Input: Angiotensin-(1-7) modulates renin-angiotensin system associated with reducing oxidative stress and attenuating neuronal apoptosis in the brain of hypertensive rats.


Input: Angiotensin-(1-7) [Ang-(1-7)] has beneficial effects against hypertension-induced damage in heart and kidney, but its effects in brain are not clear as yet.


Input: The present study aimed to investigate the protective effects of Ang-(1-7) on the physiopathologic changes caused by hypertension in brain of spontaneously hypertensive rats (SHRs).


Input: Wistar-Kyoto rats received intracerebroventricular (I. C. V.) infusion of artificial cerebrospinal fluid (aCSF) while SHRs received I. C. V. infusion of Ang-(1-7), Mas receptor antagonist A-779 and aCSF for 4 weeks.


Input: Brain tissues were collected and analyzed by western blot, enzyme immunoassay, spectrophotometric assays and terminal deoxynucleotidyl transferase-mediated dUTP end-labeling (TUNEL) staining.

deoxynucleotidyl

dUTP


Input: Our study showed that infusion of Ang-(1-7) for 4 weeks significantly reduced the expression of Angiotensin II and Angiotensin II type 1 receptors in SHR brain.

Angiotensin II

Angiotensin II


Input: Additionally, it decreased the levels of malondialdehyde and elevated total superoxide dismutase activity, which was accompanied by reductions of NADPH oxidase subunit gp91 (phox) and inducible nitric oxide synthase in the brain of SHR.

malondialdehyde

superoxide

NADPH

nitric oxide


Input: The increases of the percentage of TUNEL-positive neurons and Bax to Bcl-2 ratio in SHR brain were also attenuated by Ang-(1-7).


Input: The anti-oxidative and anti-apoptosis effects of Ang-(1-7) are independent of blood pressure reduction and can be partially abolished by A-779.


Input: These findings suggest that chronic treatment with Ang-(1-7) is beneficial to attenuate hypertension-induced physiopathologic changes in brain and may be helpful to prevent hypertension-related cerebrovascular diseases.


Input: Cell cycle regulation by glucosamine in human pulmonary epithelial cells.

glucosamine


Input: Airway epithelial cells play an important role against intruding pathogens.


Input: Glucosamine, a commonly used supplemental compound, has recently begun to be regarded as a potential anti-inflammatory molecule.

Glucosamine


Input: This study aimed to uncover how glucosamine impacts on cellular proliferation in human alveolar epithelial cells (A549) and bronchial epithelial cells (HBECs).

glucosamine


Input: With trypan blue-exclusion assay, we observed that glucosamine (10, 20, 50 mM) caused a decrease in cell number at 24 and 48 h; with a flow cytometric analysis, we also noted an enhanced cell accumulation within the G (0)/G (1) phase at 24 h and induction of late apoptosis at 24 and 48 h by glucosamine (10, 20, 50 mM) in A549 cells and HBECs.

trypan blue

glucosamine

glucosamine


Input: Examination of phosphorylation in retinoblastoma (Rb) protein, we found an inhibitory effect by glucosamine at 20 and 50 mM.

glucosamine


Input: Glucosamine at 50 mM was demonstrated to elevate both the mRNA and protein expression of p53 and heme oxygenase-1 (HO-1), but also caused a reduction in p21 protein expression.

Glucosamine

heme


Input: In addition, glucosamine attenuated p21 protein stability via the proteasomal proteolytic pathway, as well as inducing p21 nuclear accumulation.

glucosamine


Input: Altogether, our results suggest that a high dose of glucosamine may inhibit cell proliferation through apoptosis and disturb cell cycle progression with a halt at G (0)/G (1) phase, and that this occurs, at least in part, by a reduction in Rb phosphorylation together with modulation of p21, p53 and HO-1 expression, and nuclear p21 accumulation.

glucosamine


Input: Symmetrically reduced stiffness and increased extensibility in compression and tension at the mineralized fibrillar level in rachitic bone.


Input: In metabolic bone diseases, the alterations in fibrillar level bone-material quality affecting macroscopic mechanical competence are not well-understood quantitatively.


Input: Here, we quantify the fibrillar level deformation in cantilever bending in a mouse model for hereditary rickets (Hpr).


Input: Microfocus in-situ synchrotron small-angle X-ray scattering (SAXS) combined with cantilever bending was used to resolve nanoscale fibril strain in tensile-and compressive tissue regions separately, with quantitative backscattered scanning electron microscopy used to measure microscale mineralization.


Input: Tissue-level flexural moduli for Hpr mice were significantly (p < 0. 01) smaller compared to wild-type (~ 5 to 10-fold reduction).


Input: At the fibrillar level, the fibril moduli within the tensile and compressive zones were significantly (p < 0. 05) lower by ~ 3-to 5-fold in Hpr mice compared to wild-type mice.


Input: Hpr mice have a lower mineral content (24. 2 +/- 2. 1Cawt.% versus 27. 4 +/- 3. 3Ca wt.%) and its distribution was more heterogeneous compared to wild-type animals.


Input: However, the average effective fibril modulus did not differ significantly (p > 0. 05) over ages (4, 7 and 10weeks) between tensile and compressive zones.


Input: Our results indicate that incompletely mineralized fibrils in Hpr mice have greater deformability and lower moduli in both compression and tension, and those compressive and tensile zones have similar moduli at the fibrillar level.


Input: Prediction of crizotinib-midazolam interaction using the Simcyp population-based simulator: comparison of CYP3A time-dependent inhibition between human liver microsomes versus hepatocytes.

crizotinib

midazolam


Input: Crizotinib (Xalkori) is an orally available potent inhibitor of multiple tyrosine kinases, including anaplastic lymphoma kinase and mesenchymal-epithelial transition factor.

Crizotinib

Xalkori

tyrosine


Input: Objectives of the present study were as follows: 1) to characterize crizotinib time-dependent inhibition (TDI) potency for CYP3A in human liver microsomes (HLM) and cryopreserved human hepatocytes suspended in human plasma (HSP); 2) to characterize crizotinib enzyme induction potency on CYP3A4 in cryopreserved human hepatocytes; 3) to predict crizotinib steady-state plasma concentrations in patients (e. g., autoinhibition and autoinduction) using the mechanistic dynamic model, Simcyp population-based simulator; and 4) to predict a clinical crizotinib-midazolam interaction using the dynamic model as well as the static mathematical model.

crizotinib

crizotinib

crizotinib

crizotinib

midazolam


Input: Crizotinib inactivation constant (K (I)) and maximum inactivation rate constant (k (inact)) for TDI were estimated as, respectively, 0. 37 micro M and 6. 9 h (-1) in HLM and 0. 89 micro M and 0. 78 h (-1) in HSP.

Crizotinib


Input: Thus, crizotinib inactivation efficiency (k (inact)/K (I)) was ~ 20-fold lower in HSP relative to HLM.

crizotinib


Input: Crizotinib E (max) and EC (50) for CYP3A4 induction (measured as mRNA expression) were estimated as 6. 4-to 29-fold and 0. 47 to 3. 1 micro M, respectively.

Crizotinib


Input: Based on these in vitro parameters, the predicted crizotinib steady-state area under plasma concentration-time curve (AUC) with HLM-TDI was 2. 1-fold higher than the observed AUC, whereas that with HSP-TDI was consistent with the observed result (<= 1. 1-fold).

crizotinib


Input: The increase in midazolam AUC with coadministration of crizotinib (21-fold) was significantly overpredicted using HLM-TDI, whereas the prediction using HSP-TDI (3. 6-fold) was consistent with the observed result (3. 7-fold).

midazolam

crizotinib


Input: Collectively, the present study demonstrated the value of HSP to predict in vivo CYP3A-mediated drug-drug interaction.


Input: Arsenic and arsenic species in cultured oyster (Crassostrea gigas and C. corteziensis) from coastal lagoons of the SE Gulf of California, Mexico.

Arsenic

arsenic


Input: The aim of this study was to evaluate the bioavailability of arsenic (As) through cultured oyster Crassostrea gigas and Crassostrea corteziensis from four coastal lagoons (SE Gulf of California).

arsenic

As


Input: Organisms were collected in two seasons (rainy and dry season), and they were analyzed for total arsenic and chemical speciation of this element.

arsenic


Input: The concentrations of As in oyster soft tissue fluctuated between 5. 44 and 9. 56 mu g/g for rainy season and 6. 46 and 8. 33 mu g/g for dry season (dry weight) in C. gigas.

As


Input: In C. corteziensis, the As concentrations were < 5 mu g/g for both seasons (dry weight).

As


Input: Arsenic speciation indicated arsenobetaine as the major arseno-compound accounting for 43. 2-76. 3% of total content of As.

Arsenic

arsenobetaine

arseno

As


Input: Lower contributions were obtained for non-extractable As (11. 3-17. 5%) and other molecules such as arsenocholine and methyl-arsonate (< 5%).

As

arsenocholine

methyl-arsonate


Input: Inorganic arsenic was detectable in only two samples, at concentrations lower than < 0. 1 mu g/g.

arsenic


Input: These As data are the first generated for these mollusks in NW Mexico and indicate that C. gigas and C. corteziensis farmed in this area are safe for human consumption in terms of arseno-compounds.

As

arseno


Input: Probing the binding of cationic lipids with dendrimers.


Input: Polycationic polymers are used extensively in biology to disrupt cell membranes and thus enhance the transport of materials into the cell.


Input: We report the bindings of several lipids cholesterol (Chol), 1, 2-dioleoyl-3-trimethylammonium-propane (DOTAP), dioctadecyldimethylammoniumbromide (DDAB), and dioleoylphosphatidylethanolamine (DOPE) to dendrimers of different compositions such as mPEG-PAMAM (G3), mPEG-PAMAM (G4), and PAMAM (G4) under physiological conditions.

cholesterol

Chol

1, 2-dioleoyl-3-trimethylammonium-propane

DOTAP

dioctadecyldimethylammoniumbromide

DDAB

dioleoylphosphatidylethanolamine

DOPE

mPEG-PAMAM

mPEG-PAMAM

PAMAM


Input: FTIR, UV-visible spectroscopic, methods and molecular modeling were used to analyze the lipid binding mode, the binding constant, and the effects of lipid complexation on the dendrimer structure.


Input: The structural analysis showed that lipids bind dendrimers through both hydrophilic and hydrophobic contacts with overall binding constants of K (chol-mPEG-G3) = 1. 7 x 10 (3) M (-1), K (chol-mPEG-PAMAM-G4) = 2. 7 x 10 (3) M (-1), K (chol-PAMAM-G4) = 1. 0 x 10 (3) M (-1), K (DOPE-mPEG-G3) = 1. 5 x 10 (3) M (-1), K (DOPE-mPEG-PAMAM-G4) = 1. 6 x 10 (3) M (-1), K (DOPE-PAMAM-G4) = 5. 3 x 10 (2) M (-1), K (DDAB-mPEG-G3) = 1. 5 x 10 (3) M (-1), K (DDAB-mPEG-PAMAM-G4) = 1. 9 x 10 (2) M (-1), K (DDAB-PAMAM-G4) = 7. 0 x 10 (2) M (-1), K (DOTAP-mPEG-G3) = 1. 9 x 10 (3) M (-1), K (DOTAP-mPEG-PAMAM-G4) = 1. 5 x 10 (3) M (-1), and K (DOTAP-PAMAM-G4) = 5. 7 x 10 (2) M (-1).


Input: Weaker interaction was observed as dendrimer cationic charges increased.


Input: The free binding energies from docking were-5. 15 (cholesterol),-5. 79 (DDAB), and-5. 36 kcal/mol (DOTAP) with the order of stability DDAB-PAMAM-G-4 > DOTAP-PAMAM-G4 > cholesterol-PAMAM-G4, consistent with the spectroscopic results.

cholesterol

DDAB

DOTAP

cholesterol


Input: Dendrimers might act as carriers to transport lipids in vitro.


Input: Glycolytic enzymes PGK1 and PKM2 as novel transcriptional targets of PPAR gamma in breast cancer pathophysiology.


Input: Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor and plays important roles in breast cancer cell proliferation.


Input: The complexity of the underlying biochemical and molecular mechanisms of breast cancer and the involvement of PPAR gamma in breast cancer pathophysiology are unclear.


Input: In this study, we carried out prediction of the peroxisome proliferator response element (PPRE) motifs in 2332 genes reported to be involved in breast cancer in literature.


Input: A total of 178 genes were found to have PPRE (DR1/DR2) and/or PPAR-associated conserved motif (PACM) motifs.


Input: We further constructed protein-protein interaction network, disease gene network and gene ontology (GO) analyses to identify novel key genes for experimental validation.


Input: We identified two genes in the glycolytic pathway (phosphoglycerate kinase 1 (PGK1) and pyruvate kinase M2 (PKM2)) at the ATP production steps and experimentally validated their repression by PPAR gamma in two breast cancer cell lines MDA-MB-231 and MCF-7.

phosphoglycerate

pyruvate

ATP


Input: Further analysis suggested that this repression leads to decrease in ATP levels and apoptosis.

ATP


Input: These investigations will help us in understanding the molecular mechanisms by which PPAR gamma regulates the cellular energy pathway and the use of its ligands in human breast cancer therapeutics.


Input: Evaluation of the metabolism and hepatotoxicity of xenobiotics utilizing precision-cut slices.


Input: Precision-cut liver slices are a valuable in vitro model system to study the metabolism and toxicity of xenobiotics.


Input: Liver slices retain tissue architecture so that all cell types are present and intercellular communication between the various cell types is retained.


Input: Precision-cut liver slices from humans and other species have been used to study pathways of phase I (e. g. cytochrome P450-dependent biotransformations) and II (e. g. conjugation with D-glucuronic acid, sulphate and glutathione) metabolism of a wide range of xenobiotics.

D-glucuronic acid

sulphate

glutathione


Input: Liver slices can also be employed to investigate the induction and inhibition of xenobiotic metabolizing enzymes and to obtain kinetic data on the rates of metabolism of xenobiotics.


Input: Precision-cut liver slices from humans and other species have been used to study the toxicity of a wide variety of xenobiotics.


Input: Toxicity can be assessed by various techniques including gene expression, morphological examination and a wide range of biochemical endpoints.


Input: Precision-cut liver slices can be utilized to examine species differences in hepatic xenobiotic metabolism and xenobiotic-induced toxicity, thus permitting comparisons between animal species and humans.


Input: In vitro and in vivo evaluation of an in situ gel forming system for the delivery of PEGylated octreotide.

PEGylated octreotide


Input: The objective of this study was to develop a controlled delivery system for PEGylated octreotide using a Poloxamer based in situ gel forming polymer.

PEGylated octreotide

Poloxamer


Input: PEGylated octreotide kept its full biological activity and higher serum half-life compared to the original octreotide.

PEGylated octreotide

octreotide


Input: The designed drug delivery system contained low concentration of Poloxamer 407 (P407) (< 0. 16%) with polyvinyl alcohol (PVA) as a polymeric additive.

Poloxamer 407

polyvinyl alcohol

PVA


Input: Rheological measurements of gel vehicle formulations indicated that the in situ gel forming system with optimum sol-gel transition temperature of 28. 7 degrees C could be formed using a combination of P407 and PVA at ratio of 15-10% (w/v).

PVA


Input: The effect of formulation additives such as buffering agents on rheological behavior demonstrated that sodium bicarbonate and lactic acid have opposite effect on sol-gel transition temperature of the system.

sodium bicarbonate

lactic acid


Input: Using buffering agents, it was possible to shift the sol-gel transition to lower or higher temperatures.


Input: The in vitro release profiles of octreotide and PEGylated octreotide from the selected P407/PVA formulations were measured using a membrane-less device.

octreotide

PEGylated octreotide

PVA


Input: PEGylated octreotide showed slower release rate from the gel system with different release kinetic compared to octreotide.

PEGylated octreotide

octreotide


Input: In animal studies, a sustained release rate was achieved with both PEGylated and non-PEGylated octreotide, but longer delivery was observed for PEGylated octreotide.

PEGylated and non-PEGylated octreotide

PEGylated octreotide


Input: Tissue histopathological studies confirmed the biocompatibility of the delivery system for PEGylated octreotide, supporting the suitability of P407/PVA mixture as an injectable drug delivery system.

PEGylated octreotide

PVA


Input: The total effects of increasing PEGylated peptide half-life and prolonged release from thermoresponsive gel system offer the potential for sustained delivery of PEGylated octreotide.

PEGylated octreotide


Input: Regulation of glycogen synthase from mammalian skeletal muscle--a unifying view of allosteric and covalent regulation.


Input: It is widely accepted that insufficient insulin-stimulated activation of muscle glycogen synthesis is one of the major components of non-insulin-dependent (type 2) diabetes mellitus.


Input: Glycogen synthase, a key enzyme in muscle glycogen synthesis, is extensively regulated, both allosterically (by glucose-6-phosphate, ATP, and others) and covalently (by phosphorylation).

ATP


Input: Although glycogen synthase has been a topic of intense study for more than 50 years, its kinetic characterization has been confounded by its large number of phosphorylation states.


Input: Questions remain regarding the function of glycogen synthase regulation and the relative importance of allosteric and covalent modification in fulfilling this function.


Input: In this review, we consider both earlier kinetic studies and more recent site-directed mutagenesis and crystal structure studies in a detailed qualitative discussion of the effects of regulation on the kinetics of glycogen synthase.


Input: We propose that both allosteric and covalent modification of glycogen synthase may be described by a Monod-Wyman-Changeux model in terms of apparent changes to L, the equilibrium constant for transition between the T and R conformers.


Input: As, with the exception of L, all parameters of this model are independent of the glycogen synthase phosphorylation state, the need to determine kinetic parameters for all possible states is eliminated; only the relationship between a particular state and L must be established.


Input: We conclude by suggesting that renewed efforts to characterize the relationship between phosphorylation and the kinetics of glycogen synthase are essential in order to obtain a better quantitative understanding of the function of glycogen synthesis regulation.


Input: The model we propose may prove useful in this regard.


Input: LARGE2 generates the same xylose-and glucuronic acid-containing glycan structures as LARGE.

xylose

glucuronic acid


Input: LARGE (like-glycosyltransferase) and LARGE2 (glycosyltransferase-like 1B (GYLTL1B)) are homologous Golgi glycosyltransferases possessing two catalytic domains with homology to members of glycosyltransferase families GT8 and GT49.


Input: Mutations in human and mouse Large result in muscular dystrophy due to underglycosylation of dystroglycan.


Input: The systemic function of LARGE2 is unknown, but at a cellular level the enzyme can substitute for LARGE in glycosylating dystroglycan.


Input: Here, we show that LARGE2 catalyzes the same glycosylation reaction as LARGE.


Input: It is a bifunctional glycosyltransferase using uridine diphosphate (UDP)-xylose (Xyl) and UDP-glucuronic acid (GlcA) as donor sugars to produce a xyloglucuronan with alternating Xyl and GlcA residues.

uridine diphosphate

UDP

xylose

Xyl

UDP

glucuronic acid

GlcA

sugars

Xyl

GlcA


Input: Electric field-induced dipole switching at the donor/acceptor interface in organic solar cells.


Input: Order of dipole moment layers at donor and acceptor interfaces in bilayer organic solar cells is manipulated reversibly by applying bias voltages.


Input: The energy level shifts at the interfaces induce reversible changes in the open circuit voltage and the diode properties.


Input: This finding could lead to a better understanding of the structure-property relationship at the materials interfaces in organic optoelectronic devices.


Input: Reversible and cyclical transformations between solid and hollow nanostructures in confined reactions of manganese oxide and silica within nanosized spheres.

manganese oxide

silica


Input: Annealing of MnO @SiO (2) nanospheres in a reducing gas environment resulted in the transformation of the core-shell structure into a hollow structure as a result of outward diffusion of MnO species into the thermodynamically more stable silicate phase.

MnO

SiO (2)

MnO

silicate


Input: When the hollow silicate nanospheres were oxidized, the interior cavities were refilled with a Mn (3) O (4) phase segregated from the silicate phase, and the hollow structure reverted to the initial core-shell structure.

silicate

Mn (3) O (4)

silicate


Input: More interestingly, when catalytically active Pt nanocrystals were introduced into the manganese oxide/silica system, the Mn (3) O (4) was readily reduced to the chemically reactive MnO, even at low temperature, which enabled reconversion of the solid nanospheres with a Mn (3) O (4) core to hollow nanostructures during reductive annealing.

Pt

manganese oxide

silica

Mn (3) O (4)

MnO

Mn (3) O (4)


Input: Therefore, when MnO @SiO (2)/Pt (II) nanospheres were subjected to an oxidation/reduction cycle by repeatedly switching the flowing gas between air and hydrogen, the nanospheres underwent a reversible change between solid and hollow structures, depending on the gas environment.

MnO

SiO (2)

Pt (II)

hydrogen


Input: The solid-to-hollow-to-solid transformation was successfully cycled many times simply by repeatedly switching the flowing gas during annealing.


Input: Polydatin ameliorates renal injury by attenuating oxidative stress-related inflammatory responses in fructose-induced urate nephropathic mice.

Polydatin

fructose

urate


Input: A series of studies have recently demonstrated that the oxidative stress, nuclear factor-kappa B (NF-kappa B) activation and the subsequent coordinated inflammatory responses played an important role in the pathogenesis of urate nephropathy (UN).

urate


Input: Polydatin has been suggested to have the properties of anti-oxidative, anti-inflammatory and nephroprotective effects.

Polydatin


Input: However, the possible protective and beneficial effects of polydatin on UN are not fully elucidated.

polydatin


Input: Therefore, we investigated the potential beneficial effects and possible mechanisms of polydatin on UN.

polydatin


Input: In this study, polydatin showed inhibitory activities on xanthine oxidase to repress the level of serum uric acid in vivo and in vitro.

polydatin

xanthine

uric acid


Input: Further investigations revealed that polydatin displayed little toxic effects and significantly ameliorated the renal function in fructose-induced UN mice.

polydatin

fructose


Input: The nephroprotective activities of polydatin was not only due to the effects on remarkably attenuating the oxidative stress induced by uric acid, but also on markedly suppressing the oxidative stress-related inflammatory cascade, including decreasing the expressions of NF-kappa B p65, COX-2 and iNOS proteins and inhibiting the productions of TNF-alpha, PGE (2) and IL-1 beta.

polydatin

uric acid


Input: These findings elucidated that polydatin exhibited prominent nephroprotective activities and low toxic effects.

polydatin


Input: Alleviation effects of magnesium on copper toxicity and accumulation in grapevine roots evaluated with biotic ligand models.

magnesium

copper


Input: Copper toxicity and accumulation in plants are affected by physicochemical characteristics of soil solutions such as the concentrations of coexistent cations (e. g., Ca (2 +), Mg (2 +), K (+), Na (+), and H (+)).

Copper

Ca (2 +)

Mg (2 +)

K (+)

Na (+)

H (+)


Input: The biotic ligand model (BLM) approach has been proposed to predict metal phyto-toxicity and-accumulation by taking into account the effects of coexistent cations, given the assumption of the partition equilibrium of metal ions between soil solution and solid phase.


Input: The alleviation effects of Mg on Cu toxicity and accumulation in grapevine roots were the main concerns in this study and were investigated by using a hydroponic experiment of grapevine cuttings.

Mg

Cu


Input: The BLM approach, which incorporated competition of Mg (2 +) with Cu (2 +) to occupy the biotic ligands on root surfaces, was developed to predict Cu rhizotoxicity and accumulation by grapevine roots.

Mg (2 +)

Cu (2 +)

Cu


Input: In the results, the effective activity of Cu, {Cu (2 +)}, resulting in a 50% reduction of root elongation (EA (50)), linearly increased with increments of Mg activity, {Mg (2 +)}.

Cu

Cu (2 +)

Mg

Mg (2 +)


Input: In addition, the Cu concentration in root, Cu (root), was retarded by an increase of {Mg (2 +)}.

Cu

Cu

Mg (2 +)


Input: The linear model was significantly fitted to the relationship between {Cu (2 +)}/Cu (root) and {Mg (2 +)}.

Cu (2 +)

Cu

Mg (2 +)


Input: According to the concept of BLM, the present results revealed that the amelioration effects of Mg on Cu toxicity and accumulation in roots could arise from competition between Mg (2 +) and Cu (2 +) on the binding sites (i. e., the biotic ligands).

Mg

Cu

Mg (2 +)

Cu (2 +)


Input: Then, the developed Cu-BLMs incorporating the Mg (2 +) competition effectiveness were validated provide accurate predictions of Cu toxicity and accumulation in grapevine roots.

Cu

Mg (2 +)

Cu


Input: To our knowledge this is the first report of the successful development of BLMs for a woody plant.


Input: This BLM approach shows promise of being widely applicable for various terrestrial plants.


Input: High yield, reproducible and quasi-automated bilayer formation in a microfluidic format.


Input: A microfluidic platform is reported for various experimentation schemes on cell membrane models and membrane proteins using a combination of electrical and optical measurements, including confocal microscopy.


Input: Bilayer lipid membranes (BLMs) are prepared in the device upon spontaneous and instantaneous thinning of the lipid solution in a 100-mu m dry-etched aperture in a 12. 5-mu m thick Teflon foil.

Teflon


Input: Using this quasi-automated approach, a remarkable 100% membrane formation yield is reached (including reflushing in 4% of the cases), and BLMs are stable for up to 36 h.


Input: Furthermore, the potential of this platform is demonstrated for (i) the in-depth characterization of BLMs comprising both synthetic and natural lipids (1, 2-diphytanoyl-sn-glycero-3-phosphocholine (DPhPC) and L-alpha-phosphatidylcholine (L-alpha-PC)/cholesterol, respectively) in terms of seal resistance, capacitance, surface area, specific capacitance, and membrane hydrophobic thickness; (ii) confocal microscopy imaging of phase separation in sphingomyelin/L-alpha-PC/cholesterol ternary membranes; (iii) electrical measurements of individual nanopores (alpha-hemolysin, gramicidin); and (iv) indirect assessment of the alteration of membrane properties upon exposure to chemical stimuli using the natural nanopore gramicidin as a sensor.

1, 2-diphytanoyl-sn-glycero-3-phosphocholine

DPhPC

L-alpha-phosphatidylcholine

L-alpha-PC

cholesterol

sphingomyelin

L-alpha-PC

cholesterol

gramicidin

gramicidin


Input: Hierarchical porous materials: catalytic applications.


Input: In this review, we discuss the phenomenon of complementary macropore incorporation into mesoporous and/or microporous solids in order to enhance their catalytic performance in fuels and chemicals synthesis.


Input: C3'/C4'-Stereochemical Effects of Digitoxigenin alpha-L-/alpha-D-Glycoside in Cancer Cytotoxicity.

Digitoxigenin alpha-L-/alpha-D-Glycoside


Input: Sweet' n low in stereo: A Wharton reaction was employed along with a diastereoselective palladium-catalyzed glycosylation and other post-glycosylation transformations to synthesize digitoxin analogues.

palladium

digitoxin


Input: Cytotoxic evaluation against a panel of cancer cell lines uncovered the stereochemical and substitutional limits of the C3'/C4'-hydroxy functionality in digitoxin monosaccharide.

digitoxin monosaccharide


Input: Investigating the motion of diblock copolymer assemblies in ionic liquids by in situ electron microscopy.


Input: The movement of individual block copolymer micelles in free-standing films of ionic liquids is investigated by transmission electron microscopy with the aim of providing an easily accessible high-resolution imaging tool for the in situ observation of particle movement in a liquid environment.


Input: A proof of concept and first studies on the behavior of individual particles in the fluid are demonstrated.


Input: The peri-islet basement membrane, a barrier to infiltrating leukocytes in type 1 diabetes in mouse and human.


Input: We provide the first comprehensive analysis of the extracellular matrix (ECM) composition of peri-islet capsules, composed of the peri-islet basement membrane (BM) and subjacent interstitial matrix (IM), in development of type 1 diabetes in NOD mice and in human type 1 diabetes.


Input: Our data demonstrate global loss of peri-islet BM and IM components only at sites of leukocyte infiltration into the islet.


Input: Stereological analyses reveal a correlation between incidence of insulitis and the number of islets showing loss of peri-islet BM versus islets with intact BMs, suggesting that leukocyte penetration of the peri-islet BM is a critical step.


Input: Protease-and protease inhibitor-specific microarray analyses (CLIP-CHIP) of laser-dissected leukocyte infiltrated and noninfiltrated pancreatic islets and confirmatory quantitative real time PCR and protein analyses identified cathepsin S, W, and C activity at sites of leukocyte penetration of the peri-islet BM in association with a macrophage subpopulation in NOD mice and human type 1 diabetic samples and, hence, potentially a novel therapeutic target specifically acting at the islet penetration stage.


Input: Interestingly, the peri-islet BM and underlying IM are reconstituted once inflammation subsides, indicating that the peri-islet BM-producing cells are not lost due to the inflammation, which has important ramifications to islet transplantation studies.


Input: Neuronal androgen receptor regulates insulin sensitivity via suppression of hypothalamic NF-kappa B-mediated PTP1B expression.

androgen


Input: Clinical investigations highlight the increased incidence of metabolic syndrome in prostate cancer (PCa) patients receiving androgen deprivation therapy (ADT).

androgen


Input: Studies using global androgen receptor (AR) knockout mice demonstrate that AR deficiency results in the development of insulin resistance in males.

androgen


Input: However, mechanisms by which AR in individual organs coordinately regulates insulin sensitivity remain unexplored.


Input: Here we tested the hypothesis that functional AR in the brain contributes to whole-body insulin sensitivity regulation and to the metabolic abnormalities developed in AR-deficient male mice.


Input: The mouse model selectively lacking AR in the central nervous system and AR-expressing GT1-7 neuronal cells were established and used to delineate molecular mechanisms in insulin signaling modulated by AR.


Input: Neuronal AR deficiency leads to reduced insulin sensitivity in middle-aged mice.


Input: Neuronal AR regulates hypothalamic insulin signaling by repressing nuclear factor-kappa B (NF-kappa B)-mediated induction of protein-tyrosine phosphatase 1B (PTP1B).

tyrosine


Input: Hypothalamic insulin resistance leads to hepatic insulin resistance, lipid accumulation, and visceral obesity.


Input: The functional deficiency of AR in the hypothalamus leads to male mice being more susceptible to the effects of high-fat diet consumption on PTP1B expression and NF-kappa B activation.


Input: These findings suggest that in men with PCa undergoing ADT, reduction of AR function in the brain may contribute to insulin resistance and visceral obesity.


Input: Pharmacotherapies targeting neuronal AR and NF-kappa B may be developed to combat the metabolic syndrome in men receiving ADT and in elderly men with age-associated hypogonadism.


Input: Identification of cross-species shared transcriptional networks of diabetic nephropathy in human and mouse glomeruli.


Input: Murine models are valuable instruments in defining the pathogenesis of diabetic nephropathy (DN), but they only partially recapitulate disease manifestations of human DN, limiting their utility.


Input: To define the molecular similarities and differences between human and murine DN, we performed a cross-species comparison of glomerular transcriptional networks.


Input: Glomerular gene expression was profiled in patients with early type 2 DN and in three mouse models (streptozotocin DBA/2, C57BLKS db/db, and eNOS-deficient C57BLKS db/db mice).

streptozotocin


Input: Species-specific transcriptional networks were generated and compared with a novel network-matching algorithm.


Input: Three shared human-mouse cross-species glomerular transcriptional networks containing 143 (Human-DBA STZ), 97 (Human-BKS db/db), and 162 (Human-BKS eNOS (-/-) db/db) gene nodes were generated.

STZ


Input: Shared nodes across all networks reflected established pathogenic mechanisms of diabetes complications, such as elements of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) and vascular endothelial growth factor receptor (VEGFR) signaling pathways.


Input: In addition, novel pathways not previously associated with DN and cross-species gene nodes and pathways unique to each of the human-mouse networks were discovered.


Input: The human-mouse shared glomerular transcriptional networks will assist DN researchers in selecting mouse models most relevant to the human disease process of interest.


Input: Moreover, they will allow identification of new pathways shared between mice and humans.


Input: Metabolite profiling reveals normal metabolic control in carriers of mutations in the glucokinase gene (MODY2).


Input: Mutations in the gene encoding glucokinase (GCK) cause a mild hereditary form of diabetes termed maturity-onset diabetes of the young (MODY) 2 or GCK-MODY.


Input: The disease does not progress over time, and diabetes complications rarely develop.


Input: It has therefore been suggested that GCK-MODY represents a metabolically compensated condition, but experimental support for this notion is lacking.


Input: Here, we profiled metabolites in serum from patients with MODY1 (HNF4A), MODY2 (GCK), MODY3 (HNF1A), and type 2 diabetes and from healthy individuals to characterize metabolic perturbations caused by specific mutations.


Input: Analysis of four GCK-MODY patients revealed a metabolite pattern similar to that of healthy individuals, while other forms of diabetes differed markedly in their metabolite profiles.


Input: Furthermore, despite elevated glucose concentrations, carriers of GCK mutations showed lower levels of free fatty acids and triglycerides than healthy control subjects.

glucose

fatty acids

triglycerides


Input: The metabolite profiling was confirmed by enzymatic assays and replicated in a cohort of 11 GCK-MODY patients.


Input: Elevated levels of fatty acids are known to associate with beta-cell dysfunction, insulin resistance, and increased incidence of late complications.

fatty acids


Input: Our results show that GCK-MODY represents a metabolically normal condition, which may contribute to the lack of late complications and the nonprogressive nature of the disease.


Input: Intrahypothalamic estradiol regulates glucose metabolism via the sympathetic nervous system in female rats.

estradiol

glucose


Input: Long-term reduced hypothalamic estrogen signaling leads to increased food intake and decreased locomotor activity and energy expenditure, and ultimately results in obesity and insulin resistance.

estrogen


Input: In the current study, we aimed to determine the acute obesity-independent effects of hypothalamic estrogen signaling on glucose metabolism.

estrogen

glucose


Input: We studied endogenous glucose production (EGP) and insulin sensitivity during selective modulation of systemic or intrahypothalamic estradiol (E2) signaling in rats 1 week after ovariectomy (OVX).

glucose

estradiol


Input: OVX caused a 17% decrease in plasma glucose, which was completely restored by systemic E2.

glucose


Input: Likewise, the administration of E2 by microdialysis, either in the hypothalamic paraventricular nucleus (PVN) or in the ventromedial nucleus (VMH), restored plasma glucose.

glucose


Input: The infusion of an E2 antagonist via reverse microdialysis into the PVN or VMH attenuated the effect of systemic E2 on plasma glucose.

glucose


Input: Furthermore, E2 administration in the VMH, but not in the PVN, increased EGP and induced hepatic insulin resistance.


Input: E2 administration in both the PVN and the VMH resulted in peripheral insulin resistance.


Input: Finally, sympathetic, but not parasympathetic, hepatic denervation blunted the effect of E2 in the VMH on both EGP and hepatic insulin sensitivity.


Input: In conclusion, intrahypothalamic estrogen regulates peripheral and hepatic insulin sensitivity via sympathetic signaling to the liver.

estrogen


Input: Comparative analysis of four oxidized guanine lesions from reactions of DNA with peroxynitrite, singlet oxygen, and gamma-radiation.

guanine

peroxynitrite

oxygen


Input: Oxidative damage to DNA has many origins, including irradiation, inflammation, and oxidative stress, but the chemistries are not the same.


Input: The most oxidizable base in DNA is 2-deoxyguanosine (dG), and the primary oxidation products are 8-oxodG and 2-amino-imidazolone.


Input: The latter rapidly converts to 2, 2-diamino-oxazolone (Ox), and 8-oxodG is further oxidized to spiroiminodihydantoin (Sp) and guanidinohydantoin (Gh).

2, 2-diamino-oxazolone

spiroiminodihydantoin

guanidinohydantoin


Input: In this study, we have examined the dose-response relationship for the formation of the above four products arising in calf thymus DNA exposed to gamma irradiation, photoactivated rose bengal, and two sources of peroxynitrite.

rose bengal

peroxynitrite


Input: In order to carry out these experiments, we developed a chromatographic system and synthesized isotopomeric internal standards to enable accurate and precise analysis based upon selected reaction monitoring mass spectrometry.


Input: 8-OxodG was the most abundant products in all cases, but its accumulation was highly dependent on the nature of the oxidizing agent and the subsequent conversion to Sp and Gh.


Input: Among the other oxidation products, Ox was the most abundant, and Sp was formed in significantly greater yield than Gh.


Input: Inactivation of Escherichia coli by sonoelectrocatalytic disinfection using TiO2 as electrode.


Input: This is the first study to demonstrate sonoelectrocatalytic disinfection using titanium dioxide (TiO (2)) as an anode for effective inactivation of Escherichia coli.

titanium dioxide

TiO (2)


Input: In brief, a non-woven TiO (2) fabric used as an anode and a platinum cathode were immersed in an E. coli suspension in which a positive potential was applied to TiO (2) concomitant with ultrasound (US) irradiation.

TiO (2)

platinum

TiO (2)


Input: Two control experiments were performed using E. coli suspensions to exhibit the effects of the sonoelectrocatalytic disinfection.


Input: One was disinfection by applying a positive potential to a TiO (2) electrode, but without US irradiation (electrochemical disinfection).

TiO (2)


Input: The other was disinfection without applying a potential, but with US irradiation in the presence of TiO (2) (sonocatalytic disinfection).

TiO (2)


Input: The cell inactivation rate in sonoelectrocatalytic disinfection was synergistically much more enhanced than the combined inactivation rates in electrochemical disinfection and sonocatalytic disinfection.


Input: This synergistically enhanced inactivation rate of E. coli cells was attributable to effective reaction of the sonocatalytically generated OH radicals with E. coli cells at the surface of the TiO (2) anode, which resulted from the electroadsorption of E. coli cells toward the TiO (2) anode.

OH

TiO (2)

TiO (2)


Input: Recurrent major depressive disorder: Imbalance of neurokinin (NK)-1 and NK-2 receptor expression in monocytes.


Input: Increasing evidence suggests that tachykinins are involved in the control of different pathological conditions, including psychiatric disorders.


Input: In this study we evaluated the expression of NK (1) and NK (2) receptors (NK-1R and NK-2R), as well as the effects of substance P (SP) and neurokinin A (NKA), in monocytes isolated from 15 healthy subjects and 15 patients with recurrent major depressive disorder (RMDD), under stable antidepressant therapy.

substance P

neurokinin A

NKA


Input: NK-1R expression in monocytes from RMDD patients was significantly decreased as compared to healthy subjects, whereas NK-2R expression was markedly increased.


Input: Both NK-1R and NK-2R expression correlated with HAM-D, but not HAM-A, score.


Input: SP, NKA and selective NK-1R and NK-2R agonists stimulated TNF-alpha release in monocytes of both groups, with a significant higher effect observed in RMDD.

NKA


Input: Moreover they induced NF-kappa B activation, which was reversed by selective NK-1R and NK-2R antagonists, so demonstrating that it was receptor-mediated.


Input: The occurrence of a profound alteration in NK receptor expression in RMDD is a novel finding that suggests NK-1R and NK-2R pathways as possible relevant players in major depressive disorder, so improving our understanding of the complex pathogenesis of the disease.


Input: The role of mitochondria and biotransformation in abamectin-induced cytotoxicity in isolated rat hepatocytes.

abamectin


Input: Abamectin (ABA), which belongs to the family of avermectins, is used as a parasiticide; however, ABA poisoning can impair liver function.

Abamectin

ABA

avermectins

ABA


Input: In a previous study using isolated rat liver mitochondria, we observed that ABA inhibited the activity of adenine nucleotide translocator and FoF1-ATPase.

ABA

adenine nucleotide


Input: The aim of this study was to characterize the mechanism of ABA toxicity in isolated rat hepatocytes and to evaluate whether this effect is dependent on its metabolism.

ABA


Input: The toxicity of ABA was assessed by monitoring oxygen consumption and mitochondrial membrane potential, intracellular ATP concentration, cell viability, intracellular Ca (2 +) homeostasis, release of cytochrome c, caspase 3 activity and necrotic cell death.

ABA

oxygen

ATP

Ca (2 +)


Input: ABA reduces cellular respiration in cells energized with glutamate and malate or succinate.

ABA

glutamate

malate

succinate


Input: The hepatocytes that were previously incubated with proadifen, a cytochrome P450 inhibitor, are more sensitive to the compound as observed by a rapid decrease in the mitochondrial membrane potential accompanied by reductions in ATP concentration and cell viability and a disruption of intracellular Ca (2 +) homeostasis followed by necrosis.

proadifen

ATP

Ca (2 +)


Input: Our results indicate that ABA biotransformation reduces its toxicity, and its toxic action is related to the inhibition of mitochondrial activity, which leads to decreased synthesis of ATP followed by cell death.

ABA

ATP


Input: 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism-related enzymes gene polymorphisms, NNK metabolites levels and urothelial carcinoma.

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone

NNK

NNK


Input: Gene polymorphisms of the 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism-related enzymes-cytochrome P450 (CYP) monooxygenase 2A13 (CYP2A13) and UDP-glucuronosyltransferases (UGT)-2B7 could contribute to the levels of NNK-related metabolites in urine, thereby increasing the susceptibility to urothelial carcinoma (UC).

4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone

NNK

UDP

NNK


Input: Therefore, our study aimed to evaluate the roles of two gene polymorphisms (CYP2A13 and UGT2B7) of NNK metabolism-related enzymes in the carcinogenesis of UC in Taiwan.

NNK


Input: A hospital-based pilot case-control study was conducted.


Input: There were 121 UC cases and 121 age-and sex-matched healthy participants recruited from March 2007 to April 2009.


Input: Urine samples were analyzed for NNK-related metabolites using the liquid chromatography-tandem mass spectrometry method.

NNK


Input: Genotyping was conducted using a polymerase chain reaction-restriction fragment length polymorphism technique.


Input: ANCOVA and multivariate logistic regression were applied for data analyses.


Input: In healthy controls, former smokers had significantly higher total NNAL and higher NNAL-Gluc than never smokers or current smokers.

NNAL

NNAL-Gluc


Input: Subjects carrying the UGT2B7 268 His/Tyr or Tyr/Tyr genotype had significantly lower total NNAL than those carrying His/His genotype.

His

Tyr

Tyr

Tyr

NNAL

His

His


Input: However, no association was seen between gene polymorphisms of CYP2A13 and UGT2B7 and UC risk after adjustment for age and sex.


Input: Significant dose-response associations between total NNAL, free NNAL, the ratios of free NNAL/total NNAL and NNAL-Gluc/total NNAL and UC risk were observed.

NNAL

NNAL

NNAL

NNAL

NNAL-Gluc

NNAL


Input: In the future, large-scale studies will be required to verify the association between the single nucleotide polymorphisms of NNK metabolism-related enzymes and UC risk.

nucleotide

NNK


Input: Novel potassium channel blocker venom peptides from Mesobuthus gibbosus (Scorpiones: Buthidae).

potassium


Input: In the present study, we report for the first time, the molecular, biochemical and electrophysiological characterization of the components present in the soluble venom from Mesobuthus gibbosus (Brull e, 1832).


Input: According to the epidemiological and clinical situation of scorpion envenomation cases M. gibbosus scorpion is one of the most important health-threatening species of Turkey.


Input: Despite the medical importance reported for M. gibbosus, there is no additional information on toxin peptides and venom components to clarify the toxic effect of the M. gibbosus sting.


Input: Biochemical characterization of the venom was performed using different protocols and techniques following a bioassay-guided strategy (HPLC, mass spectrometry and Edman degradation sequencing).


Input: Venom fractions were tested in electrophysiological assays on a panel of six K (+) channels (K (v) 1. 1-1. 6) by using the two-electrode voltage clamp technique.

K (+)

K


Input: Three new alpha-KTx peptides were found and called MegKTx1, MegKTx2 and MegKTx3 (M. gibbosus, K (+) channel toxin number 1-3).

K (+)


Input: A cDNA library from the telson was constructed and specific screening of transcripts was performed.


Input: Biochemical and molecular characterization of MegKTx peptides and transcripts shows a relation with toxins of three different alpha-KTx subfamilies (alpha-KTx3. x, alpha-KTx9. x and alpha-KTx16. x).


Input: Use of high content image analyses to detect chemical-mediated effects on neurite sub-populations in primary rat cortical neurons.


Input: Traditional developmental neurotoxicity tests performed in vivo are costly, time-consuming and utilize a large number of animals.


Input: In order to address these inefficiencies, in vitro models of neuronal development have been used in a first tier screening approach for developmental neurotoxicity hazard identification.


Input: One commonly used endpoint for assessing developmental neurotoxicity in vitro is measurement of neurite outgrowth.


Input: This biological process is amenable to high-throughput measurement using high content imaging (HCI) based methodologies.


Input: To date, a majority of HCI studies of neurite outgrowth have focused on measurements of total neurite outgrowth without examining whether stereotypic neuronal growth patterns are disrupted or whether specific sub-populations of neurites (i. e. axons or dendrites) are selectively affected.


Input: The present study describes the development and implementation of two HCI based analysis methods for assessing chemical effects on neuronal maturation.


Input: These methods utilize the stereotypical growth pattern of primary rat cortical neurons in culture (i. e. the Staging Method), as well as the differential cytoplasmic distribution of beta (III)-tubulin and MAP2 (i. e. the Subtraction Method), to quantify inhibition of neurite initiation, axon outgrowth and secondary neurite (or dendrite) outgrowth in response to chemical exposure.


Input: Results demonstrate that these distinct maturational processes are differentially affected by pharmacological compounds (K252a, Na (3) VO (4), Bis-1) known to inhibit neurite outgrowth.

Na (3) VO (4)


Input: Furthermore, a group of known developmental neurotoxicants also differentially affected the growth of axons and secondary neurites in primary cortical culture.


Input: This work improves upon previous HCI methods by providing a means in which to rapidly and specifically quantify chemical effects on the growth of axons and dendrites in vitro.


Input: Therapeutic RNA aptamers in clinical trials.


Input: RNA aptamers can fold into complex structures and bind with high affinity and selectivity to various macromolecules, viruses, and cells.


Input: They are isolated from a large pool of nucleic acids by a conceptually straightforward iterative selection process called SELEX.


Input: Aptamers have enormous potential as therapeutics due to their ability to bind to proteins and specifically inhibit their functions with minimal or no harmful side-effects.


Input: The first aptamer therapeutic was FDA approved in 2005 and a number of novel aptamer-based therapeutics are currently undergoing clinical trials for treating diseases such as macular degeneration, choroidal neovascularization, intravascular thrombus, acute coronary syndrome, von Willebrand factor related disorders, von Hippel-Lindau syndrome (VHL), angiomas, acute myeloid leukemia, renal cell carcinoma, non-small cell lung cancer, thrombotic thrombocytopenic purpura, and several others.


Input: In this review, we present aptamers in on-going, completed, and terminated clinical studies highlighting their mechanism of action as well as the inherent challenges of aptamer production and use.


Input: Superoxide anion mediates the L-selectin down-regulation induced by non-steroidal anti-inflammatory drugs in human neutrophils.

Superoxide


Input: Non-steroidal anti-inflammatory drugs (NSAIDs) induce the shedding of L-selectin in human neutrophils through a mechanism still not well understood.


Input: In this work we studied both the functional effect of NSAIDs on the neutrophils/endothelial cells dynamic interaction, and the potential involvement of reactive oxygen species (ROS) in the NSAIDs-mediated down-regulation of L-selectin.

oxygen


Input: When human neutrophils were incubated with diclofenac, a significant reduction in the number of cells that rolled on activated endothelial cells was observed.

diclofenac


Input: Different NSAIDs (flufenamic acid, meclofenamic acid, diclofenac, indomethacin, nimesulide, flurbiprofen, meloxicam, phenylbutazone, piroxicam, ketoprofen and aspirin) caused variable increase in neutrophil intracellular ROS concentration, which was inversely proportional to the change produced in L-selectin surface expression.

flufenamic acid

meclofenamic acid

diclofenac

indomethacin

nimesulide

flurbiprofen

meloxicam

phenylbutazone

piroxicam

ketoprofen

aspirin


Input: Pre-incubation of neutrophils with superoxide dismutase, but not with catalase, showed both a significant protective effect on the L-selectin down-regulation induced by several NSAIDs and a diminished effect of diclofenac on neutrophil rolling.

superoxide

diclofenac


Input: Interestingly, diclofenac and flufenamic acid but not piroxicam significantly increased the extracellular superoxide anion production by neutrophils, and inhibition of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase activity with diphenyleneiodonium prevented the down-regulation of L-selectin by diclofenac.

diclofenac

flufenamic acid

piroxicam

superoxide

nicotinamide adenine dinucleotide phosphate

NADPH

diphenyleneiodonium

diclofenac


Input: In accordance with these results, neutrophils from patients with chronic granulomatous disease, a hereditary disease in which neutrophils show a reduced capacity to form superoxide radicals, exhibited a lower down-regulation of L-selectin (IC50: 15. 3 mu g/ml) compared to normal controls (IC50: 5. 6 mu g/ml) in response to diclofenac.

superoxide

diclofenac


Input: CONCLUSION: A group of NSAIDs is capable of interfering with the ability of neutrophils to interact with endothelial cells by triggering L-selectin-shedding through the NADPH-oxidase-dependent generation of superoxide anion at the plasma membrane.

NADPH

superoxide


Input: Proteasome inhibition attenuates heart failure during the late stages of pressure overload through alterations in collagen expression.


Input: Although the role of the ubiquitin-proteasome system (UPS) in cardiac hypertrophy induced by pressure overload has been consistently studied, the fundamental importance of the UPS in cardiac fibrosis has received much less attention.


Input: Our previous study found that proteasome inhibitor (MG132) treatment attenuated cardiac fibrosis and heart failure during the early and middle stages of pressure overload.


Input: However, the effects of this inhibitor on late-stage pressure overload hearts remain unclear and controversial.


Input: The present study was designed to investigate the effects and possible mechanisms of MG132 on cardiac fibrosis and dysfunction during the late stages of pressure overload.


Input: Male Sprague Dawley rats with abdominal aortic constriction (AAC) or a sham operation received an intraperitoneal injection of MG132 (0. 1 mg kg-(1) day-(1)) or vehicle for 16 weeks.


Input: Left ventricular (LV) function, collagen deposition and Ang II levels were evaluated at study termination.


Input: Ang II-stimulated adult rat cardiac fibroblasts were utilized to examine the effects of MG132 on collagen synthesis and the relationship between the renin-angiotensin-aldosterone system (RAAS) and the UPS.

aldosterone


Input: MG132 treatment attenuated ventricular dysfunction by suppressing cardiac fibrosis rather than inhibiting cardiac hypertrophy during the late-stages of pressure overload.


Input: We also found that Ang II activates UPS in the heart and MG132 attenuates Ang II-induced collagen synthesis via suppression of the NF-kappa B/TGF-beta/Smad2 signaling pathways.


Input: Proteasome inhibition therefore could provide a new promising therapeutic strategy to prevent cardiac fibrosis and progression of heart failure even during the late-stages of pressure overload.


Input: Yuwen02f1 suppresses LPS-induced endotoxemia and adjuvant-induced arthritis primarily through blockade of ROS formation, NFkB and MAPK activation.


Input: Phagocytes release inflammatory mediators to defense harmful stimuli upon bacterial invasion, however, excessive inflammatory reaction leads to tissue damage and manifestation of pathological states.


Input: Therefore, targeting on uncontrolled inflammation seems feasible to control numerous inflammation-associated diseases.


Input: Under the drug screening process of synthetic diphenylpyrazole derivatives, we discovered compound yuwen02f1 possesses anti-inflammatory effects in decreasing the release of pro-inflammatory cytokines including TNF alpha and IL-6, nitric oxide, reactive oxygen species (ROS) as well as inhibiting migration of LPS-stimulated phagocytes.

diphenylpyrazole

nitric oxide

oxygen


Input: In addition, we observed that the molecular mechanism of yuwen02f1-mediated anti-inflammation is associated with decreasing phosphorylation of MAPK molecules including ERK1/2, JNK and p38, and attenuating translocation of p47 (phox) and p67 (phox) to the cell membrane.


Input: Yuwen02f1 also reverses I kappa B alpha degradation and attenuates the expression of NF kappa B-related downstream inducible enzymes like iNOS and COX-2.


Input: Furthermore, we found that yuwen02f1 attenuates some pathological syndromes of LPS-induced sepsis and adjuvant-induced arthritis in mice, as evidenced by decreasing the cytokine production, reversing thrombocytopenic syndrome, protecting the mice from tissue injury in septic mice, and attenuating paw edema in arthritic mice as well.


Input: These results suggest that yuwen02f1 is a potential anti-inflammatory agent for alleviating syndromes of acute and chronic inflammatory diseases as evidenced by attenuating the generation of cytokines and down-regulating the expression of iNOS and COX-2 through the blockade of ROS generation and NADPH oxidase, NF kappa B and MAPK activation pathways in LPS-stimulated phagocytes.

NADPH


Input: Protective effects of erythropoietin on astrocytic swelling after oxygen-glucose deprivation and reoxygenation: mediation through AQP4 expression and MAPK pathway.

oxygen

glucose


Input: Recent in vivo studies have shown that erythropoietin (EPO) offers strong protection against brain edema.


Input: However, the intracellular and molecular mechanisms behind this beneficial effect have not been specified.


Input: The aim of this study was to determine whether human erythropoietin (rhEPO) reduces the astrocytic swelling created by oxygen-glucose deprivation followed by reoxygenation (OGD/Reox) in vitro and whether this effect can be mediated through the modulation of aquaporin4 (AQP4) expression in the plasma membrane (PM) and phosphorylation of the mitogen-activated protein kinase pathway (MAPK) pathway.

oxygen

glucose


Input: Our results showed that OGD/Reox produced increase in cell volume, morphological swelling, and mitochondrial swelling.


Input: These changes were associated with the up-regulation of AQP4 in PM and the over-activation of MAPK.


Input: Silencing AQP4 expression using small interfering ribonucleic acid for AQP4 was found to block astrocytic swelling.


Input: Inhibition of the over-activation of MAPK mitigated the PM AQP4 overabundance and cellular swelling.


Input: As expected, treatment with rhEPO significantly reduced the OGD/Reox-induced increase in cell volume, morphological swelling, and mitochondrial swelling as well as the up-regulation of AQP4 in PM.


Input: In addition, cultures treated with the neutralizing anti-EPO antibody worsened the PM AQP4 abundance and cellular swelling, abolishing the protective effects mediated by rhEPO treatment.


Input: Furthermore, the over-activation of these MAPK after OGD/Reox was attenuated by rhEPO treatment significantly.


Input: In conclusion, our data strongly suggest that rhEPO can protect astrocytes from swelling caused by ischemia and reperfusion-like injury.


Input: This neuroprotective capacity is partially mediated by diminishing the MAPK-activity-dependent overabundance of AQP4 in PM.


Input: Toxicogenomic biomarkers for renal papillary injury in rats.


Input: Renal papillary injury is a common side effect observed during nonclinical and clinical investigations in drug development.


Input: The present study aimed to identify genomic biomarkers for early and sensitive detection of renal papillary injury in rats.


Input: We hypothesized that previously identified genomic biomarkers for tubular injury might be applicable for the sensitive detection of papillary injury in rats.


Input: We selected 18 genes as candidate biomarkers for papillary injury based on previously published studies and analyzed their expression profiles by RT-PCR in each kidney region, namely the cortex, cortico-medullary junction, and papilla in various nephrotoxicity models.


Input: Comparative analysis of gene expression profiles revealed that some genes were commonly upregulated or downregulated in the renal papilla, reflecting papillary injuries induced by 2-bromoethylamine hydrobromide, phenylbutazone, or n-phenylanthranilic acid.

2-bromoethylamine hydrobromide

phenylbutazone

n-phenylanthranilic acid


Input: By applying receiver operator characteristics analysis, six candidate biomarkers were identified and their usefulness was confirmed by using an independent data set.


Input: The three top-ranked genes, Timp1, Igf1, and Lamc2, exhibited the best prediction performance in an external data set with area under the curve (AUC) values of greater than 0. 91.


Input: An optimized support vector machine model consisting of three genes achieved the highest AUC value of 0. 99.


Input: In conclusion, even though definitive validation studies are required for the establishment of their usefulness and reliability, these identified genes may prove to be the most promising candidate genomic biomarkers of renal papillary injury in rats.


Input: Differential responses in ammonia excretion, sodium fluxes and gill permeability explain different sensitivities to acute high environmental ammonia in three freshwater teleosts.

ammonia

sodium

ammonia


Input: We examined the acute physiological responses to high environmental ammonia (HEA), particularly the linkages between branchial ammonia fluxes and unidirectional Na (+) fluxes, as well as urea excretion, cortisol, and indicators of gill permeability in three freshwater teleosts differing in their sensitivities to ammonia; the highly sensitive salmonid Oncorhynchus mykiss (rainbow trout), the less sensitive cyprinid Cyprinus carpio (common carp) and the highly resistant cyprinid Carassius auratus (goldfish).

ammonia

ammonia

Na (+)

urea

cortisol

ammonia


Input: Fish were acutely exposed to two sub-lethal ammonia concentrations (as NH (4) HCO (3)) at pH 7. 9: 1 mM for a period of 12 h, identical for all species, and 5 mM for the cyprinids and 1. 4 mM for the trout for 3 h.

ammonia

NH (4) HCO (3)


Input: Elevation of plasma cortisol at both levels of HEA was apparent in all species.

cortisol


Input: At 1 mM, ammonia excretion (J (amm)) was inhibited to a greater extent in trout than cyprinids and concurrently a significantly higher plasma ammonia level was evident in trout.

ammonia

amm

ammonia


Input: However J (amm) was reversed in all species at 5 or 1. 4 mM.

amm


Input: Goldfish showed a significant increase in urea excretion rate (J (urea)) during HEA exposure.

urea

urea


Input: In carp and trout, neither level of HEA elevated J (urea) but urea production was increased as evidenced by a considerable elevation of plasma urea.

urea

urea

urea


Input: At 1mM HEA, Na (+) imbalance became progressively more severe in trout and carp due to a stimulation of unidirectional Na (+) efflux (J (out) (Na)) without a concomitant increase in unidirectional Na (+) influx (J (in) (Na)).

Na (+)

Na (+)

Na (+)


Input: Additionally, a transient reduction of J (in) (Na) was evident in trout.


Input: Goldfish showed an opposite trend for J (out) (Na) with reduced efflux rates and a positive Na (+) balance during the first few hours of HEA.

Na (+)


Input: However, after 12 h of exposure, both J (in) (Na) and J (out) (Na) were also increased in both carp and goldfish, whereas only J (out) (Na) was increased in trout, leading to a net Na (+) loss.

Na (+)


Input: Na (+) homeostasis was entirely disrupted in all three species when subjected to the 5 or 1. 4 mM ammonia for 3 h: J (in) (Na) was significantly inhibited while considerable activation of J (out) (Na) was observed.

Na (+)

ammonia


Input: Diffusive water efflux rates and net K (+) loss rates across the gills were enhanced during HEA only in trout, indicating an increment in gill transcellular permeability.

K (+)


Input: Transepithelial potential was increased in all the species during ammonia exposure, but to the least extent in goldfish.

ammonia


Input: Overall, for several different physiological systems, trout were most disturbed, and goldfish were least disturbed by HEA, helping to explain the differential ammonia tolerance of the three species.

ammonia


Input: Metabolic pathways of inhaled glucocorticoids by the CYP3A enzymes.


Input: Asthma is one of the most prevalent diseases in the world, for which the mainstay treatment has been inhaled glucocorticoids (GCs).


Input: Despite the widespread use of these drugs, approximately 30% of asthma sufferers exhibit some degree of steroid insensitivity or are refractory to inhaled GCs.

steroid


Input: One hypothesis to explain this phenomenon is interpatient variability in the clearance of these compounds.


Input: The objective of this research is to determine how metabolism of GCs by the CYP3A family of enzymes could affect their effectiveness in asthmatic patients.


Input: In this work, the metabolism of four frequently prescribed inhaled GCs, triamcinolone acetonide, flunisolide, budesonide, and fluticasone propionate, by the CYP3A family of enzymes was studied to identify differences in their rates of clearance and to identify their metabolites.

triamcinolone acetonide

flunisolide

budesonide

fluticasone propionate


Input: Both interenzyme and interdrug variability in rates of metabolism and metabolic fate were observed.


Input: CYP3A4 was the most efficient metabolic catalyst for all the compounds, and CYP3A7 had the slowest rates.


Input: CYP3A5, which is particularly relevant to GC metabolism in the lungs, was also shown to efficiently metabolize triamcinolone acetonide, budesonide, and fluticasone propionate.

triamcinolone acetonide

budesonide

fluticasone propionate


Input: In contrast, flunisolide was only metabolized via CYP3A4, with no significant turnover by CYP3A5 or CYP3A7.

flunisolide


Input: Common metabolites included 6 beta-hydroxylation and Delta (6)-dehydrogenation for triamcinolone acetonide, budesonide, and flunisolide.

triamcinolone acetonide

budesonide

flunisolide


Input: The structure of Delta (6)-flunisolide was unambiguously established by NMR analysis.

Delta (6)-flunisolide


Input: Metabolism also occurred on the D-ring substituents, including the 21-carboxy metabolites for triamcinolone acetonide and flunisolide.

triamcinolone acetonide

flunisolide


Input: The novel metabolite 21-nortriamcinolone acetonide was also identified by liquid chromatography-mass spectrometry and NMR analysis.

21-nortriamcinolone acetonide


Input: IsoDGR-tagged albumin: a new alpha v beta 3 selective carrier for nanodrug delivery to tumors.


Input: A new cyclic peptide containing the isoDGR motif that, after coupling to albumin, selectively binds alpha v beta 3, an integrin overexpressed in the tumor vasculature.


Input: IsoDGR-tagged albumin binds tumor vessels and can be exploited as a carrier for the preparation of tumor vasculature-selective nanomedicines, such as gold nanoparticles (Au) carrying tumor necrosis factor alpha (TNF), a potent vascular damaging agent.

Au


Input: Enhancing the photocatalytic activity of anatase TiO2 by improving the specific facet-induced spontaneous separation of photogenerated electrons and holes.


Input: Recently, it has been proven that directional flow of photogenerated charge carriers occurs on specific facets of TiO (2) nanocrystals.

TiO (2)


Input: Herein, we demonstrate that the photocatalytic activity of anatase TiO (2) nanocrystals in both photoreduction and photooxidation processes can be enhanced by selectively depositing Pt nanoparticles on the {101} facets, which strengthens spontaneously surface-induced separation between photogenerated electrons and holes in the photocatalysis process.

TiO (2)

Pt


Input: An optimal ratio of the oxidative {001} facets to the reductive {101} facets exists with regard to the photocatalysis of the faceted TiO (2) nanocrystals, and this is crucial for balancing the recombination and redox reaction rates of photogenerated electrons and holes.

TiO (2)


Input: The present work might help us gain deeper insight into the relation between the specific surface of semiconductor photocatalysts and their photocatalytic activities and provides us with a new route to design photocatalysts with high photocatalytic activity.


Input: Noncompetitive, voltage-dependent NMDA receptor antagonism by hydrophobic anions.

NMDA


Input: NMDA receptor (NMDAR) antagonists are dissociative anesthetics, drugs of abuse, and are of therapeutic interest in neurodegeneration and neuropsychiatric disease.

NMDA


Input: Many well-known NMDAR antagonists are positively charged, voltage-dependent channel blockers.


Input: We recently showed that the hydrophobic anion dipicrylamine (DPA) negatively regulates GABA (A) receptor function by a mechanism indistinguishable from that of sulfated neurosteroids.

dipicrylamine

DPA

GABA

sulfated neurosteroids


Input: Because sulfated neurosteroids also modulate NMDARs, here we examined the effects of DPA on NMDAR function.

neurosteroids

DPA


Input: In rat hippocampal neurons DPA inhibited currents gated by 300 micro M NMDA with an IC (50) of 2. 3 micro M.

DPA

NMDA


Input: Neither onset nor offset of antagonism exhibited dependence on channel activation but exhibited a noncompetitive profile.


Input: DPA antagonism was independent of NMDAR subunit composition and was similar at extrasynaptic and total receptor populations.

DPA


Input: Surprisingly, similar to cationic channel blockers but unlike sulfated neurosteroids, DPA antagonism was voltage dependent.

sulfated neurosteroids

DPA


Input: Onset and offset of DPA antagonism were nearly 10-fold faster than DPA-induced increases in membrane capacitance, suggesting that membrane interactions do not directly explain antagonism.

DPA

DPA


Input: Furthermore, voltage dependence did not derive from association of DPA with a site on NMDARs directly accessible to the outer membrane leaflet, assessed by DPA translocation experiments.

DPA

DPA


Input: Consistent with the expected lack of channel block, DPA antagonism did not interact with permeant ions.

DPA


Input: Therefore, we speculate that voltage dependence may arise from interactions of DPA with the inherent voltage dependence of channel gating.

DPA


Input: Overall, we conclude that DPA noncompetitively inhibits NMDA-induced current by a novel voltage-dependent mechanism and represents a new class of anionic NMDAR antagonists.

DPA

NMDA


Input: Structural optimization of 2, 5-thiophene amides as highly potent and selective 17 beta-hydroxysteroid dehydrogenase type 2 inhibitors for the treatment of osteoporosis.

2, 5-thiophene amides

17 beta-hydroxysteroid


Input: Inhibition of 17 beta-HSD2 is an attractive mechanism for the treatment of osteoporosis.


Input: We report here the optimization of human 17 beta-HSD2 inhibitors in the 2, 5-thiophene amide class by varying the size of the linker (n equals 0 and 2) between the amide moiety and the phenyl group.

2, 5-thiophene amide

amide

phenyl


Input: While none of the phenethylamides (n = 2) were active, most of the anilides (n = 0) turned out to moderately or strongly inhibit 17 beta-HSD2.

phenethylamides

anilides


Input: The four most active compounds showed an IC 5 0 of around 60 nM and a very good selectivity toward 17 beta-HSD1, 17 beta-HSD4, 17 beta-HSD5, 11 beta-HSD1, 11 beta-HSD2 and the estrogen receptors alpha and beta.

estrogen


Input: The investigated compounds inhibited monkey 17 beta-HSD2 moderately, and one of them showed good inhibitory activity on mouse 17 beta-HSD2.


Input: SAR studies allowed a first characterization of the human 17 beta-HSD2 active site, which is predicted to be considerably larger than that of 17 beta-HSD1.


Input: P2Y purinergic receptors: new targets for analgesic and antimigraine drugs.


Input: Millions of individuals worldwide suffer from acute and, more severely, chronic pain conditions (e. g., neuropathic pain, and migraine).


Input: The latter bear tremendous personal, familial, and social costs, since sufferers and their relatives undergo a complete turnaround of their lives with the search of relief from pain becoming their pivotal thought.


Input: Sadly, to date no effective pharmacological approaches are available which can alleviate chronic pain significantly or in the long run in all patients.


Input: The current central strategy for the development of new and effective painkillers lies in the hypothesis that cellular and/or molecular players in nociception must exists that are not targeted by " classical " analgesics, and therefore researchers have put tremendous efforts into the in-depth analysis of the pathways leading to pain development and maintenance over time.


Input: In this complex scenario, two outsiders are now taking the center stage: glial cells in sensory ganglia and in the central nervous system, thanks to their ability to communicate with neurons and to modulate their firing, and the purinergic system.


Input: Extracellular purine and pyrimidine nucleotides are involved in the physiology of virtually every body district, and their extracellular concentrations massively increase under pathological situations, suggesting that they might represent potential targets for the modulation of disease-associated symptoms, like pain.

purine and pyrimidine nucleotides


Input: Here, we provide an overview of the present knowledge of the role of nucleotides in nociception, with a particular emphasis on G protein-coupled P2Y receptors and their involvement in the communication between first-and second-order neurons in sensory nerve pathways and surrounding glial cells.

nucleotides


Input: Answers to critics: Why there is a long term toxicity due to a Roundup-tolerant genetically modified maize and to a Roundup herbicide.


Input: Our recent work (S e ralini et al., 2012) remains to date the most detailed study involving the life-long consumption of an agricultural genetically modified organism (GMO).


Input: This is true especially for NK603 maize for which only a 90-day test for commercial release was previously conducted using the same rat strain (Hammond et al., 2004).


Input: It is also the first long term detailed research on mammals exposed to a highly diluted pesticide in its total formulation with adjuvants.


Input: This may explain why 75% of our first criticisms arising within a week, among publishing authors, come from plant biologists, some developing patents on GMOs, even if it was a toxicological paper on mammals, and from Monsanto Company who owns both the NK603 GM maize and Roundup herbicide (R).


Input: Our study has limits like any one, and here we carefully answer to all criticisms from agencies, consultants and scientists, that were sent to the Editor or to ourselves.


Input: At this level, a full debate is biased if the toxicity tests on mammals of NK603 and R obtained by Monsanto Company remain confidential and thus unavailable in an electronic format for the whole scientific community to conduct independent scrutiny of the raw data.


Input: In our article, the conclusions of long-term NK603 and Roundup toxicities came from the statistically highly discriminant findings at the biochemical level in treated groups in comparison to controls, because these findings do correspond in an blinded analysis to the pathologies observed in organs, that were in turn linked to the deaths by anatomopathologists.


Input: GM NK603 and R cannot be regarded as safe to date.


Input: Decreased levels of AKR1B1 and AKR1B10 in cancerous endometrium compared to adjacent non-cancerous tissue.


Input: Endometrial cancer is associated with enhanced cell proliferation due to high concentrations of estrogens, and decreased cell differentiation due to low levels of progesterone and retinoic acid.

estrogens

progesterone

retinoic acid


Input: It is also associated with aberrant inflammatory responses and concomitant increased production of prostaglandins.

prostaglandins


Input: The human members of the aldo-keto reductase 1B (AKR1B) subfamily, AKR1B1 and AKR1B10, have roles in these processes and can thus be implicated in endometrial cancer.


Input: To date, there have been no reports on the expression of AKR1B1 in endometrial cancer, while AKR1B10 has only been studied at the cellular level.


Input: To evaluate the roles of these AKR1B enzymes, we investigated expression of AKR1B1 and AKR1B10 in 47 paired samples of cancerous and adjacent control endometrium at the mRNA and protein levels, by quantitative PCR, Western blotting and immunohistochemistry staining.


Input: There were significantly lower mRNA and protein levels of AKR1B1 in cancerous tissues compared to adjacent endometrium.


Input: The gene expression of AKR1B10 at the mRNA level was significantly increased, while there were significantly decreased protein levels.


Input: Immunohistochemistry revealed that both of these enzymes were present in all of the samples, and are located in epithelial cells of cancerous and control endometrial glands.


Input: Elevated levels in adjacent non-cancerous tissues imply that these enzymes are more important in the initiation of endometrial cancer than in its progression.


Input: To the best of our knowledge, this is the first report on the expression of AKR1B1 and AKR1B10 in endometrial cancer.


Input: Further studies are needed to define the precise roles of these enzymes in the pathogenesis of endometrial cancer.


Input: Effects of arsenite in astrocytes on neuronal signaling transduction.

arsenite


Input: The main purpose of this study was to test the hypothesis that arsenite induces neurotoxicity via effects on astrocytes.

arsenite


Input: Astrocytes were exposed to 0, 5 or 10 mu M arsenite in medium for 24 h, and then astrocyte-conditioned medium (ACM) was collected after incubation with fresh medium for 6 h.

arsenite


Input: Primary neuron cultures were divided into four groups due to ACM, which were neurons without ACM exposure (group I) and neurons exposed to ACM from 0, 5 or 10 mu M arsenite treated astrocytes (group II-IV).

arsenite


Input: Protein expression of N-methyl-d-aspartate receptors (NR1, NR2A, NR2B), calmodulin-dependent protein kinase II (CaMKII) and adenylate cyclase (AC) in neurons were measured after incubation with ACM for 4, 8 or 12 h.

N-methyl-d-aspartate

adenylate


Input: Morphological changes and synaptic formation were observed after a 72 h-incubation with ACM.


Input: Compared to group II, synaptic formation and protein expression of NR2A, NR2B, CaMKII and AC in group III and IV were significantly suppressed.


Input: Moreover, synaptic formation and protein expression of CaMKII and AC in group II were significantly enhanced when compared with group I.


Input: Taken together, findings from this study suggested that arsenic in astrocytes might impair synaptic formation through disturbing astrocytic effects on neuronal signal transduction.

arsenic


Input: Toxicity of the synthetic polymeric 3-alkylpyridinium salt (APS3) is due to specific block of nicotinic acetylcholine receptors.

3-alkylpyridinium salt

acetylcholine


Input: The in vivo and in vitro toxic effects of the synthetic polymeric 3-alkylpyridinium salt (APS3), from the Mediterranean marine sponge Reniera sarai, were evaluated on mammals, with emphasis to determine its mode of action.

3-alkylpyridinium salt


Input: The median lethal doses of APS3 were 7. 25 and higher that 20mg/kg in mouse and rat, respectively.


Input: Intravenous administration of 7. 25 and 20mg/kg APS3 to rat caused a significant fall followed by an increase in mean arterial blood pressure accompanied by tachycardia.


Input: In addition, cumulative doses of APS3 (up to 60 mg/kg) inhibited rat nerve-evoked skeletal muscle contraction in vivo, with a median inhibitory dose (ID (50)) of 37. 25mg/kg.


Input: When administrated locally by intramuscular injection to mouse, APS3 decreased the compound muscle action potential recorded in response to in vivo nerve stimulation, with an ID (50) of 0. 5mg/kg.


Input: In vitro experiments confirmed the inhibitory effect of APS3 on mouse hemidiaphragm nerve-evoked muscle contraction with a median inhibitory concentration (IC (50)) of 20. 3 mu M, without affecting directly elicited muscle contraction.


Input: The compound inhibited also miniature endplate potentials and nerve-evoked endplate potentials with an IC (50) of 7. 28 mu M in mouse hemidiaphragm.


Input: Finally, APS3 efficiently blocked acetylcholine-activated membrane inward currents flowing through Torpedo nicotinic acetylcholine receptors (nAChRs) incorporated to Xenopus oocytes, with an IC (50) of 0. 19 mu M.

acetylcholine

acetylcholine


Input: In conclusion, our results strongly suggest that APS3 blocks muscle-type nAChRs, and show for the first time that in vivo toxicity of APS3 is likely to occur through an antagonist action of the compound on these receptors.


Input: Characteristic molecular signature for the early detection and prediction of polycyclic aromatic hydrocarbons in rat liver.

polycyclic aromatic hydrocarbons


Input: Predictions of toxicity are central for the assessment of chemical toxicity, and the effects of environmental toxic compounds are still a major issue for predicting potential human health risks.


Input: Among the various environmental toxicants, polycyclic aromatic hydrocarbons (PAHs) are an important class of environmental pollutant, and many PAHs are known or suspected carcinogens.

polycyclic aromatic hydrocarbons

PAHs

PAHs


Input: In the present study, to investigate whether characteristic expression profiles of PAHs exist in rat liver and whether a characteristic molecular signature can discriminate and predict among different PAHs at an early exposure time, we analyzed the genome-wide expression profiles of rat livers exposed to PAHs [benzo [a] anthracene (BA), benzo [a] pyrene (BP), phenanthrene (PA) and naphthalene (NT)].

PAHs

PAHs

PAHs

benzo [a] anthracene

benzo [a] pyrene

phenanthrene

naphthalene


Input: At early time-point PAH exposure, large-scale gene expression analysis resulted in characteristic molecular signatures for each PAH, and supervised analysis identified 1183 outlier genes as a distinct molecular signature discerning PAHs from the normal control group.

PAH

PAH

PAHs


Input: We identified 158 outlier genes as early predictive and surrogate markers for predicting each tested PAH by combination of two different multi-classification algorithms with 100% accuracy through a leave-one out cross-validation method.

PAH


Input: In conclusion, the characteristic gene expression signatures from a rat model system could be used as predictable and discernible gene-based biomarkers for the detection and prediction of PAHs, and these molecular markers may provide insights into the underlying mechanisms for genotoxicity of exposure to PAHs from environmental aspect.

PAHs

PAHs


Input: Combined and interactive effects of global climate change and toxicants on populations and communities.


Input: Increased temperature and other environmental effects of global climate change (GCC) have documented impacts on many species (e. g., polar bears, amphibians, coral reefs) as well as on ecosystem processes and species interactions (e. g., the timing of predator-prey interactions).


Input: A challenge for ecotoxicologists is to predict how joint effects of climatic stress and toxicants measured at the individual level (e. g., reduced survival and reproduction) will be manifested at the population level (e. g., population growth rate, extinction risk) and community level (e. g., species richness, food-web structure).


Input: The authors discuss how population-and community-level responses to toxicants under GCC are likely to be influenced by various ecological mechanisms.


Input: Stress due to GCC may reduce the potential for resistance to and recovery from toxicant exposure.


Input: Long-term toxicant exposure can result in acquired tolerance to this stressor at the population or community level, but an associated cost of tolerance may be the reduced potential for tolerance to subsequent climatic stress (or vice versa).


Input: Moreover, GCC can induce large-scale shifts in community composition, which may affect the vulnerability of communities to other stressors.


Input: Ecological modeling based on species traits (representing life-history traits, population vulnerability, sensitivity to toxicants, and sensitivity to climate change) can be a promising approach for predicting combined impacts of GCC and toxicants on populations and communities.


Input: Linking GABA (A) receptor subunits to alcohol-induced conditioned taste aversion and recovery from acute alcohol intoxication.

GABA

alcohol

alcohol


Input: GABA type A receptors (GABA (A)-R) are important for ethanol actions and it is of interest to link individual subunits with specific ethanol behaviors.

GABA

GABA

ethanol

ethanol


Input: We studied null mutant mice for six different GABA (A)-R subunits (alpha 1, alpha 2, alpha 3, alpha 4, alpha 5 and delta).

GABA


Input: Only mice lacking the alpha 2 subunit showed reduction of conditioned taste aversion (CTA) to ethanol.

ethanol


Input: These results are in agreement with data from knock-in mice with mutation of the ethanol-sensitive site in the alpha 2-subunit (Blednov et al., 2011).

ethanol


Input: All together, they indicate that aversive property of ethanol is dependent on ethanol action on alpha 2-containing GABA (A)-R.

ethanol

ethanol

GABA


Input: Deletion of the alpha 2-subunit led to faster recovery whereas absence of the alpha 3-subunit slowed recovery from ethanol-induced incoordination (rotarod).

ethanol


Input: Deletion of the other four subunits did not affect this behavior.


Input: Similar changes in this behavior for the alpha 2 and alpha 3 null mutants were found for flurazepam motor incoordination.

flurazepam


Input: However, no differences in recovery were found in motor-incoordinating effects of an alpha 1-selective modulator (zolpidem) or an alpha 4-selective agonist (gaboxadol).

zolpidem

gaboxadol


Input: Therefore, recovery of rotarod incoordination is under control of two GABA (A)-R subunits: alpha 2 and alpha 3.

GABA


Input: For motor activity, alpha 3 null mice demonstrated higher activation by ethanol (1 g/kg) whereas both alpha 2 (-/-) and alpha 3 (-/Y) knockout mice were less sensitive to ethanol-induced reduction of motor activity (1. 5 g/kg).

ethanol

ethanol


Input: These studies demonstrate that the effects of ethanol at GABAergic synapses containing alpha 2 subunit are important for specific behavioral effects of ethanol which may be relevant to the genetic linkage of the alpha 2 subunit with human alcoholism.

ethanol

ethanol


Input: Orexin A regulates cardiovascular responses in stress-induced hypertensive rats.


Input: Several pieces of evidence indicate that the rostral ventrolateral medulla (RVLM) is probably one of the key neural structures mediating the pressor effects of orexins in the brain.


Input: Nitric oxide synthase/nitric oxide (NOS/NO) system in the RVLM modulates cardiovascular activities.

Nitric oxide

nitric oxide

NOS


Input: Our experiments were designed to test the hypothesis that orexin-A (OXA) is involved in the mechanism of stress-induced hypertension (SIH) by adjusting NOS/NO system in the RVLM.

NOS


Input: The stress-induced hypertensive rats (SIHR) model was established by electric foot-shocks and noises.


Input: Here we examined the expression of OXA immunoreactive (OXA-IR) cells in the lateral hypothalamus (LH) and the protein level of orexin 1 receptor (OX1R) in the RVLM of SIHR, and we found that the expressions of OXA-IR and OX1R were higher than those of the control group.


Input: The double-staining immunohistochemical evidence showed that OX1R immunoreactive (OX1R-IR) cells and neuronal nitric oxide synthase (nNOS) or inducible nitric oxide synthase (iNOS) immunoreactive (IR) cells were co-localizated in the RVLM.

nitric oxide

nitric oxide


Input: Microinjection of OXA (10, 50, 100 pmol/100 nl) into the unilateral (right) RVLM of control rats or SIHR produced pressor and tachycardiac effects in a dose-dependent manner.


Input: SB-408124 (100 pmol/100 nl, an antagonist of OX1R) or TCS OX2 29 (100 pmol/100 nl, an antagonist of OX2R) partly abolished the cardiovascular effects of exogenously-administrated OXA into the RVLM of control rats and SIHR, and lowered the increased systolic blood pressure (SBP) and heart rate (HR) of SIHR, with no difference in statistical significance between the two antagonists' effects.

TCS OX2 29


Input: Microinjection into the RVLM of both control and SIHR groups of 7-Ni (0. 05 pmol/100 nl, nNOS inhibitor) or Methylene Blue [100 pmol/100 nl, an inhibitor of soluble guanylate cyclase (sGC)] suppressed the OXA-induced increase of SBP and HR, whereas microinjection of AG (1, 10, 100 pmol/100 nl) had no obvious effects on the OXA-induced increase of SBP and HR.

Methylene Blue

guanylate


Input: Our results indicate that OXA in the RVLM may participate in the central regulation of cardiovascular activities in SIHR, and OX1R and OX2R both have important roles in it.


Input: The cardiovascular effects of OXA in the RVLM may be induced by nNOS-derived NO, which activated sGC-associated signaling pathway.


Input: Implications of global climate change for the assessment and management of human health risks of chemicals in the natural environment.


Input: Global climate change (GCC) is likely to alter the degree of human exposure to pollutants and the response of human populations to these exposures, meaning that risks of pollutants could change in the future.


Input: The present study, therefore, explores how GCC might affect the different steps in the pathway from a chemical source in the environment through to impacts on human health and evaluates the implications for existing risk-assessment and management practices.


Input: In certain parts of the world, GCC is predicted to increase the level of exposure of many environmental pollutants due to direct and indirect effects on the use patterns and transport and fate of chemicals.


Input: Changes in human behavior will also affect how humans come into contact with contaminated air, water, and food.


Input: Dietary changes, psychosocial stress, and coexposure to stressors such as high temperatures are likely to increase the vulnerability of humans to chemicals.


Input: These changes are likely to have significant implications for current practices for chemical assessment.


Input: Assumptions used in current exposure-assessment models may no longer apply, and existing monitoring methods may not be robust enough to detect adverse episodic changes in exposures.


Input: Organizations responsible for the assessment and management of health risks of chemicals therefore need to be more proactive and consider the implications of GCC for their procedures and processes.


Input: Biological network inference for drug discovery.


Input: A better understanding of the pathophysiology should help deliver drugs whose targets are involved in the causative processes underlying a disease.


Input: Biological network inference uses computational methods for deducing from high-throughput experimental data, the topology and the causal structure of the interactions among the drugs and their targets.


Input: Therefore, biological network inference can support and contribute to the experimental identification of both gene and protein networks causing a disease as well as the biochemical networks of drugs metabolism and mechanisms of action.


Input: The resulting high-level networks serve as a foundational basis for more detailed mechanistic models and are increasingly used in drug discovery by pharmaceutical and biotechnology companies.


Input: We review and compare recent computational technologies for network inference applied to drug discovery.


Input: Spontaneous electric fields in films of CF3Cl, CF2Cl2 and CFCl3.


Input: Data are presented showing the spontaneous formation of electric fields within solid films of the chlorofluorocarbons (CFCs) CF (3) Cl, CF (2) Cl (2) and CFCl (3) as a function of film deposition temperature from 40 K and above.

chlorofluorocarbons

CFCs

CF (3) Cl

CF (2) Cl (2)

CFCl (3)


Input: Electric fields, which arise through dipole alignment and lie in the range of a few times 10 (7) V m (-1) to a few times 10 (6) V m (-1), decrease as the degree of chlorination increases.


Input: Maximum deposition temperatures for display of an electric field lie at ~ 50 K, ~ 65 K and ~ 52 K for CF (3) Cl, CF (2) Cl (2) and CFCl (3) respectively.

CF (3) Cl

CF (2) Cl (2)

CFCl (3)


Input: CFCl (3) films possess electric fields which show an onset of temporal metastability between deposition temperatures of 46 K and 50 K.

CFCl (3)


Input: CF (3) Cl and CF (2) Cl (2) demonstrate temperatures of ~ 65 K and ~ 80 K at which the electric field in the film is removed by heating, so-called Curie points, with decay of the field spread over more than 10 K.

CF (3) Cl

CF (2) Cl (2)


Input: CFCl (3) displays a comparatively sharp Curie point at 55 K.

CFCl (3)


Input: This variety of behaviour arises despite the resemblance of these three species in terms of electronic structure and gas phase dipole moment, emphasising the requirement for detailed chemical models of this phenomenon.


Input: Toxicity of diesel contaminated soils to the subantarctic earthworm Microscolex macquariensis.


Input: Several fuel spills have occurred on subantarctic Macquarie Island (54 degrees 30' S 158 degrees 57' E) associated with storing fuel and generating power for the island' s research station.


Input: The Australian Antarctic Division began full-scale, on-site remediation of these sites in 2009.


Input: To develop appropriate target concentrations for remediation, acute and chronic tests were developed with the endemic earthworm, Microscolex macquariensis, using avoidance, survival, and reproduction as endpoints.


Input: Uncontaminated low (3%), medium (11%), and high (38-48%) carbon content soils from Macquarie Island were used to examine the influence of soil carbon on toxicity.

carbon

carbon


Input: Soils were spiked with Special Antarctic Blend (SAB) diesel and used either immediately to simulate a fresh spill or after four weeks to simulate an aged spill.


Input: Earthworms were sensitive to fresh SAB, with significant avoidance at 181 mg/kg; acute 14-d survival median lethal concentration (LC50) of 103 mg/kg for low carbon soil; and juvenile production median effective concentration (EC50) of 317 mg/kg for high carbon soil.

carbon

carbon


Input: Earthworms were less sensitive to aged SAB than to fresh SAB in high carbon soil for juvenile production (EC50 of 1, 753 and 317 mg/kg, respectively), but were more sensitive for adult survival (LC50 of 2, 322 and 1, 364 mg/kg, respectively).

carbon


Input: Using M. macquariensis as a surrogate for soil quality, approximately 50 to 200 mg SAB/kg soil would be a sufficiently protective remediation target.


Input: Extraction of sediment-associated polycyclic aromatic hydrocarbons with granular activated carbon.

polycyclic aromatic hydrocarbons

carbon


Input: Addition of activated carbon (AC) to sediments has been proposed as a method to reduce ecotoxicological risks of sediment-bound contaminants.

carbon


Input: The present study explores the effectiveness of granular AC (GAC) in extracting polycyclic aromatic hydrocarbon (PAH) from highly contaminated sediments.

polycyclic aromatic hydrocarbon

PAH


Input: Four candidate GAC materials were screened in terms of PAH extraction efficiency using single-step 24-h GAC extractions, with traditional 24-h Tenax extraction as a reference.

PAH


Input: Subsequently, sorption of native PAHs to the best performing GAC 1240W (0. 45-1. 70 mm) was studied for sediment only and for GAC-sediment mixtures at different GAC-sediment weight ratios, using 76-micro m polyoxymethylene (POM) passive samplers.

PAHs

polyoxymethylene

POM


Input: Granular AC sorption parameters for PAHs were determined by subtracting the contribution of PAH sorption to sediment from PAH sorption to the GAC-sediment mixture.

PAHs

PAH

PAH


Input: It appears that the binding of PAHs and the effectiveness of GAC to reduce sediment porewater concentrations were highly dependent on the GAC-sediment mixing ratio and hydrophobicity of the PAH.

PAHs

PAH


Input: Despite the considerable fouling of GAC by organic matter and oil, 50 to 90% of the most available PAH was extracted by the GAC during a 28-d contact time, at a dose as low as 4%, which also is a feasible dose in field-scale applications aimed at cleaning the sediment by GAC addition and removal.

PAH


Input: Runt-related transcription factor 1 (RUNX1) stimulates tumor suppressor p53 protein in response to DNA damage through complex formation and acetylation.


Input: Representative tumor suppressor p53 plays a critical role in the regulation of proper DNA damage response.


Input: In this study, we have found for the first time that Runt-related transcription factor 1 (RUNX1) contributes to p53-dependent DNA damage response.


Input: Upon adriamycin (ADR) exposure, p53 as well as RUNX1 were strongly induced in p53-proficient HCT116 and U2OS cells, which were closely associated with significant transactivation of p53 target genes, such as p21 (WAF) (1), BAX, NOXA, and PUMA.

adriamycin

ADR


Input: RUNX1 was exclusively expressed in the cell nucleus and formed a complex with p53 in response to ADR.

ADR


Input: Chromatin immunoprecipitation assay demonstrated that p53 together with RUNX1 are efficiently recruited onto p53 target gene promoters following ADR exposure, indicating that RUNX1 is involved in p53-mediated transcriptional regulation.

ADR


Input: Indeed, forced expression of RUNX1 stimulated the transcriptional activity of p53 in response to ADR.

ADR


Input: Consistent with these observations, knockdown of RUNX1 attenuated ADR-mediated induction of p53 target genes and suppressed ADR-dependent apoptosis.

ADR

ADR


Input: Furthermore, RUNX1 was associated with p300 histone acetyltransferase, and ADR-dependent acetylation of p53 at Lys-373/382 was markedly inhibited in RUNX1 knockdown cells.

ADR

Lys


Input: In addition, knockdown of RUNX1 resulted in a significant decrease in the amount of p53-p300 complex following ADR exposure.

ADR


Input: Taken together, our present results strongly suggest that RUNX1 is required for the stimulation of p53 in response to DNA damage and also provide novel insight into understanding the molecular mechanisms behind p53-dependent DNA damage response.


Input: Control of stem cells and cancer stem cells by Hedgehog signaling: pharmacologic clues from pathway dissection.


Input: Hedgehog is a key morphogen regulating embryonic development and tissue repair.