Input: Until then, IVIg (and SCIg) remains the mainstay of treatment in MMN, and the use of other immune therapies should only be considered for patients not responding to, or becoming resistant to, IVIg.


Input: Surface topography effects in protein adsorption on nanostructured carbon allotropes.

carbon


Input: We report a molecular dynamics (MD) simulation study of protein adsorption on the surface of nanosized carbon allotropes, namely single-walled carbon nanotubes (SWNT) considering both the convex outer surface and the concave inner surface, together with a graphene sheet for comparison.

carbon

carbon

graphene


Input: These systems are chosen to investigate the effect of the surface curvature on protein adsorption at the same surface chemistry, given by sp (2) carbon atoms in all cases.

carbon


Input: The simulations show that proteins do favorably interact with these hydrophobic surfaces, as previously found on graphite which has the same chemical nature.

graphite


Input: However, the main finding of the present study is that the adsorption strength does depend on the surface topography: in particular, it is slightly weaker on the outer convex surfaces of SWNT and is conversely enhanced on the inner concave SWNT surface, being therefore intermediate for flat graphene.

graphene


Input: We additionally find that oligopeptides may enter the cavity of common SWNT, provided their size is small enough and the tube diameter is large enough for both entropic and energetic reasons.


Input: Therefore, we suggest that proteins can effectively be used to solubilize in water single-walled (and by analogy also multiwalled) carbon nanotubes through adsorption on the outer surface, as indeed experimentally found, and to functionalize them after insertion of oligopeptides within the cavity of nanotubes of appropriate size.

carbon


Input: Nanofiber near-field light-matter interactions for enhanced detection of molecular level displacements and dynamics.


Input: We experimentally demonstrate that plasmonic nanoparticles embedded in the evanescent field of subwavelength optical waveguides (WGs) are highly sensitive to distances normal to the propagation of light, showing an ~ 10 x increase in spatial resolution compared to the optical field decay of the WG.


Input: The scattering cross-section of the Au nanoparticle is increased by the plasmon-dielectric coupling interaction when the nanoparticle is placed near the dielectric surface of the WG, and the decay of the scattering signal is enhanced, showing angstrom level distance sensitivity within 10 nm from the WG.

Au


Input: Numerical studies with the finite-difference time-domain (FDTD) method correlate well with the experimental results.


Input: To demonstrate real-time monitoring of a single molecule stretching in the evanescent field, we linked individual single-stranded DNA molecules between the WG and plasmonic nanoparticles and pushed on the nanoparticles with fluidic forces.


Input: The simple design and ease of obtaining optical feedback on molecular displacements makes our approach ideal for new in situ force sensing devices, imaging technologies, and high-throughput molecular analysis.


Input: Biophysical Fragment Screening of the beta 1-Adrenergic Receptor: Identification of High Affinity Arylpiperazine Leads Using Structure-Based Drug Design.

Arylpiperazine


Input: Biophysical fragment screening of a thermostabilized beta 1-adrenergic receptor (beta 1AR) using surface plasmon resonance (SPR) enabled the identification of moderate affinity, high ligand efficiency (LE) arylpiperazine hits 7 and 8.

arylpiperazine


Input: Subsequent hit to lead follow-up confirmed the activity of the chemotype, and a structure-based design approach using protein-ligand crystal structures of the beta 1AR resulted in the identification of several fragments that bound with higher affinity, including indole 19 and quinoline 20.

indole

quinoline


Input: In the first example of GPCR crystallography with ligands derived from fragment screening, structures of the stabilized beta 1AR complexed with 19 and 20 were determined at resolutions of 2. 8 and 2. 7 A, respectively.


Input: Genomics-Guided Discovery of Thailanstatins A, B, and C As Pre-mRNA Splicing Inhibitors and Antiproliferative Agents from Burkholderia thailandensis MSMB43.

Thailanstatins A, B, and C


Input: Mining the genome sequence of Burkholderia thailandensis MSMB43 revealed a cryptic biosynthetic gene cluster resembling that of FR901464 (4), a prototype spliceosome inhibitor produced by Pseudomonas sp.


Input: No. 2663.


Input: Transcriptional analysis revealed a cultivation condition in which a regulatory gene of the cryptic gene cluster is adequately expressed.


Input: Consequently, three new compounds, named thailanstatins A (1), B (2), and C (3), were isolated from the fermentation broth of B. thailandensis MSMB43.

thailanstatins


Input: Thailanstatins are proposed to be biosynthesized by a hybrid polyketide synthase-nonribosomal peptide synthetase pathway.

Thailanstatins


Input: They differ from 4 by lacking an unstable hydroxyl group and by having an extra carboxyl moiety; those differences endow thailanstatins with a significantly greater stability than 4 as tested in phosphate buffer at pH 7. 4.

hydroxyl

carboxyl

thailanstatins

phosphate


Input: In vitro assays showed that thailanstatins inhibit pre-mRNA splicing as potently as 4, with half-maximal inhibitory concentrations in the single to sub-mu M range.

thailanstatins


Input: Cell culture assays indicated that thailanstatins also possess potent antiproliferative activities in representative human cancer cell lines, with half-maximal growth inhibitory concentrations in the single nM range.

thailanstatins


Input: This work provides new chemical entities for research and development and new structure-activity information for chemical optimization of related spliceosome inhibitors.


Input: Growth Inhibition of Human Colon Carcinoma Cells by Sesquiterpenoids and Tetralones of Zygogynum calothyrsum.

Sesquiterpenoids

Tetralones


Input: Bioassay-guided phytochemical investigation of Zygogynum calothyrsum using the human colon carcinoma cell lines COLO205 and KM12 led to the isolation of three new drimane-type sesquiterpenoids, 1 beta-p-hydroxy-E-cinnamoyldrimeninol (1), 1 beta-p-hydroxy-E-cinnamoyl-5 alpha-hydroxydrimeninol (2), and methyl ether of 1 beta-p-hydroxy-E-cinnamoyl-12 alpha-methoxydrimeninol (3).

sesquiterpenoids

1 beta-p-hydroxy-E-cinnamoyldrimeninol

1 beta-p-hydroxy-E-cinnamoyl-5 alpha-hydroxydrimeninol

methyl ether of 1 beta-p-hydroxy-E-cinnamoyl-12 alpha-methoxydrimeninol


Input: Also isolated was the known 1 beta-p-coumaroyloxypolygodial (4) together with two new tetralones, 3'-deoxyisozygolone A (5) and calothyrlone A (9), three known tetralones, isozygolone A (6), zygolone A (7), and 4'-O-methylzygolone A (8), and a known cinnamolide (10).

1 beta-p-coumaroyloxypolygodial

tetralones

3'-deoxyisozygolone A

calothyrlone A

isozygolone A

zygolone A

4'-O-methylzygolone A

cinnamolide


Input: Compounds 1, 7, and 8 demonstrated higher cytotoxicity against COLO205 (GI50 18, 17, and 11 mu M, respectively) and KM12 (GI50 14, 14, and 17 mu M, respectively) than the other compounds.


Input: Anti-inflammatory Lanostanoids and Lactone Derivatives from Antrodia camphorata.

Lanostanoids

Lactone


Input: Four new lanostanoids, ethyl lucidenate A (1), ethyl lucidenate F (2), 15-O-acetylganolucidate A (3), and 3, 11, 15, 23-tetraoxo-27 xi-lanosta-8, 16-dien-26-oic acid (4), and two new lactone derivatives, 5-hydroxy-5-(methoxymethyl)-4-methylfuran-2 (5H)-one (5) and 3-(4-methoxy-2-oxo-2H-pyran-6-yl) propanoic acid (6), together with four known compounds, 11 alpha-hydroxy-3, 7-dioxolanost-8, 24 (E)-dien-26-oic acid (7), 3, 7, 11-trioxo-5 alpha-lanosta-8, 24 (E)-dien-26-oic acid (8), methyl 3, 7, 11, 12, 15, 23-hexaoxo-5 alpha-lanost-8-en-26-oate (9), and ethyl 3, 7, 11, 12, 15, 23-hexaoxo-5 alpha-lanost-8-en-26-oate (10), were characterized from Antrodia camphorata.

lanostanoids

ethyl lucidenate A

ethyl lucidenate F

15-O-acetylganolucidate A

3, 11, 15, 23-tetraoxo-27 xi-lanosta-8, 16-dien-26-oic acid

lactone

5-hydroxy-5-(methoxymethyl)-4-methylfuran-2 (5H)-one

3-(4-methoxy-2-oxo-2H-pyran-6-yl) propanoic acid

11 alpha-hydroxy-3, 7-dioxolanost-8, 24 (E)-dien-26-oic acid

3, 7, 11-trioxo-5 alpha-lanosta-8, 24 (E)-dien-26-oic acid

methyl 3, 7, 11, 12, 15, 23-hexaoxo-5 alpha-lanost-8-en-26-oate

ethyl 3, 7, 11, 12, 15, 23-hexaoxo-5 alpha-lanost-8-en-26-oate


Input: The structures of these new compounds were determined by analysis of their spectroscopic data, including 1D and 2D NMR experiments.


Input: Ten components were evaluated for anti-inflammatory activity by examining their effect on LPS-iNOS-dependent NO production in murine macrophage (RAW 264. 7) cells.


Input: Among them, compounds 1, 3, 7, 8, 9, and 10 significantly suppressed the NO concentration in LPS-treated RAW 264. 7 cells with IC50 values <= 10 mu M.

NO


Input: Generating Long Supramolecular Pathways with a Continuous Density of States by Physically Linking Conjugated Molecules via Their End Groups.


Input: Self-assembly of conjugated 2, 5-dialkoxy-phenylene-thienylene-based oligomers on epitaxial monolayer graphene was studied in ultrahigh vacuum by low-temperature scanning tunneling microscopy (STM).

2, 5-dialkoxy-phenylene-thienylene

graphene


Input: The formation of long one-dimensional (1D) supramolecular chain-like structures has been observed, associated to a physical linking of their ends which involved the rotation of the end thiophene rings in order to allow pi-pi stacking of these end-groups.

thiophene


Input: dI/dV maps taken at an energy corresponding to the excited states showed a continuous electronic density of states, which tentatively suggests that within such molecular chains conjugation of electrons is preserved even across physically linked molecules.


Input: Thus, in a self-organization process conjugation may be extended by appropriately adapting conformations of neighboring molecules.


Input: Our STM results on such self-organized end-linked molecules potentially represent a direct visualization of J-aggregates.


Input: Light-Triggered Cross-Linking of Alginates with Caged Ca (2 +)


Input: A strategy to light-trigger ionic cross-linking of alginates by incorporating a photosensitive Ca (2 +) cage (nitr-T) is presented.

Ca (2 +)


Input: Upon irradiation, free Ca (2 +) was released, and this caused gelation of the alginate solution.

Ca (2 +)


Input: Addition of Ca (2 +) " on-demand " allowed us to obtain homogeneous alginate (ALG) gels using concentrated initial ALG solutions (10%), not possible with other ionic gelation approaches.

Ca (2 +)


Input: The cross-linking degree and derived mechanical properties of the hydrogel were modulated by the exposure dose.


Input: The light-mediated cross-linked alginate hydrogel displayed a significant improvement in the mechanical properties and homogeneity when compared to mixtures of alginate and soluble Ca (2 +) at comparable concentrations.

Ca (2 +)


Input: Cations Bind Only Weakly to Amides in Aqueous Solutions.

Amides


Input: We investigated salt interactions with butyramide as a simple mimic of cation interactions with protein backbones.

butyramide


Input: The experiments were performed in aqueous metal chloride solutions using two spectroscopic techniques.

chloride


Input: In the first, which provided information about contact pair formation, the response of the amide I band to the nature and concentration of salt was monitored in bulk aqueous solutions via attenuated total reflection Fourier transform infrared spectroscopy.

amide


Input: It was found that molar concentrations of well-hydrated metal cations (Ca (2 +), Mg (2 +), Li (+)) led to the rise of a peak assigned to metal cation-bound amides (1645 cm (-1)) and a decrease in the peak associated with purely water-bound amides (1620 cm (-1)).

Ca (2 +)

Mg (2 +)

Li (+)

amides

amides


Input: In a complementary set of experiments, the effect of cation identity and concentration was investigated at the air/butyramide/water interface via vibrational sum frequency spectroscopy.

butyramide


Input: In these studies, metal ion-amide binding led to the ordering of the adjacent water layer.

amide


Input: Such experiments were sensitive to the interfacial partitioning of cations in either a contact pair with the amide or as a solvent separated pair.

amide


Input: In both experiments, the ordering of the interactions of the cations was: Ca (2 +) > Mg (2 +) > Li (+) > Na (+) =~ K (+).

Ca (2 +)

Mg (2 +)

Li (+)

Na (+)

K (+)


Input: This is a direct cationic Hofmeister series.


Input: Even for Ca (2 +), however, the apparent equilibrium dissociation constant of the cation with the amide carbonyl oxygen was no tighter than ~ 8. 5 M.

Ca (2 +)

amide carbonyl oxygen


Input: For Na (+) and K (+), no evidence was found for any binding.

Na (+)

K (+)


Input: As such, the interactions of metal cations with amides are far weaker than the analogous binding of weakly hydrated anions.

amides


Input: Comparative pharmacokinetics of N (omega)-hydroxy-nor-L-arginine, an arginase inhibitor, after single-dose intravenous, intraperitoneal and intratracheal administration to brown Norway rats.

N (omega)-hydroxy-nor-L-arginine


Input: Abstract 1. Rodent studies have documented that N (omega)-hydroxy-nor-L-arginine (nor-NOHA), an arginase inhibitor, has therapeutic potential in the treatment of cardiovascular and obstructive airway diseases.

N (omega)-hydroxy-nor-L-arginine

nor-NOHA


Input: However, its bioavailability and pharmacokinetics have not been described so far.


Input: 2. Anesthetized brown Norway rats were administered single doses of nor-NOHA (10, 30 or 90 mg/kg) intravenously (i. v.), intraperitonealy (i. p.) or via intratracheal (i. t.) instillation of aerosol.

nor-NOHA


Input: Plasma nor-NOHA was assayed using a validated HPLC method.

nor-NOHA


Input: 3. Upon i. v. administration, the mean concentration showed a biphasic decline and its value dropped below 10% of the maximum after 20 min.


Input: The pharmacokinetics were linear with the total and inter-compartmental clearances of 33 and 17 mL/min/kg, central and peripheral volumes of distribution of 0. 19 and 0. 43 L/kg and terminal half-life of 30 min.


Input: 4. The average absolute bioavailability of nor-NOHA after i. p. and i. t. delivery was 98% and 53%, respectively.

nor-NOHA


Input: The absorption from the airways was rate-limiting and its extent decreased with the dose.


Input: 5. In conclusion, nor-NOHA is rapidly cleared from the plasma in concordance with the short time window of its in vivo inhibitory activity reported in the literature.

nor-NOHA


Input: I. t. instillation of aerosol for topical effects of nor-NOHA in the airways is characterized with significant systemic availability.

nor-NOHA


Input: All Zinc-Blende GaAs/(Ga, Mn) As Core-Shell Nanowires with Ferromagnetic Ordering.

Zinc-Blende GaAs

(Ga, Mn) As


Input: Combining self-catalyzed vapor-liquid-solid growth of GaAs nanowires and low-temperature molecular-beam epitaxy of (Ga, Mn) As, we successfully synthesized all zinc-blende (ZB) GaAs/(Ga, Mn) As core-shell nanowires on Si (111) substrates.

GaAs

(Ga, Mn) As

zinc-blende

GaAs

(Ga, Mn) As

Si


Input: The ZB GaAs nanowire cores are first fabricated at high temperature by utilizing the Ga droplets as the catalyst and controlling the triple phase line nucleation, then the (Ga, Mn) As shells are epitaxially grown on the side facets of the GaAs core at low temperature.

GaAs

Ga

(Ga, Mn) As

GaAs


Input: The growth window for the pure phase GaAs/(Ga, Mn) As core-shell nanowires is found to be very narrow.

GaAs

(Ga, Mn) As


Input: Both high-resolution transmission electron microscopy and scanning electron microscopy observations confirm that all-ZB GaAs/(Ga, Mn) As core-shell nanowires with smooth side surface are obtained when the Mn concentration is not more than 2% and the growth temperature is 245 degrees C or below.

GaAs

(Ga, Mn) As

Mn


Input: Magnetic measurements with different applied field directions provide strong evidence for ferromagnetic ordering in the all-ZB GaAs/(Ga, Mn) As nanowires.

GaAs

(Ga, Mn) As


Input: The hybrid nanowires offer an attractive platform to explore spin transport and device concepts in fully epitaxial all-semiconductor nanospintronic structures.


Input: N-Methyldihydroquinazolinone Derivatives of Retro-2 with Enhanced Efficacy against Shiga Toxin.

N-Methyldihydroquinazolinone


Input: The Retro-2 molecule protects cells against Shiga toxins by specifically blocking retrograde transport from early endosomes to the trans-Golgi network.


Input: A SAR study has been carried out to identify more potent compounds.


Input: Cyclization and modifications of Retro-2 led to a compound with roughly 100-fold improvement of the EC50 against Shiga toxin cytotoxicity measured in a cell protein synthesis assay.


Input: We also demonstrated that only one enantiomer of the dihydroquinazolinone reported herein is bioactive.

dihydroquinazolinone


Input: Nitroxide TEMPO: A genotoxic and oxidative stress inducer in cultured cells.

Nitroxide TEMPO


Input: 2, 2, 6, 6-Tetramethylpiperidine-1-oxyl (TEMPO) is a low molecular weight nitroxide and stable free radical.

2, 2, 6, 6-Tetramethylpiperidine-1-oxyl

TEMPO


Input: In this study, we investigated the cytotoxicity and genotoxicity of TEMPO in mammalian cells using the mouse lymphoma assay (MLA) and in vitro micronucleus assay.

TEMPO


Input: In the absence of metabolic activation (S9), 3mM TEMPO produced significant cytotoxicity and marginal mutagenicity in the MLA; in the presence of S9, treatment of mouse lymphoma cells with 1-2mM TEMPO resulted in dose-dependent decreases of the relative total growth and increases in mutant frequency.

TEMPO

TEMPO


Input: Treatment of TK6 human lymphoblastoid cells with 0. 9-2. 3mM TEMPO increased the frequency of both micronuclei (a marker for clastogenicity) and hypodiploid nuclei (a marker of aneugenicity) in a dose-dependent manner; greater responses were produced in the presence of S9.

TEMPO


Input: Within the dose range tested, TEMPO induced reactive oxygen species and decreased glutathione levels in mouse lymphoma cells.

TEMPO

oxygen

glutathione


Input: In addition, the majority of TEMPO-induced mutants had loss of heterozygosity at the Tk locus, with allele loss of >= 34Mbp.

TEMPO


Input: These results indicate that TEMPO is mutagenic in the MLA and induces micronuclei and hypodiploid nuclei in TK6 cells.

TEMPO


Input: Oxidative stress may account for part of the genotoxicity induced by TEMPO in both cell lines.

TEMPO


Input: Testosterone exposure in childhood: discerning pathology from physiology.

Testosterone


Input: Introduction: Testosterone (T) drives normal male sexual development both in utero and at puberty.

Testosterone


Input: Aberrant T exposure manifests as virilization of a female fetus, contrasexual precocity in girls, and isosexual precocity in boys.


Input: Evidence of pathologic T exposure warrants a prompt evaluation.


Input: Areas covered: The authors introduce the topic of T exposure in children by reviewing its physiology in the fetus and during childhood and adolescence.


Input: Pathologic conditions leading to virilization of a female fetus as well as androgen-mediated gonadotropin-independent precocious puberty in both genders are then discussed.

androgen


Input: The authors finish by noting exogenous T exposure in children and adolescents, focusing specifically on secondary exposure to topical T preparations.


Input: Expert opinion: Contrasexual precocity in a girl or sexual precocity in a boy should prompt evaluation for causes of gonadotropin-independent pubertal changes.


Input: Initial biochemical evaluation includes a bone age, T, 17-hydroxyprogesterone, androstenedione, dehydroepiandrosterone sulfate (DHEA-S) and high sensitivity gonadotropin levels.

androstenedione

dehydroepiandrosterone sulfate

DHEA-S


Input: The provider must query exposure to topical androgen-containing preparations as unintentional secondary exposure to topical T must be considered.

androgen


Input: Hyperandrogenism is temporally related to exposure of topical T and removal of exposure results in a marked decrease in serum T as well as resolution or stabilization of the signs and symptoms.


Input: Efficient induction of apoptosis in HeLa cells by a novel cationic porphycene photosensitizer.

porphycene


Input: In the present study we analyze the photobiological properties of 2, 7, 12-tris (alpha-pyridinio-p-tolyl)-17-(p-(methoxymethyl) phenyl) porphycene (Py3MeO-TBPo) in Hela cells, in order to assess its potential as a new photosensitizer for photodynamic therapy of cultured tumor cells.

2, 7, 12-tris (alpha-pyridinio-p-tolyl)-17-(p-(methoxymethyl) phenyl) porphycene


Input: Using 0. 5 mu M Py3MeO-TBPo, flow cytometry studies demonstrated an increase of intracellular drug levels related to the incubation time, reaching a maximum at 18 h.


Input: LysoTracker ((R)) Green (LTG) and MitoTracker ((R)) Green (MTG) probes were used to identify the subcellular localization.


Input: Upon exposure to ultraviolet excitation, red porphycene fluorescence was detected as red granules in the cytoplasm that colocalized with LTG.

porphycene


Input: No significant toxic effects were detected for Py3MeO-TBPo in the dark at concentrations below 1 mu M.


Input: In contrast, Py3MeO-TBPo combined with red-light irradiation induced concentration-and fluence-dependent HeLa cells inactivation.


Input: Besides, all photodynamic protocols assayed induced a clear effect of cell detachment inhibition after trypsin treatment.


Input: Both apoptotic and necrotic cell death mechanisms can occur in HeLa cells depending on the experimental protocol.


Input: After 18 h incubation with 0. 5 mu M Py3MeO-TBPo and subsequent red light irradiation (3. 6 J/cm (2)), a high number of cells die by apoptosis, as evaluated by morphological alterations, immunofluorescent relocalization of Bax from cytosol to mitochondria, and TUNEL assay.


Input: Likewise, immunofluorescence techniques showed that cytochrome c is released from mitochondria into cytosol in cells undergoing apoptosis, which occurs immediately after relocation of Bax in mitochondria.


Input: The highest amount of apoptosis appeared 24 h after treatment (70%) and this cell death occurred without cell detachment to the substrate.


Input: In contrast, with 0. 75 mu M Py3MeO-TBPo and 3. 6 J/cm (2) irradiation, morphological changes showed a preferential necrotic cell death.


Input: Singlet oxygen was identified as the cytotoxic agent involved in cell photoinactivation.

oxygen


Input: Moreover, cell cultures pre-exposed to the singlet oxygen scavenger sodium azide showed pronounced protection against the loss of viability induced by Py3MeO-TBPo and light.

oxygen

sodium azide


Input: Different changes in distribution and organization of cytoskeletal elements (microtubules and actin microfilaments) as well as the protein vinculin, after apoptotic and necrotic photodynamic treatments have been analyzed.


Input: Neither of these two cell death mechanisms (apoptosis or necrosis) induced cell detachment.


Input: In summary, Py3MeO-TBPo appears to meet the requirements for further scrutiny as a very good photosensitizer for photodynamic therapy: it is water soluble, has a high absorption in the red spectral region (where light penetration in tissue is higher), and is able to induce effective high apoptotic rate (70%) related to the more widely studied photosensitizers.


Input: The life history of a botulinum toxin molecule.


Input: There is an emerging literature describing the absorption, distribution, metabolism and elimination of botulinum toxin.


Input: This work reveals that the toxin can be absorbed by both the oral and inhalation routes.


Input: The primary mechanism for absorption is binding and transport across epithelial cells.


Input: Toxin that enters the body undergoes a distribution phase, which is quite short, and an elimination phase, which is comparatively long.


Input: During the distribution phase, botulinum toxin migrates to the peri-neuronal microcompartment in the vicinity of vulnerable cells, such as cholinergic nerve endings.


Input: Only these cells have the ability to selectively accumulate the molecule.


Input: When the toxin moves from the cell membrane to the cell interior, it undergoes programmed death.


Input: This is coincident with release of the catalytically active light chain that paralyzes transmission.


Input: Intraneuronal metabolism of light chain is via the ubiquitination-proteasome pathway.


Input: Systemic metabolism and elimination is assumed to be via the liver.


Input: The analysis of absorption, distribution, metabolism and elimination of the toxin helps to create a life history of the molecule in the body.


Input: This has many benefits, including: a) clarifying the mechanisms that underlie the disease botulism, b) providing insights for development of medical countermeasures against the toxin, and c) helping to explain the meaning of a lethal dose of toxin.


Input: It is likely that work intended to enhance understanding of the fate of botulinum toxin in the body will intensify.


Input: These efforts will include new and powerful analytic tools, such as single molecule-single cell analyses in vitro and real time, 3-dimensional pharmacokinetic studies in vivo.


Input: A novel GIP-oxyntomodulin hybrid peptide acting through GIP, glucagon and GLP-1 receptors exhibits weight reducing and anti-diabetic properties.


Input: Oxyntomodulin (Oxm) is a 37-amino acid peptide linked to alleviation of obesity-diabetes through a dual mode of action mediated at both glucagon and GLP-1 receptors.


Input: GIP is the principle physiological regulator of postprandial insulin secretion.


Input: Therefore, the primary aim was to design a novel GIP-Oxm peptide incorporating the actions of GIP, GLP-1 and glucagon in a single molecule.


Input: The first 11 N-terminal residues of Oxm were substituted with the sequence of stable dA (2) GIP molecule to generate a novel GIP-Oxm peptide (dA (2) GIP-Oxm).

N


Input: dA (2) GIP-Oxm was resistant to DPP-IV and significantly stimulated in vitro insulin release.


Input: dA (2) GIP-Oxm stimulated cAMP production in GIP-R, glucagon-R and GLP-1-R transfected cells by up to 95%, 83% and 77% of that elicited by respective native ligands.

cAMP


Input: Acute administration of dA (2) GIP-Oxm to HFF mice resulted in reduced plasma glucose (45% reduction) and increased insulin concentrations (1. 7-fold increase).

glucose


Input: Furthermore, dA (2) GIP-Oxm lowered plasma glucose (42% reduction) and increased plasma insulin (1. 6-fold increase) when administered to HFF mice four hours prior to a glucose load.

glucose

glucose


Input: Once-daily administration of dA (2) GIP-Oxm for 15 days in HFF mice lowered body weight (13% reduction), reduced plasma glucose (40% reduction) and increased plasma insulin (1. 7-fold increase).

glucose


Input: Furthermore, glycemic responses were improved (38% reduction) and glucose-mediated plasma insulin concentrations enhanced (2-fold increase).

glucose


Input: These improvements in metabolic control were independent of changes in food intake and insulin sensitivity.


Input: dA (2) GIP-Oxm exerts positive beneficial actions on glucose homeostasis, beta-cell insulin secretion and body weight, mediated through GIP, glucagon and GLP-1 receptors.

glucose


Input: Such multiple-acting peptides may hold promise as novel therapies for obesity-diabetes.


Input: Acetaminophen prevents oxidative burst and delays apoptosis in human neutrophils.

Acetaminophen


Input: Acetaminophen is a frequently prescribed over-the-counter drug to reduce fever and pain in the event of inflammatory process.

Acetaminophen


Input: As neutrophils are relevant cells in inflammatory processes, the putative interaction of acetaminophen with these cells, if present, would be of paramount importance.

acetaminophen


Input: The present study was undertaken to evaluate the effect of acetaminophen in human neutrophils' oxidative burst and lifespan in vitro.

acetaminophen


Input: The obtained results demonstrate that acetaminophen efficiently modulates neutrophils' oxidative burst in phorbol myristate acetate-activated neutrophils, in a concentration-dependent manner, at in vivo relevant concentrations.

acetaminophen

phorbol myristate acetate


Input: It was clearly demonstrated that acetaminophen is a strong scavenger of HOCl and H2O2, which probably contributed to the effect observed in neutrophils.

acetaminophen

HOCl


Input: Acetaminophen also induced the depletion of glutathione in stimulated neutrophils, suggesting its transformation into a reactive intermediate.

Acetaminophen

glutathione


Input: Obtained results further revealed that acetaminophen affects programmed cell death of human neutrophils, resulting in a delay of previously stimulated neutrophils-mediated apoptosis.

acetaminophen


Input: Overall, our data suggested that acetaminophen has considerable potential to be included in anti-inflammatory therapeutic strategies, by preventing biological damage induced by an excessive production of reactive species generated in activated neutrophils and by extending the lifespan of neutrophils, favoring the elimination of pathogens, thus contributing to tissue healing and resolution of inflammation.

acetaminophen


Input: Estrogenic and androgenic effects in mosquitofish (Gambusia affinis) from streams contaminated by municipal effluent in Guangzhou, China.


Input: The study reported in this paper used mosquitofish to investigate the estrogenic and androgenic effects of municipal wastewater contamination on the stream system in Guangzhou, China.


Input: Western mosquitofish collected from a reference site and five study sites in streams forming part of the Pearl River network were dissected and analyzed for their morphological characteristics (anal fin and hemal spine characteristics) and target mRNA expression of genes (VTG alpha and ER alpha mRNA expression).


Input: Increased VTG alpha mRNA expression in males and decreased VTG alpha mRNA expression in females were observed in samples taken from four of the five study sites, with no such observations being made at the reference site.


Input: Correlation analysis indicated a significant correlation between the hemal spine morphology index and the gene transcription relative to the reference site.


Input: The multiple index also indicated that both male and female mosquitofish in contaminated streams were altered by discharged wastewater, as reflected in their morphological changes and relative induction of mRNA expression of genes in comparison to fish collected from the reference site.


Input: Effects of rare-earth co-doping on the local structure of rare-earth phosphate glasses using high and low energy X-ray diffraction.

rare-earth phosphate


Input: Rare-earth co-doping in inorganic materials has a long-held tradition of facilitating highly desirable optoelectronic properties for their application to the laser industry.

Rare-earth


Input: This study concentrates specifically on rare-earth phosphate glasses, (R2O3) x (R' 2O3) y (P2O5) 1-(x + y), where (R, R') denotes (Ce, Er) or (La, Nd) co-doping and the total rare-earth composition corresponds to a range between metaphosphate, RP3O9, and ultraphosphate, RP5O14.

rare-earth phosphate

(R2O3) x (R' 2O3) y (P2O5) 1-(x + y)

Ce

Er

La

Nd

rare-earth

metaphosphate

ultraphosphate


Input: Thereupon, the effects of rare-earth co-doping on the local structure are assessed at the atomic level.

rare-earth


Input: Pair-distribution function analysis of high-energy X-ray diffraction data (Qmax = 28 A (-1)) is employed to make this assessment.


Input: Results reveal a stark structural invariance to rare-earth co-doping which bears testament to the open-framework and rigid nature of these glasses.

rare-earth


Input: A range of desirable attributes of these glasses unfold from this finding; in particular, a structural simplicity that will enable facile molecular engineering of rare-earth phosphate glasses with' dial-up' lasing properties.

rare-earth phosphate


Input: When considered together with other factors, this finding also demonstrates additional prospects for these co-doped rare-earth phosphate glasses in nuclear waste storage applications.

rare-earth phosphate


Input: This study also reveals, for the first time, the ability to distinguish between P-O and P [double bond, length as m-dash] O bonding in these rare-earth phosphate glasses from X-ray diffraction data in a fully quantitative manner.

P-O

P

O

rare-earth phosphate


Input: Complementary analysis of high-energy X-ray diffraction data on single rare-earth phosphate glasses of similar rare-earth composition to the co-doped materials is also presented in this context.

rare-earth phosphate


Input: In a technical sense, all high-energy X-ray diffraction data on these glasses are compared with analogous low-energy diffraction data; their salient differences reveal distinct advantages of high-energy X-ray diffraction data for the study of amorphous materials.


Input: Non-bonding interactions and internal dynamics in CH2F2H2CO: a rotational and model calculations study.


Input: The rotational spectra of three isotopologues of the 1: 1 complex between difluoromethane and formaldehyde have been observed and assigned using pulsed jet Fourier transform microwave spectroscopy.

difluoromethane

formaldehyde


Input: The formaldehyde lies in the FCF plane of difluoromethane, linked through a C-HF and a bifurcated CH2O weak hydrogen bonds.

formaldehyde

FCF

difluoromethane

C-HF

hydrogen


Input: The rotational transitions are split into two component lines with a relative intensity ratio of 1: 3, due to the internal rotation of the formaldehyde moiety along its symmetry axis.

formaldehyde


Input: The barrier to this motion has been estimated by using a flexible model to be V2 = 180 (10) cm (-1).


Input: An Essential Role for Insulin and IGF1 Receptors in Regulating Sertoli Cell Proliferation, Testis Size, and FSH Action in Mice.


Input: Testis size and sperm production are directly correlated to the total number of adult Sertoli cells (SCs).


Input: Although the establishment of an adequate number of SCs is crucial for future male fertility, the identification and characterization of the factors regulating SC survival, proliferation, and maturation remain incomplete.


Input: To investigate whether the IGF system is required for germ cell (GC) and SC development and function, we inactivated the insulin receptor (Insr), the IGF1 receptor (Igf1r), or both receptors specifically in the GC lineage or in SCs.


Input: Whereas ablation of insulin/IGF signaling appears dispensable for GCs and spermatogenesis, adult testes of mice lacking both Insr and Igf1r in SCs (SC-Insr; Igf1r) displayed a 75% reduction in testis size and daily sperm production as a result of a reduced proliferation rate of immature SCs during the late fetal and early neonatal testicular period.


Input: In addition, in vivo analyses revealed that FSH requires the insulin/IGF signaling pathway to mediate its proliferative effects on immature SCs.


Input: Collectively, these results emphasize the essential role played by growth factors of the insulin family in regulating the final number of SCs, testis size, and daily sperm output.


Input: They also indicate that the insulin/IGF signaling pathway is required for FSH-mediated SC proliferation.


Input: Tuning the electronic and photophysical properties of heteroleptic iridium (iii) phosphorescent emitters through ancillary ligand substitution: a theoretical perspective.

iridium (iii)


Input: The development and application of phosphorescent emitters in organic light-emitting diodes (OLEDs) have played a critical role in the push to commercialization of OLED-based display and lighting technologies.


Input: Here, we use density functional theory methods to study how modifying the ancillary ligand influences the electronic and photophysical properties of heteroleptic bis (4, 6-difluorophenyl) pyridinato-N, C [dfppy] iridium (iii) complexes.

bis (4, 6-difluorophenyl) pyridinato-N, C [dfppy] iridium (iii)


Input: We examine three families of bidentate ancillary ligands based on acetylacetonate, picolinate, and pyridylpyrazolate.

acetylacetonate

picolinate

pyridylpyrazolate


Input: It is found that the frontier molecular orbitals of the heteroleptic complexes can be substantially modulated both as a function of the bidentate ligand family and of the substitution patterns within a family.


Input: As a consequence, considerable control over the first absorption and phosphorescence emission transitions, both of which are dominated by one-electron transitions between the HOMO and LUMO, is obtained.


Input: Tuning the nature of the ancillary ligand, therefore, can be used to readily modulate the photophysical properties of the emitters, providing a powerful tool in the design of the emitter architecture.


Input: The early molecular processes underlying the neurological manifestations of an animal model of Wilson' s disease.


Input: The Long-Evans Cinnamon (LEC) rat shows age-dependent hepatic manifestations that are similar to those of Wilson' s disease (WD).


Input: The pathogenic process in the brain has, however, not been evaluated in detail due to the rarity of the neurological symptoms.


Input: However, copper accumulation is noted in LEC rat brain tissue from 24 weeks of age, which results in oxidative injuries.

copper


Input: The current study investigated the gene expression profiles of LEC rat brains at 24 weeks of age in order to identify the important early molecular changes that underlie the development of neurological symptoms in WD.


Input: Biological ontology-based analysis revealed diverse altered expressions of the genes related to copper accumulation.

copper


Input: Of particular interest, we found altered expression of genes connected to mitochondrial respiration (Sdhaf2 and Ndufb7), calcineurin-mediated cellular processes (Ppp3ca, Ppp3cb, and Camk2a), amyloid precursor protein (Anks1b and A2m) and alpha-synuclein (Snca).


Input: In addition to copper-related changes, compensatory upregulations of Cp and Hamp reflect iron-mediated neurotoxicity.

copper

iron


Input: Of note, reciprocal expression of Asmt and Bhmt is an important clue that altered S-adenosylhomocysteine metabolism underlies brain injury in WD, which is directly correlated to the decreased expression of S-adenosylhomocysteine hydrolase in hepatic tissue in LEC rats.

S-adenosylhomocysteine

S-adenosylhomocysteine


Input: In conclusion, our study indicates that diverse molecular changes, both variable and complex, underlie the development of neurological manifestations in WD.


Input: Copper-related injuries were found to be the principal pathogenic process, but Fe-or adenosylhomocysteine-related injuries were also implicated.

Copper

Fe

adenosylhomocysteine


Input: Investigations using other animal models or accessible human samples will be required to confirm our observations.


Input: Opposite modulation of cell migration by distinct subregions of urokinase connecting Peptide.


Input: Functional analysis of isolated protein domains may uncover cryptic activities otherwise missed.


Input: The serine protease urokinase (uPA) has a clear-cut motogen activity that is catalytically independent and resides in its amino-terminal growth factor domain (GFD, residues 1-49) and connecting peptide region (CP, residues 132-158).

serine

amino


Input: To functionally dissect the CP region, we analysed the biological activity of two synthetic peptides corresponding to the N-terminal [uPA-(135-143), residues 135-143] and C-terminal [uPA-(144-158), residues 144-158] CP subregions.

N

C


Input: Most of the chemotactic activity of connecting peptide-derived peptide (CPp, [uPA-(135-158)]) for embryonic kidney HEK293/uPAR-25 cells is retained by uPA-(144-158) at nanomolar concentrations.


Input: In contrast, uPA-(135-143) inhibits basal, CPp-, vitronectin-and fibronectin-induced cell migration.


Input: Radioreceptor binding assays on intact HEK293 cells revealed that uPA-(135-143) and uPA-(144-158) are both able to compete with [(125) I]-CPp, albeit with different binding affinities.

(125) I


Input: The consequences of phospho-mimicking, S138E substitution, were studied using [138E] uPA-(135-158) and [138E] uPA-(135-143) peptides.

phospho


Input: Unlike CPp, [138E] uPA-(135-158) and [138E] uPA-(135-143) exhibit remarkable inhibitory properties.


Input: Finally, analysis of the conformational preferences of the peptides allowed to identify secondary structure elements exclusively characterising the stimulatory CPp and uPA-(144-158) versus the inhibitory uPA-(135-143), [138E] uPA-(135-158) and [138E] uPA-(135-143) peptides.


Input: In conclusion, these data shed light on the cryptic activities of uPA connecting peptide, revealing the occurrence of two adjacent regions, both competing for binding to cell surface but conveying opposite signalling on cell migration.


Input: Effects of Prior Intensive versus Conventional Therapy and History of Glycemia on Cardiac Function in Type 1 Diabetes in the DCCT/EDIC.


Input: Intensive diabetes therapy reduces the prevalence of coronary calcification and progression of atherosclerosis, and the risk of cardiovascular disease events in the DCCT/EDIC study.


Input: The effects of intensive therapy on measures of cardiac function and structure and their association with glycemia have not been explored in type 1 diabetes (T1DM).


Input: We assess whether intensive treatment compared to conventional treatment during the DCCT led to differences in these parameters during EDIC.


Input: After 6. 5 years of intensive versus conventional therapy in the DCCT, and 15 years additional follow-up in EDIC, left ventricular indices were measured by cardiac magnetic resonance (CMR) imaging in 1017 of the 1371 members of the DCCT cohort.


Input: There were no differences between the DCCT intensive versus conventional treatment in end diastolic volume, end systolic volume, stroke volume, cardiac output, left ventricular mass, ejection fraction, LV mass/EDV, nor aortic distensibility.


Input: Mean DCCT/EDIC HbA1c over time was associated with EDV, SV, CO, LVmass, LVmass/EDV, and AD.


Input: These associations persisted after adjustment for CVD risk factors.


Input: Cardiac function and remodeling in T1DM assessed by CMR in the EDIC cohort was associated with prior glycemic exposure, but there was no effect of intensive versus conventional treatment during the DCCT on cardiac parameters.


Input: Barriers to superfast water transport in carbon nanotube membranes.

carbon


Input: Carbon nanotube (CNT) membranes hold the promise of extraordinary fast water transport for applications such as energy efficient filtration and molecular level drug delivery.

Carbon


Input: However, experiments and computations have reported flow rate enhancements over continuum hydrodynamics that contradict each other by orders of magnitude.


Input: We perform large scale molecular dynamics simulations emulating for the first time the micrometer thick CNTs membranes used in experiments.


Input: We find transport enhancement rates that are length dependent due to entrance and exit losses but asymptote to 2 orders of magnitude over the continuum predictions.


Input: These rates are far below those reported experimentally.


Input: The results suggest that the reported superfast water transport rates cannot be attributed to interactions of water with pristine CNTs alone.


Input: Bioassay-guided isolation and identification of antitermitic active compound from the leaf of Chinese cedar (Cryptomeria fortunei Hooibrenk).


Input: The persistent use of synthetic termiticides is at present of environmental concern and has resulted in the need to search for plant-derived compounds as an alternative for termite control.


Input: Antitermitic activity of Chinese cedar (Cryptomeria fortunei Hooibrenk) against Reticulitermes chinensis was demonstrated in laboratory tests.


Input: Bioactivity tests against the termite R. chinensis demonstrate that the lethal concentration (LC50) value of leaf essential oil is 2. 80 mg/mL.


Input: Furthermore, alpha-terpineol, which was responsible for the antitermitic property and isolated from Chinese cedar that exhibited very strong antitermitic activity, was found to be significantly effective against R. chinensis with median LC50 values of 0. 86 mg/mL.

alpha-terpineol


Input: The findings suggested that the essential oil from Chinese cedar leaf and alpha-terpineol might be considered as a potent source for the production of effective, environmentally friendly and safe termiticides.

alpha-terpineol


Input: New methylated flavonol glucosides from Fumana montana Pomel.

methylated flavonol glucosides


Input: Three new methylated flavonol glucosides: 3-methoxy-7-O-beta-(6''-galloylgluco-pyranoside) quercetin (1), 3, 4'-dimethoxy-7-O-beta-(6''-galloyl-glucopyranoside) quercetin (2) and 3-methoxy-7-O-beta-(6''-galloylgluco-pyranoside) kaempferol (3), in addition to six known flavonols, were isolated from the ethyl acetate extract of Fumana montana Pomel.

methylated flavonol glucosides

3-methoxy-7-O-beta-(6''-galloylgluco-pyranoside) quercetin

3, 4'-dimethoxy-7-O-beta-(6''-galloyl-glucopyranoside) quercetin

3-methoxy-7-O-beta-(6''-galloylgluco-pyranoside) kaempferol

flavonols

ethyl acetate


Input: Their structures were assigned by spectroscopic methods.


Input: Phase diagram of solvophilic nanodiscs in a polymer solution: depletion attraction.


Input: Entropic attraction between anisotropic nanoparticles in nonadsorbing polymer solutions is significantly greater than that between nanospheres.


Input: In this study, depletion attraction between two solvophilic nanodiscs and the aggregation behavior of a nanodisc suspension are explored by dissipative particle dynamics.


Input: The depletion force due to polymer addition is proportional to the product of the osmotic pressure and the area of the nanodisc, even for concentrated polymer solutions.


Input: For a suspension of nanodiscs, three possible equilibrium states are observed upon polymer addition: dispersion, pretransition, and phase separation.


Input: By varying nanodisc concentration (phi D) and polymer concentration (phi P), the phase diagram is obtained.


Input: Dispersion exists for small phi D and phi P.


Input: As phi D exceeds critical aggregation concentration, finite sized clusters are mainly formed with columnar structure in the pretransition regime, similar to micellization associated with typical surfactants.


Input: The mean size of columnar clusters seems to grow with phi D (1/2) and phi P.


Input: For high enough phi D and phi P, finite sized clusters vanish and phase separation appears.


Input: The nanodisc-rich phase is formed by a bundle of columns or a pack of columns owing to face-to-side and side-to-side depletion attractions.


Input: Molecular Dynamics Simulations of DPPC Bilayers Using " LIME ", a New Coarse-Grained Model.

DPPC


Input: A new intermediate resolution model for phospholipids, LIME, designed for use with discontinuous molecular dynamics (DMD) simulations is presented.


Input: The implicit-solvent model was developed using a multiscale modeling approach in which the geometric and energetic parameters are obtained by collecting data from atomistic simulations of a system composed of 1, 2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) molecules and explicit water.

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

DPPC


Input: In the model, 14 coarse-grained sites that are classified as 1 of 6 types represent DPPC.

DPPC


Input: DMD simulations performed on a random solution of DPPC resulted in the formation of a defect-free bilayer in less than 4 h.

DPPC


Input: The bilayer formed quantitatively reproduces the main structural properties (e. g., area per lipid, bilayer thickness, bond order parameters) that are observed experimentally.


Input: In addition, the bilayer transitions from a liquid-crystalline phase to a tilted gel phase when the temperature is reduced.


Input: Transbilayer movement of a lipid from the bottom leaflet to the top leaflet is observed when the temperature is increased.


Input: Dose-ranging study with the glucokinase activator AZD1656 as monotherapy in Japanese patients with type 2 diabetes mellitus.


Input: AIM: To assess the glucose-lowering effects of monotherapy with the glucokinase activator AZD1656 in Japanese patients with type 2 diabetes mellitus.


Input: METHODS: This was a randomized, double-blind, placebo-controlled study performed in Japan (NCT01152385).


Input: Patients (n = 224) were randomized to AZD1656 (40-200, 20-140 or 10-80 mg titrated doses) or placebo.


Input: The primary variable was the placebo-corrected change from baseline to 4 months in glycated haemoglobin (HbA1c).


Input: Effects on fasting plasma glucose (FPG) and safety were also assessed.

glucose


Input: RESULTS: HbA1c was reduced numerically from baseline by 0. 3-0. 8% with AZD1656 and by 0. 1% with placebo over the first 2 months of treatment, after which effects of AZD1656 started to decline.


Input: The changes from baseline to 4 months in HbA1c were not significant for the AZD1656 40-200 mg group versus placebo [mean (95% CI) placebo-corrected change:-0. 22 (-0. 65, 0. 20)%; p = 0. 30].


Input: Formal significance testing was not carried out for the other two AZD1656 dose groups.


Input: A higher percentage of patients on AZD1656 achieved HbA1c <= 7% after 4 months versus placebo, but responder rates were low.


Input: Results for FPG reflected those for HbA1c.


Input: Cases of hypoglycaemia were rare with AZD1656 (one patient) and no safety concerns were raised.


Input: CONCLUSIONS: Although initially favourable plasma glucose reductions were observed, there was a loss of effect over time with sustained AZD1656 treatment.

glucose


Input: The study design did not allow an evaluation of the reasons for this lack of long-term efficacy.


Input: Addition of artificial salt bridge by Ile646Lys mutation in gp41 coiled-coil domain regulates 6-helical bundle formation.


Input: HIV entry is mediated by the envelope glycoproteins gp120 and gp41.


Input: The gp41 subunit contains several functional domains: the N-terminal heptad repeat (NHR) domains fold a triple stranded coiled-coil forming a meta-stable prefusion intermediate.

N


Input: C-terminal heptad repeat (CHR) subsequently folds onto the hydrophobic grooves of the NHR coiled-coil to form a stable 6-helix bundle, which juxtaposes the viral and cellular membranes for fusion.

C


Input: The C34 which has 34 amino acid residues is known as the core structure in CHR.

amino acid


Input: A highly anti-HIV peptide inhibitor derived from C34 was designed.


Input: An artificial salt bridge was added in the 6-helical bundle by substitution of lysine for Ile646.

lysine


Input: With a cholesterol modification at C-terminal, the inhibitor containing I646K mutation represented higher anti-viral activity than C34-cholesterol combination without mutation.

cholesterol

C

cholesterol


Input: Cu (OTf) 2 catalyzed three component reaction: Efficient synthesis of spiro [indoline-3, 4'-pyrano [3, 2-b] pyran derivatives and their anticancer potency towards A549 human lung cancer cell lines.

Cu (OTf) 2

spiro [indoline-3, 4'-pyrano [3, 2-b] pyran


Input: Cu (OTf) 2 catalyzed efficient synthesis of spiropyrano [3, 2-b] pyran-4 (8H)-ones is accomplished via one-pot three component reaction between isatin, kojic acid and active methylenes.

Cu (OTf) 2

spiropyrano [3, 2-b] pyran-4 (8H)-ones

isatin

kojic acid

methylenes


Input: This synthetic protocol is operationally simple and affords product with good to excellent yields at a short reaction time.


Input: The synthesized compounds were evaluated for their tumor cell growth inhibitory activity against the human lung cancer cell line (A549) and found that 13 compounds exhibited moderate to good anticancer potency.


Input: Molecular docking studies were performed for all the synthesized compounds and the results showed that compound 4e showed greater affinity for anaplastic lymphoma kinase (ALK) receptor.


Input: Ginkgetin induces apoptosis via activation of caspase and inhibition of survival genes in PC-3 prostate cancer cells.

Ginkgetin


Input: Ginkgetin is a natural biflavonoid isolated from leaves of Ginkgo biloba L.

Ginkgetin

biflavonoid


Input: Though it was known to have anti-inflammatory, anti-influenza virus, anti-fungal activity, osteoblast differentiation stimulating activity and neuro-protective effects, the underlying antitumor mechanism of ginkgetin still remains unclear.

ginkgetin


Input: Thus, in the present study, anti-cancer mechanism of ginkgetin was elucidated in human prostate cancer PC-3 cells.

ginkgetin


Input: Ginkgetin suppressed the viability of PC-3 cells in a concentration-dependent manner and also significantly increased the sub-G1 DNA contents of cell cycle in PC-3 cells.

Ginkgetin


Input: Ginkgetin activated caspase-3 and attenuated the expression of survival genes such as Bcl-2, Bcl-xL, survivin and Cyclin D1 at protein and mRNA levels.

Ginkgetin


Input: Consistently, pan-caspase inhibitor Z-DEVD-fmk blocked sub G1 accumulation and cleavages of PRAP and caspase 3 induced by ginkgetin in PC-3 cells.

Z-DEVD-fmk

ginkgetin


Input: Overall, these findings suggest that ginkgetin induces apoptosis in PC-3 cells via activation of caspase 3 and inhibition of survival genes as a potent chemotherapeutic agent for prostate cancer treatment.

ginkgetin


Input: In vivo effect of Schisandrin B on cytochrome P450 enzyme activity.

Schisandrin B


Input: To investigate the possible drug interaction, this study is designed to evaluate the ability of Schisandrin B (Sch B) to modulate cytochrome P450 3A activity (CYP3A) in vivo and to alter the pharmacokinetic profiles of CYP3A substrate (midazolam) in treated rats.

Schisandrin B

Sch B

midazolam


Input: Rats were repeated administered with physiological saline (negative control group), ketoconazole (75mg/kg, positive control group) or varied doses of Sch B (experimental groups) for three consecutive days.

ketoconazole

Sch B


Input: Subsequently, changes in hepatic microsomal CYP3A activity and the pharmacokinetic profiles of midazolam and 1'-hydroxy midazolam in plasma were studied to evaluate CYP3A activity.

midazolam

1'-hydroxy midazolam


Input: The results indicated that Sch B significantly dose-dependently inhibited rat hepatic microsomal CYP3A activity with Ki value of 16. 64mg/kg and showed the characteristic of a noncompetitive inhibitor.

Sch B


Input: Oral administration of Sch B for 3 days in rats produced significant effect on the pharmacokinetics of oral midazolam.

Sch B

midazolam


Input: Sch B resulted in a significant, dose-dependent increase in midazolam AUC0-infinity except at the dose of 2mg/kg, while AUC0-infinity increased by 26. 1% (8mg/kg) and 60. 6% (16mg/kg), respectively.

Sch B

midazolam


Input: In the pharmacokinetic profiles of 1'-hydroxy midazolam, the significant, dose-dependent decrease in AUC0-infinity was observed except at the dose of 2mg/kg, while AUC0-infinity reduced by 44. 5% (8mg/kg) and 49. 2% (16mg/kg), respectively.

1'-hydroxy midazolam


Input: These results suggested that 3-day treatment of Sch B could increase concentration and oral bioavailability of drug metabolized by CYP3A.

Sch B


Input: When the drug, consisting of Sch B, is used in the clinic for more than 3 days, the possible drug-drug interactions should be taken into consideration.

Sch B


Input: A Mammalian Pre-mRNA 5' End Capping Quality Control Mechanism and an Unexpected Link of Capping to Pre-mRNA Processing.


Input: Recently, we reported that two homologous yeast proteins, Rai1 and Dxo1, function in a quality control mechanism to clear cells of incompletely 5' end-capped messenger RNAs (mRNAs).


Input: Here, we report that their mammalian homolog, Dom3Z (referred to as DXO), possesses pyrophosphohydrolase, decapping, and 5'-to-3' exoribonuclease activities.


Input: Surprisingly, we found that DXO preferentially degrades defectively capped pre-mRNAs in cells.


Input: Additional studies show that incompletely capped pre-mRNAs are inefficiently spliced at all introns, a fact that contrasts with current understanding, and are also poorly cleaved for polyadenylation.


Input: Crystal structures of DXO in complex with substrate mimic and products at a resolution of up to 1. 5 A provide elegant insights into the catalytic mechanism and molecular basis for their three apparently distinct activities.


Input: Our data reveal a pre-mRNA 5' end capping quality control mechanism in mammalian cells, indicating DXO as the central player for this mechanism, and demonstrate an unexpected intimate link between proper 5' end capping and subsequent pre-mRNA processing.


Input: Lipidic spherulites: Formulation optimisation by paired optical and cryoelectron microscopy.


Input: Objective of this study was to assess the various steps leading to spherulite obtention by means of optical and cryoelectron microscopy.


Input: The formulation, resting and hydration steps were optimised.


Input: Green-based process and organic-based process were compared.


Input: It was found that spherulites could be obtained only when two key steps were followed: a prior resting phase of excipients and the shearing stress of the hydrated excipients.


Input: Moreover, the new formulation under study formed spherulites in the 100-200nm range, which is smaller than previously reported spherulites.


Input: Such laboratory scale optimised process led the integration of spherulites in a larger number of prospective studies.


Input: Indeed, we finally showed that the encapsulated payload of a hydrophobic compound, such as the anti-angiogenic agent fisetin, was increased to a much higher degree than with a liposomal encapsulation.


Input: Pharmacokinetic evaluation in mice of amorphous itraconazole-based dry powder formulations for inhalation with high bioavailability and extended lung retention.

itraconazole


Input: Three Itraconazole (ITZ) dry powders for inhalation (DPI) were prepared by spray-drying a mannitol solution in which the ITZ was in suspension (F1) or was in solution without (F2) or with phospholipid (PL) (F3).

Itraconazole

ITZ

mannitol

ITZ


Input: These powders were endotracheally insufflated in vivo at a single dose of 0. 5mg/kg for pharmacokinetic profile (lung and plasma concentration) determination in ICR CD-1 mice.


Input: ITZ was crystalline in F1 and assumed to be amorphous in the F2 and F3 formulations.

ITZ


Input: The amorphous nature of ITZ in F2 and F3 formulations allowed the in vitro formation of an ITZ supersaturated solution with a maximum solubility of 450 +/- 124ng/ml (F2) and 498 +/- 44ng/ml (F3), in contrast to formulation F1 (< 10ng/ml).

ITZ

ITZ


Input: As a result of these higher solubilities, absorption into the systemic compartment after endotracheal administration was faster for formulations F2 and F3 (shorter tmax) and in larger quantities compared to the F1 formulation (plasmatic AUC0-24h of 182ngh/ml, 491. 5ngh/ml and 376. 8ngh/ml, and tmax of 60min, 30min and 5min for F1, F2 and F3, respectively).


Input: PL increased the systemic bioavailability of ITZ (determined by the AUCplasma to AUClung ratio) as a consequence of their wetting and absorption enhancement effect.

ITZ


Input: ITZ lung concentrations after pulmonary administration remained higher than the targeted dose, based on the minimal inhibitory concentrations for Aspergillus Fumigatus (2 mu g/gwetlung), 24h post-administration for both F1 and F2 formulations.

ITZ


Input: However, this was not the case for formulation F3, which exhibited a faster elimination rate from the lung, with an elimination half-life of 4. 1h vs. 6. 5h and 14. 7h for F1 and F2, respectively.


Input: Antagonism of the transient receptor potential ankyrin 1 (TRPA1) attenuates hyperalgesia and urinary bladder overactivity in cyclophosphamide-induced haemorrhagic cystitis.

cyclophosphamide


Input: The aim of this study was to investigate the involvement of the transient receptor potential ankyrin 1 (TRPA1) in haemorrhagic cystitis, the main side effect of cyclophosphamide-based chemotherapy.

cyclophosphamide


Input: Hannover female rats received intraperitoneal (i. p.) injection of cyclophosphamide (three doses of 100mg/kg, every other day, in a total of five days).

cyclophosphamide


Input: This treatment was followed by the treatment with TRPA1 antagonist HC 030031 (50mg/kg, p. o.).

HC 030031


Input: The threshold for hindpaw withdrawal or abdominal retraction to von Frey Hair and the locomotor activity were measured.


Input: The treatment with the TRPA1 antagonist HC 030031 significantly decreased mechanical hyperalgesia induced by cyclophosphamide without interfere with locomotor activity.

HC 030031

cyclophosphamide


Input: Urodynamic parameters were performed by cystometry 24h after a single treatment with cyclophosphamide (200mg/kg, i. p.) in control and HC 030031 treated rats.

cyclophosphamide

HC 030031


Input: Analyses of the urodynamic parameters showed that a single dose of cyclophosphamide was enough to significantly increase the number and amplitude of non-voiding contractions and to decrease the voided volume and voiding efficiency, without significantly altering basal, threshold or maximum pressure.

cyclophosphamide


Input: The treatment with HC 030031 either before (100mg/kg, p. o.) or after (30mg/kg, i. v.) cyclophosphamide inhibited the non-voiding contractions but failed to counteract the loss in voiding efficiency.

HC 030031

cyclophosphamide


Input: Our data demonstrates that nociceptive symptoms and urinary bladder overactivity caused by cyclophosphamide, in part, are dependent upon the activation of TRPA1.

cyclophosphamide


Input: In this context, the antagonism of the receptor may be an alternative to minimise the urotoxic symptoms caused by this chemotherapeutic agent.


Input: Differential responses to omega-agatoxin IVA in murine frontal cortex and spinal cord derived neuronal networks.


Input: omega-Agatoxin-IVA is a well known P/Q-type Ca (2 +) channel blocker and has been shown to affect presynaptic Ca (2 +) currents as well postsynaptic potentials.

Ca (2 +)

Ca (2 +)


Input: P/Q-type voltage gated Ca (2 +) channels play a vital role in presynaptic neurotransmitter release and thus play a role in action potential generation.

Ca (2 +)


Input: Monitoring spontaneous activity of neuronal networks on microelectrode arrays (MEAs) provides an important tool for examining this neurotoxin.


Input: Changes in extracellular action potentials are readily observed and are dependent on synaptic function.


Input: Given the efficacy of murine frontal cortex and spinal cord networks to detect neuroactive substances, we investigated the effects of omega-agatoxin on spontaneous action potential firing within these networks.


Input: We found that networks derived from spinal cord are more sensitive to the toxin than those from frontal cortex; a concentration of only 10nM produced statistically significant effects on activity from spinal cord networks whereas 50nM was required to alter activity in frontal cortex networks.


Input: Furthermore, the effects of the toxin on frontal cortex are more complex as unit specific responses were observed.


Input: These manifested as either a decrease or increase in action potential firing rate which could be statistically separated as unique clusters.


Input: Administration of bicuculline, a GABAA inhibitor, isolated a single response to omega-agatoxin, which was characterized by a reduction in network activity.

bicuculline


Input: These data support the notion that the two clusters detected with omega-agatoxin exposure represent differential responses from excitatory and inhibitory neuronal populations.


Input: Pharmacokinetic, neurochemical, stereological and neuropathological studies on the potential effects of paraquat in the substantia nigra pars compacta and striatum of male C57BL/6J mice.

paraquat


Input: The pharmacokinetics and neurotoxicity of paraquat dichloride (PQ) were assessed following once weekly administration to C57BL/6J male mice by intraperitoneal injection for 1, 2 or 3 weeks at doses of 10, 15 or 25mg/kg/week.

paraquat dichloride


Input: Approximately 0. 3% of the administered dose was taken up by the brain and was slowly eliminated, with a half-life of approximately 3 weeks.


Input: PQ did not alter the concentration of dopamine (DA), homovanillic acid (HVA) or 3, 4-dihydroxyphenylacetic acid (DOPAC), or increase dopamine turnover in the striatum.

dopamine

homovanillic acid

HVA

3, 4-dihydroxyphenylacetic acid

DOPAC

dopamine


Input: There was inconsistent stereological evidence of a loss of DA neurons, as identified by chromogenic or fluorescent-tagged antibodies to tyrosine hydroxylase in the substantia nigra pars compacta (SNpc).

tyrosine


Input: There was no evidence that PQ induced neuronal degeneration in the SNpc or degenerating neuronal processes in the striatum, as indicated by the absence of uptake of silver stain or reduced immunolabeling of tyrosine-hydroxylase-positive (TH (+)) neurons.

silver

tyrosine


Input: There was no evidence of apoptotic cell death, which was evaluated using TUNEL or caspase 3 assays.


Input: Microglia (IBA-1 immunoreactivity) and astrocytes (GFAP immunoreactivity) were not activated in PQ-treated mice 4, 8, 16, 24, 48, 96 or 168h after 1, 2 or 3 doses of PQ.


Input: In contrast, mice dosed with the positive control substance, 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP; 10mg/kg/dose x 4 doses, 2h apart), displayed significantly reduced DA and DOPAC concentrations and increased DA turnover in the striatum 7 days after dosing.

1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine

MPTP

DOPAC


Input: The number of TH (+) neurons in the SNpc was reduced, and there were increased numbers of degenerating neurons and neuronal processes in the SNpc and striatum.


Input: MPTP-mediated cell death was not attributed to apoptosis.

MPTP


Input: MPTP activated microglia and astrocytes within 4h of the last dose, reaching a peak within 48h.

MPTP


Input: The microglial response ended by 96h in the SNpc, but the astrocytic response continued through 168h in the striatum.


Input: These results bring into question previous published stereological studies that report loss of TH (+) neurons in the SNpc of PQ-treated mice.


Input: This study also suggests that even if the reduction in TH (+) neurons reported by others occurs in PQ-treated mice, this apparent phenotypic change is unaccompanied by neuronal cell death or by modification of dopamine levels in the striatum.

dopamine


Input: Berberine attenuates bleomycin induced pulmonary toxicity and fibrosis via suppressing NF-kappa B dependant TGF-beta activation: A biphasic experimental study.

Berberine

bleomycin


Input: Idiopathic pulmonary fibrosis (IPF) is a progressive, debilitating and fatal lung disorder with high mortality rate.


Input: Unfortunately, to date the treatment for IPF remains unsatisfying and in severe cases lung transplantations are performed as a therapeutic measure.


Input: Thus, it becomes great interest to find novel agents to treat IPF.


Input: Berberine, a plant alkaloid known for its broad pharmacological activities remains a remedy against multiple diseases.

Berberine


Input: This study was hypothesized to investigate the antifibrotic potential of berberine against bleomycin-induced lung injury and fibrosis, a tentative animal model.

berberine

bleomycin


Input: Male wistar rats were subjected to single intratracheal instillation of 2. 5U/kg of bleomycin on day 0.

bleomycin


Input: Berberine treatments were either provided in preventive or therapeutic mode respectively.

Berberine


Input: Berberine administration significantly ameliorated the bleomycin mediated histological alterations and reduced the inflammatory cell infiltrate in BALF.

Berberine

bleomycin


Input: Berberine significantly blocked collagen accumulations with parallel reduction in the hydroxyproline level.

Berberine

hydroxyproline


Input: The immunological sign of bleomycin stimulated mast cell deposition and histamine release were considerably reduced by berberine.

bleomycin

histamine

berberine


Input: Berberine enhanced the antioxidant status, through upregulating the redox sensing transcription factor nuclear factor E2-related factor 2 (Nrf2).

Berberine


Input: Berberine inhibited the bleomycin mediated activation of inflammatory mediator nuclear factor kappa B (NF-kappa B) and suppressed its downstream target inducible nitric oxide synthase (iNOS).

Berberine

bleomycin

nitric oxide


Input: Strikingly, berberine exhibited target attenuation of tumor necrosis factor alpha (TNF-alpha) and key pro-fibrotic mediator, transforming growth factor beta 1 (TGF-beta 1).

berberine


Input: Taken together, this study reveals the beneficial effects of berberine against bleomycin mediated fibrotic challenge through activating Nrf2 and suppressing NF-kappa B dependent inflammatory and TGF-beta 1 mediated fibrotic events.

berberine

bleomycin


Input: Protective effect of crocin on diazinon induced cardiotoxicity in rats in subchronic exposure.

crocin

diazinon


Input: This study was designed to evaluate the effectiveness of crocin, main component of Crocus sativus L.

crocin


Input: (Saffron) against subchronic diazinon (DZN) induced cardiotoxicity in rats.

diazinon

DZN


Input: METHODS: Rats were divided into 7 groups; control (corn oil, gavage), DZN (15mg/kg/day, gavage,), crocin (12. 5, 25 or 50mg/kg/day, i. p) plus DZN, vitamin E (200IU/kg, i. p, three times per week) plus DZN and crocin (50mg/kg/day, i. p) groups.

crocin

DZN

vitamin E

DZN

crocin


Input: Treatments were continued for 4weeks.


Input: Creatine phosphokinase MB (CK-MB), malondealdehyde (MDA) and glutathione (GSH) levels were evaluated in heart tissue at the end of treatments.

Creatine

malondealdehyde

MDA

glutathione

GSH


Input: Levels of apoptotic proteins (Bax, Bcl2, caspase 3) and cytosolic cytochrome c were analyzed by Western blotting.


Input: Transcript levels of Bax and Bcl2 were also determined using qRT PCR.


Input: RESULTS: DZN induced histophatological damages and elevated the level of cardiac marker CK-MB.

DZN


Input: These effects were associated with increased MDA level, lower level of reduced GSH and induction of apoptosis through elevation of Bax/Bcl2 ratio (both protein and mRNA levels), cytochrome c release to the cytosol and activation caspase 3 in cardiac tissue.

MDA

GSH


Input: Crocin (25 and 50mg/kg) or vitamin E improved histopathological damages, decreased MDA and CK-MB, increased GSH content and attenuated the increase of Bax/Bcl2 ratio, activation of caspase 3 and release of cytochrome c to the cytosol induced by DZN.

Crocin

vitamin E

MDA

GSH

DZN


Input: In summary, DZN induced mitochondrial-mediated apoptosis in heart tissue of rat following subchronic exposure.

DZN


Input: Crocin, as an antioxidant, showed protective effects against DZN cardiotoxicity by reducing lipid peroxidation and alleviating apoptosis.

Crocin

DZN


Input: Effect of naloxone on ischemic acute kidney injury in the mouse.

naloxone


Input: Renal ischemia produces sympathoexcitation, which is responsible for the development of ischemic acute kidney injury.


Input: Stimulation of central opioid receptors activates the renal sympathetic nerve.


Input: The present study examined the effect of an opioid receptor antagonist naloxone on the ischemia/reperfusion-induced renal dysfunction in mice.

naloxone


Input: Blood urea nitrogen (BUN) and plasma creatinine increased 24 h after the renal ischemia/reperfusion.

urea nitrogen

creatinine


Input: Intraperitoneal or intracerebroventricular, but not intrathecal, pretreatment with naloxone suppressed the renal ischemia/reperfusion-induced increases in BUN and plasma creatinine.

naloxone

creatinine


Input: This effect of naloxone was reversed by subcutaneous pretreatment with morphine.

naloxone

morphine


Input: Selective MOP receptor antagonist beta-funaltrexamine (FNA) also suppressed the renal ischemia/reperfusion-induced increases in BUN and plasma creatinine.

beta-funaltrexamine

FNA

creatinine


Input: Moreover, tyrosine hydroxylase expression in the renal tissue increased 24 h after renal ischemia/reperfusion, which was abolished by intraperitoneal or intracerebroventricular pretreatment with naloxone and FNA.

tyrosine

naloxone

FNA


Input: Immunohistochemical experiments revealed a significant increase in the number of the Fos family proteins (c-Fos, FosB, Fra-1, and Fra-2) positive cells in the paraventricular nucleus of hypothalamus and supraoptic nucleus 24 h after the renal ischemia/reperfusion.


Input: Intracerebroventricular pretreatment with naloxone attenuated the renal ischemia/reperfusion-induced increase in the number of the Fos family proteins positive cells in these areas.

naloxone


Input: Finally, we observed that i. c. v. pretreatment with antiserum against beta-endorphin also suppressed the increased blood urea and plasma creatinine.

urea

creatinine


Input: These results suggest that the blockade of central opioid receptors can attenuate the ischemic acute kidney injury through the inhibition of renal sympathoexcitation.


Input: The central opioid receptors may thus be a new target for the treatment of ischemic organ failures.


Input: Clinical toxinology specialty training.


Input: Clinical toxinology is the medical discipline dealing with the diagnosis, treatment and prevention of toxin diseases caused by exposure to venomous animals and poisonous animals, plants and mushrooms.


Input: Currently there is no national or international organisation accrediting or training doctors in this discipline, but the role of the IST in this area is the subject of a recently approved revised Constitution.


Input: A few courses covering some aspects of clinical toxinology exist, either with limited curricula, or with only a minor clinical focus, or with a very regional, non-global focus.


Input: The only comprehensive clinical toxinology course is the one provided in Adelaide, Australia, running regularly since 1997.


Input: This course may form the nucleus from which IST can develop a global accredited training scheme in clinical toxinology.


Input: Such a scheme will require input from diverse global regions and will be far more comprehensive and over a much longer time than the current Short Course, though may incorporate the Short Course in some way, or a derivative of it.


Input: Accreditation of medical expertise in clinical toxinology will be required at the national level and this might be accomplished by the IST working with existing national medical specialty organisations and governments, with the IST supervising the training and accreditation requirements and the national organisations providing the framework for registration of medical expertise at the local level.


Input: Synthesis and biological evaluation of novel pyrrolidine-2, 5-dione derivatives as potential antidepressant agents.

pyrrolidine-2, 5-dione


Input: Part 1.


Input: A series of 3-(1H-indol-3-yl) pyrrolidine-2, 5-dione derivatives was synthesized and their biological activity was evaluated.

3-(1H-indol-3-yl) pyrrolidine-2, 5-dione


Input: The chemical structures of the newly prepared compounds were confirmed by (1) H NMR, (13) C NMR and ESI-HRMS spectra data.

(1) H

(13) C


Input: All tested compounds proved to be potent 5-HT1A receptor and serotonin transporter protein (SERT) ligands.

serotonin


Input: Among them, compounds 15, 18, 19 and 30 showed significant affinity for 5-HT1A and SERT.


Input: Computer docking simulations carried out for compounds 15, 31 and 32 to models of 5-HT1A receptor and SERT confirm the results of biological tests.


Input: Due to high affinity for the 5-HT1A receptor and moderate affinity for SERT, compounds 31, 32, 35, and 37 were evaluated for their affinity for D2L, 5-HT6, 5-HT7 and 5-HT2A receptors.


Input: In vivo tests, in turn, resulted in determining the functional activity of compounds 15, 18, 19 and 30 to the 5-HT1A receptor.


Input: The results of these tests indicate that all of the ligands possess properties characteristic of 5-HT1A receptor agonists.


Input: Mild hyperthermia triggered doxorubicin release from optimized stealth thermosensitive liposomes improves intratumoral drug delivery and efficacy.

doxorubicin


Input: Liposome mediated anticancer drug delivery has the advantage of reducing cytotoxicity in healthy tissues.


Input: However, undesired slow drug release impedes the therapeutic efficacy of clinically applied PEG-liposomal doxorubicin (Dox).

PEG

doxorubicin

Dox


Input: The aim of this study is to combine stealth thermosensitive liposomes (TSL) and local mild hyperthermia (HT) to increase bioavailable Dox levels in tumors.

Dox


Input: Dox was encapsulated in stealth TSL (~ 80nm) with optimized PEG concentration in the membrane, and compared with lysolipid-based Dox-LTSL for in vitro stability, release kinetics, and in vivo tumor growth control.

Dox

PEG

Dox


Input: In vitro cytotoxicity of Dox-TSL against murine BFS-1 sarcoma and, human BLM melanoma cell lines and Human Umbilical Vein Endothelial Cells (HUVEC) under normothermia (37 degrees C) and HT (42 degrees C) was compared with non-encapsulated Dox.

Dox

Dox


Input: In vitro Dox uptake in nuclei was imaged in BLM and HUVEC.

Dox


Input: In vivo intravascular Dox release from TSL in BFS-1 tumors under local mild HT in dorsal skin flap window chamber models was captured by intravital confocal microscopy.

Dox


Input: Intravascular Dox-TSL release kinetics, penetration depth and interstitial Dox density were subjected to quantitative image analysis.

Dox

Dox


Input: Systemic Dox-TSL administration in combination with local mild HT on subcutaneous tumor growth control was compared to Dox-LTSL plus local mild HT.

Dox

Dox


Input: Dox-TSL was stable at 37 degrees C, while released over 95% Dox within 1min in 90% serum at 42 degrees C.

Dox

Dox


Input: Dox-TSL demonstrated efficient in vivo intratumoral Dox release under local mild HT, followed by significant Dox uptake by tumor and tumor vascular endothelial cells.

Dox

Dox

Dox


Input: Dox-TSL plus mild HT showed improved tumor growth control over Dox-LTSL plus mild HT.

Dox

Dox


Input: Survival after a single treatment of Dox-TSL plus mild HT was 67%, while survival after Dox-LTSL plus mild HT was 22%.

Dox

Dox


Input: This combination of Dox-TSL and local mild HT offers promising clinical opportunities to improve liposomal Dox delivery to solid tumors.

Dox

Dox


Input: Mesenchymal stem cells as delivery vehicle of porphyrin loaded nanoparticles: Effective photoinduced in vitro killing of osteosarcoma.

porphyrin


Input: Mesenchymal stem cells (MSC) have the unique ability to home and engraft in tumor stroma.


Input: These features render them potentially a very useful tool as targeted delivery vehicles which can deliver therapeutic drugs to the tumor stroma.


Input: In the present study, we investigate whether fluorescent core-shell PMMA nanoparticles (FNPs) post-loaded with a photosensitizer, namely meso-tetrakis (4-sulfonatophenyl) porphyrin (TPPS) and uploaded by MSC could trigger osteosarcoma (OS) cell death in vitro upon specific photoactivation.

meso-tetrakis (4-sulfonatophenyl) porphyrin

TPPS


Input: In co-culture studies we demonstrate using laser confocal microscopy and time lapse imaging, that only after laser irradiation MSC loaded with photosensitizer-coated fluorescent NPs (TPPS @FNPs) undergo cell death and release reactive oxygen species (ROS) which are sufficient to trigger cell death of all OS cells in the culture.

TPPS

oxygen


Input: These results encourage further studies aimed at proving the efficacy of this novel tri-component system for PDT applications.


Input: Compound promiscuity: what can we learn from current data?


Input: The specificity paradigm that assigns central relevance to achieving target specificity of drug candidates has recently been revisited.


Input: Evidence is mounting that polypharmacological drug behavior is often responsible for therapeutic efficacy suggesting the consideration of new drug development strategies.


Input: Target promiscuity of compounds is at the origin of polypharmacology.


Input: For many bioactive compounds, multiple target annotations are available indicating that compound promiscuity is a general phenomenon.


Input: However, careful analysis of compound activity data reveals that the degree of apparent promiscuity is strongly influenced by data selection criteria and the type of activity measurements that are considered.


Input: Furthermore, promiscuity involving unrelated targets is less common.


Input: Apparent target promiscuity might often better be interpreted as activity promiscuity in different assays.


Input: Cosmetics Europe multi-laboratory pre-validation of the SkinEthic (TM) reconstituted human corneal epithelium test method for the prediction of eye irritation.


Input: Cosmetics Europe, The Personal Care Association, known as Colipa before 2012, conducted a program of technology transfer and assessment of Within/Between Laboratory (WLV/BLV) reproducibility of the SkinEthic (TM) Reconstituted Human Corneal Epithelium (HCE) as one of two human reconstructed tissue eye irritation test methods.


Input: The SkinEthic (TM) HCE test method involves two exposure time treatment procedures-one for short time exposure (10min-SE) and the other for long time exposure (60min-LE) of tissues to test substance.


Input: This paper describes pre-validation studies of the SkinEthic (TM) HCE test method (SE and LE protocols) as well as the Eye Peptide Reactivity Assay (EPRA).


Input: In the SE WLV study, 30 substances were evaluated.


Input: A consistent outcome with respect to viability measurement across all runs was observed with all substances showing an SD of less than 18%.


Input: In the LE WLV study, 44 out of 45 substances were consistently classified.


Input: These data demonstrated a high level of reproducibility within laboratory for both the SE and LE treatment procedures.


Input: For the LE BLV, 19 out of 20 substances were consistently classified between the three laboratories, again demonstrating a high level of reproducibility between laboratories.


Input: The results for EPRA WLV and BLV studies demonstrated that all substances analysed were categorised similarly and that the method is reproducible.


Input: The SkinEthic (TM) HCE test method entered into the experimental phase of a formal ECVAM validation program in 2010.


Input: Mechanochemical activation of vincamine mediated by linear polymers: Assessment of some " critical " steps.

vincamine


Input: The aim of the research was to investigate three " critical steps " that deserve particular attention during the mechanochemical activation of vincamine.

vincamine


Input: The first step consisted in the selection of the best polymeric carrier/most affine stabiliser between linear PVP and NaCMC by using the GRID and the GRID based AutoDock software packages which permit to calculate their surface features and interactions.

PVP


Input: Moreover, the calculation of the partial and total solubility parameters supported the results obtained by GRID and AutoDock software.


Input: Then, after the selection of linear PVP-K30 as the suitable carrier, the influence of process and formulation variables on the amorphisation degree and solubility enhancement was studied, to select the most suitable process conditions and formulation parameters.


Input: Subsequently, the best performing samples were widely characterised using XRPD, TEM and SSNMR (including the proton relaxation ((1) H T1 NMR) time) techniques.

(1) H


Input: These studies highlighted that all the coground samples were nanocrystalline solid dispersions indicating a dramatic difference between the amorphisation capacities of linear PVP-K30 and cross-linked PVP, used in previous analogous experiences.

PVP


Input: In particular, (13) C, (15) N and (1) H T1 NMR data point to a description of the system as a dispersion of nanocrystals in the polymer.

(13) C

(15) N

(1) H


Input: In these dispersions vincamine is in a disordered crystalline state due to extensive interactions and contacts with PVP-K30 but the main hydrogen bonding motif characterising its packing remains.

vincamine

hydrogen


Input: Again, differently from cross-linked PVP, dissolution studies revealed that linear PVP-K30 was able to promote a complete in vitro solubilisation of vincamine in some coground samples.

PVP

vincamine


Input: What is more important, by using a linear polymer, drug-to-polymer and milling time variables appeared less influent on the solid state and in vitro properties of the composites.


Input: Finally, stability studies conducted for a period of 1year highlighted the high physical stability of the selected samples.


Input: Binding pattern and toxicological effects of lectins from genus Canavalia on bovine sperm.


Input: The aim of this study was to determine the binding patterns of Canavalia ensiformis (ConA), Canavalia boliviana (ConBol) and Canavalia brasiliensis (ConBr) lectins to bovine sperm and their effects on sperm motility, viability, lipid peroxidation, reactive oxygen species production and fertilization ability.

oxygen


Input: ConA bound to whole spermatozoa, with the exception of the equatorial segment, ConBol did not interact with the acrosome region and ConBr exhibited a fragmented binding pattern.


Input: The three lectins decreased sperm motility but did not affect cell viability or lipid peroxidation.


Input: Nevertheless, ROS production was increased in comparison to controls and a reduction in the cleavage and blastocyst ratio was induced in comparison to controls.


Input: In conclusion, this study determined that structurally similar lectins interact differently with bovine sperm and affect sperm motility, viability, lipid peroxidation, ROS production and fertilization ability in various ways.


Input: Selective class IIa histone deacetylase inhibition via a nonchelating zinc-binding group.

zinc


Input: In contrast to studies on class I histone deacetylase (HDAC) inhibitors, the elucidation of the molecular mechanisms and therapeutic potential of class IIa HDACs (HDAC4, HDAC5, HDAC7 and HDAC9) is impaired by the lack of potent and selective chemical probes.


Input: Here we report the discovery of inhibitors that fill this void with an unprecedented metal-binding group, trifluoromethyloxadiazole (TFMO), which circumvents the selectivity and pharmacologic liabilities of hydroxamates.

trifluoromethyloxadiazole

TFMO

hydroxamates


Input: We confirm direct metal binding of the TFMO through crystallographic approaches and use chemoproteomics to demonstrate the superior selectivity of the TFMO series relative to a hydroxamate-substituted analog.

TFMO

TFMO

hydroxamate


Input: We further apply these tool compounds to reveal gene regulation dependent on the catalytic active site of class IIa HDACs.


Input: The discovery of these inhibitors challenges the design process for targeting metalloenzymes through a chelating metal-binding group and suggests therapeutic potential for class IIa HDAC enzyme blockers distinct in mechanism and application compared to current HDAC inhibitors.


Input: A 3D-RISM-SCF method with dual solvent boxes for a highly polarized system: application to 1, 6-anhydrosugar formation reaction of phenyl alpha-and beta-d-glucosides under basic conditions.

1, 6-anhydrosugar

phenyl alpha-and beta-d-glucosides


Input: One of the difficulties in application of the usual reference interaction site model self-consistent field (RISM-SCF) method to a highly polarized and bulky system arises from the approximate evaluation of electrostatic potential (ESP) with pure point charges.


Input: To improve this ESP evaluation, the ESP near a solute is directly calculated with a solute electronic wavefunction, that distant from a solute is approximately calculated with solute point charges, and they are connected with a switching function.


Input: To evaluate the fine solvation structure near the solute by incorporating the long-range solute-solvent Coulombic interaction with low computational cost, we introduced the dual solvent box protocol; one small box with the fine spacing is employed for the first and the second solvation shells and the other large box with the normal spacing is employed for long-range solute-solvent interaction.


Input: The levoglucosan formation from phenyl alpha-and beta-d-glucosides under basic conditions is successfully inspected by this 3D-RISM-SCF method at the MP2 and SCS-MP2 levels, though the 1D-RISM-SCF could not be applied to this reaction due to the presence of highly polarized and bulky species.

levoglucosan

phenyl alpha-and beta-d-glucosides


Input: This 3D-RISM-SCF calculation reproduces the experimentally reported higher reactivity of the beta-anomer.


Input: The 3D-RISM-SCF-calculated activation free energy for the beta-anomer is closer to the experimental value than the PCM-calculated one.


Input: Interestingly, the solvation effect increases the difference in reactivity between these two anomers.


Input: The reason is successfully elucidated with 3D-RISM-SCF-calculated microscopic solvation structure and decomposition analysis of solute-solvent interaction.


Input: Nuclear Factor kappa B Mediates Suppression of Canonical Transient Receptor Potential 6 Expression by Reactive Oxygen Species and Protein Kinase C in Kidney Cells.

Oxygen


Input: This study was carried out to explore the molecular mechanism for down-regulation of TRPC6 expression in the reactive oxygen species (ROS)/PKC signaling in kidney cells.

oxygen


Input: In cultured human mesangial cells, H2O2 and TNF-alpha inhibited TRPC6 mRNA expression in a time-dependent manner.


Input: Inhibition of NF-kappa B reversed both H2O2-and phorbol 12-myristate 13-acetate (PMA)-induced decrease in TRPC6 protein expression.

phorbol 12-myristate 13-acetate

PMA


Input: Activation of NF-kappa B by knocking down I kappa B alpha using siRNA could mimic the suppressive effect of ROS/PKC on TRPC6.


Input: a Ca (2 +) imaging study showed that activation and inhibition of NF-kappa B significantly decreased and increased the TRPC6-mediated Ca (2 +) entry, respectively.

Ca (2 +)

Ca (2 +)


Input: Further experiments showed that PMA, but not its inactive analog 4 alpha-phorbol 12, 13-didecanoate (4 alpha-PDD), caused phosphorylation of I kappa B alpha and stimulated the nuclear translocation of NF-kappa B p50 and p65 subunits.

PMA

4 alpha-phorbol 12, 13-didecanoate

4 alpha-PDD


Input: The PMA-dependent I kappa B alpha phosphorylation was significantly inhibited by G o 6976.

PMA

G o 6976


Input: Electrophoretic mobility shift assay revealed that PMA stimulated DNA binding activity of NF-kappa B.

PMA


Input: Furthermore, specific knockdown of p65, but not p50, prevented an H2O2 inhibitory effect on TRPC6 protein expression, suggesting p65 as a predominant NF-kappa B subunit repressing TRPC6.


Input: In agreement with a major role of p65, chromatin immunoprecipitation assays showed that PMA treatment induced p65 binding to the TRPC6 promoter.

PMA


Input: Moreover, PMA treatment increased the association of p65 with histone deacetylase (HDAC) and decreased histone acetylation at the TRPC6 promoter.

PMA


Input: Consistently, knockdown of HDAC2 by siRNA or inhibition of HDAC with trichostatin A prevented a H2O2-induced decrease in TRPC6 mRNA and protein expressions, respectively.

trichostatin A


Input: Taken together, our findings imply an important role of NF-kappa B in a negative regulation of TRPC6 expression at the gene transcription level in kidney cells.


Input: Single-molecule surface-enhanced Raman spectroscopy: a perspective on the current status.


Input: This perspective presents an overview of single-molecule surface-enhanced Raman scattering (sm-SERS).


Input: Our overview is organized as a brief theoretical background, discussion of the factors that enhance SERS, various experimental preparations for inserting a single molecule in a hot spot, recent sm-SERS experiments, and a perspective.


Input: Although, there have been numerous review papers on sm-SERS, we mainly concentrated on the logical development of sm-SERS on the basis of the fundamental concepts and their physical significance, so that readers outside this field can understand the motivation and the underlying physics when describing current sm-SERS measurements.


Input: Indeed, understanding such current sm-SERS experiments conducted by representative groups would be very helpful for readers to answer for themselves the fundamental and practical questions surrounding sm-SERS: (1) what information can sm-SERS provide?


Input: (2) Which factors based on the SERS mechanism should be considered to significantly amplify the SERS signal?


Input: (3) What kinds of related microscopy techniques could be combined with sm-SERS to attain more meaningful results?


Input: (4) Which statistical approaches can be used and how they can be applied to properly analyze sm-SERS data?


Input: We hope that this review article can help readers answer these questions.


Input: NMR characterisation of dynamics in solvates and desolvates of formoterol fumarate.

formoterol fumarate


Input: Solid-state NMR is used to characterise dynamics in the ethanol solvate of the pharmaceutical material formoterol fumarate and its associated desolvate.

ethanol

formoterol fumarate


Input: Jump rates and activation barriers for dynamic processes such as phenyl ring rotation and methyl group rotational diffusion are derived from 1D-EXSY and (13) C spin-lattice relaxation times respectively.

phenyl

methyl

(13) C


Input: (2) H and (13) C spin-lattice relaxation times measured under magic-angle spinning conditions are used to show that the fumarate ion in the desolvate is undergoing small-amplitude motion on a frequency scale of 100s of MHz at ambient temperature with an activation parameter of about 32 kJ mol (-1).

(2) H

(13) C

fumarate


Input: Exact calculations of relaxation times under MAS provide a simple and robust means to test motional models in cases where relaxation rate maxima are observed, including for systems where the crystal structure of the material is unknown.


Input: Two populations of glucocorticoid receptor-binding sites in the male rat hippocampal genome.


Input: In the present study, genomic binding sites of glucocorticoid receptors (GR) were identified in vivo in the rat hippocampus applying chromatin immunoprecipitation followed by next-generation sequencing.


Input: We identified 2470 significant GR-binding sites (GBS) and were able to confirm GR binding to a random selection of these GBS covering a wide range of P values.


Input: Analysis of the genomic distribution of the significant GBS revealed a high prevalence of intragenic GBS.


Input: Gene ontology clusters involved in neuronal plasticity and other essential neuronal processes were overrepresented among the genes harboring a GBS or located in the vicinity of a GBS.


Input: Male adrenalectomized rats were challenged with increasing doses of the GR agonist corticosterone (CORT) ranging from 3 to 3000 mu g/kg, resulting in clear differences in the GR-binding profile to individual GBS.

corticosterone

CORT


Input: Two groups of GBS could be distinguished: a low-CORT group that displayed GR binding across the full range of CORT concentrations, and a second high-CORT group that displayed significant GR binding only after administering the highest concentration of CORT.

CORT

CORT

CORT

CORT


Input: All validated GBS, in both the low-CORT and high-CORT groups, displayed mineralocorticoid receptor binding, which remained relatively constant from 30 mu g/kg CORT upward.

CORT

CORT

CORT


Input: Motif analysis revealed that almost all GBS contained a glucocorticoid response element resembling the consensus motif in literature.


Input: In addition, motifs corresponding with new potential GR-interacting proteins were identified, such as zinc finger and BTB domain containing 3 (Zbtb3) and CUP (CG11181 gene product from transcript CG11181-RB), which may be involved in GR-dependent transactivation and transrepression, respectively.

zinc


Input: In conclusion, our results highlight the existence of 2 populations of GBS in the rat hippocampal genome.


Input: State-Dependent Etomidate Occupancy of its Allosteric Agonist Sites Measured in a Cysteine-Substituted GABAA Receptor.

Cysteine


Input: A central axiom of ligand-receptor theory is that agonists bind more tightly to active than to inactive receptors.


Input: However, measuring agonist affinity in inactive receptors is confounded by concomitant activation.


Input: We identified a cysteine substituted mutant GABAA receptor with unique characteristics allowing determination of allosteric agonist site occupancy in both inactive and active receptors.

cysteine


Input: Etomidate, the allosteric agonist, is an anesthetic that activates/modulates alpha 1 beta 2 gamma 2L GABAA receptors via transmembrane sites near beta 2M286 residues in M3 domains.

Etomidate


Input: Voltage-clamp electrophysiology studies of alpha 1 beta 2M286C gamma 2L receptors show that GABA is an efficacious agonist, and etomidate modulates GABA-activated activity, but direct etomidate agonism is absent.

GABA

etomidate

GABA

etomidate


Input: Quantitative analysis of mutant activity using an established Monod-Wyman-Changeux (MWC) allosteric model indicates that the intrinsic efficacy of etomidate, defined as its relative affinity for active vs. inactive receptors, is lower than in wild-type receptors.

etomidate


Input: Para-chloromercuribenzene sulfonate (pCMBS) covalently modifies beta 2M286C sidechain sulfhydryls, irreversibly altering GABA-induced currents.

Para-chloromercuribenzene sulfonate

pCMBS

sulfhydryls

GABA


Input: Etomidate concentration-dependently reduces the apparent rate of beta 2M286C-pCMBS bond formation, tracked electrophysiologically.

Etomidate


Input: High etomidate concentrations completely protect the beta 2M286C suflhydryl from covalent modification, suggesting close steric interactions.

etomidate

suflhydryl