Input: Using the relationship between these responses to 4-week inhalation and intratracheal instillation, it may be possible to estimate what aerosol concentrations of other nanomaterials might cause the same responses of PMN production as intratracheal instillation tests.


Input: Hedgehog pathway inhibitors: a patent review (2009--present).


Input: INTRODUCTION: The hedgehog (Hh) pathway is a developmental signaling pathway that plays a key role in directing cellular growth and tissue patterning during embryonic development.


Input: Dysregulation of Hh signaling has been linked to the development of a variety of human tumors, and numerous drug development programs in both academia and industry are actively exploring inhibitors of the pathway as anti-cancer agents.


Input: AREAS COVERED: This review surveys the recent patent literature (2009-2012) for Hh pathway inhibitors as treatments for a variety of human malignancies.


Input: EXPERT OPINION: To date, all of the pathway inhibitors that have entered clinical trials and the majority of compounds identified via high-throughput screens target smoothened (Smo), a transmembrane protein that is essential for pathway signaling.


Input: While these compounds have shown initial promise in preclinical and clinical trials, several mechanisms of resistance to Smo inhibitors have been identified.


Input: Even with this knowledge, the majority of small-molecule pathway inhibitors disclosed in the recent patent literature directly target Smo.


Input: The continued identification of Hh pathway inhibitors that function either upstream or downstream is warranted not only to combat these emerging resistance mechanisms, but also to help elucidate the various cellular mechanisms that control both normal and oncogenic pathway signaling.


Input: Density of GM1 in nanoclusters is a critical factor in the formation of a spherical assembly of amyloid beta-protein on synaptic plasma membranes.


Input: The deposition of amyloid beta-protein (A beta) is a pathological hallmark of Alzheimer' s disease (AD).


Input: We previously found that the ganglioside-enriched microdomains (ganglioside clusters) in presynaptic neuronal membranes play a key role in the initiation of the A beta assembly process.

ganglioside

ganglioside


Input: However, not all ganglioside clusters accelerate A beta assembly.

ganglioside


Input: In the present study, we directly observed a spherical A beta in an atomic force microscopic study on the morphology of a reconstituted lipid bilayer composed of lipids that were extracted from a detergent-resistant membrane microdomain (DRM) fraction of synaptosomes prepared from aged mouse brain.


Input: The A beta assembly was generated on a distinctive GM1 domain, which was characterized as the A beta-sensitive ganglioside nanocluster (ASIGN).

ganglioside


Input: By using an artificial GM1 cluster-binding peptide, ASIGN was found to have a high density of GM1; therefore, there would be a critical density of GM1 in nanoclusters to induce A beta binding and assembly.


Input: These results suggest that ganglioside-bound A beta (GA beta), which acts as an endogenous seed for A beta fibril formation in AD brains, is generated on ASIGN on synaptosomal membranes.

ganglioside


Input: Anterior gradient 2 and 3--two prototype androgen-responsive genes transcriptionally upregulated by androgens and by oestrogens in prostate cancer cells.

androgen

androgens

oestrogens


Input: Androgens and oestrogens have been implicated in prostatic carcinogenesis and tumour progression.

Androgens

oestrogens


Input: Although the actions of androgens have been studied extensively, the mechanisms underlying oestrogen signalling in prostate cancer are not fully understood.

androgens

oestrogen


Input: In the present study, we analyzed the effect of androgens and oestrogens on the expression of anterior gradient 2 (AGR2) and anterior gradient 3 (AGR3), comprising two highly-related genes encoding secretory proteins that are expressed in prostate cancer and one of which (AGR2) has been associated with tumour metastasis.

androgens

oestrogens


Input: Quantitative reverse-transcriptase PCR and western blot analysis showed androgen induction of AGR2 and AGR3 in three androgen receptor positive cell lines, starting at concentrations of 0. 1 nm.

androgen

androgen


Input: Both AGR genes were also transcriptionally activated by >= 5 nM oestradiol but not by isotype selective or nonselective oestrogen receptor agonists in DUCaP cells that harbour a high-level of wild-type androgen receptor.

oestradiol

oestrogen

androgen


Input: A functional androgen receptor but not oestrogen receptor turned out to be required for both androgen and oestrogen regulation.

androgen

oestrogen

androgen

oestrogen


Input: This pattern of androgen and oestrogen regulation was confirmed in VCaP cells and was also observed for FKBP5, a well-characterized androgen-regulated gene.

androgen

oestrogen

androgen


Input: Genome-wide chromatin-immunoprecipitation studies coupled with deep sequencing identified androgen receptor binding sites localized in the distal promoter and intron regions of the AGR2 and AGR3 genes, respectively.

androgen


Input: The androgen responsiveness of these enhancers was verified by luciferase reporter gene assays and site-directed mutagenesis analysis.

androgen


Input: Androgen treatment also induced p300 and RNA Pol II recruitment to androgen receptor enhancers of AGR2 and initiated local chromatin remodelling and the formation of RNA Pol II-containing androgen receptor transcription complexes.

Androgen

androgen

androgen


Input: Pentacyclic hemiacetal sterol with antifouling and cytotoxic activities from the soft coral Nephthea sp.

Pentacyclic hemiacetal sterol


Input: A novel unusual pentacyclic hemiacetal sterol nephthoacetal (1), was isolated from soft coral Nephthea sp.

pentacyclic hemiacetal sterol nephthoacetal


Input: The structure of this sterol was inferred from its two acetyl derivatives (2) and (3), by means of spectroscopic methods, and quantum chemical calculations.

sterol

acetyl


Input: Anti-fouling activity of compounds 1-3 against Bugula neritina larvae was evaluated, sterol (1) exhibited significant inhibitory effect with EC (50) value of 2. 5 mu g/mL, while having low toxicity with LC (50) > 25. 0 mu g/mL.

sterol


Input: The in vitro cytotoxic activity of compounds 1-3 against HeLa cells was also evaluated, all of them exhibited moderate cytotoxicity with IC (50) values of 12. 3 (1), 10. 1 (2), and 19. 6 mu g/mL (3), respectively.


Input: Aspirin and aspirin resistance in coronary artery disease.

Aspirin

aspirin


Input: Aspirin is still the mainstay of antiplatelet therapy in the secondary prevention of coronary artery disease.

Aspirin


Input: However certain patients do not benefit from the antithrombotic effects of aspirin.

aspirin


Input: The phenomenon of so-called aspirin resistance can be considered from the clinical and laboratory perspective.

aspirin


Input: A variety of methods have emerged for the laboratory diagnosis of aspirin resistance.

aspirin


Input: None of them is considered ideal as they provide conflicting information with significant inter-individual variability and weak correlation between them.


Input: With the mechanisms of aspirin resistance not fully understood and the phenomenon commonly observed in individuals with poor compliance, the existence of aspirin resistance has been challenged.

aspirin

aspirin


Input: The aim of this review is to present recent data on the impact of aspirin resistance in primary and secondary prevention of coronary artery disease.

aspirin


Input: L-Carnitine protects against arterial hypertension-related cardiac fibrosis through modulation of PPAR-gamma expression.

L-Carnitine


Input: Cardiac fibrosis is a pathogenic factor in a variety of cardiovascular diseases and is characterized by an abnormal accumulation of extracellular matrix protein that leads to cardiac dysfunction.


Input: l-Carnitine (LC) plays an essential role in the beta-oxidation of long-chain fatty acids in lipid metabolism.

l-Carnitine

fatty acids


Input: We have previously demonstrated the beneficial effects of LC in hypertensive rats.


Input: The aim of this study was to analyze the effect of LC on arterial hypertension-associated cardiac fibrosis and to explore the mechanisms of LC action.


Input: To this end, four groups of rats were used: Wistar (control), rats treated with 400mg/kg/day of LC, rats treated with 25mg/kg/day of l-NAME (to induce hypertension), and rats treated with LC + l-NAME simultaneously.

l-NAME

l-NAME


Input: We found an elevation in the myocardial expression of profibrotic factors (TGF-beta 1 and CTGF), types I and III of collagen, and NADPH oxidase subunits (NOX2 and NOX4), in hypertensive rats when compared with normotensive ones.

NADPH


Input: In addition, an increase in myocardial fibrosis was also found in the l-NAME group.

l-NAME


Input: These results were accompanied by a down-regulation of PPAR-gamma in the heart of hypertensive animals.


Input: When hypertensive rats were treated with LC, all these alterations were reversed.


Input: Moreover, a significant negative correlation was observed between myocardial interstitial fibrosis and mRNA expression of PPAR-gamma.


Input: In conclusion, the reduction of cardiac fibrosis and the down-regulation of NOX2, NOX4, TGF-beta 1 and CTGF induced by LC might be, at least in part, mediated by an upregulation of PPAR-gamma, which leads to a reduction on hypertension-related cardiac fibrosis.


Input: Anti-human VWF monoclonal antibody SZ-123 prevents arterial thrombus formation by inhibiting VWF-collagen and VWF-platelet interactions in Rhesus monkeys.


Input: The interactions between collagen, von Willebrand factor (VWF), and glycoprotein Ib (GPIb) are crucial for hemostasis and thrombosis.


Input: This axis represents a promising target for the development of new antithrombotic agents.


Input: In this study, we investigate the in vivo antithrombotic efficacy of an anti-VWF monoclonal antibody SZ-123 and its potential underlying mechanisms.


Input: Cyclic flow reductions (CFRs), an indicator of arterial thrombosis, were measured in the femoral artery of anesthetized Rhesus monkeys before and after intravenous administration of SZ-123.


Input: Ex vivo VWF binding to collagen, platelet agglutination, platelet count, and template bleeding time were used as measurements of antithrombotic activity.


Input: In addition, plasma VWF and SZ-123 levels, and VWF occupancy were measured by ELISA.


Input: Administration of 0. 1, 0. 3, and 0. 6 mg/kg SZ-123 resulted in 45. 3%, 78. 2%, and 100% reductions in CFRs, respectively.


Input: When 0. 3 and 0. 6 mg/kg SZ-123 were administered, 100% of VWF was occupied by the antibody.


Input: Moreover, 100% ex vivo inhibition of VWF-collagen binding and 60-95% inhibition of platelet agglutination were observed from 15 min to 1 h.


Input: None of the doses resulted in significant prolongation of bleeding time.


Input: In vitro experiments revealed that SZ-123 not only blocks the collagen-VWF A3 interaction but also indirectly inhibits VWF A1 binding to GPIb alpha induced by ristocetin.


Input: Thus, we demonstrate that SZ-123 prevents in vivo arterial thrombus formation under high shear conditions by inhibiting VWF A3-collagen and VWF A1-platelet interactions and does not significantly prolong bleeding time.


Input: A novel transcriptional repressor PhaR for the steroid-inducible expression of the 3, 17 beta-hydroxysteroid dehydrogenase gene in Comamonas testosteroni ATCC11996.

steroid

3, 17 beta-hydroxysteroid


Input: Comamonas testosteroni is able to catabolize a variety of steroids and polycyclic aromatic hydrocarbons and might be used in the bioremediation of contaminated environments.

steroids

polycyclic aromatic hydrocarbons


Input: 3, 17 beta-Hydroxysteroid dehydrogenase (3, 17 beta-HSD) from C. testosteroni is a member of the short-chain dehydrogenase/reductase (SDR) superfamily and a key enzyme in steroid degradation.

3, 17 beta-Hydroxysteroid

steroid


Input: The genome of C. testosteroni ATCC11996 was sequenced in our previous work.


Input: In addition to the gene coding for 3, 17 beta-HSD (beta hsd), a novel transcriptional repressor phaR gene (phaR) which locates 2290 bp upstream of the beta hsd gene was found.


Input: PhaR knock-out mutants of C. testosteroni were prepared and shown to grow better than wild-type C. testosteroni in the presence of 1 mM testosterone, 0. 5 mM estradiol or 0. 5 mM cholesterol in both Standard 1 Nutrient (SIN) medium and 1: 10 diluted SIN medium.

testosterone

estradiol

cholesterol


Input: After 1 mM testosterone induction, 3, 17 beta-HSD expression in the mutant was 2. 5 times higher than in wild type C. testosteroni.

testosterone


Input: Accordingly, PhaR is a repressor that controls 3, 17 beta-HSD expression.


Input: Moreover, phaR knock-out mutants grow at higher rates and produce more protein in the presence of steroids as carbon source.

steroids

carbon


Input: However, ELISA results showed that 0. 5 mM estradiol and cholesterol could not induce beta hsd gene expression in both wild-type and mutant C. testosteroni.

estradiol

cholesterol


Input: Probably, in addition to the beta hsd gene, PhaR regulates some other genes that relate to steroid degradation.

steroid


Input: The genes coding for PhaR and 3, 17 beta-HSD together with their promoter domains were cloned into plasmids pK18 and pUC19.


Input: Escherichia coli HB101 was co-transformed with these plasmids.


Input: The results suggest that PhaR is a repressor, which might bind on a special beta hsd promoter domain (214 bp).


Input: A 2509 bp DNA fragment that contained a putative promoter for the beta hsd gene (without the phaR gene) was cloned into plasmid pUC2. 5-3.


Input: The plasmid was transformed into HB101 (E. coli) and induced with testosterone.

testosterone


Input: As a result, 3, 17 beta-HSD expression was at a high level, but could not be further enhanced by testosterone.

testosterone


Input: Taken together, phaR knock-out mutants have better ability to degrade steroids than wild-type C. testosteroni ATCC11996 and might therefore be used in bioremediation.

steroids


Input: Biocatalytic production of alpha-hydroxy ketones and vicinal diols by yeast and human aldo-keto reductases.

alpha-hydroxy ketones

vicinal diols


Input: The alpha-hydroxy ketones are used as building blocks for compounds of pharmaceutical interest (such as antidepressants, HIV-protease inhibitors and antitumorals).

alpha-hydroxy ketones


Input: They can be obtained by the action of enzymes or whole cells on selected substrates, such as diketones.

diketones


Input: We have studied the enantiospecificities of several fungal (AKR3C1, AKR5F and AKR5G) and human (AKR1B1 and AKR1B10) aldo-keto reductases in the production of alpha-hydroxy ketones and diols from vicinal diketones.

alpha-hydroxy ketones

diols

vicinal diketones


Input: The reactions have been carried out with pure enzymes and with an NADPH-regenerating system consisting of glucose-6-phosphate and glucose-6-phosphate dehydrogenase.

NADPH


Input: To ascertain the regio and stereoselectivity of the reduction reactions catalyzed by the AKRs, we have separated and characterized the reaction products by means of a gas chromatograph equipped with a chiral column and coupled to a mass spectrometer as a detector.


Input: According to the regioselectivity and stereoselectivity, the AKRs studied can be divided in two groups: one of them showed preference for the reduction of the proximal keto group, resulting in the S-enantiomer of the corresponding alpha-hydroxy ketones.

keto

alpha-hydroxy ketones


Input: The other group favored the reduction of the distal keto group and yielded the corresponding R-enantiomer.

keto


Input: Three of the AKRs used (AKR1B1, AKR1B10 and AKR3C1) could produce 2, 3-butanediol from acetoin.

2, 3-butanediol

acetoin


Input: We have explored the structure/function relationships in the reactivity between several yeast and human AKRs and various diketones and acetoin.

diketones

acetoin


Input: In addition, we have demonstrated the utility of these AKRs in the synthesis of selected alpha-hydroxy ketones and diols.

alpha-hydroxy ketones

diols


Input: Fluorescence lifetime analysis and effect of magnesium ions on binding of NADH to human aldehyde dehydrogenase 1.

magnesium

NADH

aldehyde


Input: Aldehyde dehydrogenase 1 (ALDH1A1) catalyzes the oxidation of toxic aldehydes to carboxylic acids.

Aldehyde

aldehydes

carboxylic acids


Input: Physiologic levels of Mg (2 +) ions decrease ALDH1 activity in part by increasing NADH binding affinity to the enzyme.

Mg (2 +)

NADH


Input: By using time-resolved fluorescence spectroscopy, we have resolved the fluorescent lifetimes (tau) of free NADH in solution (tau = 0. 4 ns) and two enzyme-bound NADH states (tau = 2. 0 ns and tau = 7. 7 ns).

NADH

NADH


Input: We used this technique to investigate the effects of Mg (2 +) ions on the ALDH1A1-NADH binding characteristics and enzyme catalysis.

Mg (2 +)

NADH


Input: From the resolved free and bound NADH fluorescence signatures, the KD values for both NADH conformations in ALDH1A1 ranged from about 24 mu M to 1 mu M for Mg (2 +) ion concentrations of 0-6000 mu M, respectively.

NADH

NADH

Mg (2 +)


Input: The rate constants for dissociation of the enzyme-NADH complex ranged from 0. 03 s (-1) (6000 mu M Mg (2 +)) to 0. 30s (-1) (0 mu M Mg (2 +)) as determined by addition of excess NAD (+) to prevent re-association of NADH and resolving the real-time NADH fluorescence signal.

NADH

Mg (2 +)

Mg (2 +)

NAD (+)

NADH

NADH


Input: During the initial reaction of enzyme with NAD (+) and butyraldehyde, there was an immediate rise in the NADH fluorescence, due to the formation of bound NADH complexes, with a constant steady-state rate of production of free NADH.

NAD (+)

butyraldehyde

NADH

NADH

NADH


Input: As the Mg (2 +) ion concentration was increased, there was a consistent decrease of the enzyme catalytic turnover from 0. 31 s (-1) (0 mu M Mg (2 +)) to 0. 050 s (-1) (6000 mu M Mg (2 +)) and a distinct shift in steady-state conformational population from one that favors the ALDH1-NADH complex with the shorter fluorescence lifetime (33% excess) in the absence of magnesium ion to one that favors the ALDH1-NADH complex with the longer fluorescence lifetime (13% excess) at 6000 mu M Mg (2 +).

Mg (2 +)

Mg (2 +)

Mg (2 +)

NADH

magnesium

NADH

Mg (2 +)


Input: This shift in conformational population at higher Mg (2 +) ion concentrations and to lower enzyme activity may be due to longer residence time of the NADH in the ALDH1 pocket.

Mg (2 +)

NADH


Input: The results from monitoring enzyme catalysis in the absence of magnesium suggests that the ALDH1-NADH complex with the shorter fluorescence lifetime is the form initially produced, and the complex with the longer fluorescence lifetime is produced through isomerization.

magnesium

NADH


Input: Novel topical formulations of Terbinafine-HCl for treatment of onychomycosis.

Terbinafine

HCl


Input: Terbinafine hydrochloride (TBF-HCl) is an active substance that is using for treatment of onychomycosis.

Terbinafine hydrochloride

TBF

HCl


Input: Onychomycosis is a fungal infection which is the most common disease of nail plate.


Input: The nail plate is a barrier which prevents effective topical treatment of ungual disorders.


Input: In this study, TBF-HCl loaded liposome and ethosome formulations and also gel form of these formulations were prepared.

TBF

HCl


Input: The formulations were characterized and in vitro and ex vivo release studies were performed.


Input: Nail characterization studies were also performed to examine the effect of formulations and experimental conditions on nail surface.


Input: As a result, all formulations can serve as efficient formulations for ungual application of TBF-HCl.

TBF

HCl


Input: By the way, the results of the accumulation studies suggested that liposome poloxamer gel formulation could be promising system for ungual drug delivery due to the better accumulation and easier application of the formulation.

poloxamer gel


Input: The interplay between environmental and genetic factors in Parkinson' s disease susceptibility: The evidence for pesticides.


Input: Parkinson' s disease (PD) is a common neurodegenerative disorder characterized by dopaminergic neuron loss in the substantia nigra.


Input: Several genetic and environmental factors have been implicated in the pathogenesis of PD.


Input: Single risk factors are likely to exert relatively minor effects, whereas their interaction may prove to be sufficient to cause PD.


Input: In the present review we summarize current knowledge from human genetic association studies regarding the interaction between gene polymorphisms and pesticide exposure in the risk of PD.


Input: A number of genetic association studies have investigated joint effects between genes and pesticides on PD risk.


Input: They have provided some evidence that genetic susceptibility either in metabolism, elimination and transport of pesticides or in the extent of mitochondrial dysfunction, oxidative stress and neuronal loss may predispose individuals to PD if they have been exposed to pesticides.


Input: These findings confirm the importance of considering pesticide-gene interactions in future studies in order to gain a better understanding of the pathogenic mechanisms of PD.


Input: Adaptive changes in basal and stress-induced HPA activity in lactating and post-lactating female rats.


Input: Lactation represents a period of marked adaptation of the hypothalamo-pituitary-adrenal HPA axis.


Input: We characterized basal and stress-induced HPA activity during lactation and experimental weaning using dynamic blood sampling in rats.


Input: Pulsatile and diurnal corticosterone release occurred at all reproductive stages studied (virgin; day 10 of lactation; 3 and 14 days after experimental weaning on day 10 of lactation).

corticosterone


Input: However, in lactating rats the diurnal peak was significantly reduced, resulting in a flattened rhythm, and three days after weaning, basal HPA activity was markedly suppressed: the number of pulses and underlying basal levels of corticosterone were reduced and the diurnal rise phase delayed.

corticosterone


Input: Marked changes in the HPA response to 10 min noise stress also occurred at these times: being completely absent in lactating animals, but restored and highly prolonged in early weaned animals.


Input: Injection of methylprednisolone (2 mg, iv) was used to determine whether changes in fast glucocorticoid suppression correlated with these adaptive changes.

methylprednisolone


Input: Methylprednisolone induced a rapid suppression of corticosterone in virgin animals, but this effect was markedly attenuated in lactating and early weaned animals and was accompanied by significant changes in relative expression of hippocampal glucocorticoid and mineralocorticoid receptor mRNA.

Methylprednisolone

corticosterone


Input: All effects were reversed or partially reversed 14 days after experimental weaning.


Input: Thus, the presence of the pups has an important influence on regulation of the HPA axis, and while postpartum adaptations are reversible, acute weaning evokes marked reorganisation of basal and stress-induced HPA activity.


Input: Tamoxifen represses miR-200 microRNAs and promotes epithelial-to-mesenchymal transition by up-regulating c-Myc in endometrial carcinoma cell lines.

Tamoxifen


Input: Although tamoxifen (TAM), a selective estrogen receptor modulator, has been widely used in the treatment of hormone-responsive breast cancer, its estrogen-like effect increases the risk of endometrial cancer.

tamoxifen

TAM

estrogen

estrogen


Input: However, the molecular mechanisms of TAM-induced endometrial carcinoma still remain unclear.

TAM


Input: In this report, we explored the role of microRNAs (miRNAs) in TAM-induced epithelial-mesenchymal transition (EMT) in ECC-1 and Ishikawa endometrial cancer cell lines and found miR-200 is involved in this process via the regulation of c-Myc.

TAM


Input: When treated with TAM, ECC-1 and Ishikawa cells were characterized by higher invasiveness and motility and underwent EMT.

TAM


Input: miR-200, a miRNA family with tumor suppressive functions in a wide range of cancers, was found reduced in response to TAM treatment.

TAM


Input: Consistent with zinc finger E-box binding homeobox 2, which was confirmed as a direct target of miR-200b in endometrial cancer cell lines, some other key factors of EMT such as Snail and N-cadherin increased, whereas E-cadherin decreased in the TAM-treated cells, contributing to TAM-induced EMT in these endometrial cancer cells.

zinc

TAM

TAM


Input: In addition, we showed that c-Myc directly binds to and represses the promoter of miR-200 miRNAs, and its up-regulation in TAM-treated endometrial cancer cells leads to the down-regulation of miR-200 and eventually to EMT.

TAM


Input: Collectively, our data suggest that TAM can repress the miR-200 family and induce EMT via the up-regulation of c-Myc in endometrial cancer cells.

TAM


Input: These findings describe a possible mechanism of TAM-induced EMT in endometrial cancer and provide a potential new therapeutic strategy for it.

TAM


Input: Apoptotic transcriptional profile remains activated in late remodeled left ventricle after myocardial infarction in swine infarcted hearts with preserved ejection fraction.


Input: Apoptosis is involved in both acute and chronic loss of cardiomyocytes after myocardial infarction (MI).


Input: To date, the pathophysiological significance of an apoptotic transcriptional profile activated in the post-ischemic remodeled myocardium, in the absence of hemodynamic factors secondary to left ventricular (LV) dysfunction, still remains to be determined.


Input: The mRNA expression of pro-and anti-apoptotic factors was determined in a swine model of non-reperfused MI with preserved LV ejection fraction.


Input: The extent of cell death was evaluated by histological analysis.


Input: Male adult farm pigs with MI (n = 5), induced by permanent surgical ligation of the left anterior descending coronary artery and sham-operated adult farm pigs as control (n = 7) were studied.


Input: Tissue samples were collected from the border (BZ) and remote zone (RZ) of the infarcted area to identify possible regional effects.


Input: After 4 weeks post-MI, the infarct size was 13 +/- 1% of the LV wall mass in absence of contractile dysfunction.


Input: In BZ, there was increased mRNA expression of Casp-3 (BZ vs Controls: 0. 51 +/- 0. 15 vs 1. 39 +/- 0. 04, p < 0. 001), a significant decrease in Bcl-2 (by 63%), associated with an increase in apoptotic cells, as revealed by TUNEL staining and cleaved-Casp-3 presence.


Input: In contrast, in the RZ there was a significant reduction of pro-apoptotic factors compared to BZ (by 80% for Casp-3), in presence of scattered apoptotic cells, increased gene expression of Hsp72 (1. 82 +/- 0. 21 vs 1. 34 +/- 0. 08, p = 0. 037) and iNOS (1. 51 +/- 0. 14 vs 1. 19 +/- 0. 05, p < 0. 05) compared to control.


Input: In conclusion, the LV distribution of apoptotic transcriptional profile revealed that apoptotic cell death is highly detectable in BZ, possibly explaining the local abnormalities of myocardial cell survival in a porcine model of MI with normal overall function.


Input: Poor definitions threaten drug trial safety in India.


Input: India has become a hotbed of clinical trials, but recent reports of safety lapses have prompted calls for better regulation in this area.


Input: Currently, trial requirements can be relaxed if doing so is in the' public interest', but a clearer definition of what this means is needed before this provision should be used.


Input: Combined analytical ultracentrifugation, light scattering and fluorescence spectroscopy studies on the functional associations of the bacterial division FtsZ protein.


Input: The combined application of different biophysical techniques-analytical ultracentrifugation, light scattering and fluorescence-based assays-to study the ligand-linked self-association and assembly properties of the cell division protein FtsZ from Escherichia coli is described.


Input: These reactions are thought to be important for the formation of the dynamic division ring that drives bacterial cytokinesis.


Input: In addition, the use of this orthogonal experimental approach to measure the interactions between FtsZ oligomers (GDP forms) and polymers (GTP forms) with two variants (a soluble form and a full-length protein incorporated in phospholipid bilayer nanodiscs) of the ZipA protein, which provides membrane tethering to FtsZ, is described as well.

GDP

GTP


Input: The power of a global analysis of the results obtained from complementary biophysical methods to discriminate among alternative self-and hetero-associating schemes and to propose a more robust description of the association reactions involved is emphasized.


Input: This orthogonal approach will contribute to complete our quantitative understanding of the initial events of bacterial division.


Input: Manganese-induced oxidative DNA damage in neuronal SH-SY5Y cells: attenuation of thymine base lesions by glutathione and N-acetylcysteine.

Manganese

thymine

glutathione

N-acetylcysteine


Input: Manganese (Mn) is an essential trace element required for normal function and development.

Manganese

Mn


Input: However, exposure to this metal at elevated levels may cause manganism, a progressive neurodegenerative disorder with neurological symptoms similar to idiopathic Parkinson' s disease (IPD).


Input: Elevated body burdens of Mn from exposure to parental nutrition, vapors in mines and smelters and welding fumes have been associated with neurological health concerns.

Mn


Input: The underlying mechanism of Mn neurotoxicity remains unclear.

Mn


Input: Accordingly, the present study was designed to investigate the toxic effects of Mn (2 +) in human neuroblastoma SH-SY5Y cells.

Mn (2 +)


Input: Mn (2 +) caused a concentration dependent decrease in SH-SY5Y cellular viability compared to controls.

Mn (2 +)


Input: The LD50 value was 12. 98 mu M Mn (2 +) (p < 0. 001 for control vs. 24h Mn treatment).

Mn (2 +)

Mn


Input: Both TUNEL and annexin V/propidium iodide (PI) apoptosis assays confirmed the induction of apoptosis in the cells following exposure to Mn (2 +) (2 mu M, 62 mu M or 125 mu M).

propidium iodide

Mn (2 +)


Input: In addition, Mn (2 +) induced both the formation and accumulation of DNA single strand breaks (via alkaline comet assay analysis) and oxidatively modified thymine bases (via gas chromatography/mass spectrometry analysis).

Mn (2 +)

thymine


Input: Pre-incubation of the cells with characteristic antioxidants, either 1mM N-acetylcysteine (NAC) or 1mM glutathione (GSH) reduced the level of DNA strand breaks and the formation of thymine base lesions, suggesting protection against oxidative cellular damage.

N-acetylcysteine

NAC

glutathione

GSH

thymine


Input: Our findings indicate that (1) exposure of SH-SY5Y cells to Mn promotes both the formation and accumulation of oxidative DNA damage, (2) SH-SY5Y cells with accumulated DNA damage are more likely to die via an apoptotic pathway and (3) the accumulated levels of DNA damage can be abrogated by the addition of exogenous chemical antioxidants.

Mn


Input: This is the first known report of Mn (2 +)-induction and antioxidant protection of thymine lesions in this SH-SY5Y cell line and contributes new information to the potential use of antioxidants as a therapeutic strategy for protection against Mn (2 +)-induced oxidative DNA damage.

Mn (2 +)

thymine

Mn (2 +)


Input: Acrolein induces Alzheimer' s disease-like pathologies in vitro and in vivo.

Acrolein


Input: The pathologic mechanisms of Alzheimer' s disease (AD) have not been fully uncovered.


Input: Acrolein, a ubiquitous dietary pollutant and by-product of oxidative stress, can induce cytotoxicity in neurons, which might play an important role in the etiology of AD.

Acrolein


Input: Here, we examined the effects of Acrolein on the AD pathologies in vitro and in vivo.

Acrolein


Input: We found Acrolein induced HT22 cells death in concentration-and time-dependent manners.

Acrolein


Input: Interestingly, Acrolein increased proteins' levels of amyloid precursor protein (APP), beta-secretase (BACE-1) and the amyloid beta-peptide transporter receptor for advanced glycation end products, and decreased A-disintegrin and metalloprotease (ADAM) 10 levels.

Acrolein


Input: In vivo, chronic oral exposure to Acrolein (2. 5 mg/kg/day by intragastric gavage for 8 weeks) induced mild cognitive declination and pyknosis/atrophy of hippocampal neurons.

Acrolein


Input: The activity of superoxide dismutase was down-regulated while the level of malondialdehyde was up-regulated in rat brain.

superoxide

malondialdehyde


Input: Moreover, Acrolein resulted in activation of astrocytes, up-regulation of BACE-1 in cortex and down-regulation of ADAM-10 in hippocampus and cortex.

Acrolein


Input: Taken together, our findings suggest that exposure to Acrolein induces AD-like pathology in vitro and in vivo.

Acrolein


Input: Scavenging Acrolein might be beneficial for the therapy of AD.

Acrolein


Input: Inhalation of uranium nanoparticles: respiratory tract deposition and translocation to secondary target organs in rats.

uranium


Input: Uranium nanoparticles (< 100 nm) can be released into the atmosphere during industrial stages of the nuclear fuel cycle and during remediation and decommissioning of nuclear facilities.

Uranium


Input: Explosions and fires in nuclear reactors and the use of ammunition containing depleted uranium can also produce such aerosols.

uranium


Input: The risk of accidental inhalation of uranium nanoparticles by nuclear workers, military personnel or civilian populations must therefore be taken into account.

uranium


Input: In order to address this issue, the absorption rate of inhaled uranium nanoparticles needs to be characterised experimentally.

uranium


Input: For this purpose, rats were exposed to an aerosol containing 10 7 particles of uranium per cm (3) (CMD = 38 nm) for 1h in a nose-only inhalation exposure system.

uranium


Input: Uranium concentrations deposited in the respiratory tract, blood, brain, skeleton and kidneys were determined by ICP-MS.

Uranium


Input: Twenty-seven percent of the inhaled mass of uranium nanoparticles was deposited in the respiratory tract.

uranium


Input: One-fifth of UO 2 nanoparticles were rapidly cleared from lung (T ((1/2)) = 2. 4 h) and translocated to extrathoracic organs.

UO 2


Input: However, the majority of the particles were cleared slowly (T ((1/2)) = 141. 5 d).


Input: Future long-term experimental studies concerning uranium nanoparticles should focus on the potential lung toxicity of the large fraction of particles cleared slowly from the respiratory tract after inhalation exposure.

uranium


Input: A RASSCF study of free base, magnesium and zinc porphyrins: accuracy versus efficiency.

magnesium and zinc porphyrins


Input: The restricted-active-space self-consistent-field methodology is successfully applied to the study of free base-and regular metalloporphyrins, the latter containing magnesium and zinc central ions.

metalloporphyrins

magnesium

zinc


Input: It is shown that inclusion of all excitations involving the Gouterman frontier orbitals in the RAS2 subspace results in a numerically stable approach, producing highly accurate results at a fraction of the computational cost of the complete-active-space self-consistent-field method, whereas increasing RAS2 beyond this size leads to only modest improvement.


Input: Topological and orbital analysis shows that the approach is also able to give a highly accurate description of the electronic wavefunction.


Input: Inclusion of the entire pi-conjugated subsystem in the active space results in more accurate excitation energies and a reduction in the dependence on the exact form of the perturbational Hamiltonian used to include dynamic correlation.


Input: The larger active space also resolves a quantitative disagreement in results obtained with and without the inclusion of dynamic correlation.


Input: Role of immunoglobulin G fragment C receptor polymorphism-mediated antibody-dependant cellular cytotoxicity in colorectal cancer treated with cetuximab therapy.


Input: Antibody-dependent cellular cytotoxicity (ADCC), which is activated by effector cells via immunoglobulin G (IgG) fragment C receptors (FcRs), was proposed as a mechanism of cetuximab efficacy.


Input: Peripheral blood mononuclear cells (PBMCs) from 23 healthy donors and 13 patients with metastatic colorectal cancer (mCRC) treated with cetuximab were tested for Fc gamma R polymorphisms and cetuximab-mediated ADCC.


Input: ADCC was measured by chromium-51 release on a epidermal growth factor receptor (EGFR)-positive human colon cancer cell line.


Input: Overall, 86 mCRC patients were genotyped for study purposes.


Input: PBMCs harbouring the Fc gamma RIIIa 158 V/V genotype had a significantly higher cetuximab-mediated ADCC.


Input: No correlation was found between Fc gamma R polymorphisms and response rate or time to progression after cetuximab-based therapy.


Input: Despite the in vitro analysis showing that the Fc gamma RIIIa 158 V/V genotype is associated with higher ADCC, clinical data do not support a predictive role of Fc gamma RIIIa polymorphisms in mCRC treated with cetuximab. The Pharmacogenomics Journal advance online publication, 8 January 2013; doi: 10. 1038/tpj. 2012. 54.


Input: Inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature: proper classification and nomenclature.


Input: Increased urinary 3-methylglutaconic acid excretion is a relatively common finding in metabolic disorders, especially in mitochondrial disorders.

3-methylglutaconic acid


Input: In most cases 3-methylglutaconic acid is only slightly elevated and accompanied by other (disease specific) metabolites.

3-methylglutaconic acid


Input: There is, however, a group of disorders with significantly and consistently increased 3-methylglutaconic acid excretion, where the 3-methylglutaconic aciduria is a hallmark of the phenotype and the key to diagnosis.

3-methylglutaconic acid


Input: Until now these disorders were labelled by roman numbers (I-V) in the order of discovery regardless of pathomechanism.


Input: Especially, the so called " unspecified " 3-methylglutaconic aciduria type IV has been ever growing, leading to biochemical and clinical diagnostic confusion.


Input: Therefore, we propose the following pathomechanism based classification and a simplified diagnostic flow chart for these " inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature ".


Input: One should distinguish between " primary 3-methylglutaconic aciduria " formerly known as type I (3-methylglutaconyl-CoA hydratase deficiency, AUH defect) due to defective leucine catabolism and the-currently known-three groups of " secondary 3-methylglutaconic aciduria ".

leucine


Input: The latter should be further classified and named by their defective protein or the historical name as follows: i) defective phospholipid remodelling (TAZ defect or Barth syndrome, SERAC1 defect or MEGDEL syndrome) and ii) mitochondrial membrane associated disorders (OPA3 defect or Costeff syndrome, DNAJC19 defect or DCMA syndrome, TMEM70 defect).


Input: The remaining patients with significant and consistent 3-methylglutaconic aciduria in whom the above mentioned syndromes have been excluded, should be referred to as " not otherwise specified (NOS) 3-MGA-uria " until elucidation of the underlying pathomechanism enables proper (possibly extended) classification.


Input: Neuroprotective and anti-inflammatory properties of a coffee component in the MPTP model of Parkinson' s disease.

MPTP


Input: Consumption of coffee is associated with reduced risk of Parkinson' s disease (PD), an effect that has largely been attributed to caffeine.


Input: However, coffee contains numerous components that may also be neuroprotective.


Input: One of these compounds is eicosanoyl-5-hydroxytryptamide (EHT), which ameliorates the phenotype of alpha-synuclein transgenic mice associated with decreased protein aggregation and phosphorylation, improved neuronal integrity and reduced neuroinflammation.

EHT


Input: Here, we sought to investigate if EHT has an effect in the MPTP model of PD.

EHT

MPTP


Input: Mice fed a diet containing EHT for four weeks exhibited dose-dependent preservation of nigral dopaminergic neurons following MPTP challenge compared to animals given control feed.

EHT

MPTP


Input: Reductions in striatal dopamine and tyrosine hydroxylase content were also less pronounced with EHT treatment.

dopamine

tyrosine

EHT


Input: The neuroinflammatory response to MPTP was markedly attenuated, and indices of oxidative stress and JNK activation were significantly prevented with EHT.

MPTP

EHT


Input: In cultured primary microglia and astrocytes, EHT had a direct anti-inflammatory effect demonstrated by repression of lipopolysaccharide-induced NF kappa B activation, iNOS induction, and nitric oxide production.

EHT

nitric oxide


Input: EHT also exhibited a robust anti-oxidant activity in vitro.

EHT


Input: Additionally, in SH-SY5Y cells, MPP (+)-induced demethylation of phosphoprotein phosphatase 2A (PP2A), the master regulator of the cellular phosphoregulatory network, and cytotoxicity were ameliorated by EHT.

MPP (+)

EHT


Input: These findings indicate that the neuroprotective effect of EHT against MPTP is through several mechanisms including its anti-inflammatory and antioxidant activities as well as its ability to modulate the methylation and hence activity of PP2A.

EHT

MPTP


Input: Our data, therefore, reveal a strong beneficial effect of a novel component of coffee in multiple endpoints relevant to PD.


Input: Urinary chromium excretion in response to an insulin challenge is not a biomarker for chromium status.

chromium

chromium


Input: Over 50 years ago, chromium (Cr) was proposed to be an essential trace element; however, recent studies indicate that this status should be removed as the effects of Cr supplementation appear to be pharmacological rather than nutritional.

chromium

Cr

Cr


Input: The pharmacological basis for Cr' s effects can explain the inability of investigators to discover a biomarker for Cr status.

Cr

Cr


Input: One potential biomarker has not been examined to date.


Input: Cr is known to be mobilized in the body in response to insulin (or insulin release in response to a glucose challenge), resulting in an increase in urinary Cr excretion.

Cr

glucose

Cr


Input: The magnitude of increase in urinary Cr loss as a function of dietary Cr intake was tested as a potential biomarker for Cr.

Cr

Cr

Cr


Input: Zucker lean rats housed in carefully controlled metal-free conditions were provided a series of purified diets containing variable Cr contents (from 16 mu g/kg diet to 2, 000 mu g/kg) for 23 weeks.

Cr


Input: The 16 mu g/kg diet contained less Cr than any diet examined to date.

Cr


Input: Urine samples were collected before and after insulin and glucose challenges (0, 2, 6, and 12 h postinjection).

glucose


Input: Urinary Cr levels were analyzed by the standard method of addition using graphite furnace atomic absorption.

Cr

graphite


Input: The rate of urinary Cr loss after a glucose or insulin challenge was found to not be dependent on the Cr content of the rats' diets.

Cr

glucose

Cr


Input: Blood iron levels of the rats were also measured to determine if the addition of Cr to the diet altered iron status.

iron

Cr

iron


Input: The Cr content of the diet was found to have no affect on blood iron levels.

Cr

iron


Input: Overall, the study demonstrated that insulin-stimulated urinary Cr excretion cannot be used as a biomarker for Cr status.

Cr

Cr


Input: Chrysin and Luteolin Attenuate Diabetes-Induced Impairment in Endothelial-Dependent Relaxation: Effect on Lipid Profile, AGEs and NO Generation.

Chrysin

Luteolin

NO


Input: Chrysin and luteolin are two important plant flavonoids.

Chrysin

luteolin

flavonoids


Input: In the present study, we hypothesized that they protect against deleterious vascular effects of diabetes.


Input: Diabetes was induced in rats by streptozotocin (STZ) injection, while chrysin and luteolin were administered two weeks after STZ administration for 6 weeks.

streptozotocin

STZ

chrysin

luteolin

STZ


Input: Then, blood pressure (BP) and serum levels of glucose, advanced glycation end products (AGEs), triglycerides (TGs), total cholesterol and low density lipoprotein-cholesterol (LDL-C) were determined.

glucose

triglycerides

TGs

cholesterol

cholesterol


Input: Concentration response curves for KCl, phenylephrine (PE), acetylcholine (ACh) and ACh-induced NO generation were obtained in isolated aorta.

KCl

phenylephrine

acetylcholine

ACh

ACh

NO


Input: Compared with control, diabetes increased diastolic and systolic BP, while chrysin and luteolin attenuated diastolic BP elevation without affecting the developed hyperglycemia.

chrysin

luteolin


Input: Diabetes increased contractile response of aorta to KCl, PE, decreased relaxation response to ACh, while chrysin and luteolin prevented the impaired response to ACh.

KCl

ACh

chrysin

luteolin

ACh


Input: In addition, diabetes was accompanied by elevated levels of TGs, total and LDL cholesterol, while both chrysin and luteolin prevented this dyslipidemia.

TGs

cholesterol

chrysin

luteolin


Input: Furthermore, chrysin decreased the elevated AGEs level in serum of diabetic animals, while luteolin abrogated the impaired NO generation in diabetic aorta.

chrysin

luteolin

NO


Input: Collectively, chrysin and luteolin attenuate diabetes-evoked impairment in endothelial-dependent relaxation possibly via ameliorating detrimental changes in lipid profile, AGEs and NO generation.

chrysin

luteolin

NO


Input: Copyright (c) 2013 John Wiley & Sons, Ltd.


Input: Anti-platelet Activity of Erythro-(7S, 8R)-7-acetoxy-3, 4, 3 `, 5 `-tetramethoxy-8-O-4 `-neolignan from Myristica fragrans.

Erythro-(7S, 8R)-7-acetoxy-3, 4, 3 `, 5 `-tetramethoxy-8-O-4 `-neolignan


Input: Platelets play a critical role in pathogenesis of cardiovascular disorders and strokes.


Input: The inhibition of platelet function is beneficial for the treatment and prevention of these diseases.


Input: In this study, we investigated the anti-platelet activity of erythro-(7S, 8R)-7-acetoxy-3, 4, 3 `, 5 `-tetramethoxy-8-O-4 `-neolignan (EATN), a neolignan isolated from Myristica fragrans, using human platelets.

erythro-(7S, 8R)-7-acetoxy-3, 4, 3 `, 5 `-tetramethoxy-8-O-4 `-neolignan

EATN

neolignan


Input: EATN preferentially inhibited thrombin-and platelet-activating factor (PAF)-induced platelet aggregation without affecting platelet damage in a concentration-dependent manner with IC (50) values of 3. 2 +/- 0. 4 and 3. 4 +/- 0. 3 mu M, respectively.

EATN


Input: However, much higher concentrations of EATN were required to inhibit platelet aggregation induced by arachidonic acid.

EATN

arachidonic acid


Input: EATN also inhibited thrombin-induced serotonin and ATP release, and thromboxane B (2) formation in human platelets.

EATN

serotonin

ATP

thromboxane B (2)


Input: Moreover, EATN caused an increase in cyclic AMP (cAMP) levels and attenuated intracellular Ca (2 +) mobilization in thrombin-activated human platelets.

EATN

cyclic AMP

cAMP

Ca (2 +)


Input: Therefore, we conclude that the inhibitory mechanism of EATN on platelet aggregation may increase cAMP levels and subsequently inhibit intracellular Ca (2 +) mobilization by interfering with a common signaling pathway rather than by directly inhibiting the binding of thrombin or PAF to their receptors.

EATN

cAMP

Ca (2 +)


Input: This is the first report of the anti-platelet activity of EATN isolated from M. fragrans.

EATN


Input: Copyright (c) 2013 John Wiley & Sons, Ltd.


Input: Materiomics: an-omics approach to biomaterials research.


Input: The past fifty years have seen a surge in the use of materials for clinical application, but in order to understand and exploit their full potential, the scientific complexity at both sides of the interface--the material on the one hand and the living organism on the other hand--needs to be considered.


Input: Technologies such as combinatorial chemistry, recombinant DNA as well as computational multi-scale methods can generate libraries with a very large number of material properties whereas on the other side, the body will respond to them depending on the biological context.


Input: Typically, biological systems are investigated using both holistic and reductionist approaches such as whole genome expression profiling, systems biology and high throughput genetic or compound screening, as already seen, for example, in pharmacology and genetics.


Input: The field of biomaterials research is only beginning to develop and adopt these approaches, an effort which we refer to as " materiomics ".


Input: In this review, we describe the current status of the field, and its past and future impact on the biomedical sciences.


Input: We outline how materiomics sets the stage for a transformative change in the approach to biomaterials research to enable the design of tailored and functional materials for a variety of properties in fields as diverse as tissue engineering, disease diagnosis and de novo materials design, by combining powerful computational modelling and screening with advanced experimental techniques.


Input: Hydrogen sulfide, the next potent preventive and therapeutic agent in aging and age-associated diseases.

Hydrogen sulfide


Input: Hydrogen sulfide (H (2) S) is the third endogenous signaling gasotransmitter, following nitric oxide and carbon monoxide.

Hydrogen sulfide

H (2) S

nitric oxide

carbon monoxide


Input: It is physiologically generated by cystathionine-gamma-lyase, cystathionine-beta-synthase, and 3-mercaptopyruvate sulfurtransferase.

cystathionine

cystathionine


Input: H (2) S has been gaining increasing attention as an important endogenous signaling molecule because of its significant effects on the cardiovascular and nervous systems.

H (2) S


Input: Substantial evidence shows that H (2) S is involved in aging by inhibiting free-radical reactions, activating SIRT1, and probably interacting with the age-related gene Klotho.

H (2) S


Input: Moreover, H (2) S has been shown to have therapeutic potential in age-associated diseases.

H (2) S


Input: This article provides an overview of the physiological functions and effects of H (2) S in aging and age-associated diseases, and proposes the potential health and therapeutic benefits of H (2) S.

H (2) S

H (2) S


Input: Chemical composition and antibacterial activities of the essential oils isolated from Juniperus thurifera L. var.


Input: Africana.


Input: This study describes the chemical composition and antibacterial activities of essential oils of Moroccan Juniperus thurifera L. var.


Input: Africana (Cupressaceae).


Input: The essential oil of dried leaves was isolated by hydrodistillation, vapohydrodistillation and microwaves.


Input: Sixty-four compounds in J. thurifera L. var.


Input: Africana oils were identified (79. 9%, 92. 4% and 98. 4% of the oil, respectively).


Input: The most abundant compound in J. thurifera L. var.


Input: Africana oils is sabinene (38%, 36. 2% and 39. 4%).

sabinene


Input: Antibacterial activities of J. thurifera essential oils was tested against bacteria Gram (-) and Gram (+).


Input: The oil is very active against all bacteria tested except Pseudomonas, which turned out to be very resistant.


Input: Composition and evaluation of the anti-inflammatory and anticancer activities of the essential oil from Annona sylvatica A.


Input: St.-Hil.


Input: The essential oil from the leaves of Annona sylvatica (EOAS) was extracted by hydrodistillation, and the analysis was performed by gas chromatography-mass spectrometry.


Input: The main compounds identified in the EOAS were sesquiterpenes, such as hinesol, z-caryophyllene, beta-maaliene, gamma-gurjunene, silphiperfol-5-en-3-ol, ledol, cubecol-1-epi, and muurola-3, 5-diene.

sesquiterpenes

hinesol

z-caryophyllene

beta-maaliene

gamma-gurjunene

ledol

muurola-3, 5-diene


Input: Oral administration of the EOAS (20 and 200 mg/kg) and subcutaneous injection of dexamethasone (0. 5 mg/kg, reference drug) significantly inhibited carrageenan-and complete Freund' s adjuvant-induced mouse paw edema.

dexamethasone


Input: The anticancer activity the EOAS showed growth inhibitory activity on all cell lines when administered in a high concentration.


Input: The EOAS inhibited the growth of human cancer cell lines with GI (50) values in the range of 36. 04-45. 37 mu g/mL on all of the cell lines tested.


Input: This work describes for the first time the anti-inflammatory and anticancer effects of the essential oil of A. sylvatica and its composition.


Input: Considering that drugs currently available for the treatment of inflammatory and cancer conditions show undesirable side-effects, the present results may have clinical relevance and open new possibilities for the development of novel anti-inflammatory and anticancer drugs.


Input: Topical wound-healing effects and phytochemical composition of heartwood essential oils of Juniperus virginiana L., Juniperus occidentalis Hook., and Juniperus ashei J.


Input: Buchholz.


Input: Ethnobotanical surveys indicated that in the traditional medicines worldwide, several Juniperus species are utilized as antihelmintic, diuretic, stimulant, antiseptic, carminative, stomachic, antirheumatic, antifungal, and for wound healing.


Input: In the present study, essential oils obtained from heartwood samples of Juniperus virginiana L., Juniperus occidentalis Hook. and Juniperus ashei J.


Input: Buchholz were evaluated for wound healing and anti-inflammatory activities by using in vivo experimental methods.


Input: The essential oils were obtained by the supercritical carbon dioxide extraction method.

carbon dioxide


Input: Linear incision and circular excision wound models were performed for the wound-healing activity assessment.


Input: The tissues were also evaluated for the hydroxyproline content as well as histopathologically.

hydroxyproline


Input: To evaluate the anti-inflammatory activity of the essential oils, the test used was an acetic acid-induced increase in capillary permeability.

acetic acid


Input: The essential oil of J. occidentalis showed the highest activity on the in vivo biological activity models.


Input: Additionaly, the oil of J. virginiana was found highly effective in the anti-inflammatory activity method.


Input: The experimental data demonstrated that essential oil of J. occidentalis displayed significant wound-healing and anti-inflammatory activities.


Input: Isolation and anti-HIV-1 activity of a new sesquiterpene lactone from Calocephalus brownii F.

sesquiterpene lactone


Input: Muell.


Input: As part of our ongoing collaborative effort to discover potential anti-HIV-1 agents from plants, the CH (2) Cl (2) extract of Calocephalus brownii F.

CH (2) Cl (2)


Input: Muell. was phytochemically investigated, which resulted in the isolation of two sesquiterpene lactones of the cis-fused guaianolides type, one new identified as 1 alpha-hydroxy-3 beta H-3 alpha, 4 alpha-epoxy-4, 10-dimethyl-5 alpha H, 7 alpha H, 8 beta H, 10 alpha H-guai-11 (13)-ene-7, 8-olide (1) and one known identified 1 alpha H-4 alpha-hydroxy-4, 10-dimethyl-5 alpha H, 7 alpha H, 8 beta H, 10 alpha H-guai-11 (13)-ene-7, 8-olide (2).

sesquiterpene lactones

cis-fused guaianolides

1 alpha-hydroxy-3 beta H-3 alpha, 4 alpha-epoxy-4, 10-dimethyl-5 alpha H, 7 alpha H, 8 beta H, 10 alpha H-guai-11 (13)-ene-7, 8-olide

1 alpha H-4 alpha-hydroxy-4, 10-dimethyl-5 alpha H, 7 alpha H, 8 beta H, 10 alpha H-guai-11 (13)-ene-7, 8-olide


Input: Their structures were elucidated on the bases of IR, UV, 1D-NMR, 2D-NMR, DIFNOE and high-resolution ESI-TOF-MS.


Input: The anti-HIV-1 activity was evaluated and revealed that STLs (1 and 2) caused a reduction for the viability of mock-infected MT-4 cells by CC (50) = 29. 1 and 0. 5 mu g/mL, respectively, and caused 50% protection of MT-4 cells against HIV-1 induced cytopathogeneticy by EC (50) = 29. 1 and 0. 5 mu g/mL, respectively, as compared with Efavirenz (EFV) as positive control that showed a CC (50) = 11. 6 and EC (50) = 0. 0006 mu g/mL, using the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide method.

Efavirenz

EFV

3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide


Input: Risk of completed suicide after bariatric surgery: a systematic review.


Input: Bariatric surgery is one of the most effective treatments for morbid obesity, and a large body of research indicates significant long-term weight loss.


Input: While overall mortality decreases in patients who received bariatric surgery, a number of studies have shown that suicide rates are higher in bariatric patients than in control groups.


Input: The objective of this study was to present a systematic review of suicide mortality after bariatric surgery and calculate an estimate for the suicide rate.


Input: Literature researches of the databases PubMed, Web of Knowledge, PsychInfo, ScienceDirect and Google Scholar were conducted.


Input: Thirty studies concerning bariatric surgery and completed suicides met the inclusion criteria.


Input: We included 28 studies in the estimation of a suicide rate for the bariatric population.


Input: Only one study (Tindle et al.) put a main focus on suicide after bariatric surgery; this was therefore chosen as an adequate reference figure for comparison.


Input: The other 27 chosen studies were compared with World Health Organization data and the suicide rate reported by Tindle et al.


Input: Twenty-three thousand eight hundred eighty-five people were included in the analysis.


Input: In the literature, we found a total of 95 suicides when examining 190, 000 person-years of post-bariatric surgery data.


Input: Little information was provided describing the reasons for suicide and the time-point of these events after surgery.


Input: We estimated a suicide rate of 4. 1/10, 000 person-years (95% confidence interval [3. 2, 5. 1]/10, 000 person-years).


Input: A comparison with Tindle et al. demonstrates that their rate is significantly higher than our estimate (P = 0. 03).


Input: Bariatric surgery patients show higher suicide rates than the general population.


Input: Therefore, there is a great need to identify persons at risk and post-operative psychological monitoring is recommended.


Input: CO oxidation on colloidal Au (0. 80) Pd (0. 20)-Fe (x) O (y) dumbbell nanocrystals.

CO

Au (0. 80) Pd (0. 20)-Fe (x) O (y)


Input: We report a colloidal synthesis of Au (0. 80) Pd (0. 20)-Fe (x) O (y) dumbbell nanocrystals (NCs) derived from Au (0. 75) Pd (0. 25) NCs by metal oxide overgrowth.

Au (0. 80) Pd (0. 20)-Fe (x) O (y)

Au (0. 75) Pd (0. 25)

metal oxide


Input: We compared the catalytic activity of the two types of NCs in the CO oxidation reaction (CO + 1/2O (2) --> CO (2)), after they had been dispersed on an alumina nanopowder support.

CO

CO

1/2O (2)

CO (2)

alumina


Input: In both cases, the surface active sites were identified by means of in situ diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS).


Input: The enhanced catalytic performance of the dumbbell NCs (Au (0. 80) Pd (0. 20)-Fe (x) O (y)) catalyst over that of the initial Au (0. 75) Pd (0. 25) NCs could be correlated to the presence of the epitaxial connection between the Fe (x) O (y) and the Au (0. 80) Pd (0. 20) domains (as the main factor).

Au (0. 80) Pd (0. 20)-Fe (x) O (y)

Au (0. 75) Pd (0. 25)

Fe (x) O (y)

Au (0. 80) Pd (0. 20)


Input: Such connection should result in an electron flow from the metal oxide (Fe (x) O (y)) domain to the noble metal (Au (0. 80) Pd (0. 20)) domain and appears to influence favorably the nature and composition of the catalytically active surface sites of the dumbbells.

metal oxide

Fe (x) O (y)

Au (0. 80) Pd (0. 20)


Input: Our experiments indicate indeed that, when the metal alloy domain is attached to the metal oxide domain (that is, in the dumbbell), surface Pd species are more active than in the case of the initial Au (0. 75) Pd (0. 25) NCs and also Au (delta-) sites are formed that were not present on the initial Au (0. 75) Pd (0. 25) NCs.

metal oxide

Pd

Au (0. 75) Pd (0. 25)

Au

Au (0. 75) Pd (0. 25)


Input: Honey as a source of dietary antioxidants: structures, bioavailability and evidence of protective effects against human chronic diseases.


Input: In the long human tradition honey has been used not only as a nutrient but also as a medicine.


Input: Its composition is rather variable and depends on the floral source and on external factors, such as seasonal, environmental conditions and processing.


Input: In this review, specific attention is focused on absorption, metabolism, and beneficial biological activities of honey compounds in human.


Input: Honey is a supersaturated solution of sugars, mainly composed of fructose (38%) and glucose (31%), containing also minerals, proteins, free amino acids, enzymes, vitamins and polyphenols.

sugars

fructose

glucose

free amino acids

polyphenols


Input: Among polyphenols, flavonoids are the most abundant and are closely related to its biological functions.

polyphenols

flavonoids


Input: Honey positively affects risk factors for cardiovascular diseases by inhibiting inflammation, improving endothelial function, as well as the plasma lipid profile, and increasing low-density lipoprotein resistance to oxidation.


Input: Honey also displays an important antitumoral capacity, where polyphenols again are considered responsible for its complementary and overlapping mechanisms of chemopreventive activity in multistage carcinogenesis, by inhibiting mutagenesis or inducing apoptosis.

polyphenols


Input: Moreover, honey positively modulates the glycemic response by reducing blood glucose, serum fructosamine or glycosylated hemoglobin concentrations and exerts antibacterial properties caused by its consistent amount of hydrogen peroxide and non-peroxide factors as flavonoids, methylglyoxal and defensin-1 peptide.

glucose

fructosamine

hydrogen peroxide

peroxide

flavonoids

methylglyoxal


Input: In conclusion, the evidence of the biological actions of honey can be ascribed to its polyphenolic contents which, in turn, are usually associated to its antioxidant and anti-inflammatory actions, as well as to its cardiovascular, antiproliferative and antimicrobial benefits.


Input: Enhanced Electrical Conductivity in Poly (3-hexylthiophene)/Fluorinated Tetracyanoquinodimethane Nanowires Grown with a Porous Alumina Template.

Poly (3-hexylthiophene)

Fluorinated Tetracyanoquinodimethane

Alumina


Input: We report on improved electrical conductivity in poly (3-hexylthiophene) (P3HT)/2, 3, 5, 6-tetrafluoro-7, 7, 8, 8-tetracyanoquinodimethane (F4-TCNQ) composite nanowires grown using an anodized aluminum oxide (AAO) template.

poly (3-hexylthiophene)

2, 3, 5, 6-tetrafluoro-7, 7, 8, 8-tetracyanoquinodimethane

aluminum oxide


Input: The electrical conductivity of individual nanowire measured by four-probe scanning tunneling microscopy shows that F4-TCNQ molecules are effectively doped into P3HT by capillary force.


Input: The resistivity is tuned in the 0. 1-10 Omega cm range by changing the F4-TCNQ concentration from 10 to 0. 1 wt% and is 2-4 orders of magnitude smaller than that of the corresponding P3HT/F4-TNCQ thin film composites.


Input: The AAO template-assisted synthesis approach thus appears to be effective for high chemical doping and for improving the electrical conductivity of the molecular wires.


Input: Timed-release polymer nanoparticles.


Input: Triggered-release of encapsulated therapeutics from nanoparticles without remote or environmental triggers was demonstrated in this work.


Input: Disassembly of the polymer nanoparticles to unimers at precise times allowed the controlled release of oligo DNA.


Input: The polymers used in this study consisted of a hydrophilic block for stabilization and second thermoresponsive block for self-assembly and disassembly.


Input: At temperatures below the second block' s LCST (i. e., below 37 degrees C for in vitro assays), the diblock copolymer was fully water-soluble, and when heated to 37 degrees C, the polymer self-assembled into a narrow size distribution of nanoparticles with an average diameter of approximately 25 nm.


Input: The thermoresponsive nature of the second block could be manipulated in situ by the self-catalyzed degradation of cationic 2-(dimethylamino) ethyl acrylate (DMAEA) units to negatively charged acrylic acid groups and when the amount of acid groups was sufficiently high to increase the LCST of the second block above 37 degrees C.

2-(dimethylamino) ethyl acrylate

DMAEA

acrylic acid


Input: The disassembly of the nanoparticles could be controlled from 10 to 70 h.


Input: The use of these nanoparticles as a combined therapy, in which one or more agents can be released in a predetermined way, has the potential to improve the personal point of care treatment of patients.


Input: Advancements in the field of intravaginal siRNA delivery.


Input: The vaginal tract is a suitable site for the administration of both local and systemic acting drugs.


Input: There are numerous vaginal products on the market such as those approved for contraception, treatment of yeast infection, hormonal replacement therapy, and feminine hygiene.


Input: Despite the potential in drug delivery, the vagina is a complex and dynamic organ that requires greater understanding.


Input: The recent discovery that injections of double stranded RNA (dsRNA) in Caenorhabditis elegans (C. elegans) results in potent gene specific silencing, was a major scientific revolution.


Input: This phenomenon known as RNA interference (RNAi), is believed to protect host genome against invasion by mobile genetic elements such as transposons and viruses.


Input: Gene silencing or RNAi has opened new potential opportunities to study the function of a gene in an organism.


Input: Furthermore, its therapeutic potential is being investigated in the field of sexually transmitted infections such as human immunodeficiency virus (HIV) and other diseases such as age-related macular degeneration (AMD), diabetes, hypercholesterolemia, respiratory disease, and cancer.


Input: This review will focus on the therapeutic potential of siRNA for the treatment and/or prevention of infectious diseases such as HIV, HPV, and HSV within the vaginal tract.


Input: Specifically, formulation design parameters to improve siRNA stability and therapeutic efficacy in the vaginal tract will be discussed along with challenges, advancements, and future directions of the field.


Input: Synthesis and biological evaluation of substituted benzoxazoles as inhibitors of mPGES-1: use of a conformation-based hypothesis to facilitate compound design.

benzoxazoles


Input: Microsomal prostaglandin E (2) synthase-1 (mPGES-1) is a novel therapeutic target for the treatment of inflammation and pain.

prostaglandin E (2)


Input: In the preceding letter, we detailed the discovery of clinical candidate PF-04693627, a potent mPGES-1 inhibitor possessing a novel benzoxazole structure.

benzoxazole


Input: While PF-04693627 was undergoing further preclinical profiling, we sought to identify a back-up mPGES-1 inhibitor that differentiated itself from PF-04693627.


Input: The design, synthesis, mPGES-1 activity and in vivo PK of a novel set of substituted benzoxazoles are described herein.

benzoxazoles


Input: Also described is a conformation-based hypothesis for mPGES-1 activity based on the preferred conformation of the cyclohexane ring within this class of inhibitors.

cyclohexane


Input: Effects of asymmetric dimethylarginine on inflammatory cytokines (TNF-alpha, IL-6 and IL-10) in rats.

dimethylarginine


Input: This study is intended to examine the effects of administration of asymmetric dimethylarginine (ADMA) on the levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and IL-10.

dimethylarginine


Input: A total of 30 Wistar adult albino rats were used.


Input: Group I was administrated (n = 10) with 1 mg/kg/day of ADMA, group II (n = 10) was administrated with 2 mg/kg/day of ADMA and the control group was administrated (n = 10) with 0. 9% sodium chloride.

sodium chloride


Input: ADMA was intraperitoneally administrated for 7 days.


Input: The serum levels of IL-6, TNF-alpha and IL-10 were measured.


Input: There was a significant decrease in the levels of TNF-alpha, IL-6 and IL-10 in group I compared with that of the control group (p < 0. 001).


Input: There was also a significant decrease in the levels of IL-10 in group II compared with that of the control group (p < 0. 05) but the increase was much more distinct in the levels of IL-6 and TNF-alpha (p < 0. 001).


Input: When comparing the groups by the doses given, no difference between the levels of IL-6 and IL-10 in groups I and II (p > 0. 05) was observed; the levels of TNF-alpha in group II were significantly lower than those of group I (p < 0. 05).


Input: A significant decrease in the serum levels of inflammatory cytokines IL-6, TNF-alpha and IL-10, after administration of 1 mg/kg/day and 2 mg/kg/day of ADMA, indicates that ADMA has an effect on inflammation.


Input: Increase in ADMA levels in the rats shows that the effects of inflammatory cytokines were suppressed.


Input: Protective effect of Lygodium flexuosum (family: Lygodiaceae) against excision, incision and dead space wounds models in experimental rats.


Input: Ethnopharmacological relevance: Lygodium flexuosum (Linn) Sw.


Input: is a climbing fern, and it is the sole genus in the family Lygodiaceae.


Input: It commonly grows epiphytically on moss covered tree trunks and branches as lithophytes on shady boulders along with moss.


Input: It has been reported as a traditional folkloric medicine for a variety of ailments particularly useful for carbuncles, inflammation, ulcer, various respiratory diseases, general disorders, muscle sprains and acts as panacea for wounds.


Input: However, there are no scientific reports on wound healing activity of the plant L. flexuosum (Linn) Sw. Aim of the study: To explore the protective effect of L. flexuosum against excision, incision and dead space wounds models in experimental rats.


Input: METHODS: Wistar albino rats of either sex weighing between 180 and 220 g were topically treated with extract formulated in ointment using simple ointment BP as base.


Input: Ointments, 4% and 5% (w/w), were applied once daily in excision wound model.


Input: L. flexuosum ethanolic extract was given orally at a dose of 100, 200 and 400 mg/kg in incision and dead space wound healing models.


Input: Rats of standard groups were treated with 0. 2% nitrofurazone ointment topically.

nitrofurazone


Input: The percentage wound contraction, epithelization time in excision wound model; breaking strength in incision wound model and wet and dry granulation weight, hydroxyproline content were measured.

hydroxyproline


Input: RESULTS: Topical application of L. flexuosum in excision wound model increased the percentage of wound contraction, and the epithelization time was decreased.


Input: In the incision wound model, the breaking strength of wounds increased and in dead space model the weight of dry and wet granuloma of wounds and hydroxyproline was increased.

hydroxyproline


Input: Conclusively, the data of present study indicated that the leaf extract of L. flexuosum accelerated wound healing in rats and thus supports its traditional use.


Input: Gender differences in drug bioequivalence: time to rethink practices.


Input: Currently, bioequivalence (BE) studies are carried out exclusively in males, assuming that intrasubject variabilities are similar between the sexes.


Input: This article challenges this hypothesis on the basis of available evidence and urges that studies of BE of sufficient power be undertaken in women also for all generic drugs aimed at women.


Input: Spatial modeling for refining and predicting surface potential mapping with enhanced resolution.


Input: Quantitatively mapping surface properties with nanometer or even subnanometer resolutions is critical for advanced scanning probe microscopy (SPM) characterization.


Input: However, the characterization performance often suffers from noises and artifacts due to instrumentation or environmental limitations.


Input: In this paper, we proposed a novel statistical approach with bivariate spatial modeling to efficiently refine and predict surface property mapping.


Input: Scanning Kelvin probe microscopy (SKPM) was selected as a representative example to test our proposed method on lateral nanowire assemblies.


Input: We revealed that the proposed method can effectively retrieve the artifact-free surface potential distribution by automatically identifying topological artifacts from surface potential maps.


Input: Furthermore, the statistical model built upon low spatial resolution was successfully used to predict the potential values from higher-resolution topography data.


Input: Compared to conventional regression model, our model is able to predict the surface potential distribution from less raw data but yields much higher accuracy.


Input: Through this means, the spatial resolution of SKPM surface potential maps can be significantly improved.


Input: This statistics-enabled predictive method opens a new route toward high-precision and high-resolution SPM characterizations without the enhancement of instrumentation capabilities.


Input: Interruption or deferral of antiretroviral therapy reduces markers of bone turnover compared with continuous therapy: The SMART Body Composition substudy.


Input: Bone mineral density (BMD) declines significantly in HIV patients on antiretroviral therapy (ART).


Input: We compared the effects of intermittent versus continuous ART on markers of bone turnover in the Body Composition substudy of the Strategies for Management of AntiRetroviral Therapy (SMART) trial and determined whether early changes in markers predicted subsequent change in BMD.


Input: For 202 participants (median age 44 years, 17% female, 74% on ART) randomised to continuous or intermittent ART, plasma markers of inflammation and bone turnover were evaluated at baseline, months 4 and 12; BMD at the spine (dual X-ray absorptiometry [DXA] and computed tomography) and hip (DXA) was evaluated annually.


Input: Compared to the continuous ART group, mean bone-specific alkaline phosphatase (bALP), osteocalcin, procollagen type 1 N-terminal propeptide (P1NP), N-terminal cross-linking telopeptide of type 1 collagen (NTX), and C-terminal cross-linking telopeptide of type 1 collagen (beta CTX) decreased significantly in the intermittent ART group, whereas RANKL and the RANKL: osteoprotegerin (OPG) ratio increased (all p < 0. 002 at month 4 and month 12).

N


Input: Increases in bALP, osteocalcin, P1NP, NTX, and beta CTX at month 4 predicted decrease in hip BMD at month 12, while increases in RANKL and the RANKL: OPG ratio at month 4 predicted increase in hip and spine BMD at month 12.


Input: This study has shown that compared with continuous ART, interruption of ART results in a reduction in markers of bone turnover and increase in BMD at hip and spine, and that early changes in markers of bone turnover predict BMD changes at 12 months.


Input: (c) 2013 American Society for Bone and Mineral Research.


Input: Influence of rare earth elements on metabolism and related enzyme activity and isozyme expression in Tetrastigma hemsleyanum cell suspension cultures.


Input: The effects of rare earth elements (REEs) not only on cell growth and flavonoid accumulation of Tetrastigma hemsleyanum suspension cells but also on the isoenzyme patterns and activities of related enzymes were studied in this paper.

flavonoid


Input: There were no significant differences in enhancement of flavonoid accumulation in T. hemsleyanum suspension cells among La (3 +), Ce (3 +), and Nd (3 +).

flavonoid

La (3 +)

Ce (3 +)

Nd (3 +)


Input: Whereas their inductive effects on cell proliferation varied greatly.


Input: The most significant effects were achieved with 100 mu M Ce (3 +) and Nd (3 +).

Ce (3 +)

Nd (3 +)


Input: Under treatment over a 25-day culture period, the maximal biomass levels reached 1. 92-and 1. 74-fold and the total flavonoid contents are 1. 45-and 1. 49-fold, than that of control, respectively.

flavonoid


Input: Catalase, phenylalanine ammonia-lyase (PAL), and peroxidase (POD) activity was activated significantly when the REE concentration range from 0 to 300 mu M, whereas no significant changes were found in superoxide dismutase activity.

phenylalanine ammonia

superoxide


Input: Differences of esterase isozymes under REE treatment only laid in expression level, and there were no specific bands.


Input: The expression level of some POD isozymes strengthened with increasing concentration of REEs within the range of 50-200 mu M.


Input: When REE concentration was higher than 300 mu M, the expression of some POD isozymes was inhibited; meanwhile, some other new POD isozymes were induced.


Input: Our results also showed REEs did not directly influence PAL activity.


Input: So, we speculated that 50-200 mu M REEs could activate some of antioxidant enzymes, adjust some isozymes expression, trigger the defense responses of T. hemsleyanum suspension cells, and stimulate flavonoid accumulation by inducing PAL activity.


Input: Determination of key receptor-ligand interactions of dopaminergic arylpiperazines and the dopamine D2 receptor homology model.

arylpiperazines

dopamine


Input: Interest in structure-based G-protein-coupled receptor (GPCR) ligand discovery is huge, given that almost 30% of all approved drugs belong to this category of active compounds.


Input: The GPCR family includes the dopamine receptor subtype D2 (D2DR), but unfortunately--as is true of most GPCRs--no experimental structures are available for these receptors.

dopamine


Input: In this publication, we present the molecular model of D2DR based on the previously published crystal structure of the dopamine D3 receptor (D3DR).

dopamine


Input: A molecular modeling study using homology modeling and docking simulation provided a rational explanation for the behavior of the arylpiperazine ligand.

arylpiperazine


Input: The observed binding modes and receptor-ligand interactions provided us with fresh clues about how to optimize selectivity for D2DR receptors.


Input: A G protein-biased ligand at the mu-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine.

morphine


Input: The concept of ligand bias at G protein-coupled receptors broadens the possibilities for agonist activities and provides the opportunity to develop safer, more selective therapeutics.


Input: Morphine pharmacology in beta-arrestin-2 knockout mice suggested that a ligand that promotes coupling of the mu-opioid receptor (MOR) to G proteins, but not beta-arrestins, would result in higher analgesic efficacy, less gastrointestinal dysfunction, and less respiratory suppression than morphine.

Morphine

morphine


Input: Here we report the discovery of TRV130 ([(3-methoxythiophen-2-yl) methyl] ({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro [4. 5] decan-9-yl] ethyl}) amine), a novel MOR G protein-biased ligand.

[(3-methoxythiophen-2-yl) methyl] ({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro [4. 5] decan-9-yl] ethyl}) amine


Input: In cell-based assays, TRV130 elicits robust G protein signaling, with potency and efficacy similar to morphine, but with far less beta-arrestin recruitment and receptor internalization.

morphine


Input: In mice and rats, TRV130 is potently analgesic while causing less gastrointestinal dysfunction and respiratory suppression than morphine at equianalgesic doses.

morphine


Input: TRV130 successfully translates evidence that analgesic and adverse MOR signaling pathways are distinct into a biased ligand with differentiated pharmacology.


Input: These preclinical data suggest that TRV130 may be a safer and more tolerable therapeutic for treating severe pain.


Input: The Akt DUBbed InAktive.


Input: Akt is a central node in the phosphoinositide-3 kinase-Akt-mammalian target of rapamycin pathway and is activated by a multistep process in response to growth factor stimulation.

rapamycin


Input: An additional layer of posttranslational modification has emerged as a new paradigm in the regulation of Akt.


Input: The identification of an E3 ligase for Lys (63)-linked ubiquitination of Akt has now been complemented with the discovery of the tumor suppressor cylindromatosis as a deubiquitinating enzyme (DUB) for Akt.

Lys


Input: Thus, like phosphorylation and dephosphorylation, cycles of ubiquitination and deubiquitination provide additional on-off switches that keep Akt activity in balance, and disturbances in this balance have pathological consequences.


Input: Dye sensitised solar cells with nickel oxide photocathodes prepared via scalable microwave sintering.

nickel oxide


Input: Photoactive NiO electrodes for cathodic dye-sensitised solar cells (p-DSCs) have been prepared with thicknesses ranging between 0. 4 and 3. 0 mu m by spray-depositing pre-formed NiO nanoparticles on fluorine-doped tin oxide (FTO) coated glass substrates.

NiO

NiO

fluorine

tin oxide

FTO


Input: The larger thicknesses were obtained in sequential sintering steps using a conventional furnace (CS) and a newly developed rapid discharge sintering (RDS) method.


Input: The latter procedure is employed for the first time for the preparation of p-DSCs.


Input: In particular, RDS represents a scalable procedure that is based on microwave-assisted plasma formation that allows the production in series of mesoporous NiO electrodes with large surface areas for p-type cell photocathodes.

NiO


Input: RDS possesses the unique feature of transmitting heat from the bulk of the system towards its outer interfaces with controlled confinement of the heating zone.


Input: The use of RDS results in a drastic reduction of processing times with respect to other deposition methods that involve heating/calcination steps with associated reduced costs in terms of energy.


Input: P1-dye sensitized NiO electrodes obtained via the RDS procedure have been tested in DSC devices and their performances have been analysed and compared with those of cathodic DSCs derived from CS-deposited samples.

NiO


Input: The largest conversion efficiencies (0. 12%) and incident photon-to-current conversion efficiencies, IPCEs (50%), were obtained with sintered NiO electrodes having thicknesses of ~ 1. 5-2. 0 mu m.

NiO


Input: In all the devices, the photogenerated holes in NiO live significantly longer (tau (h) ~ 1 s) than have previously been reported for P1-sensitized NiO photocathodes.

NiO

NiO


Input: In addition, P1-sensitised sintered electrodes give rise to relatively high photovoltages (up to 135 mV) when the triiodide-iodide redox couple is used.

triiodide

iodide


Input: Cyanide antidotes for mass casualties: water-soluble salts of the dithiane (sulfanegen) from 3-mercaptopyruvate for intramuscular administration.

Cyanide

dithiane

sulfanegen


Input: Current cyanide antidotes are administered by IV infusion, which is suboptimal for mass casualties.


Input: Therefore, in a cyanide disaster, intramuscular (IM) injectable antidotes would be more appropriate.

cyanide


Input: We report the discovery of the highly water-soluble sulfanegen triethanolamine as a promising lead for development as an IM injectable cyanide antidote.

sulfanegen triethanolamine

cyanide


Input: Effects of water concentration on the structural and diffusion properties of imidazolium-based ionic liquid-water mixtures.

imidazolium


Input: We have used molecular dynamics simulations to study the properties of three ionic liquid (IL)-water systems: 1-butyl-3-methylimidazolium chloride ([bmim] Cl), 1-ethyl-3-methylimidazolium acetate ([emim] [Ac]), and 1, 3-dimethylimidazolium dimethylphosphate ([dmim] [DMP]).

1-butyl-3-methylimidazolium chloride

[bmim] Cl

1-ethyl-3-methylimidazolium acetate

[emim] [Ac]

1, 3-dimethylimidazolium dimethylphosphate

[dmim] [DMP]


Input: We observe the transition of those mixtures from pure IL to aqueous solution by analyzing the changes in important bulk properties (density) and structural and bonding properties (radial distribution functions, water clustering, hydrogen bonding, and cationic stacking) as well as dynamical properties (diffusion coefficients) at 12 different concentration samplings of each mixture, ranging from 0. 0 to 99. 95 mol% water.


Input: Our simulations revealed across all of the different structural, bonding, and dynamical properties major structural changes consistent with a transition from IL-water mixture to aqueous solution in all three ILs at water concentrations around 75 mol%.


Input: Among the structural changes observed were rapid increase in the frequency of hydrogen bonds, both water-water and water-anion.

hydrogen


Input: Similarly, at these critical concentrations, the water clusters formed begin to span the entire simulation box, rather than existing as isolated networks of molecules.


Input: At the same time, there is a sudden decrease in cationic stacking at the transition point, followed by a rapid increase near 90 mol% water.


Input: Finally, the diffusion coefficients of individual cations and anions show a rapid transition from rates consistent with diffusion in IL' s to rates consistent with diffusion in water beginning at 75 mol% water.


Input: The location of this transition is consistent, for [bmim] Cl and [dmim] [DMP], with the water concentration limit above which the ILs are unable to dissolve cellulose.

[bmim] Cl

[dmim] [DMP]


Input: Benzoquinones and terphenyl compounds as phosphodiesterase-4B inhibitors from a fungus of the order Chaetothyriales (MSX 47445).

Benzoquinones

terphenyl


Input: Three bioactive compounds were isolated from an organic extract of an ascomycete fungus of the order Chaetothyriales (MSX 47445) using bioactivity-directed fractionation as part of a search for anticancer leads from filamentous fungi.


Input: Of these, two were benzoquinones [betulinan A (1) and betulinan C (3)], and the third was a terphenyl compound, BTH-II0204-207: A (2).

benzoquinones

betulinan A

betulinan C

terphenyl

BTH-II0204-207: A


Input: The structures were elucidated using a set of spectroscopic and spectrometric techniques; the structure of the new compound (3) was confirmed via single-crystal X-ray diffraction.


Input: Compounds 1-3 were evaluated for cytotoxicity against a human cancer cell panel, for antimicrobial activity against Staphylococcus aureus and Candida albicans, and for phosphodiesterase (PDE4B2) inhibitory activities.


Input: The putative binding mode of 1-3 with PDE4B2 was examined using a validated docking protocol, and the binding and enzyme inhibitory activities were correlated.


Input: Spectral marker for C alpha damage in beta peptides.


Input: The work in this article describes a spectral signature for the detection of a C (alpha) radical damaged peptide, which should enable the use of infrared spectroscopic methods to directly monitor oxidative events.


Input: Spectra for radical damaged peptides are computed with ab initio methods.


Input: The amide bands A, I, II, and III are analyzed for trends in the damage site.

amide


Input: The spectral signature is found in a region (i. e., 1700-1620 cm (-1)) normally void of vibrational absorption bands from stable undamaged beta peptides.


Input: An analysis of the vibrational motions of the spectral signature is described.


Input: The uniqueness of the spectral signature is explored by an examination and comparison with C (alpha) monoradicals and polyradicals, as well as with other bioradicals that could act as spectral interferences.


Input: The identification of unique infrared spectral features for C (alpha) damage could have important implications in diagnostics for beta conformational peptides damaged by oxidative stress processes.


Input: Design, synthesis and biological evaluation of novel 7-mercaptocoumarin derivatives as alpha (1)-adrenoceptor antagonists.


Input: Study on the pharmacophore model of alpha (1)-adrenoceptor (alpha (1)-AR) antagonists led to design a series of novel 7-mercaptocoumarin derivatives as alpha (1)-AR antagonists.


Input: All designed compounds have been synthesized and biologically evaluated.


Input: The results showed that most of them exhibited strong antagonistic activity.


Input: Especially compound 6 showed excellent activity, which was better than that of the reference compound prazosin.

prazosin


Input: Structure-activity relationship studies revealed that small hydrophobic group at the terminal heterocyclic ring and ortho substituents on the phenyl ring of phenylpiperazine moiety were the essential structural factors for alpha (1)-AR antagonistic activity.

phenylpiperazine


Input: The pharmacophore modeling studies further clarified their structural contributions to antagonistic activity and also demonstrated that 7-mercaptocoumarin moiety could be a useful scaffold for design of alpha (1)-AR antagonists.


Input: Himeic acids E-G, new 4-pyridone derivatives from a culture of Aspergillus sp.

Himeic acids E-G


Input: Three new himeic acids E-G were isolated from a marine-derived fungus, Aspergillus sp., and their structures were determined by spectroscopic analysis.

himeic acids E-G


Input: Although himeic acid A inhibited the activity of ubiquitin-activating enzyme (E1), the three new derivatives did not.

himeic acid A


Input: Hyaluronan synthase 1 (HAS1) requires higher cellular UDP-GlcNAc concentration than HAS2 and HAS3.

UDP

GlcNAc


Input: Mammals have three homologous genes encoding proteins with hyaluronan synthase activity (Has1-3), all producing an identical polymer from UDP-N-acetylglucosamine and UDP-glucuronic acid.

UDP

N-acetylglucosamine

UDP

glucuronic acid


Input: To compare the properties of these isoenzymes, COS-1 cells, with minor endogenous hyaluronan synthesis, were transfected with human Has1-3 isoenzymes.


Input: HAS1 was almost unable to secrete hyaluronan or form a hyaluronan coat, in contrast to HAS2 and HAS3.


Input: This failure of HAS1 to synthesize hyaluronan was compensated by increasing the cellular content of UDP-N-acetyl glucosamine by ~ 10-fold with 1 mm glucosamine in the growth medium.

UDP

N-acetyl glucosamine

glucosamine


Input: Hyaluronan synthesis driven by HAS2 was less affected by glucosamine addition, and HAS3 was not affected at all.

glucosamine


Input: Glucose-free medium, leading to depletion of the UDP-sugars, markedly reduced hyaluronan synthesis by all HAS isoenzymes while raising its concentration from 5 to 25 mm had a moderate stimulatory effect.

Glucose

UDP

sugars


Input: The results indicate that HAS1 is almost inactive in cells with low UDP-sugar supply, HAS2 activity increases with UDP-sugars, and HAS3 produces hyaluronan at high speed even with minimum substrate content.

UDP

sugar

UDP

sugars


Input: Transfected Has2 and particularly Has3 consumed enough UDP-sugars to reduce their content in COS-1 cells.

UDP

sugars


Input: Comparison of different human cell types revealed ~ 50-fold differences in the content of UDP-N-acetylhexosamines and UDP-glucuronic acid, correlating with the expression level of Has1, suggesting cellular coordination between Has1 expression and the content of UDP-sugars.

UDP

N-acetylhexosamines

UDP

glucuronic acid

UDP

sugars


Input: Antihypertensive and metabolic effects of high-dose olmesartan and telmisartan in type 2 diabetes patients with hypertension.

olmesartan

telmisartan


Input: We performed a crossover study in hypertensive patients with type 2 diabetes to compare olmesartan (40 mg/day) with telmisartan (80 mg/day) in terms of their antihypertensive and metabolic effects.

olmesartan

telmisartan


Input: The subjects were 36 patients (20 men and 16 women) with type 2 diabetes who did not achieve a blood pressure < 130/80 mmHg following treatment with olmesartan at 40 mg/day or telmisartan at 80 mg/day for 8 weeks or more.

olmesartan

telmisartan


Input: The primary endpoint was the blood pressure reduction rate, while the secondary endpoints were BMI, parameters of glucose metabolism, HMW-adiponectin, hs-CRP and lipids metabolism.

glucose


Input: All parameters were measured in Weeks 0, 12, and 24.


Input: Treatments were switched in Week 0, and Week 12 and the following results were obtained.


Input: There were 1) no significant differences in baseline characteristics; 2) no significant difference of the blood pressure reduction rate; 3) significant reductions of HbA1c (NGSP), FPG and HOMA-IR in olmesartan group; 4) a significant increase of HDL-C in olmesartan group; 5) a decrease of hs-CRP and a increase of HMW-adiponectin in olmesartan group; and 6) a positive correlation between the percent changes of HOMA-IR and hs-CRP in olmesartan group.

olmesartan

olmesartan

olmesartan

olmesartan


Input: In conclusion, there was no difference of the blood pressure reduction achieved at the highest dose in olmesartan group and telmisartan group.

olmesartan

telmisartan


Input: But improvement of glycemic control and insulin resistance was only observed in olmesartan group.

olmesartan


Input: Because there was a correlation between the percent changes of HOMA-IR and hs-CRP, these effects of olmesartan might be mediated by an anti-inflammatory action.

olmesartan


Input: Global CNS gene delivery and evasion of anti-AAV-neutralizing antibodies by intrathecal AAV administration in non-human primates.


Input: Injection of adeno-associated virus (AAV) into the cerebrospinal fluid (CSF) offers a means to achieve widespread transgene delivery to the central nervous system, where the doses can be readily translated from small to large animals.


Input: In contrast to studies with other serotypes (AAV2, AAV4 and AAV5) in rodents, we report that a naturally occurring capsid (AAV9) and rationally engineered capsid (AAV2. 5) are able to achieve broad transduction throughout the brain and spinal cord parenchyma following a single injection into the CSF (via cisterna magna or lumbar cistern) in non-human primates (NHP).


Input: Using either vector at a dose of ~ 2 x 10 (12) vector genome (vg) per 3-6 kg animal, approximately 2% of the entire brain and spinal cord was transduced, covering all regions of the central nervous system (CNS).


Input: AAV9 in particular displayed efficient transduction of spinal cord motor neurons.


Input: The peripheral organ biodistribution was highly reduced compared with intravascular delivery, and the presence of circulating anti-AAV-neutralizing antibodies up to a 1: 128 titer had no inhibitory effect on CNS gene transfer.


Input: Intra-CSF delivery effectively translates from rodents to NHPs, which provides encouragement for the use of this approach in humans to treat motor neuron and lysosomal storage diseases.


Input: Evaluation of hepatic disposition of paroxetine using sandwich-cultured rat and human hepatocytes.

paroxetine


Input: Paroxetine, a selective serotonin reuptake inhibitor, is metabolized in the liver and excreted into bile and urine as metabolites, but species differences have been observed in hepatic disposition between rats and humans.

Paroxetine


Input: A major metabolite in rats is M1-glucuronide, whereas M1-glucuronide and M1-sulfate are found in humans.

sulfate


Input: The primary excretion route of paroxetine-derived radioactivity in rats and humans is bile and urine, respectively.

paroxetine


Input: The aim of this study was to examine the usefulness of sandwich-cultured hepatocytes (SCH) to evaluate in vivo species differences of the hepatic disposition of paroxetine between rats and humans.

paroxetine


Input: The metabolite profile of [(3) H] paroxetine in SCH was similar to that in hepatocytes in suspension, and the in vitro metabolite profiles were similar to the published in vivo metabolic pathways for both species.

[(3) H] paroxetine


Input: Furthermore, the biliary excretion index (BEI) of formed M1-glucuronide in rat SCH (25. 8-50. 9%) was higher than that in human SCH (15. 1-16. 7%).


Input: The BEI of formed M1-sulfate (16. 4-29. 1%) was comparable to that of M1-glucuronide in human SCH, whereas the BEIs of paroxetine were negligible in SCH of both species.

sulfate

paroxetine


Input: Moreover, M1-glucuronide was demonstrated to be a multidrug resistance-associated protein 2 substrate in both species, as determined by its uptake into ATP-binding cassette transporter-expressing membrane vesicles.

ATP


Input: SCH should prove to be useful to evaluate the processes of hepatic uptake and metabolism of parent drugs and the simultaneous examination of the biliary excretion of both parent drug and liver-derived metabolites.


Input: Synthetic strategies for the biotinylation of bioactive small molecules.


Input: Biotinylation, the functional appendage of a biotin moiety to a bioactive compound (including small molecules and biological macromolecules), represents a common technique for identification of the intracellular binding partners that underlie the foundation of observed biological activity.

biotin


Input: Introduction of an attachment tether to the framework of a compound of interest must be planned at an early stage of development, and many considerations apply: 1) region of attachment, so as not to impede the pharmacophore; 2) stability of the parent molecular architecture to biotinylation conditions; 3) regioselectivity for the chosen tethering location over other reactive functionalities; 4) toxicity of reagents if biotinylation is to be performed in vitro; and 5) overall ease of synthesis.


Input: This review is intended to serve as a guide for the selection of appropriate tethering modalities.


Input: Examples of the common techniques used to affix biotin, including amide bond formation, [3 + 2] cycloadditions through " click " chemistry, Staudinger ligation, and thioether formation will be discussed, along with analysis of the wider applications of synthetic methodology that have been applied toward the biotinylation of small molecules.

biotin

amide

thioether