Input: Synergistic GABA-Enhancing Therapy against Seizures in a Mouse Model of Dravet Syndrome.

GABA


Input: Seizures remain uncontrolled in 30% of patients with epilepsy, even with concurrent use of multiple drugs, and uncontrolled seizures result in increased morbidity and mortality.


Input: An extreme example is Dravet syndrome (DS), an infantile-onset severe epilepsy caused by heterozygous loss of function mutations in SCN1A, the gene encoding the brain type-I voltage-gated sodium channel NaV1. 1.

sodium


Input: Studies in Scn1a heterozygous knockout mice demonstrate reduced excitability of GABAergic interneurons, suggesting that enhancement of GABA signaling may improve seizure control and comorbidities.

GABAergic


Input: We studied the efficacy of two GABA-enhancing drugs, clonazepam and tiagabine, alone and in combination, against thermally evoked myoclonic and generalized tonic-clonic seizures.

GABA

clonazepam

tiagabine


Input: Clonazepam, a positive allosteric modulator of GABA-A receptors, protected against myoclonic and generalized tonic-clonic seizures.

Clonazepam

GABA


Input: Tiagabine, a presynaptic GABA reuptake inhibitor, was protective against generalized tonic-clonic seizures but only minimally protective against myoclonic seizures and enhanced myoclonic seizure susceptibility at high doses.

Tiagabine

GABA


Input: Combined therapy with clonazepam and tiagabine was synergistic against generalized tonic-clonic seizures but was additive against myoclonic seizures.

clonazepam

tiagabine


Input: Toxicity determined by rotorod testing was additive for combination therapy.


Input: The synergistic actions of clonazepam and tiagabine gave enhanced seizure protection and reduced toxicity, suggesting that combination therapy may be well tolerated and effective for seizures in DS.

clonazepam

tiagabine


Input: Binding of glyco-acridine derivatives to lysozyme leads to inhibition of amyloid fibrillization.

acridine


Input: While amyloid-related diseases are at the center of intense research efforts, no feasible cure is currently available for these diseases.


Input: The experimental and computational techniques were used to study the ability of glyco-acridines to prevent lysozyme amyloid fibrillization in vitro.

acridines


Input: Fluorescence spectroscopy and atomic force microscopy have shown that glyco-acridines inhibit amyloid aggregation of lysozyme; the inhibition efficiency characterized by the half-maximal inhibition concentration IC50 was affected by the structure and concentration of the derivative.

acridines


Input: We next investigated relationship between the binding affinity and the inhibitory activity of the compounds.


Input: The semiempirical quantum PM6-DH + method provided a good correlation pointing to the importance of quantum effects on the binding of glyco-acridine derivatives to lysozyme.

acridine


Input: The contribution of linkers may be explained by the valence bond theory.


Input: Our data provide a basis for the development of new small molecule inhibitors effective in therapy of amyloid-related diseases.


Input: Small-molecule inhibitors/modulators of amyloid-beta peptide aggregation and toxicity for the treatment of Alzheimer' s disease: a patent review (2010-2012).


Input: Introduction: Genetic, physiological, and biochemical data indicate that agglomerates of the 42-amino acid form of the amyloid-beta (A beta 42) peptide are strongly linked to Alzheimer' s disease (AD) etiology and thus represent a particularly attractive target for the development of an effective disease-modifying approach for AD treatment.


Input: A plethora of chemical entities able to modulate A beta 42 self-assembly have been developed in recent years, among them, several are in clinical or preclinical development.


Input: Areas covered: This review accounts for small-molecule inhibitors of A beta peptide polymerization and toxicity, reported in the patent literature during the 2010-2012 period, and their potential use as disease-modifying therapeutics for AD cure.


Input: Expert opinion: The earliest pathogenic event is the formation of soluble A beta oligomers that disrupt synaptic communication.


Input: Drug design strategies targeting these primary toxic agents could hold considerable promises for obtaining effective anti-AD drugs candidate.


Input: The heterogeneous aggregation of A beta and the resulting difficulty to structurally characterize the peptide represent important drawbacks.


Input: Essential oil composition and antibacterial activity of the different parts of Thymus maroccanus Ball: an endemic species in Morocco (+).


Input: Three essential oils from three samples: stems, leaves and inflorescences of Thymus maroccanus Ball, obtained by hydrodistillation, were analysed by gas chromatography and gas chromatography coupled to mass spectrometry.


Input: The oils of stems, leaves and inflorescences afforded 68, 49 and 51 constituents, respectively.


Input: Quantitative and qualitative differences have been found between the analysed parts.


Input: The most abundant components in the stems oil included carvacrol (60. 8%), alpha-terpineol (4. 7%) and p-cymene (2. 4%), while carvacrol (33%), p-cymene (25. 3%) and alpha-pinene (11. 6%) were the main components in the leaves.

carvacrol

alpha-terpineol

p-cymene

carvacrol

p-cymene

alpha-pinene


Input: In the inflorescences, carvacrol (84. 9%) is the major component.

carvacrol


Input: Antibacterial activity of the T. maroccanus Ball leaves oil was tested against eight Gram-positive and Gram-negative bacteria by the disc diffusion method.


Input: The values of inhibition zones for bacterial strains, which were sensitive to the essential oil of T. maroccanus leaves, were in the range of 11-43 mm.


Input: Quantum mechanics/molecular mechanics modeling of fatty acid amide hydrolase reactivation distinguishes substrate from irreversible covalent inhibitors.

fatty acid amide


Input: Carbamate and urea derivatives are important classes of fatty acid amide hydrolase (FAAH) inhibitors that carbamoylate the active-site nucleophile Ser241.

Carbamate

urea

fatty acid amide

carbamoylate


Input: In the present work, the reactivation mechanism of carbamoylated FAAH is investigated by means of a quantum mechanics/molecular mechanics (QM/MM) approach.


Input: The potential energy surfaces for decarbamoylation of FAAH covalent adducts, derived from the O-aryl carbamate URB597 and from the N-piperazinylurea JNJ1661610, were calculated and compared to that for deacylation of FAAH acylated by the substrate oleamide.

O

N

oleamide


Input: Calculations show that a carbamic group bound to Ser241 prevents efficient stabilization of transition states of hydrolysis, leading to large increments in the activation barrier.

carbamic


Input: Moreover, the energy barrier for the piperazine carboxylate was significantly lower than that for the cyclohexyl carbamate derived from URB597.

piperazine carboxylate

cyclohexyl carbamate


Input: This is consistent with experimental data showing slowly reversible FAAH inhibition for the N-piperazinylurea inhibitor and irreversible inhibition for URB597.

N-piperazinylurea


Input: Conference Report: Bioanalysis-related topics presented at the International Conference and Exhibition on Biowaivers and Biosimilars.


Input: This conference of approximately 30 professionals attracted a diverse group of attendees, whose expertise spanned the broad topics of development, production, testing and regulation of biosimilars.


Input: The topics covered during this meeting were varied in scope due to the breadth of knowledge of the attendees.


Input: Topics of discussion included: biowaivers for small molecules; patent law and interpretation of the Biologics Price Competition and Innovation Act; analytical tools for the characterization of a biosimilar; novel production methods; bioanalytical methods; immunogenicity considerations; formulation techniques; and the characterization of the glycosylation of biosimilars.


Input: Gel electrophoretic methods for the analysis of biosimilar pharmaceuticals using the example of recombinant erythropoietin.


Input: Due to their versatility and cost-effectiveness, gel electrophoretic methods provide an important set of tools for the analysis of therapeutic proteins.


Input: As an increasing number of biosimilar pharmaceuticals are entering the market, techniques are required that allow reliable demonstration of comparability of these products with the reference products.


Input: Isoelectric focusing, SDS-PAGE, native PAGE and 2D electrophoresis (2D-PAGE) have been frequently applied for this purpose.

SDS


Input: Supplementary techniques are fluorophore-assisted carbohydrate electrophoresis and sarcosyl-PAGE.

carbohydrate

sarcosyl


Input: Of additional importance is the comparison of recombinant with endogenously synthesized glycoproteins.


Input: Reagent array analysis combined with SDS-PAGE and western blotting proved especially useful for this purpose.

SDS


Input: As an example for the application of these methods, the analysis of recombinant originator erythropoietins and some of their biosimilar counterparts is described.


Input: Silver-zwitterion organic-inorganic nanocomposite with antimicrobial and antiadhesive capabilities.

Silver


Input: In this work, we demonstrate a convenient, efficient, and environmentally benign strategy to achieving antimicrobial and antiadhesive purposes using a silver-zwitterion nanocomposite.

silver


Input: The synthesis of the nanocomposite relies on loading zwitterionic polymer brushes with Ag (+) precursor ions, followed by their in situ reduction to Ag nanoparticle by ultraviolet (UV) irradiation.

Ag (+)

Ag


Input: Both poly (sulfobetaine methacrylate) (pSBMA) and poly (carboxybetaine methacrylate) (pCBMA) have been studied as matrices for the embedding of silver.

poly (sulfobetaine methacrylate)

pSBMA

poly (carboxybetaine methacrylate)

pCBMA

silver


Input: Well-dispersed silver nanoparticles are embedded into pCBMA matrices.

silver

pCBMA


Input: The obtained pCBMA-silver hybrid (CB-Ag) is capable of killing bacteria upon contact and releasing dead bacteria under wet conditions.

pCBMA

silver

Ag


Input: Results suggest the feasibility of using this nanocomposite system as a robust and reliable antimicrobial and antiadhesive platform for the prevention of microbial colonization.


Input: Synthesis, in vitro antiplatelet activity and molecular modelling studies of 10-substituted 2-(1-piperazinyl) pyrimido [1, 2-a] benzimidazol-4 (10H)-ones.

10-substituted 2-(1-piperazinyl) pyrimido [1, 2-a] benzimidazol-4 (10H)-ones


Input: The multistep preparation of the new 10-substituted 2-(1-piperazinyl) pyrimido [1, 2-a] benzimidazol-4 (10H)-ones 6a-o, and of the two isomers 10-ethyl-2-(diethylamino) pyrimido [1, 2-a] benzimidazol-4 (10H)-one 6p and 10-ethyl-4-(diethylamino) pyrimido [1, 2-a] benzimidazol-2 (10H)-one 13, as well as the in vitro evaluation of their inhibitory activity on human platelet aggregation induced in platelet-rich plasma by ADP, collagen or the Ca (2 +) ionophore A23187 were here described.

10-substituted 2-(1-piperazinyl) pyrimido [1, 2-a] benzimidazol-4 (10H)-ones

10-ethyl-2-(diethylamino) pyrimido [1, 2-a] benzimidazol-4 (10H)-one

10-ethyl-4-(diethylamino) pyrimido [1, 2-a] benzimidazol-2 (10H)-one

ADP

Ca (2 +)


Input: Nine out of fifteen 2-(1-piperazinyl) derivatives (6g-o) showed good inhibitory properties towards all the platelet aggregation agonists used.


Input: Moreover, a molecular modelling study has been performed on two of the best compounds of this series (6i and 6o) to confirm in silico their interactions with the catalytic site of human platelet PDE3, using the X-ray data of the PDE3B isoform in complex with an inhibitor.


Input: Synthesis and biological evaluation of novel pyranochalcone derivatives as a new class of microtubule stabilizing agents.

pyranochalcone


Input: Twenty-five novel pyranochalcone derivatives were synthesized and evaluated for their in vitro and in vivo antiproliferative activities.

pyranochalcone


Input: Among them, compound 10i exhibited superior potent activity against 21 tumor cell lines including multidrug resistant phenotype with the IC50 values ranged from 0. 09 to 1. 30 mu M.


Input: In addition, 10i significantly induced cell cycle arrest in G2/M phase, promoted tubulin polymerization into microtubules and caused microtubule stabilization.


Input: Further studies confirmed that 10i significantly suppressed the growth of tumor volume in HepG2 xenograft tumor model.


Input: Our study demonstrated that 10i could have beneficial antitumor activity as a novel microtubule stabilizing agent.


Input: Improved excitation uniformity in multiple-quantum NMR experiments of mixtures.


Input: Multiple-quantum (1) H NMR spectroscopy has been finding a renewed interest for its possible applications in the analysis of mixtures of small molecules, due to its simplification properties.

(1) H


Input: A crucial aspect of this application of multiple-quantum NMR is the sensitivity of the spectrum intensity to the molecular structure and to the parameterization of the experiment, which could result in the missing of some components.


Input: We demonstrate that a general scheme to overcome this drawback consists in varying the experiment parameterizations over a small number of values, selected according the values of the couplings and the relaxation rates.


Input: Experimental models of disseminated scedosporiosis with cerebral involvement.


Input: Scedosporium apiospermum is a soil fungus which can cause severe and often fatal cerebral infections in both immunocompetent patients in the event of near drowning and immunosuppressed patients such as lung transplant recipients.


Input: Because of the low susceptibility of this fungus to antifungal drugs, and the low permeability of the blood-brain barrier (BBB), therapeutic drug monitoring is necessary to reach an effective tissue concentration with limited side effects.


Input: Indeed, diffusion of the drug in the brain is dependent on several parameters, such as the integrity of the BBB and the activity of efflux pumps.


Input: To evaluate drug diffusion, two experimental models were developed in immunocompetent and immunosuppressed rats.


Input: Inocula were administered via the penile vein and a clinical scale (0-9) was established, based on weight and clinical and neurologic signs evaluated by the tail suspension test.


Input: Cerebral involvement was confirmed by magnetic resonance imaging and histologic examination of brain sections after hematoxylin-eosin-safran or silver staining.

hematoxylin

eosin

silver


Input: Voriconazole or posaconazole was given to the rats at doses ranging from 10 to 75 mg/kg/day via i. v. or oral routes, respectively.

Voriconazole

posaconazole


Input: Whatever the immune status, the effective doses (defined by a doubling of the survival time and the absence of neurologic sequelae) were 30 mg/kg/day for voriconazole and 50 mg/kg/day for posaconazole.

voriconazole

posaconazole


Input: Overall, the results demonstrated that these models may constitute valuable tools for the performance of pharmacokinetic and pharmacodynamic studies for pharmacokinetic-pharmacodynamic modeling.


Input: Modeling toxic stress by atrazine in a marine consumer-resource system.

atrazine


Input: The present study combines short-term experiments with food chain modeling to explore the long-term effects of the herbicide atrazine on consumer-resource dynamics in a marine intertidal ecosystem.

atrazine


Input: Short-term (28 d) lab experiments indicated that the intrinsic rate of increase (r) and carrying capacity (K) of the marine diatom Seminavis robusta decreased with increasing atrazine exposure.

atrazine


Input: This decrease did not show the concave shape expected from the lifetime productivity for nonexposed diatoms and from single-species toxicity data in the literature but instead was described best by a linear model.


Input: These experimentally observed atrazine-induced decreases of r and K were used to parameterize a Rosenzweig-MacArthur model representing a simple food chain including the tested diatom and its grazer, the harpacticoid copepod Delavalia palustris var. palustris.

atrazine


Input: Stable oscillation zoo-phytobenthos systems were produced at diatom exposures of 0, 100, and 150 micro g/L atrazine.

atrazine


Input: An atrazine concentration of 150 micro g/L contributed to a 15% increase of the oscillation periods of both diatoms and copepods as well as a 52% reduction of oscillation amplitudes compared with the control situation.

atrazine


Input: Although the amplitudes of copepods increased only 7% at 150 micro g/L atrazine, the maximum and minimum copepod densities at that concentration were reduced 61 and 63%, respectively.

atrazine


Input: The effects of atrazine on periodicity and amplitudes were robust to 20% changes in the food-chain model parameters that represented allometric relationships.

atrazine


Input: The simulations in the present study suggest food chain-mediated indirect effects on zoobenthos populations, indicating a reduced diatom and copepod availability throughout the year.


Input: Environ.


Input: Toxicol.


Input: Chem.


Input: 2013; 32: 1088-1095.


Input: (c) 2013 SETAC.


Input: KBP-cytoskeleton interactions underlie developmental anomalies in Goldberg-Shprintzen syndrome.


Input: Goldberg-Shprintzen syndrome (GOSHS, MIM #609460) is an autosomal recessive disorder of intellectual disability, specific facial gestalt and Hirschsprung' s disease (HSCR).


Input: In 2005, homozygosity mapping in a large consanguineous family identified KIAA1279 as the disease-causing gene.


Input: KIAA1279 encodes KIF-binding protein (KBP), whose function is incompletely understood.


Input: Studies have identified either the mitochondria or the cytoskeleton as the site of KBP localization and interactions.


Input: To better delineate the KIAA1279-related clinical spectrum and the molecular mechanisms involved in GOSHS, we studied five new patients from three different families.


Input: The homozygous KIAA1279 mutations in these patients (p. Arg90X, p. Ser200X or p. Arg202IlefsX2) led to nonsense-mediated mRNA decay and loss of KBP function.


Input: Despite the absence of functional KBP, respiratory chain complex activity in patient fibroblasts was normal.


Input: KBP did not co-localize with mitochondria in control human fibroblasts, but interacted with the actin and tubulin cytoskeleton.


Input: KBP expression directly affected neurite growth in a neuron-like cell line (human neuroblastoma SH-SY5Y), in keeping with the central (polymicrogyria) and enteric (HSCR) neuronal developmental defects seen in GOSHS patients.


Input: The KBP interactions with actin filaments and microtubules (MTs) demonstrated in our study constitute the first evidence that an actin MT cross-link protein is involved in neuronal development in humans.


Input: The effects of the phosphodiesterase type 5 inhibitor vardenafil on cognitive performance in healthy adults: a behavioral-electroencephalography study.

vardenafil


Input: Phosphodiesterase type 5 inhibitors (PDE5-Is) improve cognitive performance of rodents, but the few human studies investigating their effects did not systematically investigate cognitive effects and the results have been quite contradictory.


Input: Therefore, we examined whether the PDE5-I vardenafil improves memory and executive functioning and affect electroencephalography (EEG) in healthy young adults.

vardenafil


Input: Participants were selected out of a group of volunteers, based on their performance on a memory screening and they were orally treated with vardenafil (10-20 mg or placebo).

vardenafil


Input: Memory and executive functioning were tested while EEG activity was recorded.


Input: Additionally, a simple reaction time task and questionnaires addressing various complaints were presented.


Input: No prominent effects of vardenafil on cognition were found: participants only made more mistakes on a reaction time task after 20 mg vardenafil.

vardenafil

vardenafil


Input: During encoding of words, the P300 was generally smaller after vardenafil treatment.

vardenafil


Input: Furthermore, the N400 was larger after vardenafil 10 mg than placebo treatment in a spatial memory task at Fz.

vardenafil


Input: Finally, headache and feeling weak were reported more after vardenafil treatment.

vardenafil


Input: Vardenafil did not affect cognitive performance of healthy adults and showed only some incidental effects on ERPs.

Vardenafil


Input: These findings in humans do not corroborate the cognition-enhancing effects of PDE5-Is in healthy animals.


Input: Comparison of the anti-dopamine D2 and anti-serotonin 5-HT2A activities of chlorpromazine, bromperidol, haloperidol and second-generation antipsychotics parent compounds and metabolites thereof.

dopamine

serotonin

chlorpromazine

bromperidol

haloperidol


Input: Second-generation antipsychotics, which have become the standard drug therapies for schizophrenia, are known to have a serotonin 5-HT2A receptor blocking effect in addition to a dopamine D2 receptor blocking effect.

serotonin

dopamine


Input: However, although chlorpromazine (CPZ) has a 5-HT2A receptor blocking effect and has the profile of a second-generation antipsychotic in vitro, it loses this pharmacological profile in vivo.

chlorpromazine

CPZ


Input: In order to elucidate the differences between the in vivo and in vitro pharmacological characteristics of CPZ, we used a radioreceptor assay to measure the anti-D2 activity and the anti-5-HT2A activity of CPZ and five major metabolites of CPZ, and compared the results to the anti-D2 activity and anti-5-HT2A activity of risperidone, zotepine, perospirone, the major metabolites of each of these drugs, and olanzapine, bromperidol, and haloperidol.

CPZ

CPZ

CPZ

risperidone

zotepine

perospirone

olanzapine

bromperidol

haloperidol


Input: The subjects were 182 patients who had received diagnoses of schizophrenia based on the DSM-IV criteria.


Input: The results revealed that CPZ exhibited little anti-5-HT2A activity, regardless of the anti-D2 activity level, and that none of the metabolites possessed anti-5-HT2A activity.

CPZ


Input: However, both the parent compounds and the metabolites of each of the second-generation antipsychotics possessed both anti-D2 activity and anti-5-HT2A activity.


Input: This clarified that, unlike second-generation antipsychotics, the reason CPZ loses its second-generation antipsychotic profiles in vivo is because it does not have any metabolites that possess anti-5-HT2A activity.

CPZ


Input: Vapor-solid growth of high optical quality MoS 2 monolayers with near-unity valley polarization.

MoS 2


Input: Monolayers of transition metal dichalcogenides (TMDCs) are atomically thin direct-gap semiconductors with potential applications in nanoelectronics, optoelectronics, and electrochemical sensing.

transition metal dichalcogenides

TMDCs


Input: Recent theoretical and experimental efforts suggest that they are ideal systems for exploiting the valley degrees of freedom of Bloch electrons.


Input: For example, Dirac valley polarization has been demonstrated in mechanically exfoliated monolayer MoS2 samples by polarization-resolved photoluminescence, although polarization has rarely been seen at room temperature.


Input: Here we report a new method for synthesizing high optical quality monolayer MoS2 single crystals up to 25 mu m in size on a variety of standard insulating substrates (SiO2, sapphire, and glass) using a catalyst-free vapor-solid growth mechanism.

sapphire


Input: The technique is simple and reliable, and the optical quality of the crystals is extremely high, as demonstrated by the fact that the valley polarization approaches unity at 30 K and persists at 35% even at room temperature, suggesting a virtual absence of defects.


Input: This will allow greatly improved optoelectronic TMDC monolayer devices to be fabricated and studied routinely.

TMDC


Input: 2-Arylpyrazolo [4, 3-d] pyrimidin-7-amino derivatives as new potent and selective human A3 Adenosine receptor antagonists.

2-Arylpyrazolo [4, 3-d] pyrimidin-7-amino

Adenosine


Input: Molecular modeling studies and pharmacological evaluation.


Input: On the basis of our previously reported 2-arylpyrazolo [4, 3-d] pyrimidin-7-ones, a set of 2-arylpyrazolo [4, 3-d] pyrimidin-7-amines were designed as new human (h) A3 adenosine receptor (AR) antagonists.

2-arylpyrazolo [4, 3-d] pyrimidin-7-ones

2-arylpyrazolo [4, 3-d] pyrimidin-7-amines

adenosine


Input: Lipophilic groups with different steric bulk were introduced at the 5-position of the bicyclic scaffold (R5 = Me, Ph, CH2Ph), and different acyl and carbamoyl moieties (R7) were appended on the 7-amino group, as well as a para-methoxy group inserted on the 2-phenyl ring.

Me

Ph

acyl

carbamoyl

para-methoxy


Input: The presence of acyl groups turned out to be of paramount importance for an efficient and selective binding at the hA3 AR.

acyl


Input: In fact, most of the 7-acylamino derivatives showed low nanomolar affinity (Ki = 2. 5-45 nM) and high selectivity toward this receptor.


Input: A few selected pyrazolo [4, 3-d] pyrimidin-7-amides were effective in counteracting oxaliplatin-induced apoptosis in rat astrocyte cell cultures, an in vitro model of neurotoxicity.

pyrazolo [4, 3-d] pyrimidin-7-amides

oxaliplatin


Input: Through an in silico receptor-driven approach the obtained binding data were rationalized and the molecular bases of the observed hA3 AR affinity and hA3 versus hA2A AR selectivity were explained.


Input: Absolute Configurations of Fungal and Plant Metabolites by Chiroptical Methods.


Input: ORD, ECD, and VCD Studies on Phyllostin, Scytolide, and Oxysporone.

Phyllostin

Scytolide

Oxysporone


Input: The absolute configuration (AC) of the bioactive metabolites phyllostin (1) and scytolide (2), two hexahydro-1, 4-benzodioxines produced by Phyllosticta cirsii, and oxysporone (3), a dihydrofuropyranone recently isolated from a strain of Diplodia africana, has been assigned by computational analysis of their optical rotatory dispersion (ORD), electronic circular dichroism (ECD), and vibrational circular dichroism (VCD) spectra.

phyllostin

scytolide

hexahydro-1, 4-benzodioxines

oxysporone

dihydrofuropyranone


Input: Computational prediction of ORD, ECD, and VCD allowed us to assign (3S, 4aR, 8S, 8aR) AC to naturally occurring (-)-1, while (4aR, 8S, 8aR) AC was assigned to (-)-2 employing only ECD and VCD, because in this case ORD analysis turned out to be unsuitable for AC assignment.


Input: Theoretical prediction of both ORD and ECD spectra of 3 led to assignment of (4S, 5R, 6R) AC to (+)-3.


Input: In this case a satisfactory agreement between experimental and calculated VCD spectra was obtained only after taking into account solvent effects.


Input: This study shows that in the case of flexible and complex natural products only a concerted application of more than a single chiroptical technique permits unambiguous assignment of absolute configuration.


Input: Generalized indirect Fourier transformation as a valuable tool for the structural characterization of aqueous nanocrystalline cellulose suspensions by small angle X-ray scattering.


Input: Small angle X-ray scattering (SAXS) is employed to characterize the inner structure and shape of aqueous nanocrystalline cellulose suspensions using the generalized indirect Fourier transformation (GIFT).


Input: The use of the GIFT approach provides a single fitting procedure for the determination of intra-and interparticle interactions due to a simultaneous treatment of the form factor P (q) and the structure factor S (q).


Input: Moreover, GIFT allows for the determination of particle charges and polydispersity indices.


Input: As test material, aqueous nanocrystalline cellulose suspensions (aNCS) prepared by the H2SO4 route have been investigated and characterized (SAXS, dynamic light scattering, zeta potential).


Input: Evaluation of difluoromethyl ketones as agonists of the gamma-aminobutyric acid type B (GABAB) receptor.

difluoromethyl ketones

gamma-aminobutyric acid


Input: The design, synthesis, biological evaluation, and in vivo studies of difluoromethyl ketones as GABAB agonists that are not structurally analogous to known GABAB agonists, such as baclofen or 3-aminopropyl phosphinic acid, are presented.

difluoromethyl ketones

baclofen

3-aminopropyl phosphinic acid


Input: The difluoromethyl ketones were assembled in three synthetic steps using a trifluoroacetate-release aldol reaction.

difluoromethyl ketones

trifluoroacetate


Input: Following evaluation at clinically relevant GABA receptors, we have identified a difluoromethyl ketone that is a potent GABAB agonist, obtained its X-ray structure, and presented preliminary in vivo data in alcohol-preferring mice.

GABA

difluoromethyl ketone

alcohol


Input: The behavioral studies in mice demonstrated that this compound tended to reduce the acoustic startle response, which is consistent with an anxiolytic profile.


Input: Structure-activity investigations determined that replacing the fluorines of the difluoromethyl ketone with hydrogens resulted in an inactive analogue.

fluorines

difluoromethyl ketone

hydrogens


Input: Resolution of the individual enantiomers of the difluoromethyl ketone provided a compound with full biological activity at concentrations less than an order of magnitude greater than the pharmaceutical, baclofen.

difluoromethyl ketone

baclofen


Input: Platinum-modulated cobalt nanocatalysts for low-temperature aqueous-phase Fischer-Tropsch synthesis.

Platinum

cobalt


Input: Fischer-Tropsch synthesis (FTS) is an important catalytic process for liquid fuel generation, which converts coal/shale gas/biomass-derived syngas (a mixture of CO and H2) to oil.

CO


Input: While FTS is thermodynamically favored at low temperature, it is desirable to develop a new catalytic system that could allow working at a relatively low reaction temperature.


Input: In this article, we present a one-step hydrogenation-reduction route for the synthesis of Pt-Co nanoparticles (NPs) which were found to be excellent catalysts for aqueous-phase FTS at 433 K.

Pt-Co


Input: Coupling with atomic-resolution scanning transmission electron microscopy (STEM) and theoretical calculations, the outstanding activity is rationalized by the formation of Co overlayer structures on Pt NPs or Pt-Co alloy NPs.

Coupling

Pt

Pt-Co


Input: The improved energetics and kinetics from the change of the transition states imposed by the lattice mismatch between the two metals are concluded to be the key factors responsible for the dramatically improved FTS performance.


Input: Hyperthyroidism causes cardiac dysfunction by mitochondrial impairment and energy depletion.


Input: This study elucidates the role of metabolic remodeling in cardiac dysfunction induced by hyperthyroidism.


Input: Cardiac hypertrophy, structural remodeling, and expression of the genes associated with fatty acid metabolism were examined in rats treated with triiodothyronine (T3) alone (8 mu g/100 g body weight (BW), i. p.) for 15 days or along with a peroxisome proliferator-activated receptor alpha agonist bezafibrate (Bzf; 30 mu g/100 g BW, oral) and were found to improve in the Bzf co-treated condition.

fatty acid

triiodothyronine

bezafibrate

Bzf

Bzf


Input: Ultrastructure of mitochondria was damaged in T3-treated rat heart, which was prevented by Bzf co-administration.

Bzf


Input: Hyperthyroidism-induced oxidative stress, reduction in cytochrome c oxidase activity, and myocardial ATP concentration were also significantly checked by Bzf.

ATP

Bzf


Input: Heart function studied at different time points during the course of T3 treatment shows an initial improvement and then a gradual but progressive decline with time, which is prevented by Bzf co-treatment.

Bzf


Input: In summary, the results demonstrate that hyperthyroidism inflicts structural and functional damage to mitochondria, leading to energy depletion and cardiac dysfunction.


Input: Cyclopia maculata and Cyclopia subternata (honeybush tea) inhibits adipogenesis in 3T3-L1 pre-adipocytes.


Input: The stems, leaves and flowers of Cyclopia have been consumed as a herbal tea' honeybush tea' to treat various medical ailments since the 19th century.


Input: Plant polyphenols are reported to inhibit adipogenesis in cell and animal models of obesity.

polyphenols


Input: The aim of this study was to assess the effect of hot water extracts of two Cyclopia species, C. maculata and C. subternata on obesity in an in vitro model.


Input: The total polyphenol content of unfermented C. subternata, unfermented C. maculata and fermented C. maculata extracts was 25. 6, 22. 4 and 10. 8g GAE/100g, respectively.

polyphenol


Input: The major compounds present in the extracts were: the flavonoid, phloretin-3', 5'-di-C-glucoside in C. subternata, the xanthone, mangiferin in unfermented C. maculata and the flavanone, hesperidin in fermented C. maculata.

flavonoid

phloretin-3', 5'-di-C-glucoside

xanthone

mangiferin

flavanone


Input: All of the plant extracts inhibited intracellular triglyceride and fat accumulation, and decreased PPAR gamma 2 expression.

triglyceride


Input: The higher concentrations of unfermented C. maculata (800 and 1600 mu g/ml) and C. subternata (1600 mu g/ml) were cytotoxic in terms of decreased mitochondrial dehydrogenase activity.


Input: Both fermented and unfermented C. maculata, at concentrations greater than 100 mu g/ml, decreased cellular ATP content.

ATP


Input: Cyclopia maculata and C. subternata inhibit adipogenesis in vitro, suggesting their potential as anti-obesity agents.


Input: Unraveling the mode of action of an obesogen: Mechanistic analysis of the model obesogen tributyltin in the 3T3-L1 cell line.

tributyltin


Input: Obesogenic compounds are chemicals that have an influence on obesity development.


Input: This study was designed to unravel the molecular mechanisms of the model obesogen TBT, using microarray analysis in the 3T3-L1 in vitro system, and to evaluate the use of toxicogenomics for obesogen screening.

TBT


Input: The microarray results revealed enrichment of Gene Ontology terms involved in energy and fat metabolism after 10days of TBT exposure.

TBT


Input: Pathway analysis unveiled PPAR signalling pathway as the sole pathway significantly enriched after 1day and the most significantly enriched pathway after 10days of exposure.


Input: To our knowledge, this is the first study delivering an in depth mechanistic outline of the mode of action of TBT as an obesogen, combining effects on both cell physiological and gene expression level.

TBT


Input: Furthermore, our results show that combining transcriptomics with 3T3-L1 cells is a promising tool for screening of potential obesogenic compounds.


Input: The effects of cannabidiol on the antigen-induced contraction of airways smooth muscle in the guinea-pig.

cannabidiol


Input: (-)-Delta (9)-Tetrahydrocannabinol has been demonstrated to have beneficial effects in the airways, but its psychoactive effects preclude its therapeutic use for the treatment of airways diseases.

(-)-Delta (9)-Tetrahydrocannabinol


Input: In the present study we have investigated the effects of (-)-cannabidiol, a non-psychoactive component of cannabis for its actions on bronchial smooth muscle in vitro and in vivo.

(-)-cannabidiol


Input: Guinea-pig bronchial smooth muscle contractions induced by exogenously applied spasmogens were measured isometrically.


Input: In addition, contractile responses of bronchial smooth muscle from ovalbumin-sensitized guinea-pigs were investigated in the absence or presence of (-)-cannabidiol.

(-)-cannabidiol


Input: Furthermore, the effect of (-)-cannabidiol against ovalbumin-induced airway obstruction was investigated in vivo in ovalbumin-sensitized guinea-pigs.

(-)-cannabidiol


Input: (-)-Cannabidiol did not influence the bronchial smooth muscle contraction induced by carbachol, histamine or neurokinin A.

(-)-Cannabidiol

carbachol

histamine


Input: In contrast, (-)-cannabidiol inhibited anandamide-and virodhamine-induced responses of isolated bronchi.

(-)-cannabidiol

anandamide

virodhamine


Input: A fatty acid amide hydrolase inhibitor, phenylmethanesulfonyl fluoride reversed the inhibitory effect of (-)-cannabidiol on anandamide-induced contractions.

fatty acid amide

phenylmethanesulfonyl fluoride

(-)-cannabidiol

anandamide


Input: In addition, (-)-cannabidiol inhibited the contractile response of bronchi obtained from allergic guinea-pigs induced by ovalbumin.

(-)-cannabidiol


Input: In vivo, (-)-cannabidiol reduced ovalbumin-induced airway obstruction.

(-)-cannabidiol


Input: In conclusion, our results suggest that cannabidiol can influence antigen-induced airway smooth muscle tone suggesting that this molecule may have beneficial effects in the treatment of obstructive airway disorders.

cannabidiol


Input: Serial infusions of low-dose ketamine for major depression.

ketamine


Input: Background: Single infusions of ketamine have been used successfully to achieve improvement in depressed patients.

ketamine


Input: Side effects during the infusions have been common.


Input: It is not known whether serial infusions or lower infusion rates result in greater efficacy.


Input: Methods: Ten depressed patients were treated with twice weekly ketamine infusions of ketamine 0. 5 mg/kg administered over 100 min until either remission was achieved or four infusions were given.

ketamine

ketamine


Input: Side effects were assessed with the Young Mania Rating Scale (YMRS) and the Brief Psychiatric Rating Scale (BPRS).


Input: Patients were followed naturalistically at weekly intervals for four weeks after completion of the infusions.


Input: Results: Five of 10 patients achieved remission status.


Input: There were no significant increases on the BPRS or YMRS.


Input: Two of the remitting patients sustained their improvement throughout the four week follow-up period.


Input: Conclusions: Ketamine infusions at a lower rate than previously reported have demonstrated similar efficacy and excellent tolerability and may be more practically available for routine clinical care.

Ketamine


Input: Serial ketamine infusions appear to be more effective than a single infusion.

ketamine


Input: Further research to test relapse prevention strategies with continuation ketamine infusions is indicated.

ketamine


Input: Nephroprotective effect of calcium channel blockers against toxicity of lead exposure in mice.

calcium


Input: Exposure to lead (Pb) can induce kidney damage, which is related to induction of oxidative damage and disturbance of intracellular calcium homeostasis.

Pb

calcium


Input: Pb can readily permeate through dihydropyridine-sensitive L-type calcium channels and accumulate within cells.

Pb

calcium


Input: The objective of this study was to investigate protective effects of calcium channel blockers (CCBs) verapamil and nimodipine on nephrotoxicity induced by Pb acetate in mice.

calcium

verapamil

nimodipine

Pb acetate


Input: One hundred and twenty male mice were randomly divided into 6 groups: control, Pb, low-dose verapamil, high-dose verapamil, low-dose nimodipine and high-dose nimodipine (n = 20 per group).

Pb

verapamil

verapamil

nimodipine

nimodipine


Input: Pb acetate was injected intraperitoneally (i. p.) at 40 mg/kg body weight/day for 10 days to establish the Pb toxicity model.

Pb acetate

Pb


Input: While control mice received saline, mice of the treated groups simultaneously received i. p. injections of verapamil or nimodipine daily for 10 days.

verapamil

nimodipine


Input: Both verapamil and nimodipine showed protection against Pb-induced kidney injury, including alleviation of renal pathological damage and decreasing the level of Pb in kidney homogenate and extent of apoptosis in nephrocytes.

verapamil

nimodipine

Pb

Pb


Input: Moreover, verapamil and nimodipine significantly down-regulated levels of blood urea nitrogen and creatinine in the serum.

verapamil

nimodipine

urea nitrogen

creatinine


Input: In addition, verapamil and nimodipine administration decreased malondialdehyde content and increased activities of super oxide dismutase activity and glutathione peroxidase in the kidney homogenate.

verapamil

nimodipine

malondialdehyde

super oxide

glutathione


Input: The findings in the present study implicate the therapeutic potential of CCBs for Pb-induced nephrotoxicity, which were at least partly due to the decrease of Pb uptake and inhibition of lipid peroxidation.

Pb

Pb


Input: What is Comet assay not telling us: AFLP reveals wider aspects of genotoxicity.


Input: DNA damage detected by genotoxicity biomarkers such as the Comet assay is not always a reliable indicator of the consequences that genotoxic agents can have on the genome integrity of the exposed organisms.


Input: Therefore, to reveal the existence of more permanent alterations of DNA structure after genotoxic stress, the RTG-2 rainbow trout cell line was exposed for 3days to benzo [a] pyrene (B [a] P, 0. 1-10 mu M) and ethyl methanesulfonate (EMS, 0. 1-1mM) followed by 3days of recovery period.

benzo [a] pyrene

B [a] P

ethyl methanesulfonate

EMS


Input: Primary DNA damage was evaluated by the Comet assay and DNA alterations were assessed using AFLP (amplified fragment length polymorphism).


Input: Qualitative and quantitative modifications in AFLP profiles were analyzed in order to detect genetic alterations arising from mutation events and/or DNA damage.


Input: Significant induction in DNA damage measured by the Comet assay was noticed after B [a] P treatment at all concentrations but values returned to the control level after recovery.

B [a] P


Input: Exposure to EMS induced significant DNA damage only at the highest concentration and damage persisted after the recovery period.


Input: AFLP profiles detected DNA alterations even when Comet assay indicated complete DNA repair, revealing more persistent damage.


Input: Since such DNA damage can impair its structure and function, Comet assay results should preferably be supplemented with other methods in order to predict the consequences of genotoxic insult more accurately.


Input: The sensitivity of the KeratinoSens ((TM)) assay to evaluate plant extracts: A pilot study.


Input: Several tests to assess skin sensitization hazard are in peer-review for pre-validation.


Input: These tests, as well as the animal tests they aim to replace, were developed (and validated) for the testing of pure substances.


Input: However, in the cosmetic field, active ingredients are often mixtures from natural sources.


Input: It is therefore important to understand which tests could be used to evaluate their safety.


Input: Here we describe a proof-of-concept study to test whether the KeratinoSens ((TM)) assay is able to detect sensitizing constituents within botanical mixtures.


Input: Four extracts were spiked with different doses of the sensitizers citral, cinnamic aldehyde and isoeugenol.

citral

cinnamic aldehyde

isoeugenol


Input: The tested extracts were negative in the test whereas they became positive in most cases when spiked with the sensitizers.


Input: Analysis of the results from the samples spiked with different doses allowed the determination of the minimal level of sensitizers being detectable.


Input: The contribution to sensitization potential of doses of 2% and above of the spiked sensitizers were reliably detected.


Input: There were limitations for an extract with high cytotoxicity, in which case detection of the artificially spiked sensitizers proved difficult.


Input: This study gives a proof of principle for testing of mixtures in the KeratinoSens ((TM)) assay and indicates how sensitive the assay is to detect minor components with sensitizing potential.


Input: Reversible effect of developmental exposure to chlorpyrifos on late-stage neurogenesis in the hippocampal dentate gyrus in mouse offspring.

chlorpyrifos


Input: The effect of developmental exposure to chlorpyrifos (CPF) on hippocampal neurogenesis was examined in male mice after maternal dietary exposure to CPF at 0, 4, 20, or 100ppm from gestation day 10 to postnatal day (PND) 21.

chlorpyrifos

CPF

CPF


Input: Cholinesterase activity was dose-dependently decreased in red blood cells at >= 4ppm and in the brain at 100ppm both in dams and offspring on PND 21.


Input: Immunohistochemically, doublecortin (+) cells were decreased at >= 20ppm in the subgranular zone (SGZ) of the dentate gyrus, and NeuN (+)-expressing mature neurons were decreased at 100ppm in the hilus on PND 21.


Input: There were no differences in the numbers of progenitor populations expressing Tbr2 or M1 muscarinic acetylcholine receptors.

acetylcholine


Input: Transcript levels of Dcx also decreased at >= 20ppm, and those of Pcna, Casp3, Bax, Bcl2, Pax6 and Tbr2 were unchanged in the dentate gyrus by real-time RT-PCR.


Input: At PND 77, hippocampal neurogenesis was unchanged.


Input: These results suggest that developmental CPF exposure directly but transiently suppresses maturation of late-stage granule cell lineages in the SGZ and affects interneuron populations in the hilus.

CPF


Input: The role of lipid domains in bacterial cell processes.


Input: Membranes are vital structures for cellular life forms.


Input: As thin, hydrophobic films, they provide a physical barrier separating the aqueous cytoplasm from the outside world or from the interiors of other cellular compartments.


Input: They maintain a selective permeability for the import and export of water-soluble compounds, enabling the living cell to maintain a stable chemical environment for biological processes.


Input: Cell membranes are primarily composed of two crucial substances, lipids and proteins.


Input: Bacterial membranes can sense environmental changes or communication signals from other cells and they support different cell processes, including cell division, differentiation, protein secretion and supplementary protein functions.


Input: The original fluid mosaic model of membrane structure has been recently revised because it has become apparent that domains of different lipid composition are present in both eukaryotic and prokaryotic cell membranes.


Input: In this review, we summarize different aspects of phospholipid domain formation in bacterial membranes, mainly in Gram-negative Escherichia coli and Gram-positive Bacillus subtilis.


Input: We describe the role of these lipid domains in membrane dynamics and the localization of specific proteins and protein complexes in relation to the regulation of cellular function.


Input: Intracellular localization of the BCL-2 family member BOK and functional implications.


Input: The pro-apoptotic BCL-2 family member BOK is widely expressed and resembles the multi-BH domain proteins BAX and BAK based on its amino acid sequence.

amino acid


Input: The genomic region encoding BOK was reported to be frequently deleted in human cancer and it has therefore been hypothesized that BOK functions as a tumor suppressor.


Input: However, little is known about the molecular functions of BOK.


Input: We show that enforced expression of BOK activates the intrinsic (mitochondrial) apoptotic pathway in BAX/BAK-proficient cells but fails to kill cells lacking both BAX and BAK or sensitize them to cytotoxic insults.


Input: Interestingly, major portions of endogenous BOK are localized to and partially inserted into the membranes of the Golgi apparatus as well as the endoplasmic reticulum (ER) and associated membranes.


Input: The C-terminal transmembrane domain of BOK thereby constitutes a' tail-anchor' specific for targeting to the Golgi and ER.

C


Input: Overexpression of full-length BOK causes early fragmentation of ER and Golgi compartments.


Input: A role for BOK on the Golgi apparatus and the ER is supported by an abnormal response of Bok-deficient cells to the Golgi/ER stressor brefeldin A.

brefeldin A


Input: Based on these results, we propose that major functions of BOK are exerted at the Golgi and ER membranes and that BOK induces apoptosis in a manner dependent on BAX and BAK.


Input: Cyclic stretch induces inducible nitric oxide synthase and soluble guanylate cyclase in pulmonary artery smooth muscle cells.

nitric oxide

guanylate


Input: In the pulmonary vasculature, mechanical forces such as cyclic stretch induce changes in vascular signaling, tone and remodeling.


Input: Nitric oxide is a potent regulator of soluble guanylate cyclase (sGC), which drives cGMP production, causing vasorelaxation.

Nitric oxide

guanylate

cGMP


Input: Pulmonary artery smooth muscle cells (PASMCs) express inducible nitric oxide synthase (iNOS), and while iNOS expression increases during late gestation, little is known about how cyclic stretch impacts this pathway.

nitric oxide


Input: In this study, PASMC were subjected to cyclic stretch of 20% amplitude and frequency of 1 Hz for 24 h and compared to control cells maintained under static conditions.


Input: Cyclic stretch significantly increased cytosolic oxidative stress as compared to static cells (62. 9 +/- 5. 9% vs. 33. 3 +/- 5. 7% maximal oxidation), as measured by the intracellular redox sensor roGFP.


Input: Cyclic stretch also increased sGC beta protein expression (2. 5 +/- 0. 9-fold), sGC activity (1. 5 +/- 0. 2-fold) and cGMP levels (1. 8 +/- 0. 2-fold), as well as iNOS mRNA and protein expression (3. 0 +/- 0. 9 and 2. 6 +/- 0. 7-fold, respectively) relative to control cells.

cGMP


Input: An antioxidant, recombinant human superoxide dismutase (rhSOD), significantly decreased stretch-induced cytosolic oxidative stress, but did not block stretch-induced sGC activity.

superoxide


Input: Inhibition of iNOS with 1400 W or an iNOS-specific siRNA inhibited stretch-induced sGC activity by 30% and 68% respectively vs. static controls.


Input: In conclusion, cyclic stretch increases sGC expression and activity in an iNOS-dependent manner in PASMC from fetal lambs.


Input: The mechanism that produces iNOS and sGC upregulation is not yet known, but we speculate these effects represent an early compensatory mechanism to counteract the effects of stretch-induced oxidative stress.


Input: A better understanding of the interplay between these two distinct pathways could provide key insights into future avenues to treat infants with pulmonary hypertension.


Input: A simple, rapid, low-cost diagnostic test for sickle cell disease.


Input: This communication describes a very simple, rapid and inexpensive point-of-care diagnostic test for sickle cell disease (SCD) that can conclusively differentiate between blood samples from normal healthy individuals, sickle cell trait carriers and SCD patients using the characteristic blood stain patterns produced by each sample on paper.


Input: Microfluidic oscillators with widely tunable periods.


Input: We present experiments and theory of a constant flow-driven microfluidic oscillator with widely tunable oscillation periods.


Input: This oscillator converts two constant input-flows from a syringe pump into an alternating, periodic output-flow with oscillation periods that can be adjusted to between 0. 3 s to 4. 1 h by tuning an external membrane capacitor.


Input: This capacitor allows multiple adjustable periods at a given input flow-rate, thus providing great flexibility in device operation.


Input: Also, we show that a sufficiently large external capacitance, relative to the internal capacitance of the microfluidic valve itself, is a critical requirement for oscillation.


Input: These widely tunable microfluidic oscillators are envisioned to be broadly useful for the study of biological rhythms, as on-chip timing sources for microfluidic logic circuits, and other applications that require variation in timed flow switching.


Input: The interfacial-organized monolayer water film (MWF) induced " two-step " aggregation of nanographene: both in stacking and sliding assembly pathways.

nanographene


Input: A computational investigation was carried out to understand the aggregation of nanoscale graphene with two typical pathways of stacking assembly and sliding assembly in water.

graphene


Input: The interfacial-organized monolayer water film (MWF) induced " two-step " aggregation of nanographene in both stacking and sliding assembly pathways was reported for the first time.

nanographene


Input: By means of potential mean forces (PMFs) calculation, no energy barrier was observed during the sliding assembly of two graphene nanosheets, while the PMF profiles could be impacted by the contact forms of nanographene and the MWF within the interplate of two graphene nanosheets.

graphene

nanographene

graphene


Input: To explore the potential physical basis of the " hindering role " of self-organized interfacial water, the dynamical and structural properties as well as the status of hydrogen bonds (H-bonds) for interfacial water were investigated.

hydrogen

H


Input: We found that the compact, ordered structure and abundant H-bonds of the MWF could be taken as the fundamental aspects of the " hindering role " of interfacial water for the hydrophobic assembly of nanographene.

H

nanographene


Input: These findings are displaying a potential to further understand the hydrophobic assembly which mostly dominate the behaviors of nanomaterials, proteins etc. in aqueous solutions.


Input: TCDD inhibition of canonical wnt signaling disrupts prostatic bud formation in mouse urogenital sinus.

TCDD


Input: In mice, in utero exposure to 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) reduces the number of dorsolateral prostatic buds resulting in a smaller dorsolateral prostate and prevents formation of ventral buds culminating in ventral prostate agenesis.

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

TCDD


Input: The genes and signaling pathways affected by TCDD that are responsible for disrupting prostate development are largely unknown.

TCDD


Input: Here we show that treatment of urogenital sinus (UGS) organ cultures with known inhibitors of canonical Wnt signaling also inhibits prostatic bud formation.


Input: In support of the hypothesis that TCDD decreases canonical Wnt signaling, we identify inhibitory effects of TCDD on multiple components of the canonical Wnt signaling pathway in the UGS that temporally coincide with the inhibitory effect of TCDD on prostatic bud formation: (1) expression of R-spondins (Rspo2 and Rspo3) that promote canonical Wnt signaling is reduced; (2) expression of Lef1, Tcf1, and Wif1, established canonical Wnt target genes, is decreased; (3) expression of Lgr5, a RSPO receptor that activates canonical Wnt signaling, is reduced; and (4) expression of Dickkopfs (Dkks), inhibitors of canonical Wnt signaling, is not increased by TCDD.

TCDD

TCDD

TCDD

TCDD


Input: Thus, the TCDD-induced reduction in canonical Wnt signaling is associated with a decrease in activators (Rspo2 and Rspo3) rather than an increase in inhibitors (Dkk1 and Dkk2) of the pathway.

TCDD


Input: This study focuses on determining whether treatment of TCDD-exposed UGS organ cultures with RSPO2 and/or RSPO3 is capable of rescuing the inhibitory effects of TCDD on canonical Wnt signaling and prostatic bud formation.

TCDD

TCDD


Input: We discovered that each RSPO alone or in combination partially rescues TCDD inhibition of both canonical Wnt signaling and prostatic bud formation.

TCDD


Input: Hypoxaemia affects male reproduction: a case study of how to differentiate between primary and secondary hypoxic testicular toxicity due to chemical exposure.


Input: Classification for fertility is based on two conditions, namely on evidence of an adverse effect on sexual function and fertility and that the effect is not secondary to other toxic effects.


Input: To decide on an adverse effect is a relatively simple day-to-day decision in toxicology but whether this effect is secondary often leads to serious controversy.


Input: As the seminiferous epithelium operates on the verge of hypoxia, oxygen deficit can lead to secondary impairment of testicular function.

oxygen


Input: This is well known from healthy mountaineers exposing themselves to high altitude.


Input: They have reduced blood oxygen content that goes in parallel with impairment of testicular function and this effect remains for some time in spite of a compensatory polycythaemia.

oxygen


Input: Similar findings are described for experimental animals exposed to hypobaric oxygen/high altitude.

oxygen


Input: In addition, testicular function is affected in severe diseases in humans associated with systemic oxygen deficit like chronic obstructive pulmonary disease, sickle cell disease or beta-thalassaemia as well as in transgenic animals simulating haemolytic anaemia or sickle cell disease.

oxygen


Input: The problem of insufficient oxygen supply as the underlying cause for testicular impairment has received relatively little attention in toxicology, mainly because blood oxygen content is generally not measured in these animal experiments.

oxygen

oxygen


Input: The difficulties associated with the decision whether testicular toxicity is primary or secondary to hypoxia are exemplified by the results of inhalation studies with nickel subsulphide and gallium arsenide (GaAs).

nickel subsulphide

gallium arsenide

GaAs


Input: Both of these particulate substances lead to severe lung toxicity that might impair oxygen uptake, but testicular toxicity is only observed with GaAs.

oxygen

GaAs


Input: This may first be explained by different effects on the blood: nickel subsulphide inhalation leads to a compensatory erythropoiesis that may mitigate pulmonary lack of oxygen uptake.

nickel subsulphide

oxygen


Input: In contrast, GaAs exposure is associated with microcytic haemolytic anaemia thereby aggravating any possible oxygen undersupply.

GaAs

oxygen


Input: Furthermore, the predominant pulmonary effect caused by GaAs (but not by nickel subsulphide) is alveolar proteinosis.

GaAs

nickel subsulphide


Input: Pulmonary alveolar proteinosis is also known as a severe disease in humans associated with hypoxaemia.


Input: Therefore, we conclude that the testicular effects observed after GaAs are secondary to hypoxaemia caused by the combination of pulmonary proteinosis and haemolytic anaemia.

GaAs


Input: This publication tries to raise awareness to the severe consequences of hypoxaemia on testicular function that may already be caused by reduced oxygen pressure at high altitude without any chemical exposure.

oxygen


Input: Exogenous sodium nitroprusside alleviates arsenic-induced oxidative stress in wheat (Triticum aestivum L.) seedlings by enhancing antioxidant defense and glyoxalase system.

sodium nitroprusside

arsenic


Input: The present study investigates the possible regulatory role of exogenous nitric oxide (NO) in mitigating oxidative stress in wheat seedlings exposed to arsenic (As).

nitric oxide

NO

arsenic

As


Input: Seedlings were treated with NO donor (0. 25 mM sodium nitroprusside, SNP) and As (0. 25 and 0. 5 mM Na2HAsO4. 7H2O) separately and/or in combination and grown for 72 h.

NO

sodium nitroprusside

SNP

As

Na2HAsO4. 7H2O


Input: Relative water content (RWC) and chlorophyll (chl) content were decreased by As treatment but proline (Pro) content was increased.

chlorophyll

chl

As

proline

Pro


Input: The ascorbate (AsA) content was decreased significantly with increased As concentration.

ascorbate

AsA

As


Input: The imposition of As caused marked increase in the MDA and H2O2 content.

As

MDA


Input: The amount of reduced glutathione (GSH) and glutathione disulfide (GSSG) significantly increased with an increase in the level of As (both 0. 25 and 0. 5 mM), while the GSH/GSSG ratio decreased at higher concentration (0. 5 mM).

glutathione

GSH

glutathione disulfide

GSSG

As

GSH

GSSG


Input: The ascorbate peroxidase and glutathione S-transferase activities consistently increased with an increase in the As concentration, while glutathione reductase (GR) activities increased only at 0. 25 mM.

ascorbate

glutathione S

As

glutathione


Input: The monodehydroascorbate reductase (MDHAR) and catalase (CAT) activities were not changed upon exposure to As.

monodehydroascorbate

As


Input: The activities of dehydroascorbate reductase (DHAR) and glyoxalase I (Gly I) decreased at any levels of As, while glutathione peroxidase (GPX) and glyoxalase II (Gly II) activities decreased only upon 0. 5 mM As.

dehydroascorbate

As

glutathione

As


Input: Exogenous NO alone had little influence on the non-enzymatic and enzymatic components compared to the control seedlings.

NO


Input: These inhibitory effects of As were markedly recovered by supplementation with SNP; that is, the treatment with SNP increased the RWC, chl and Pro contents; AsA and GSH contents and the GSH/GSSG ratio as well as the activities of MDHAR, DHAR, GR, GPX, CAT, Gly I and Gly II in the seedlings subjected to As stress.

As

SNP

SNP

chl

Pro

AsA

GSH

GSH

GSSG

As


Input: These results suggest that the exogenous application of NO rendered the plants more tolerant to As-induced oxidative damage by enhancing their antioxidant defense and glyoxalase system.

NO

As


Input: Design of an Escherichia coli Expressed HIV-1 gp120 Fragment Immunogen That Binds to b12 and Induces Broad and Potent Neutralizing Antibodies.


Input: b12, one of the few broadly neutralizing antibodies against HIV-1, binds to the CD4 binding site (CD4bs) on the gp120 subunit of HIV-1 Env.


Input: Two small fragments of HIV-1 gp120, b121a and b122a, which display about 70% of the b12 epitope and include solubility-enhancing mutations, were designed.


Input: Bacterially expressed b121a/b122a were partially folded and could bind b12 but not the CD4bs-directed non-neutralizing antibody b6.


Input: Sera from rabbits primed with b121a or b122a protein fragments and boosted with full-length gp120 showed broad neutralizing activity in a TZM-bl assay against a 16-virus panel that included nine Tier 2 and 3 viruses as well as in a five-virus panel previously designed to screen for broad neutralization.


Input: Using a mean IC50 cut-off of 50, sera from control rabbits immunized with gp120 alone neutralized only one virus of the 14 non-Tier 1 viruses tested (7%), whereas sera from b121a-and b122a-immunized rabbits neutralized seven (50%) and twelve (86%) viruses, respectively.


Input: Serum depletion studies confirmed that neutralization was gp120-directed and that sera from animals immunized with gp120 contained lower amounts of CD4bs-directed antibodies than corresponding sera from animals immunized with b121a/b122a.


Input: Competition binding assays with b12 also showed that b121a/2a sera contained significantly higher amounts of antibodies directed toward the CD4 binding site than the gp120 sera.


Input: The data demonstrate that it is possible to elicit broadly neutralizing sera against HIV-1 in small animals.


Input: Human Antigen R-mediated mRNA Stabilization Is Required for Ultraviolet B-induced Autoinduction of Amphiregulin in Keratinocytes.


Input: All members of the EGF family are produced as transmembrane precursors that are proteolytically processed into soluble forms by disintegrin and metalloproteinases (ADAMs) for autocrine/paracrine pathways.


Input: In turn, the ligand-activated EGF receptor (EGFR) induces the expression of EGF family members, so-called " autoinduction. " However, it is not well understood how this autoinduction occurs.


Input: In this study, we investigated the molecular mechanism of the autoinduction of amphiregulin (AREG), a member of the EGF family.


Input: We found that ultraviolet B (UVB) exposure increased the AREG mRNA level by stabilization of its mRNA in a human immortalized keratinocyte cell line, HaCaT.


Input: The 3' UTR of AREG mRNA was responsible for binding to an mRNA-binding protein, human antigen R (HuR), and the interaction between AREG mRNA and HuR was enhanced by UVB.


Input: Inducible knockdown of HuR expression significantly decreased AREG mRNA stability.


Input: Interestingly, treatment of HaCaT cells with an EGFR inhibitor, an EGFR neutralizing antibody, or an ADAM inhibitor destabilized AREG mRNA.


Input: In the case of ADAM inhibition, administration of soluble AREG restored the mRNA level, indicating that the stabilization occurs in a shedding-dependent manner of EGFR ligands.


Input: The HuR dependence of AREG mRNA and protein expression was also confirmed in human primary keratinocytes.


Input: Taken together, we propose a novel mechanism by which HuR regulates the stability of AREG mRNA in keratinocytes after UVB exposure and suggest that targeting of HuR functions might be crucial for understanding skin cancers caused by aberrant EGF family member-EGFR signaling.


Input: Bacterial infection probes and imaging strategies in clinical nuclear medicine and preclinical molecular imaging.


Input: At present, a limited number of strategies exist for diagnostic imaging of patients with bacterial infection.


Input: While radiolabeled probes and white blood cells provide robust solutions to detect bacteria in humans, they also give false positives in cases of sterile inflammation.


Input: With the onset of bacterial drug resistance, and a clinical trend toward reducing the prescription of antibiotics, the need for highly specific infection detection protocols has been renewed.


Input: The preclinical research community has recently utilized new optical imaging strategies, alongside traditional radioimaging research, to develop novel infection probes with translational potential.


Input: Here we review the current clinical methods for imaging bacteria in humans, and discuss the efforts within the preclinical community to validate new strategies.


Input: The review of preclinical infection imaging probes is limited to those probes that could be feasibly adapted for use in humans with currently available clinical modalities.


Input: Transient Receptor Potential (TRP) Channels and Cardiac Fibrosis.


Input: Cardiac fibrosis is associated with most cardiac diseases.


Input: Fibrosis is an accumulation of excessive extracellular matrix proteins (ECM) synthesized by cardiac fibroblasts and myofibroblasts.


Input: Fibroblasts are the most prevalent cell type in the heart, comprising 75% of cardiac cells.


Input: Myofibroblasts are hardly present in healthy normal heart tissue, but appear abundantly in diseased hearts.


Input: Cardiac fibroblasts are activated by a variety of pathological stimuli, such as myocardial injury, oxidative stress, mechanical stretch, and elevated autocrine-paracrine mediators, thereby undergoing proliferation, differentiation to myofibroblasts, and production of various cytokines and ECM proteins.


Input: A number of signaling pathways and bioactive molecules are involved and work in concert to activate fibroblasts and myofibroblasts in the fibrogenesis cascade.


Input: Fibroblasts and myofibroblasts are not only principal ECM producers, but also play a central role in fibrogenesis and myocardial remodeling in fibrotic heart disease.


Input: Thus, understanding the biological processes of cardiac fibroblasts will provide novel insights into the underlying mechanisms of fibrosis and provide potential targets for developing antifibrotic drugs.


Input: Recent studies demonstrate that Ca2 + signal is essential for fibroblast proliferation, differentiation, and ECM-protein production.

Ca2 +


Input: This review focuses on the recent advances in understanding molecular mechanisms of Ca2 + signaling in cardiac fibrogenesis, and potential role of Ca2 +-permeable channels, in particular, the transient potential (TRP) channels in fibrotic heart disease.

Ca2 +

Ca2 +


Input: TRP channels are highly expressed in cardiac fibroblasts.


Input: TRPM7 has been shown to be essential in TGF beta 1 mediated fibrogenesis, and TRPC3 has been demonstrated to play an essential role in regulating fibroblast function.


Input: Thus, the Ca2 +-permeable TRP channels may serve as potential novel targets for developing anti-fibrotic drugs.

Ca2 +


Input: TRP Channels in Vascular Disorders.


Input: In recent years, research on the roles of TRP channels in vascular function and disease has undergone a rapid expansion from tens of reports published in the early 2000s to several hundreds of papers published to date.


Input: Multiple TRP subtypes are expressed in vascular smooth muscle cells and endothelial cells, where they form diverse non-selective cation channels permeable to Ca2 +.

Ca2 +


Input: These channels mediate Ca2 + entry following receptor stimulation, Ca2 + store depletion and mechanical stimulation of vascular myocytes and endothelial cells.

Ca2 +

Ca2 +


Input: The complex molecular composition and signalling pathways leading to the activation of various vascular TRP channels and the growing evidence for their involvement in various vascular disorders, including dysregulation of vascular tone and hypertension, impaired endothelium-dependent vasodilatation, increased endothelial permeability, occlusive vascular disease, vascular injury and oxidative stress, are summarised and discussed in this review.


Input: Oncogenic and anti-oncogenic effects of transient receptor potential channels.


Input: Transient Receptor Potential (TRP) channels affect several inflammatory and neoplastic conditions.


Input: About thirty TRPs have been identified to date and divided into seven families: TRPC (Canonical), TRPV (Vanilloid), TRPM (Melastatin), TRPML (Mucolipin), TRPP (Polycystin), and TRPA (Ankyrin transmembrane protein) and TRPN (NomPClike).

Vanilloid


Input: Among these, the TRPC, TRPM, and TRPV families have been mainly correlated with malignant growth and progression.


Input: The aim of this review is to summarize data reported so far on the expression and functional role of TRP channels in different types of cancers.


Input: TRP channels have been recently implicated in the triggering of enhanced proliferation, aberrant differentiation, and resistance to apoptotic cell death, leading to uncontrolled tumor growth and progression.


Input: Depending on cancer stage, up and down-regulation of TRP mRNAs and protein expression have been reported.


Input: These changes have been shown to exhibit cancer promoting (oncogenic) or inhibiting/delaying (tumor suppressor) effects.


Input: We are only at the beginning, and more detailed study on the physiopathologic role of TRP channels is required to understand how the deregulation of TRP channel expression and function contributes to tumor development and progression.


Input: It is hoped that greater knowledge about TRP biology will enable future development of new chemotherapeutic agents for specific TRP targets, and the use of TRP channels as evaluable markers in diagnostic and/or prognostic analysis.


Input: Multiple Roles of Transient Receptor Potential (TRP) Channels in Inflammatory Conditions and Current Status of Drug Development.


Input: During inflammation, several Transient Receptor Potential (TRP) channels are directly or indirectly activated by inflammatory signaling molecules and microenvironmental changes including heat, oxidative conditions or low pH.


Input: In either case, specific TRP isoforms participate in chains of pro-or anti-inflammatory signaling cascades often including activation of transcription factors, protein kinases and phospholipases, which result in signal integration or amplification.


Input: In a few cases, their potentials as therapeutic targets for inflammatory conditions like pruritis, cystitis, dermatitis, asthma among other conditions are investigated pre-clinically or clinically by pioneering academic groups and industries.


Input: Significant efforts are still devoted to the understanding of the detailed physiological roles played by TRP channels during inflammation.


Input: This review intends to summarize key biological findings and reports of drug discovery activities when available, in an overview of the current status and recent developments in the field.


Input: Correlation between structural, spectroscopic, and reactivity properties within a series of structurally analogous metastable manganese (III)-alkylperoxo complexes.

manganese (III)-alkylperoxo complexes


Input: Manganese-peroxos are proposed as key intermediates in a number of important biochemical and synthetic transformations.

Manganese-peroxos


Input: Our understanding of the structural, spectroscopic, and reactivity properties of these metastable species is limited, however, and correlations between these properties have yet to be established experimentally.


Input: Herein we report the crystallographic structures of a series of structurally related metastable Mn (III)-OOR compounds, and examine their spectroscopic and reactivity properties.

Mn (III)-OOR


Input: The four reported Mn (III)-OOR compounds extend the number of known end-on Mn (III)-(eta (1)-peroxos) to six.

Mn (III)-OOR

Mn (III)-(eta (1)-peroxos)


Input: The ligand backbone is shown to alter the metal-ligand distances and modulate the electronic properties key to bonding and activation of the peroxo.


Input: The mechanism of thermal decay of these metastable species is examined via variable-temperature kinetics.


Input: Strong correlations between structural (O-O and Mn... N (py, quin) distances), spectroscopic (E (pi v * (O-O) --> Mn CT band), nu (O-O)), and kinetic (Delta H (++) and Delta S (++)) parameters for these complexes provide compelling evidence for rate-limiting O-O bond cleavage.

O-O

Mn

N (py, quin)

O-O

Mn

O-O

O-O


Input: Products identified in the final reaction mixtures of Mn (III)-OOR decay are consistent with homolytic O-O bond scission.

Mn (III)-OOR

O-O


Input: The N-heterocyclic amines and ligand backbone (Et vs Pr) are found to modulate structural and reactivity properties, and O-O bond activation is shown, both experimentally and theoretically, to track with metal ion Lewis acidity.

N-heterocyclic amines

O-O


Input: The peroxo O-O bond is shown to gradually become more activated as the N-heterocyclic amines move closer to the metal ion causing a decrease in pi-donation from the peroxo pi v * (O-O) orbital.

peroxo O-O

N-heterocyclic amines

O-O


Input: The reported work represents one of very few examples of experimentally verified relationships between structure and function.


Input: Phase discrimination through oxidant selection in low-temperature atomic layer deposition of crystalline iron oxides.

iron oxides


Input: Control over the oxidation state and crystalline phase of thin-film iron oxides was achieved by low-temperature atomic layer deposition (ALD), utilizing a novel iron precursor, bis (2, 4-methylpentadienyl) iron.

iron oxides

iron

bis (2, 4-methylpentadienyl) iron


Input: This low-temperature (T = 120 degrees C) route to conformal deposition of crystalline Fe3O4 or alpha-Fe2O3 thin films is determined by the choice of oxygen source selected for the second surface half-reaction.

oxygen


Input: The approach employs ozone to produce fully oxidized alpha-Fe2O3 or a milder oxidant, H2O2, to generate the Fe (2 +)/Fe (3 +) spinel, Fe3O4.

Fe (2 +)

Fe (3 +)


Input: Both processes show self-limiting surface reactions and deposition rates of at least 0. 6 A/cycle, a significantly high growth rate at such mild conditions.


Input: We utilized this process to prepare conformal iron oxide thin films on a porous framework, for which alpha-Fe2O3 is active for photocatalytic water splitting.

iron oxide


Input: Studies on an (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl) propionic acid (AMPA) receptor antagonist IKM-159: asymmetric synthesis, neuroactivity, and structural characterization.

(S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl) propionic acid

AMPA


Input: IKM-159 was developed and identified as a member of a new class of heterotricyclic glutamate analogues that act as AMPA receptor-selective antagonists.

glutamate

AMPA


Input: However, it was not known which enantiomer of IKM-159 was responsible for its pharmacological activities.


Input: Here, we report in vivo and in vitro neuronal activities of both enantiomers of IKM-159 prepared by enantioselective asymmetric synthesis.


Input: By employment of (R)-2-amino-2-(4-methoxyphenyl) ethanol as a chiral auxiliary, (2R)-IKM-159 and the (2S)-counterpart were successfully synthesized in 0. 70% and 1. 5% yields, respectively, over a total of 18 steps.

(R)-2-amino-2-(4-methoxyphenyl) ethanol


Input: Both behavioral and electrophysiological assays showed that the biological activity observed for the racemic mixture was reproduced only with (2R)-IKM-159, whereas the (2S)-counterpart was inactive in both assays.


Input: Racemic IKM-159 was crystallized with the ligand-binding domain of GluA2, and the structure revealed a complex containing (2R)-IKM-159 at the glutamate binding site.

Racemic IKM-159


Input: (2R)-IKM-159 locks the GluA2 in an open form, consistent with a pharmacological action as competitive antagonist of AMPA receptors.


Input: A new guaianolide from Artemisia roxburghiana.

guaianolide


Input: A new member of 5 alpha H, 6 beta H, 7 alpha H, 11 alpha H-guaian-12, 6 alpha-olides, 11-epi-8 alpha-hydroxyarborescin, together with a mixture of (24R)-and (24S)-cycloart-25-en-3b, 24-diols, palmitic acid and 1-octacosanol were isolated from the leaves of Artemisia roxburghiana Bess.

5 alpha H, 6 beta H, 7 alpha H, 11 alpha H-guaian-12, 6 alpha-olides

11-epi-8 alpha-hydroxyarborescin

(24R)-and (24S)-cycloart-25-en-3b, 24-diols

palmitic acid


Input: (Asteraceae) of Vietnam.


Input: Their structures were determined on the basis of spectroscopic methods.


Input: Challenges in exploring the cytochrome P450 system as a source of variation in canine drug pharmacokinetics.


Input: Abstract The cytochrome P450 (CYP) superfamily constitutes a collection of enzymes responsible for the metabolism of a wide array of endo-and xenobiotic compounds.


Input: Much of the knowledge on substrate specificity and genetic identification of the various CYP isoforms is derived from research in rodents and humans and only limited information has been captured in the dog.


Input: Currently, there exist many gaps in our knowledge of canine CYP diversity as a result of the paucity of studies focusing on canine CYPs, canine CYP polymorphisms, and the therapeutic consequences of these genetic variants.


Input: Challenges engendered by this lack of information is further amplified by inter-and intraspecies differences in the specificity and affinity of substrates and inhibitors, prohibiting a simple extrapolation of probe substances used in human CYP research.


Input: This creates a need to develop and validate canine-specific CYP probes.


Input: Failure to understand this potential metabolic and pharmacogenomic diversity can also influence the interpretation of data generated in dogs to support human drug development.


Input: It is with these objectives in mind that we provide an overview of what is currently known about canine CYPs with the hope that it will encourage further exploration into this important area of research.


Input: Nanobiocomposite adhesion: role of graft length and temperature in a hybrid biomimetic approach.


Input: Cellulose microspheres bearing poly (epsilon-caprolactone) grafts of different molecular weights were investigated to evaluate the effect of graft length on the interfacial properties.

poly (epsilon-caprolactone)


Input: Surface force and friction measurements were performed using an atomic force microscope in colloidal probe mode.


Input: The maximum interaction distance and adhesion is dependent on the temperature and the time in contact via a diffusion controlled mechanism.


Input: The effects are highest for the longer grafts, and molecular weight thresholds were found to lie between 21 and 34 kDa at 25 degrees C and between 9 and 21 kDa at 40 degrees C.


Input: The interpenetration of the graft into a matrix leads to " hidden length " contributions to adhesion, analogous to those in natural biocomposites.


Input: The nanotribology results display Amontonian behavior, and the friction force at zero applied load is higher at the graft-graft interface than for a bare cellulose sphere interacting with the graft.


Input: These results clearly demonstrate the benefits of the grafted polymer layer on the adhesion, toughness, and resistance to shear in the design of cellulosic nanobiocomposites.


Input: SNAIL Induces Epithelial-to-Mesenchymal Transition and Cancer Stem Cell-like Properties in Aldehyde Dehydroghenase-Negative Thyroid Cancer Cells.

Aldehyde


Input: Background: Epithelial-to-mesenchymal transition (EMT) has been thought to play a critical role in invasion and metastasis of cancer and to be associated with cancer stem cell (CSC) properties.


Input: It is not clear if there is a link between EMT and CSCs in thyroid cancers.


Input: We therefore investigated CSC properties of thyroid cancers that underwent EMT.


Input: Method: To induce EMT (spindle-like cell morphology, loss and acquisition of expression of an epithelial marker E-cadherin and a mesenchymal marker vimentin, respectively) in an epithelial type thyroid cancer cell line ACT-1, we used transforming growth factor-beta (TGF-beta), BRAFV600E and/or Snail homolog 1 (SNAI1, also known as SNAIL).


Input: CSC properties were analyzed with assays for cell proliferation, chemosensitivity, in vitro and in vivo tumor formation ability, cell surface antigens and intracellular aldehyde dehydrogenase (ALDH; a known CSC marker) activities.

aldehyde


Input: Results: EMT was induced most efficiently by SNAIL (ACT-SNAIL cells), whereas TGF-beta and BRAFV600E were less efficient.


Input: ACT-SNAIL cells showed slightly but significantly enhanced tumor formation ability in in vitro sphere assay (~ 3 fold) but not in vivo subcutaneous tumor growth assay, and showed comparable chemosensitivity, as compared to the parental ACT-1 cells.


Input: However, of interest, although in vitro sphere formation ability of ALDH + cells was almost unchanged after SNAIL induction, SNAIL overexpression induced much higher (~ 14 fold) spheres in ALDH-cells.


Input: Thus, ALDH was no longer a CSC marker in ACT-SNAIL cells.


Input: Conclusions: All these data indicate that EMT confers CSC properties in ALDH-cells and appears to influence the ability of ALDH to enrich CSCs.


Input: Metabolic Activation of Polycyclic Aromatic Hydrocarbons and Aryl and Heterocyclic Amines by Human Cytochromes P450 2A13 and 2A6.

Polycyclic Aromatic Hydrocarbons

Aryl and Heterocyclic Amines


Input: Human cytochrome P450 (P450) 2A13 was found to interact with several polycyclic aromatic hydrocarbons (PAHs) to produce Type I binding spectra, including acenaphthene, acenaphthylene, benzo [c] phenanthrene, fluoranthene, fluoranthene-2, 3-diol, and 1-nitropyrene.

polycyclic aromatic hydrocarbons

PAHs

acenaphthene

acenaphthylene

benzo [c] phenanthrene

fluoranthene

fluoranthene-2, 3-diol


Input: P450 2A6 also interacted with acenaphthene and acenaphthylene, but not with fluoranthene, fluoranthene-2, 3-diol, or 1-nitropyrene.

acenaphthene

acenaphthylene

fluoranthene

fluoranthene-2, 3-diol


Input: P450 1B1 is well-known to oxidize many carcinogenic PAHs, and we found that several PAHs (i. e., 7, 12-dimethylbenz [a] anthracene, 7, 12-dimethylbenz [a] anthracene-5, 6-diol, benzo [c] phenanthrene, fluoranthene, fluoranthene-2, 3-diol, 5-methylchrysene, benz [a] pyrene-4, 5-diol, benzo [a] pyrene-7, 8-diol, 1-nitropyrene, 2-aminoanthracene, 2-aminofluorene, and 2-acetylaminofluorene) interacted with P450 1B1, producing Reverse Type I binding spectra.

PAHs

PAHs

7, 12-dimethylbenz [a] anthracene

7, 12-dimethylbenz [a] anthracene-5, 6-diol

benzo [c] phenanthrene

fluoranthene

fluoranthene-2, 3-diol

benz [a] pyrene-4, 5-diol

benzo [a] pyrene-7, 8-diol


Input: Metabolic activation of PAHs and aryl-and heterocyclic amines to genotoxic products was examined in Salmonella typhimurium NM2009, and we found that P450 2A13 and 2A6 (as well as P450 1B1) were able to activate several of these procarcinogens.

PAHs

aryl-and heterocyclic amines


Input: The former two enzymes were particularly active in catalyzing 2-aminofluorene and 2-aminoanthracene activation, and molecular docking simulations supported the results with these procarcinogens, in terms of binding in the active sites of P450 2A13 and 2A6.


Input: These results suggest that P450 2A enzymes, as well as P450 Family 1 enzymes including P450 1B1, are major enzymes involved in activating PAHs and aryl-and heterocyclic amines, as well as tobacco-related nitrosamines.

PAHs

aryl-and heterocyclic amines

nitrosamines


Input: Immunomodulatory properties of farnesoids: the new steroids?

farnesoids

steroids


Input: Farnesylthiosalisylic acid (FTS) is a potent non-toxic anticancer drug that targets oncogenic and pathologically activated Ras.

Farnesylthiosalisylic acid

FTS


Input: The mechanism of action of FTS is well understood.

FTS


Input: It interferes with the binding of activated Ras proteins to their escort chaperons and with Ras tethering to the plasma membrane.


Input: This agent has been evaluated successfully in phase II clinical trials of pancreatic and lung cancer patients.


Input: It is generally agreed that Ras proteins play an important role in cancer, but they also drive activation of the immune system.


Input: Therefore we hypothesized that inhibiting Ras might be beneficial in autoimmune and inflammatory conditions.


Input: Over the past decade we have extensively studied the effects of FTS in multiple animal models of such diseases.

FTS


Input: We were able to show potent anti-inflammatory properties of FTS in autoimmune disease models such as systemic lupus erythematous, antiphospholipd syndrome, Guillain-Barr e syndrome, multiple sclerosis, and inflammatory bowel diseases.

FTS


Input: Its potential was also shown in type I and type II diabetes.


Input: Animal models of contact dermatitis, allergic inflammation, and proliferative nephritis were studied as well.


Input: We have also investigated the molecular mechanisms, signaling pathways, and inflammatory mediators underlying these conditions.


Input: In this review we summarize our (and others) published data, and conclude that FTS has great potential as a safe anti-inflammatory drug.

FTS


Input: Recent advances in carbon nanotubes as delivery systems for anticancer drugs.

carbon


Input: Problems associated with the administration of anticancer drugs, such as limited solubility, poor biodistribution, lack of selectivity, and healthy tissue damage, can be overcome by the implementation of drug delivery systems.


Input: A wide range of materials, including liposomes, microspheres, polymers and recently, carbon nanotubes (CNTs), have been investigated for delivering anticancer drugs on the purpose of reducing the number of necessary administrations, providing more localized and better use of the active agents, and increasing patient compliance.

carbon


Input: Carbon nanotubes (CNTs) have attracted particular attention as carriers of biologically relevant molecules due to their unique physical, chemical and physiological properties.

Carbon


Input: The exact relationship between the physical-chemical properties of carbon nanotubes, their cell to-cell interactions, reactivity, and biological/systemic consequences are relevant issues and it is important to know suchinter-relationships beforehand to employ the benefits of these nanomaterials without the hazardous consequences.

carbon


Input: The purpose of this review is to present highlight of recent developments in the application of carbon nanotubes as cargoes for anti cancer drugs and in the diagnosis of cancer diseases.

carbon


Input: Camptothecin Resistance in Cancer: Insights into the Molecular Mechanisms of a DNA-Damaging Drug.

Camptothecin


Input: Poisoning of DNA topoisomerase I is the mechanism by which camptothecins interfere with tumor growth.

camptothecins


Input: Although the clinical use of camptothecins has had a significant impact on cancer therapy, de novo or acquired clinical resistance to these drugs is common.

camptothecins


Input: Clinical resistance to camptothecins is still a poorly understood phenomenon, likely involving pharmacological and tumor-related factors.

camptothecins


Input: Experimental models including yeast and mammalian cell cultures suggest three general mechanisms of camptothecin resistance: i) reduced cellular accumulation of drugs, ii) alteration in the structure/expression of topoisomerase I, and iii) alterations in the cellular response to camptothecin-DNA-ternary complex formation.

camptothecin

camptothecin


Input: Some lines of evidence have also suggested links between cellular camptothecin resistance, the existence of a subset of tumor-initiating cells and miRNA deregulation.

camptothecin


Input: In this regard, a better definition of the molecular events clarifying the regulation of tumorigenesis and gene expression might contribute to gain insight into the molecular mechanisms on the basis of camptothecin resistance of tumors and to identify new molecular tools for targeting cancer cells.

camptothecin


Input: The relevance of these mechanisms to clinical drug resistance has not yet been completely defined, but their evaluation in clinical specimens should help to define personalized treatments including camptothecins as single agents or in combination with other cytotoxic and target-specific anticancer agents.

camptothecins


Input: The present review focuses on the cellular/molecular aspects involved in resistance of tumor cells to camptothecins, including the potential role of cancer stem cells and deregulated miRNAs, and on the approaches proposed for overcoming resistance.

camptothecins


Input: Discovery of a Novel Selective PPAR gamma Ligand with Partial Agonist Binding Properties by Integrated in Silico/in Vitro Work Flow.


Input: Full agonists to the peroxisome proliferator-activated receptor (PPAR) gamma, such as Rosiglitazone, have been associated with a series of undesired side effects, such as weight gain, fluid retention, cardiac hypertrophy, and hepatotoxicity.

Rosiglitazone


Input: Nevertheless, PPAR gamma is involved in the expression of genes that control glucose and lipid metabolism and is an important target for drugs against type 2 diabetes, dyslipidemia, atherosclerosis, and cardiovascular disease.

glucose


Input: In an effort to identify novel PPAR gamma ligands with an improved pharmacological profile, emphasis has shifted to selective ligands with partial agonist binding properties.


Input: Toward this end we applied an integrated in silico/in vitro workflow, based on pharmacophore-and structure-based virtual screening of the ZINC library, coupled with competitive binding and transactivation assays, and adipocyte differentiation and gene expression studies.


Input: Hit compound 9 was identified as the most potent ligand (IC50 = 0. 3 mu M) and a relatively poor inducer of adipocyte differentiation.


Input: The binding mode of compound 9 was confirmed by molecular dynamics simulation, and the calculated free energy of binding was-8. 4 kcal/mol.


Input: A novel functional group, the carbonitrile group, was identified to be a key substituent in the ligand-protein interactions.

carbonitrile


Input: Further studies on the transcriptional regulation properties of compound 9 revealed a gene regulatory profile that was to a large extent unique, however functionally closer to that of a partial agonist.


Input: Comprehensive insights into the structural and chemical changes in mixed-anion FeOF electrodes by using operando PDF and NMR spectroscopy.

FeOF


Input: In-depth analysis of operando X-ray pair distribution function (PDF) data is combined with Li NMR spectroscopy to gain comprehensive insights into the electrochemical reaction mechanism of high-performance iron oxyfluoride electrodes.

Li

iron oxyfluoride


Input: While the full discharge capacity could be recovered upon charge, implying reversibility of the electrochemical reaction, the atomic structure of the electrode formed after cycling (discharge-charge) differs from the pristine uncycled electrode material.


Input: Instead, the " active " electrode that forms upon cycling is a nanocomposite of an amorphous rutile phase and a nanoscale rock salt phase.


Input: Bond valence sum analysis, based on the precise structural parameters (bond lengths and coordination number) extracted from the in situ PDF data, suggests that anion partitioning occurs during the electrochemical reaction, with the rutile phase being F-rich and the rock salt phase being O-rich.

O


Input: The F-and O-rich phases react sequentially; Fe in a F-rich environment reacts preferentially during both discharge and charge.

F

O

Fe

F


Input: Design, synthesis and SAR of novel glucokinase activators.


Input: Guided by co-crystal structures of compounds 15, 22 and 30, an SBDD approach led to the discovery of the 6-methyl pyridone series as a novel class of GKAs that potently activate GK in enzyme and cell assays.

6-methyl pyridone


Input: Anti-diabetic OGTT efficacy was demonstrated with 54 in a mouse model of type 2 diabetes.


Input: The role of omega-3 derived resolvins in arthritis.

resolvins


Input: Omega-3 polyunsaturated fatty acids (PUFAs) are known to alleviate joint stiffness and pain in rheumatoid arthritis patients.

Omega-3 polyunsaturated fatty acids

PUFAs


Input: However, the mechanisms by which omega-3s exert their beneficial effects has not been fully explored.


Input: Herein we discuss a novel class of bioactive lipid mediators, which are enzymatically biosynthesized in vivo from omega-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), termed resolvins.

omega-3 eicosapentaenoic acid

EPA

docosahexaenoic acid

DHA

resolvins


Input: These lipid mediators exert anti-inflammatory and pro-resolving properties and are log-orders more potent than their precursors.


Input: We also highlight that formation of pro-resolving mediators can be enhanced by widely used anti-inflammatory and cardioprotective drugs (aspirin and statins) via the modification of cyclooxygenase-2 enzymatic activity.

aspirin


Input: These bioactive pro-resolving lipid mediators provide further rationale for the beneficial effects of dietary supplementation with fish oils, and offer new avenues for developing therapeutics for inflammatory conditions such as rheumatoid arthritis.


Input: A one-pot domino synthesis and discovery of highly functionalized dihydrobenzo [b] thiophenes as AChE inhibitors.

dihydrobenzo [b] thiophenes


Input: A library of novel 5-amino-2, 7-diaryl-2, 3-dihydrobenzo [b] thiophene-4, 6-dicarbonitriles have been synthesized regioselectively in good yields through the one-pot domino reactions of 5-aryldihydro-3 (2H)-thiophenones, malononitrile and aromatic aldehydes in the presence of morpholine.

5-amino-2, 7-diaryl-2, 3-dihydrobenzo [b] thiophene-4, 6-dicarbonitriles

5-aryldihydro-3 (2H)-thiophenones

malononitrile

aromatic aldehydes

morpholine


Input: This transformation presumably involves Knoevenagel condensation-Michael addition-intramolecular Thorpe-Ziegler cyclization-Tautomerization-Elimination sequence of reactions.


Input: These compounds were evaluated for their acetylcholinesterase (AChE) inhibitory activity and 5-amino-2, 7-bis (4-methoxyphenyl)-2, 3-dihydrobenzo [b] thiophene-4, 6-dicarbonitrile was found to be the most potent against AChE with IC50 4. 16 mu mol/L.

5-amino-2, 7-bis (4-methoxyphenyl)-2, 3-dihydrobenzo [b] thiophene-4, 6-dicarbonitrile


Input: Pyridine to aniline: an exceptional biologically driven rearrangement.

Pyridine

aniline


Input: During the course of our study on the innovative ligand for nicotinic acetylcholinergic receptors, LNAChR, and in order to assess activity and toxicity profiles of the drug' s metabolites, synthesis of the main metabolites was undertaken.


Input: This synthesis work was done in parallel by organic chemistry and by biotransformation of LNAChR.


Input: Filamentous fungus Aspergillus alliaceus (NRRL 315) neatly afforded three of the main metabolites, one of which arose from a very unexpected and very uncommon rearrangement.


Input: Synthesis and cytotoxicity evaluation of oleanolic acid derivatives.

oleanolic acid


Input: Twelve derivatives of oleanolic acid (1) have been synthesized and evaluated for their inhibitory activities against the growth of prostate PC3, breast MCF-7, lung A549, and gastric BGC-823 cancer cells by MTT assays.

oleanolic acid

MTT


Input: Within these series of derivatives, compound 17 exhibited the most potent cytotoxicity against PC3 cell line (IC50 = 0. 39 mu M) and compound 28 displayed the best activity against A549 cell line (IC50 = 0. 22 mu M).


Input: SAR analysis indicates that H-donor substitution at C-3 position of oleanolic acid may be advantageous for improvement of cytotoxicity against PC3, A549 and MCF-7 cell lines.

H

oleanolic acid


Input: The MRN-CtIP pathway is required for metaphase chromosome alignment.


Input: Faithful duplication of the genome in S phase followed by its accurate segregation in mitosis is essential to maintain genomic integrity.


Input: Recent studies have suggested that proteins involved in DNA transactions are also required for whole-chromosome stability.


Input: Here we demonstrate that the MRN (Mre11, Rad50, and Nbs1) complex and CtIP are required for accurate chromosome segregation.


Input: Depletion of Mre11 or CtIP, antibody-mediated inhibition of Mre11, or small-molecule inhibition of MRN using mirin results in metaphase chromosome alignment defects in Xenopus egg extracts.


Input: Similarly, loss of MRN function adversely affects spindle assembly around DNA-coated beads in egg extracts.


Input: Inhibition of MRN function in mammalian cells triggers a metaphase delay and disrupts the RCC1-dependent RanGTP gradient.


Input: Addition of the Mre11 inhibitor mirin to egg extracts and mammalian cells reduces RCC1 association with mitotic chromosomes.


Input: Thus, the MRN-CtIP pathway contributes to Ran-dependent mitotic spindle assembly by modulating RCC1 chromosome association.


Input: 2-(Benzothiazol-2-yl)-phenyl-beta-d-galactopyranoside derivatives as fluorescent pigment dyeing substrates and their application for the assay of beta-d-galactosidase activities.

2-(Benzothiazol-2-yl)-phenyl-beta-d-galactopyranoside


Input: 2-(Benzothiazol-2-yl)-phenyl-beta-d-galactopyranoside derivatives were synthesized as novel artificial fluorescent pigment dyeing substrates for beta-d-galactosidase.

2-(Benzothiazol-2-yl)-phenyl-beta-d-galactopyranoside