxifen


Input: ANT plays a major role in promoting apoptosis and ATP synthesis, and it is still considered as a structural component of the pore with a regulatory role in MPT formation.

ATP


Input: Therefore, our results, including the decrease in the state 3 respiration and the increase in the lag phase of phosphorylation cycle, the ATP depletion and the induction of Ca (2 +)-mediated MPT, indicate that acitretin-associated liver toxicity and apoptosis is possibly related with mitochondrial dysfunctions due to interactions with the ANT.

ATP

Ca (2 +)

acitretin


Input: Additionally, the combination of acitretin with other drugs, such as antiestrogens, which are able to inhibit the MPT, may contribute to decrease the toxicity induced by acitretin.

acitretin

acitretin


Input: Therapeutic potential of neuregulin-1 in cardiovascular disease.


Input: Neuregulin-1 (NRG-1)/ErbB signaling has an indispensable role in cardiac development and in the maintenance of the structural and functional integrity of the human adult heart in health and disease.


Input: Several animal studies have now demonstrated the therapeutic effects of NRG-1 during acute cardiac injury and during chronic heart failure, with improvements in cardiac performance and animal survival.


Input: Phase I and II clinical trials for chronic heart failure in humans are now in progress.


Input: Glucocorticoid-induced suppression of beta-cell proliferation is mediated by Mig6.


Input: Glucocorticoids can cause steroid-induced diabetes or accelerate the progression to diabetes by creating systemic insulin resistance and decreasing functional beta-cell mass, which is influenced by changes in beta-cell function, growth, and death.

steroid


Input: The synthetic glucocorticoid agonist dexamethasone (Dex) is deleterious to functional beta-cell mass by decreasing beta-cell function, survival, and proliferation.

dexamethasone

Dex


Input: However, the mechanism by which Dex decreases beta-cell proliferation is unknown.

Dex


Input: Interestingly, Dex induces the transcription of an antiproliferative factor and negative regulator of epidermal growth factor receptor signaling, Mig6 (also known as gene 33, RALT, and Errfi1).

Dex


Input: We, therefore, hypothesized that Dex impairs beta-cell proliferation by increasing the expression of Mig6 and thereby decreasing downstream signaling of epidermal growth factor receptor.

Dex


Input: We found that Dex induced Mig6 and decreased [(3) H] thymidine incorporation, an index of cellular replication, in mouse, rat, and human islets.

Dex

[(3) H] thymidine


Input: Using adenovirally delivered small interfering RNA targeted to Mig6 in rat islets, we were able to limit the induction of Mig6 upon exposure to Dex, compared with islets treated with a control virus, and completely rescued the Dex-mediated impairment in replication.

Dex

Dex


Input: We demonstrated that both Dex and overexpression of Mig6 attenuated the phosphorylation of ERK1/2 and blocked the G (1)/S transition of the cell cycle.

Dex


Input: In conclusion, Mig6 functions as a molecular brake for beta-cell proliferation during glucocorticoid treatment in beta-cells, and thus, Mig6 may be a novel target for preventing glucocorticoid-induced impairments in functional beta-cell mass.


Input: Characterization of cytosolic glutathione peroxidase and phospholipid-hydroperoxide glutathione peroxidase genes in rainbow trout (Oncorhynchus mykiss) and their modulation by in vitro selenium exposure.

glutathione

hydroperoxide glutathione

selenium


Input: Selenium (Se) is an oligonutrient with both essential biological functions and recognized harmful effects.

Selenium

Se


Input: As the selenocysteine (SeCys) amino acid, selenium is integrated in several Se-containing proteins (selenoproteins), many of which are fundamental for cell homeostasis.

selenocysteine

SeCys

amino acid

selenium

Se


Input: Nevertheless, selenium may exert toxic effects at levels marginally above those required, mainly through the generation of reactive oxygen species (ROS).

oxygen


Input: The selenium chemical speciation can strongly affect the bioavailability of this metal and its impact on metabolism, dictating the levels that can be beneficial or detrimental towards an organism.

selenium


Input: Glutathione peroxidase (GPxs) is the largest and the most studied selenoprotein family.

Glutathione


Input: Cytosolic glutathione peroxidase (cGPx, GPx1) and phospholipid hydroperoxide glutathione peroxidase (PHGPx, GPx4) are widely distributed throughout tissues, and play a pivotal role in regulating the oxidative status in the cell.

glutathione

hydroperoxide glutathione


Input: In this study we have cloned GPx1 and GPx4 genes in rainbow trout (Oncorhynchus mykiss).


Input: The constitutive mRNA expression of these GPx genes was examined in 18 trout tissues and their responsiveness to Se availability was analysed using a rainbow trout liver cell line (RTL).


Input: An inorganic (sodium selenite, Na2SeO3) and organic (selenocysteine, Cys-Se-Se-Cys) selenocompound have been used as Se sources.

sodium selenite

selenocysteine

Cys-Se-Se-Cys

Se


Input: GPx1 activity was also tested to verify the impact of transcript changes on the enzymatic function of these molecules.


Input: To understand if the results obtained from the transcript expression analysis were due to Se bioavailability or generation of ROS, the cytoxicity of the two selenocompounds was tested by measuring the impact of Se on cell membrane integrity.

Se

Se


Input: Lastly, Se availability was quantified by mass spectrophotometry to determine the amount of Se in the cell culture media, the Se background due to the foetal calf serum supplement and the contribution from the two selenocompounds used in the treatments.

Se

Se

Se


Input: Three isoforms of genes for both GPx1 (GPx1a, 1b1 and 1b2) and GPx4 (GPx4a1, a2 and b) have been identified.


Input: The discovery of a third gene encoding for GPx1 and GPx4 hints that salmonids may have the biggest selenoproteome amongst all vertebrates.


Input: Transcripts of GPx4 genes were more highly expressed in most tissues examined in vivo (except blood, head kidney and spleen), whereas those of the GPx1 genes were more responsive to selenium exposure in vitro, especially to the organic form.

selenium


Input: Interestingly, GPx1a was the most sensitive to selenium availability in non stressful conditions, whereas GPx1b1 and GPx1b2 were highly induced by exposure to selenium levels that had some toxic effects on the cells.

selenium

selenium


Input: Although the different concentrations tested of the two selenocompounds modulate GPx1 transcript expression to various degrees, no significant change of GPx1 enzymatic activity was detectable.


Input: Our results lead us to conclude that trout GPx1 transcripts expression level may represent a sensitive biomarker for selenium intake, helping to evaluate if selenium concentration and chemical speciation impact on cell homeostasis.

selenium

selenium


Input: Application of activated nucleoside analogs for the treatment of drug-resistant tumors by oral delivery of nanogel-drug conjugates.

nucleoside


Input: A majority of nanoencapsulated drugs that have shown promise in cancer chemotherapy are administered intravenously.


Input: Development of effective oral nanoformulations presents a very challenging medical goal.


Input: Here, we describe successful applications of innovative polymeric nanogels in the form of conjugates with activated nucleoside analogs for oral administration in cancer chemotherapy.

nucleoside