Input: Studies have demonstrated that several BGA species or their active components have plasma total cholesterol and triglyceride-lowering properties due to their modulation of intestinal cholesterol absorption and hepatic lipogenic gene expression.

cholesterol

triglyceride

cholesterol


Input: BGA can also reduce inflammation by inhibiting the nuclear factor kappa B activity, consequently reducing the production of proinflammatory cytokines.


Input: Furthermore, BGA inhibit lipid peroxidation and have free radical scavenging activity, which can be beneficial for the protection against oxidative stress.


Input: The aforementioned effects of BGA can contribute to the prevention of metabolic and inflammatory diseases.


Input: This review provides an overview of the current knowledge of the health-promoting functions of BGA against cardiovascular disease and nonalcoholic fatty liver disease, which are major health threats in the developed countries.


Input: Iron (II)-catalyzed intramolecular aminohydroxylation of olefins with functionalized hydroxylamines.

Iron (II)

olefins

hydroxylamines


Input: A diastereoselective aminohydroxylation of olefins with a functionalized hydroxylamine is catalyzed by new iron (II) complexes.

olefins

hydroxylamine

iron (II)


Input: This efficient intramolecular process readily affords synthetically useful amino alcohols with excellent selectivity (dr up to > 20: 1).

amino alcohols


Input: Asymmetric catalysis with chiral iron (II) complexes and preliminary mechanistic studies reveal an iron nitrenoid is a possible intermediate that can undergo either aminohydroxylation or aziridination, and the selectivity can be controlled by careful selection of counteranion/ligand combinations.

iron (II)

iron nitrenoid


Input: Ionic liquid mediated synthesis and surface modification of multifunctional mesoporous Eu: GdF3 nanoparticles for biomedical applications.

Eu


Input: A procedure for the synthesis of multifunctional europium (III)-doped gadolinium (III) fluoride (Eu: GdF3) nanoparticles (~ 85 nm) with quasispherical shape by precipitation at 120 degrees C from diethylene glycol solutions containing lanthanide chlorides and an ionic liquid (1-Butyl, 2-methylimidazolium tetrafluoroborate) as fluoride source has been developed.

europium (III)

gadolinium (III) fluoride

Eu

diethylene glycol

lanthanide chlorides

2-methylimidazolium tetrafluoroborate

fluoride


Input: These nanoparticles were polycrystalline and crystallized into a hexagonal structure, which is unusual for GdF3.


Input: They were also mesoporous (pore size = 3. 5 A), having a rather high BET surface area (75 m (2) g (-1)).


Input: The luminescent and magnetic (relaxivity) properties of the Eu: GdF3 nanoparticles have been also evaluated in order to assess their potentiality as " in vitro " optical biolabels and contrast agent for magnetic resonance imaging.

Eu


Input: Finally, a procedure for their functionalization with aspartic-dextran polymers is also reported.


Input: The functionalized Eu: GdF3 nanoparticles presented negligible toxicity for Vero cells, which make them suitable for biotecnological applications.

Eu


Input: Interactive design of generic chemical patterns.


Input: Every medicinal chemist has to create chemical patterns occasionally for querying databases, applying filters or describing functional groups.


Input: However, the representations of chemical patterns have been so far limited to languages with highly complex syntax, handicapping the application of patterns.


Input: Graphic pattern editors similar to chemical editors can facilitate the work with patterns.


Input: In this article, we review the interfaces of frequently used web search engines for chemical patterns.


Input: We take a look at pattern editing concepts of standalone chemical editors and finally present a completely new, unpublished graphical approach to pattern design, the SMARTSeditor.


Input: Nano bioresearch approach by microtechnology.


Input: To progress in basic science and drug development, convenient methodology for detecting specific biological molecules and their interaction in living organism is in high demand.


Input: After more than 20 years of increasing research efforts, micro and nanotechnologies are now mature to propose a new class of miniature devices and principles enabling compartmentalized bioassays.


Input: Among them, this review proposes various examples that include array of electro-active microwells for highly parallel single cell analysis, cost-effective nanofluidic for DNA separation, parallel enzymatic reaction in 100pL droplet and high-throughput platform for membrane proteins assays.


Input: The micro devices are presented with relevant experiments to foresee their future contribution to translational research and drug discovery.


Input: Anti-inflammatory activity of edible brown alga Saccharina japonica and its constituents pheophorbide a and pheophytin a in LPS-stimulated RAW 264. 7 macrophage cells.

pheophorbide a

pheophytin a


Input: Anti-inflammatory activity of Saccharina japonica and its active components was evaluated via in vitro inhibitory activities against lipopolysaccharide (LPS)-induced nitric oxide (NO) production, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) expression in RAW 264. 7 murine macrophage cells.

nitric oxide

NO

nitric oxide


Input: Since the methanolic extract of S. japonica showed strong anti-inflammatory activity, it was fractionated with several solvents.


Input: Among the fractions, the ethyl acetate fraction demonstrated the highest inhibition of LPS-induced NO production (IC50 = 25. 32 mu g/mL), followed by the CH2Cl2 fraction (IC50 = 75. 86 mu g/mL).

NO


Input: Considering the yield and anti-inflammatory potential together, the CH2Cl2 fraction was selected for chromatographic separation to yield two active porphyrin derivatives, pheophorbide a and pheophytin a, together with an inactive fucoxanthin.

porphyrin

pheophorbide a

pheophytin a

fucoxanthin


Input: In contrast to fucoxanthin, pheophorbide a and pheophytin a showed dose-dependent inhibition against LPS-induced NO production at nontoxic concentrations in RAW 264. 7 cells.

fucoxanthin

pheophorbide a

pheophytin a

NO


Input: Both compounds also suppressed the expression of iNOS proteins, while they did not inhibit the COX-2 expression in LPS-stimulated macrophages.


Input: These results indicate that pheophorbide a and pheophytin a are two important candidates of S. japonica as anti-inflammatory agents which can inhibit the production of NO via inhibition of iNOS protein expression.

pheophorbide a

pheophytin a

NO


Input: Thus, these compounds hold great promise for use in the treatment of various inflammatory diseases.


Input: Chlorpyrifos induced hepatotoxic and hematologic changes in rats: the role of quercetin and catechin.

Chlorpyrifos

quercetin

catechin


Input: Chlorpyrifos is an organophosphorus insecticide which is widely used throughout in the world and it caused toxic effects on nontarget organisms especially mammalian.

Chlorpyrifos

organophosphorus


Input: In the present study, catechin, quercetin, chlorpyrifos, catechin + chlorpyrifos, quercetin + chlorpyrifos were given to male rats through gavage for 4weeks.

catechin

quercetin

chlorpyrifos

catechin

chlorpyrifos

quercetin

chlorpyrifos


Input: Serum total protein, albumin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase, trigliceride, total cholesterol levels, hematological changes, superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase activities and malondialdehyde content in liver tissues and also histopathological changes of liver were investigated in the rats compared to control group.

aspartate

alanine

lactate

trigliceride

cholesterol

superoxide

glutathione

glutathione

malondialdehyde


Input: No significant differences in all investigated parameters were observed between control, catechin and quercetin groups.

catechin

quercetin


Input: There were statistically significantly changes in liver function tests, some hematological parameters, antioxidant enzyme activities and malondialdehyde levels in chlorpyrifos treated group compared to control group.

malondialdehyde

chlorpyrifos


Input: In catechin + chlorpyrifos treated group and quercetin + chlorpyrifos treated group we observed the protective effects of catechin and quercetin on examining parameters but not completely.

catechin

chlorpyrifos

quercetin

chlorpyrifos

catechin

quercetin


Input: While some histopathological changes detected in liver tissues in chlorpyrifos treated group, less histopathological changes were observed in catechin + chlorpyrifos and quercetin + chlorpyrifos treated groups at the end of the 4thweek.

chlorpyrifos

catechin

chlorpyrifos

quercetin

chlorpyrifos


Input: As a result, catechin and quercetin significantly reduce chlorpyrifos induced hepatotoxicity in rats.

catechin

quercetin

chlorpyrifos


Input: A comparative study of the modulatory effects of (-)-cubebin on the mutagenicity/recombinogenicity induced by different chemical agents.

(-)-cubebin


Input: (-)-Cubebin (CUB) is a lignan isolated from dry seeds of Piper cubeba.

(-)-Cubebin

CUB

lignan


Input: We aimed to assess its genotoxic potential and influence on chromosomal damage (frequency of micronuclei-MN) induced by doxorubicin (DXR) in V79 cells and by urethane (URE) in somatic Drosophila melanogaster cells.

doxorubicin

DXR

urethane

URE


Input: Our findings indicate an absence of a CUB-mediated genotoxic effect at the concentrations tested.

CUB


Input: The results also revealed that CUB significantly reduced the frequency of MN induced by DXR, with a mean reduction of 63. 88%.

CUB

DXR


Input: In a previous study, our research group demonstrated an absence of CUB-mediated mutagenic effects through the wing Somatic Mutation and Recombination Test (SMART) in Drosophila.

CUB


Input: In the present study, we used the standard and high bioactivation versions of the SMART to estimate the antigenotoxic effects of CUB associated with URE.

CUB

URE


Input: At lower concentrations, the recombination level decreased, but at the highest concentration, the recombination level increased.


Input: Our data and previous studies suggest that CUB may act as a free radical scavenger at low concentrations, a pro-oxidant at higher concentrations when it interacts with the enzymatic system that catalyzes the metabolic detoxification of DXR or URE, and/or an inducer of recombinational DNA repair.

CUB

DXR

URE


Input: Biotransformation and toxicokinetics of the insect repellent IR3535 (R) in male and female human subjects after dermal exposure.


Input: The absorption and excretion of the insect repellent IR3535 ((R)) was studied in human subjects (five males and five females) after dermal application of approx. 3g of a formulation containing 20% IR3535 ((R)), i. e. the amounts of IR3535 ((R)) applied were between 1. 94 and 3. 4 mmol/person (418-731 mg/person).


Input: Blood and urinary concentrations of IR3535 ((R)) and its only metabolite, IR3535 ((R))-free acid, were determined over time.


Input: In plasma, concentrations of the parent compound IR3535 ((R)) were at or below the limit of quantification (0. 037 mu mol/L).


Input: IR3535 ((R))-free acid peaked in plasma samples 2-6h after dermal application.


Input: Cmax mean values were 5. 7 mu mol/L in males, 3. 0 mu mol/L in females and 4. 2 mu mol/L in all volunteers.


Input: Mean AUC values were 41. 6, 24. 5 and 33. 9 mu molL (-1) h in males, females and all subjects, respectively.


Input: In urine samples from all human subjects, both IR3535 ((R)) and IR3535 ((R))-free acid were detectable, however, only very small amounts of IR3535 ((R)) were found.


Input: Concentrations of IR3535 ((R))-free acid were several thousand-fold higher than the parent compound and peaked at the first two sampling points (4h and 8h after dermal application).


Input: Overall, IR3535 ((R)) and IR3535 ((R))-free acid excreted with urine over 48 h representing 13. 3 +/- 3. 05% of the dose applied.


Input: Since IR3535 ((R)) is rapidly and extensively metabolized, and IR3535 ((R))-free acid has a low molecular weight and high water solubility, it is expected that urinary excretion of IR3535 ((R))-free acid and IR3535 ((R)) represents the total extent of absorption of IR3535 ((R)) in humans.


Input: Based on the results of this study, the skin penetration rate of IR3535 ((R)) is 13. 3% in humans after dermal application.


Input: RP TLC data in correlation studies with in silico pharmacokinetic properties of benzimidazole and benztriazole derivatives.

benzimidazole

benztriazole


Input: Reversed-phase thin-layer chromatographic (RP TLC) retention constants for a newly designed series benzimidazole/benztriazole with expected biological activity were determined as parameters of their lipophilicity and this series was recognized as congeneric.

benzimidazole

benztriazole


Input: Pharmacokinetic descriptors of the compounds investigated were calculated in silico with the use of the established drug design software.


Input: The bioactivity descriptors, which are assumed to predicted drug absorption, distribution, metabolism, elimination and toxicity (ADMETox) in humans, were correlated with retention constants and good statistical parameters were obtained.


Input: Multiple regression analysis which was introduced suggested that the absorption through different epithelial membranes (intestinal, blood-brain or erythrocyte membrane) and distribution process depend on retention constants (as measure of lipophilicty) and total polar surface area and molar weight/volume of the analyte.


Input: Finally, the compounds with halogen substituent (compounds A4/A7 and A5/A8 in Table 1), were suggested as the best drug candidates, because of their predicted proper pharmacokinetics and have been proposed for further biological tests.


Input: Exploring food effects on indinavir absorption with human intestinal fluids in the mouse intestine.

indinavir


Input: Food can have a significant impact on the pharmacokinetics of orally administered drugs, as it may affect drug solubility as well as permeability.


Input: Since fed state conditions cannot easily be implemented in the presently available permeability tools, including the frequently used Caco-2 system, exploring food effects during drug development can be quite challenging.


Input: In this study, we investigated the effect of fasted and fed state conditions on the intestinal absorption of the HIV protease inhibitor indinavir using simulated and human intestinal fluids in the in situ intestinal perfusion technique in mice.

indinavir


Input: Although the solubility of indinavir was 6-fold higher in fed state human intestinal fluids (FeHIF) as compared to fasted state HIF (FaHIF), the intestinal permeation of indinavir was 22-fold lower in FeHIF as compared to FaHIF.

indinavir

indinavir


Input: Dialysis experiments showed that only a small fraction of indinavir is accessible for absorption in FeHIF due to micellar entrapment, possibly explaining its low intestinal permeation.

indinavir


Input: The presence of ritonavir, a known P-gp inhibitor, increased the intestinal permeation of indinavir by 2-fold in FaHIF, while there was no increase when using FeHIF.

ritonavir

indinavir


Input: These data confirm that drug-food interactions form a complex interplay between solubility and permeability effects.


Input: The use of HIF in in situ intestinal perfusions holds great promise for biorelevant absorption evaluation as it allows to directly explore this complex solubility/permeability interplay on drug absorption.


Input: Synthesis and anti-Candida activity of novel 2-hydrazino-1, 3-thiazole derivatives.

2-hydrazino-1, 3-thiazole


Input: Eighteen new hydrazino-1, 3-thiazole derivatives were evaluated against 8 strains of multi-resistant Candida spp.

hydrazino-1, 3-thiazole


Input: Introduction of an indolyl moiety linked to the hydrazone function enhanced the in vitro anti-Candida activity, with an activity spectrum towards Candida albicans strains.

indolyl

hydrazone


Input: Introduction of a (S)-2-aminoethyl chain on the thiazole nucleus largely enhanced the in vitro antifungal activity, with a selectivity oriented towards non-C. albicans species.

thiazole


Input: The PprA protein is required for accurate cell division of gamma-irradiated Deinococcus radiodurans bacteria.


Input: Deinococcus radiodurans, one of the most radioresistant organisms known to date is able to reconstruct an intact genome from hundreds of DNA fragments.


Input: Here, we investigate the in vivo role of PprA, a radiation-induced Deinococcus specific protein.


Input: We report that DNA double strand break repair in cells devoid of PprA and exposed to 3800Gy gamma-irradiation takes place efficiently with a delay of only 1h as compared to the wild type, whereas massive DNA synthesis begins 90min after irradiation as in the wild type, a phenotype insufficient to explain the severe radiosensitivity of the Delta pprA mutant.


Input: We show that the slow kinetics of reassembly of DNA fragments in a Delta pprA Delta recA double mutant was the same as that observed in a Delta recA single mutant demonstrating that PprA does not play a major role in DNA repair through RecA-independent pathways.


Input: Using a tagged PprA protein and immunofluorescence microscopy, we show that PprA is recruited onto the nucleoid after gamma-irradiation before DNA double strand break repair completion, and then is found as a thread across the septum in dividing cells.


Input: Moreover, whereas untreated cells devoid of PprA displayed a wild type morphology, they showed a characteristic cell division abnormality after irradiation not found in other radiosensitive mutants committed to die, as DNA is present equally in the two daughter cells but not separated at the division septum.


Input: We propose that PprA may play a crucial role in the control of DNA segregation and/or cell division after DNA double strand break repair.


Input: Targeted co-delivery of docetaxel, cisplatin and herceptin by vitamin E TPGS-cisplatin prodrug nanoparticles for multimodality treatment of cancer.

docetaxel

cisplatin

vitamin E TPGS

cisplatin


Input: We developed a nanocarrier system of herceptin-conjugated nanoparticles of d-alpha-tocopheryl-co-poly (ethylene glycol) 1000 succinate (TPGS)-cisplatin prodrug (HTCP NPs) for targeted co-delivery of cisplatin, docetaxel and herceptin for multimodality treatment of breast cancer of high human epidermal growth factor receptor 2 (HER2) overexpression.

d-alpha-tocopheryl-co-poly (ethylene glycol) 1000 succinate

TPGS

cisplatin

cisplatin

docetaxel


Input: Co-polymers poly (lactic acid)-TPGS (PLA-TPGS) and carboxyl group-terminated TPGS (TPGS-COOH) were also added in the polymeric matrix to stabilize the prodrug nanoparticles and to facilitate herceptin conjugation.

poly (lactic acid)-TPGS

PLA-TPGS

carboxyl

TPGS

TPGS

COOH


Input: The HTCP NPs of high, moderate and low docetaxel versus cisplatin ratio were prepared by the nanoprecipitation method, which showed a pH-sensitive release for both anticancer drugs.

docetaxel

cisplatin


Input: The therapeutic effects of HTCP NPs were evaluated in vitro and compared with Taxotere (R) and cisplatin.

Taxotere

cisplatin


Input: The HTCP NPs of high docetaxel versus cisplatin ratio were found to have better efficacy than those of moderate and low docetaxel versus cisplatin ratio.

docetaxel

cisplatin

docetaxel

cisplatin


Input: The targeting effects of the HTCP NPs were demonstrated by a much lower IC50 value of 0. 0201 + 0. 00780 + 0. 1629 mu g/mL of docetaxel + cisplatin + herceptin for SK-BR-3 cells, which are of high HER2 overexpression, than that of 0. 225 + 0. 0875 + 1. 827 mu g/mL for NIH3T3 cells, which are of low HER2 overexpression, after 24h incubation.

docetaxel

cisplatin


Input: The same design of TPGS prodrug nanoparticles can also be applied for targeted co-delivery of other hydrophilic and hydrophobic drugs.


Input: Accurate quantum chemical energies for tetrapeptide conformations: why MP2 data with an insufficient basis set should be handled with caution.

tetrapeptide


Input: High-level quantum chemical calculations have been carried out for biologically-relevant conformers of tetrapeptides.

tetrapeptides


Input: Our results indicate potential problems if the widely-applied MP2 approach is used in such situations with basis sets of insufficient size.


Input: Efficient alternatives are discussed.


Input: Comparative study of artificial chromosome centromeres in human and murine cells.


Input: Human artificial chromosomes (HAC) are a valuable tool in the analysis of complex chromatin structures such as the human centromere because of their small size and relative simplicity compared with normal human chromosomes.


Input: This report includes a comprehensive study of the centromere and chromatin composition of HAC, expressing human genes, generated in human cells and transferred to murine cells.


Input: The analysis involved chromatin immuno-precipitation and immuno-FISH on metaphase chromosomes and chromatin fibres.


Input: In both the cell types, the HAC consisted of alphoid and non-alphoid DNA and were mainly euchromatic in composition, although a pericentromeric heterochromatic region was present on all the HAC.


Input: Fibre-FISH and chromatin immuno-precipitation data indicated that the position of the centromere differed between HAC in human cells and in murine cells.


Input: Our work highlights the importance and utilisation of HAC for understanding the epigenetic aspects of chromosome biology. European Journal of Human Genetics advance online publication, 13 February 2013; doi: 10. 1038/ejhg. 2012. 296.


Input: Synergistic effects between CA1 mu opioid and dopamine D1-like receptors in impaired passive avoidance performance induced by hepatic encephalopathy in mice.

dopamine


Input: BACKGROUND AND AIM: Numerous investigations have indicated that hepatic encephalopathy (HE) alters the levels of various neurotransmitters.


Input: However, comprehensive data regarding the effects of CA1 opioidergic and dopaminergic (DAergic) systems on HE-induced amnesia are still lacking.


Input: METHODS: Following intra-dorsal hippocampal (CA1) injection of mu opioid and dopamine D1-and D2-like receptors antagonists in male mice, one-trial step-down and hole-board paradigms were used to assess memory and exploratory behaviors, respectively.

dopamine


Input: RESULTS: Our data demonstrated that HE impairs memory 24 days after bile duct ligation (BDL).


Input: Furthermore, while the higher dose of DA D1-like receptor antagonist (SCH23390, 0. 5 mu g/mouse) induced amnesia and anxiogenic-like behaviors, mu receptor antagonist (naloxone: 0. 0125, 0. 025 and 0. 05 mu g/mouse) and DA D2-like receptor antagonist (sulpiride: 0. 0625, 0. 125 and 0. 25 mu g/mouse) by themselves, could not exert an effect on memory performance in passive avoidance task.

naloxone

sulpiride


Input: On the other hand, pre-test injection of all drugs reversed the HE-induced amnesia 24 days after BDL, while having no effect on exploratory behaviors.


Input: Pre-test co-administration of the subthreshold dose SCH23390 (0. 25 mu g/mouse) and sulpiride (0. 0625 mu g/mouse) or naloxone (0. 0125 mu g/mouse) could likewise reverse the BDL-induced amnesia.

sulpiride

naloxone


Input: However, when the subthreshold sulpiride plus naloxone were co-administered, BDL-induced amnesia was not blocked.

sulpiride

naloxone


Input: CONCLUSIONS: Memory performance is impaired 24 days post BDL and CA1 mu opioid and DA D1-like receptors antagonist synergistic effects are likely involved in this phenomenon.


Input: TRIM16 overexpression induces apoptosis through activation of caspase-2 in cancer cells.


Input: TRIM16 exhibits tumour suppressor functions by interacting with cytoplasmic vimentin and nuclear E2F1 proteins in neuroblastoma and squamous cell carcinoma cells, reducing cell migration and replication.


Input: Reduced TRIM16 expression in a range of human primary malignant tissues correlates with increased malignant potential.


Input: TRIM16 also induces apoptosis in breast and lung cancer cells, by unknown mechanisms.


Input: Here we show that overexpression of TRIM16 induces apoptosis in human breast cancer (MCF7) and neuroblastoma (BE (2)-C) cells, but not in non-malignant HEK293 cells.


Input: TRIM16 increased procaspase-2 protein levels in MCF7 and induced caspase-2 activity in both MCF7 and BE (2)-C cells.


Input: We show that TRIM16 and caspase-2 proteins directly interact in both MCF7 and BE (2)-C cells and co-localise in MCF7 cells.


Input: Most importantly, the induction of caspase-2 activity is required for TRIM16 to initiate apoptosis.


Input: Our data suggest a novel mechanism by which TRIM16 can promote apoptosis by directly modulating caspase-2 activity.


Input: Effects of induced hyperinsulinaemia with and without hyperglycaemia on measures of cardiac vagal control.


Input: AIMS/HYPOTHESIS: We examined the effects of serum insulin levels on vagal control over the heart and tested the hypothesis that higher fasting insulin levels are associated with lower vagal control.


Input: We also examined whether experimentally induced increases in insulin by beta cell secretagogues, including glucagon-like peptide-1 (GLP-1), will decrease vagal control.


Input: METHODS: Respiration and ECGs were recorded for 130 healthy participants undergoing clamps.


Input: Three variables of cardiac vagal effects (the root mean square of successive differences [rMSSD] in the interbeat interval of the heart rate [IBI], heart-rate variability [HRV] caused by peak-valley respiratory sinus arrhythmia [pvRSA], and high-frequency power [HF]) and heart rate (HR) were obtained at seven time points during the clamps, characterised by increasing levels of insulin (achieved by administering insulin plus glucose, glucose only, glucose and GLP-1, and glucose and GLP-1 combined with arginine).

glucose

glucose

glucose

glucose

arginine


Input: RESULTS: Serum insulin level was positively associated with HR at all time points during the clamps except the first-phase hyperglycaemic clamp.


Input: Insulin levels were negatively correlated with variables of vagal control, reaching significance for rMSSD and log (10) HF, but not for pvRSA, during the last four phases of the hyperglycaemic clamp (hyperglycaemic second phase, GLP-1 first and second phases, and arginine).

arginine


Input: These associations disappeared when adjusted for age, BMI and insulin sensitivity.


Input: Administration of the beta cell secretagogues GLP-1 and arginine led to a significant increase in HR, but this was not paired with a significant reduction in HRV measures.

arginine


Input: CONCLUSION/INTERPRETATION: Experimentally induced hyperinsulinaemia is not correlated with cardiac vagal control or HR when adjusting for age, BMI and insulin sensitivity index.


Input: Our findings suggest that exposure to a GLP-1 during hyperglycaemia leads to a small acute increase in HR but not to an acute decrease in cardiac vagal control.


Input: Composition and distribution of elements and ultrastructural topography of a human cardiac calculus.


Input: Trace elements (TEs) may contribute to the formation of calculi or stones or be involved in the aetiopathogenesis of stone diseases.


Input: The compositions and spatial distribution of elements from the inner nucleus to outer crust of the cardiac calculus were investigated by energy-dispersive X-ray fluorescence (EDXRF) spectrometer.


Input: The surface topograph, distribution map of elements, elemental and chemical compositions were also determined by environmental scanning electron microscope (ESEM)-energy-dispersive X-ray (EDX) analysis.


Input: Twenty-five elements were identifiable from 18 positions on the cardiac calculus by EDXRF spectrometer, in which the highest concentrations of toxic TEs (Ni, Pt, Hg, Sn, Pb, W, Au, Al, Si) and higher levels of essential TEs (Ca, Sr, Cr, P) were detected.

Ni

Pt

Hg

Sn

Pb

W

Au

Al

Si

Ca

Sr

Cr

P


Input: A moderate positive Pearson' s correlation between TEs concentrations of Mg, Ca or P and location differences from centre to periphery in the cardiac calculus was observed.

Mg

Ca

P


Input: A positive correlation was also found for Ca/Zn and Ca/Cu, indicating the gradual increase of calcium concentration from inner nucleus to outer crust of cardiac calculus.

Ca

Zn

Ca

Cu

calcium


Input: The drop-like nodules/crystals on the surface of petrous part of cardiac calculus were observed from ESEM analysis.


Input: ESEM-EDX analysis determined the calculus to be predominantly composed of calcium hydroxyapatite and cholesterol, as indicated by the petrous surface and drop-like nodules/crystals, respectively.

calcium hydroxyapatite

cholesterol


Input: This composition was confirmed using a portable Raman analyser.


Input: The spatial distribution analysis indicated a gradual increase in Mg, P and Ca concentrations from the inner nucleus to the outer crust of the cardiac calculus.

Mg

P

Ca


Input: The major chemical compositions of calcium hydroxyapatite and cholesterol were detected on this cardiac calculus.

calcium hydroxyapatite

cholesterol


Input: alpha 1A-Adrenergic Receptors Regulate Cardiac Hypertrophy In Vivo Through Interleukin-6 Secretion.


Input: The role of alpha 1-adrenergic receptors (ARs) in the regulation of cardiac hypertrophy is still unclear, because transgenic mice demonstrated hypertrophy or the lack of it despite high receptor overexpression.


Input: To further address the role of the alpha 1-ARs in cardiac hypertrophy, we analyzed unique transgenic mice that overexpress constitutively active mutation (CAM) alpha 1A-ARs or CAM alpha 1B-ARs under the regulation of large fragments of their native promoters.


Input: These constitutively active receptors are expressed in all tissues that endogenously express their wild-type counterparts as opposed to only myocyte-targeted transgenic mice.


Input: In this study, we discovered that CAM alpha 1A-AR mice in vivo have cardiac hypertrophy independent of changes in blood pressure, corroborating earlier studies, but in contrast to myocyte-targeted alpha 1A-AR mice.


Input: We also found cardiac hypertrophy in CAM alpha 1B-AR mice, in agreement with previous studies, but hypertrophy only developed in older mice.


Input: We also discovered unique alpha 1-AR-mediated hypertrophic signaling that was AR subtype-specific with CAM alpha 1A-AR mice secreting atrial naturietic factor and interleukin-6 (IL-6), whereas CAM alpha 1B-AR mice expressed activated nuclear factor-kappa B (NF-kappa B).


Input: These particular hypertrophic signals were blocked when the other AR subtype was coactivated.


Input: We also discovered that crossbreeding the two CAM models (double CAM alpha 1A/B-AR) inhibited the development of hypertrophy and was reversible with single receptor activation, suggesting that coactivation of the receptors can lead to novel antagonistic signal transduction.


Input: This was confirmed by demonstrating antagonistic signals that were even lower than normal controls in the double CAM alpha 1A/B-AR mice for p38, NF-kappa B, and the IL-6/glycoprotein 130/signal transducer and activator of transcription 3 pathway.


Input: Because alpha 1A/B double knockout mice fail to develop hypertrophy in response to IL-6, our results suggest that IL-6 is a major mediator of alpha 1A-AR cardiac hypertrophy.


Input: Optimization of marine triterpene sipholenols as inhibitors of breast cancer migration and invasion.

triterpene sipholenols


Input: Sipholenol A, a sipholane triterpene isolated from the Red Sea sponge Callyspongia siphonella, has the ability to reverse multidrug resistance in cancer cells that overexpress P-glycoprotein (P-gp).

Sipholenol A

sipholane triterpene


Input: Here, the antimigratory activity of sipholenol A and analogues are reported against the highly metastatic human breast cancer cell line MDA-MB-231 in a wound-healing assay.

sipholenol A


Input: Sipholenol A and sipholenone A were semisynthetically optimized using ligand-based strategies to generate structurally diverse analogues in an attempt to maximize their antimigratory activity.

Sipholenol A

sipholenone A


Input: A total of 22 semisynthetic ester, ether, oxime, and carbamate analogues were generated and identified by extensive one-and two-dimensional NMR spectroscopy and high-resolution mass spectrometry analyses.

ester

ether

oxime

carbamate


Input: Sipholenol A 4 beta-4-chlorobenzoate and 19, 20-anhydrosipholenol A 4 beta-4-chlorobenzoate esters were the most potent of all tested analogues in the wound-healing assay, with IC (50) values of 5. 3 and 5. 9 mu M, respectively.

Sipholenol A 4 beta-4-chlorobenzoate

19, 20-anhydrosipholenol A 4 beta-4-chlorobenzoate esters


Input: Generally, ester derivatives showed better antimigratory activities than the carbamate analogues.

carbamate


Input: A KINOMEscan of 19, 20-anhydrosipholenol A 4 beta-benzoate ester against 451 human protein kinases identified protein tyrosine kinase 6 (PTK6) as a potential target.

19, 20-anhydrosipholenol A 4 beta-benzoate ester

tyrosine


Input: In breast tumor cells, PTK6 promotes growth factor signaling and migration, and as such the semisynthetic sipholanes were evaluated for their ability to inhibit PTK6 phosphorylation in vitro.

sipholanes


Input: The two analogues with the highest antimigratory activities, sipholenol A 4 beta-4-chlorobenzoate and 19, 20-anhydrosipholenol A 4 beta-4-chlorobenzoate esters, also exhibited the most potent inhibition of PTK6 phosphorylation inhibition.

sipholenol A 4 beta-4-chlorobenzoate

19, 20-anhydrosipholenol A 4 beta-4-chlorobenzoate esters


Input: None of the compounds exhibited cytotoxicity in a normal epithelial breast cell line.


Input: These derivatives were evaluated in an in vitro invasion assay, where sipholenol A succinate potently inhibited MDA-MB-231 cell invasion at 10 mu M.

sipholenol A succinate


Input: These results highlight sipholane triterpenoids as novel antimigratory marine natural products with potential for further development as agents for the control of metastatic breast malignancies.

sipholane triterpenoids


Input: Computational studies identifying entry inhibitor scaffolds targeting the Phe43 cavity of HIV-1 gp120.


Input: Targeting protein-protein interactions, such as the HIV-1 gp120-CD4 interface, has become a cutting-edge approach in the current drug discovery scenario.


Input: Many small molecules have been developed so far as inhibitors of the interaction between CD4 and HIV-1 gp120.


Input: However, due to a variety of reasons such as solubility, drug toxicity and drug resistance, these inhibitors have failed to prove clinically useful.


Input: As such, the identification of novel compounds that bind to protein-protein interactions is still a research area of considerable interest.


Input: Here, a structure-based virtual screening approach was successfully applied with the aim of identifying novel HIV-1 entry inhibitors targeting the Phe43 pocket of HIV-1 gp120.


Input: Several compounds able to inhibit viral replication in cell culture were identified, with the best agent endowed with an EC (50) value of 0. 9 mu M.


Input: Inactivity of all the identified hits toward a mutant (Met475Ile) strain strongly suggests that they interact in the Phe43 cavity of gp120, as intended.


Input: Remarkably, all of these small molecules have a chemical scaffold unrelated to any known class of entry inhibitors reported thus far.


Input: Overall, our strategy led to the identification of four novel chemical scaffolds that inhibit HIV-1 replication through the destabilization of the HIV-1 gp120-CD4 interface.


Input: Design and evaluation of 4-aminophenol and salicylate derivatives as free-radical scavenger.

salicylate


Input: This theoretical and experimental study describes the design and evaluation of the free-radical scavenging effect for the molecular association of 4-aminophenol and salicylate derivatives.

salicylate


Input: For this purpose, we employed theoretical methods for the selection of antioxidant drugs and the rapid methods of evaluation: the 1, 1-diphenyl-2-picrylhydrazyl radical and the thiobarbituric acid reactive substances in the lipid peroxidation initiated by Fe (2 +) and ascorbic acid in human erythrocytes.

1, 1-diphenyl-2-picrylhydrazyl

thiobarbituric acid

Fe (2 +)

ascorbic acid


Input: The associate derivatives exhibited a more potent inhibition than the salicylic acid, while the benzoyl compound exhibited a more potent inhibition than paracetamol.

salicylic acid

benzoyl

paracetamol


Input: The molecular parameters related to the electron distribution and structure (ionization potential and energy of the highest occupied molecular orbital) correlated very well with the antioxidant action of the compounds studied here in different tests.


Input: A new O-prenylated flavonol from the roots of Sophora interrupta.

O-prenylated flavonol


Input: A new O-prenylated flavonol, 3', 4'-dimethoxy-7-(gamma, gamma-dimethylallyloxy) flavonol (1), together with three known compounds, 2'-hydroxy-3, 4-dimethoxychalcone (2), biochanin A (3) and kaempferol-3-O-beta-d-glucopyranoside (4), were isolated from the roots of Sophora interrupta Bedd.

O-prenylated flavonol

3', 4'-dimethoxy-7-(gamma, gamma-dimethylallyloxy) flavonol

2'-hydroxy-3, 4-dimethoxychalcone

biochanin A


Input: The structure of compound 1 was elucidated by extensive 1D and 2D NMR spectral studies.


Input: Interactions of binuclear ruthenium (II) complexes with oligonucleotides in hydrogel matrix: enantioselective threading intercalation into GC context.

ruthenium (II)


Input: A stretched poly (vinyl alcohol) (PVA) film provides a unique matrix that enables also short DNA oligonucleotide duplex to be oriented and studied by linear dichroism (LD).

poly (vinyl alcohol)

PVA


Input: This matrix further allows controlling DNA secondary structure by proper hydration (A or B form), and such humid films could potentially also mimic the molecular crowding in cellular contexts.


Input: However, early attempts to study intercalators and groove binders for probing DNA in PVA failed due to competitive matrix binding.

PVA


Input: Here we report the successful orientation in PVA of DNA oligonucleotide duplex hairpins with thread-intercalated binuclear complex [mu-(11, 11'-bidppz) (phen) 4Ru2] (4 +), and how LD depends on oligonucleotide sequence and metal center chirality.

PVA

[mu-(11, 11'-bidppz) (phen) 4Ru2] (4 +)


Input: Opposite enantiomers of the ruthenium complex, Delta Delta and Lambda Lambda, were investigated with respect to enantioselectivity toward GC stretches as long as 22 bp.

ruthenium


Input: LD, supported by emission kinetics, reveals that threading intercalation occurs only with Delta Delta whereas Lambda Lambda remains externally bound, probably in either or both of the grooves of the GC-DNA.


Input: Enantioselective binding properties of sterically rigid DNA probes such as the ruthenium complexes could find applications for targeting nucleic acids, e. g., to inhibit transcription in therapeutic context such as treatment of malaria or cancer.

ruthenium


Input: Computational study of chain transfer to monomer reactions in high-temperature polymerization of alkyl acrylates.

alkyl acrylates


Input: This article presents a computational study of chain transfer to monomer (CTM) reactions in self-initiated high-temperature homopolymerization of alkyl acrylates (methyl, ethyl, and n-butyl acrylate).

alkyl acrylates

methyl, ethyl, and n-butyl acrylate


Input: Several mechanisms of CTM are studied.


Input: The effects of the length of live polymer chains and the type of monoradical that initiated the live polymer chains on the energy barriers and rate constants of the involved reaction steps are investigated theoretically.


Input: All calculations are carried out using density functional theory.


Input: Three types of hybrid functionals (B3LYP, X3LYP, and M06-2X) and four basis sets (6-31G (d), 6-31G (d, p), 6-311G (d), and 6-311G (d, p)) are applied to predict the molecular geometries of the reactants, products and transition sates, and energy barriers.


Input: Transition state theory is used to estimate rate constants.


Input: The results indicate that abstraction of a hydrogen atom (by live polymer chains) from the methyl group in methyl acrylate, the methylene group in ethyl acrylate, and methylene groups in n-butyl acrylate are the most likely mechanisms of CTM.

hydrogen

methyl

methyl acrylate

methylene

ethyl acrylate

methylene

n-butyl acrylate


Input: Also, the rate constants of CTM reactions calculated using M06-2X are in good agreement with those estimated from polymer sample measurements using macroscopic mechanistic models.


Input: The rate constant values do not change significantly with the length of live polymer chains.


Input: Abstraction of a hydrogen atom by a tertiary radical has a higher energy barrier than abstraction by a secondary radical, which agrees with experimental findings.

hydrogen


Input: The calculated and experimental NMR spectra of dead polymer chains produced by CTM reactions are comparable.


Input: This theoretical/computational study reveals that CTM occurs most likely via hydrogen abstraction by live polymer chains from the methyl group of methyl acrylate and methylene group (s) of ethyl (n-butyl) acrylate.

hydrogen

methyl

methyl acrylate

methylene

ethyl (n-butyl) acrylate


Input: Novel triaryl sulfonamide derivatives as selective cannabinoid receptor 2 inverse agonists and osteoclast inhibitors: discovery, optimization, and biological evaluation.

triaryl sulfonamide


Input: Cannabinoid receptors have gained increasing attention as drug targets for developing potential therapeutic ligands.


Input: Here, we report the discovery and optimization of triaryl sulfonamides as a novel series possessing significant CB2 receptor affinity and selectivity.

triaryl sulfonamides


Input: Four sets of triaryl ligands were designed and synthesized for further structural modifications and led to the identification of eight compounds as potent and selective CB2 inverse agonists with high binding affinity (CB2K (i) < 10 nM).

triaryl


Input: Especially, compound 57 exhibited the strongest binding affinity on the CB2 receptor (CB2K (i) of 0. 5 nM) and the best selectivity over the CB1 receptor (selectivity index of 2594).


Input: Importantly, 57 also showed potent inhibitory activity on osteoclast formation, and it was confirmed by a cell viability assay that the inhibition effects were not derived from the cytotoxicity.


Input: Finally, 3D QSAR studies confirmed our SAR findings that three bulky groups play an important role for CB2 receptor binding affinity.


Input: Cell type determines the light-induced endosomal escape kinetics of multifunctional mesoporous silica nanoparticles.

silica


Input: We investigated uptake and individual endosome lysis events in fibroblast, normal, and carcinoma cell lines using a colloidal mesoporous silica (CMS) nanoparticle (NP)-based reporter system with a covalently attached photosensitizer.

silica


Input: Endosome lysis was induced through the activation of protoporphyrin IX (PpIX).

protoporphyrin IX

PpIX


Input: Surprisingly, this release-on-demand system resulted in more broadly distributed lysis times than expected, particularly for Renca, a renal carcinoma cell line.


Input: An analysis of the NP load per endosome, endosome size, and uptake characteristics indicate that Renca cells not only take up a lower amount of NPs in comparison with the fibroblast cells but also have larger endosomes and a lower NP load per endosome.


Input: We then created a stochastic model detailing steps downstream of uptake to understand how much factors that cannot be directly measured, such as variations in the PpIX load per NP, affect the lysis time distributions.

PpIX


Input: Model results indicate that the distributions are primarily determined by the endosome properties, rather than variations across NPs.


Input: Visualizing RNA base-pairing probabilities with RNAbow diagrams.


Input: There are many effective ways to represent a minimum free energy RNA secondary structure that make it easy to locate its helices and loops.


Input: It is a greater challenge to visualize the thermal average probabilities of all folds in a partition function sum; dot plot representations are often puzzling.


Input: Therefore, we introduce the RNAbows visualization tool for RNA base pair probabilities.


Input: RNAbows represent base pair probabilities with line thickness and shading, yielding intuitive diagrams.


Input: RNAbows aid in disentangling incompatible structures, allow comparisons between clusters of folds, highlight differences between wild-type and mutant folds, and are also rather beautiful.


Input: Imogolite-like nanotubes: structure, stability, electronic and mechanical properties of the phosphorous and arsenic derivatives.

Imogolite

phosphorous

arsenic


Input: Imogolite is a single-walled aluminosilicate nanotube (NT) found in nature that can be easily synthesized, as well as its analogue aluminogermanate NT.

Imogolite

aluminosilicate

aluminogermanate


Input: Based on geometrical assumptions and pKa values, species such as H3PO4, H3PO3, H3AsO3, H3AsO4 could also be candidates to form imogolite-like structures.

imogolite


Input: In the present work, we provide insights about the stability, electronic, structural and mechanical properties of possible imogolite like NTs by means of self-consistent charge density-functional tight-binding method (SCC-DFTB).

imogolite


Input: Similarly to aluminogermanate, where the tetrahedral silicate groups are replaced by germanate, in this work tetrahedral silicate groups are substituted by phosphate, phosphite, arsenate and arsenite units in the imogolite structure.

aluminogermanate

silicate

germanate

silicate

phosphate

phosphite

arsenate

arsenite

imogolite


Input: Detailed analysis is focused on structural properties, strain energy, band gap and Mulliken charges distribution.


Input: The calculated strain energy curves for all studied zigzag imogolite-like NTs present well-defined minima, which change as a consequence of composition variation.

imogolite


Input: Moreover, the strain energy curves of armchair imogolite-like NTs also present minima, although in all cases less stable than zigzags by at least 2. 2 meV per atom.

imogolite


Input: The insulating NT behaviour changes after internal modification from silicate to phosphate, phosphite, arsenate and arsenite, as well as the charge distribution inside and outside the nanotubes.

silicate

phosphate

phosphite

arsenate

arsenite


Input: The UDP-Glucuronosyltransferase (UGT) 1A Polymorphism c. 2042C > G (rs8330) Is Associated with Increased Human Liver Acetaminophen Glucuronidation, Increased UGT1A Exon 5a/5b Splice Variant mRNA Ratio, and Decreased Risk of Unintentional Acetaminophen-Induced Acute Liver Failure.

UDP

Acetaminophen

Acetaminophen


Input: Acetaminophen is cleared primarily by hepatic glucuronidation.

Acetaminophen


Input: Polymorphisms in genes encoding the acetaminophen UDP-glucuronosyltransferase (UGT) enzymes could explain interindividual variability in acetaminophen glucuronidation and variable risk for liver injury after acetaminophen overdose.

acetaminophen UDP

acetaminophen

acetaminophen


Input: In this study, human liver bank samples were phenotyped for acetaminophen glucuronidation activity and genotyped for the major acetaminophen-glucuronidating enzymes (UGTs 1A1, 1A6, 1A9, and 2B15).

acetaminophen

acetaminophen


Input: Of these, only three linked single nucleotide polymorphisms (SNPs) located in the shared UGT1A-3' UTR region (rs10929303, rs1042640, rs8330) were associated with acetaminophen glucuronidation activity, with rs8330 consistently showing higher acetaminophen glucuronidation at all the tested concentrations of acetaminophen.

acetaminophen

acetaminophen

acetaminophen


Input: Mechanistic studies using luciferase-UGT1A-3' UTR reporters indicated that these SNPs do not alter mRNA stability or translation efficiency.


Input: However, there was evidence for allelic imbalance and a gene-dose proportional increase in the amount of exon 5a versus exon 5b containing UGT1A mRNA spliced transcripts in livers with the rs8330 variant allele.


Input: Cotransfection studies demonstrated an inhibitory effect of exon 5b containing cDNAs on acetaminophen glucuronidation by UGT1A1 and UGT1A6 cDNAs containing exon 5a.

acetaminophen


Input: In silico analysis predicted that rs8330 creates an exon splice enhancer site that could favor exon 5a (over exon 5b) utilization during splicing.


Input: Finally, the prevalence of rs8330 was significantly lower (P = 0. 027, chi (2) test) in patients who had acute liver failure from unintentional acetaminophen overdose compared with patients with acute liver failure from other causes or a race-or ethnicity-matched population.

acetaminophen


Input: Together, these findings suggest that rs8330 is an important determinant of acetaminophen glucuronidation and could affect an individual' s risk for acetaminophen-induced liver injury.

acetaminophen

acetaminophen


Input: Anthelmintic activity of the natural compound (+)-limonene epoxide against Schistosoma mansoni.

(+)-limonene epoxide


Input: Blood fluke of the genus Schistosoma are the etiological agents of human schistosomiasis, an important neglected tropical disease that afflicts over 200 million people worldwide.


Input: The treatment for this disease relies heavily on a single drug, praziquantel.

praziquantel


Input: Recent reports of praziquantel resistance raise concerns about future control of the disease and show the importance of developing new antischistosomal drugs.

praziquantel


Input: Currently, natural products have been a good source for drug development.


Input: (+)-Limonene epoxide is a mixture of cis and trans isomers found in many plants.

(+)-Limonene epoxide


Input: Here, we report the in vitro effect of this natural compound on the survival time of Schistosoma mansoni adult worms.


Input: In addition, we examined alterations on the tegumental surface of adult schistosomes by means of confocal laser scanning microscopy.


Input: The effects of (+)-limonene epoxide at 25 micro g/mL on S. mansoni adult worms were similar to those of the positive control (praziquantel), with reduction in motility and death of all worms after 120 h.

(+)-limonene epoxide

praziquantel


Input: Confocal laser scanning microscopy revealed that (+)-limonene epoxide-mediated worm killing was associated with tegumental destruction.

(+)-limonene epoxide


Input: Our results, along with the low toxicity of the (+)-limonene epoxide, suggest that this natural compound might be promising for the development of new schistosomicidal agents.

(+)-limonene epoxide


Input: Neuronatin-mediated aberrant calcium signaling and endoplasmic reticulum stress underlie neuropathology in Lafora disease.

calcium


Input: Lafora disease (LD) is a teenage-onset inherited progressive myoclonus epilepsy characterized by the accumulations of intracellular inclusions called Lafora bodies and caused by mutations in protein phosphatase laforin or ubiquitin ligase malin.


Input: But how the loss of function of either laforin or malin causes disease pathogenesis is poorly understood.


Input: Recently, neuronatin was identified as a novel substrate of malin that regulates glycogen synthesis.


Input: Here we demonstrate that the level of neuronatin is significantly up-regulated in the skin biopsy sample of LD patients having mutations in both malin and laforin.


Input: Neuronatin is highly expressed in human fetal brain with gradual decrease in expression in developing and adult brain.


Input: However, in adult brain, neuronatin is predominantly expressed in parvalbumin-positive GABAergic interneurons and localized in their processes.


Input: The level of neuronatin is increased and accumulated as insoluble aggregates in the cortical area of LD brain biopsy samples, and there is also a dramatic loss of parvalbumin-positive GABAergic interneurons.


Input: Ectopic expression of neuronatin in cultured neuronal cells results in increased intracellular Ca (2 +), endoplasmic reticulum stress, proteasomal dysfunction, and cell death that can be partially rescued by malin.

Ca (2 +)


Input: These findings suggest that the neuronatin-induced aberrant Ca (2 +) signaling and endoplasmic reticulum stress might underlie LD pathogenesis.

Ca (2 +)


Input: Quantitative analysis of TALE-DNA interactions suggests polarity effects.


Input: Transcription activator-like effectors (TALEs) have revolutionized the field of genome engineering.


Input: We present here a systematic assessment of TALE DNA recognition, using quantitative electrophoretic mobility shift assays and reporter gene activation assays.


Input: Within TALE proteins, tandem 34-amino acid repeats recognize one base pair each and direct sequence-specific DNA binding through repeat variable di-residues (RVDs).

amino acid


Input: We found that RVD choice can affect affinity by four orders of magnitude, with the relative RVD contribution in the order NG > HD ~ NN >> NI > NK.


Input: The NN repeat preferred the base G over A, whereas the NK repeat bound G with 10 (3)-fold lower affinity.


Input: We compared AvrBs3, a naturally occurring TALE that recognizes its target using some atypical RVD-base combinations, with a designed TALE that precisely matches' standard' RVDs with the target bases.


Input: This comparison revealed unexpected differences in sensitivity to substitutions of the invariant 5'-T.


Input: Another surprising observation was that base mismatches at the 5' end of the target site had more disruptive effects on affinity than those at the 3' end, particularly in designed TALEs.


Input: These results provide evidence that TALE-DNA recognition exhibits a hitherto un-described polarity effect, in which the N-terminal repeats contribute more to affinity than C-terminal ones.

C


Input: Transient receptor potential channels-emerging novel drug targets for the treatment of pain.


Input: In mammals several members of the Transient Receptor Potential channel family (TRPs), expressed mainly in the sensory neurons and skin keratinocytes, are implicated in relevant physiological functions, including thermosensation, nociception and vision.


Input: Since the TRPV1-4, TRPA1 and TRPM8 channels from this family play a pivotal role in both the detection and possibly modulation of painful stimuli, they are regarded as a very promising target of novel analgesic drugs.


Input: A few agents acting at TRPs, such as capsaicin or menthol, have a long history of their application as analgesics, whereas others (e. g. SB705498, JTS653, JNJ17203212, AP18, A967079, Chembridge-5861528 or PBMC) are currently being evaluated both in animals and in humans.

capsaicin

menthol


Input: In this review we discuss pain physiology, as well as the pharmacological properties of the TRPs involved in pain detection as potential critical peripheral analgesic targets.


Input: We present one of the most relevant strategies in the search for novel analgesic drugs, namely the TRP channels and their ligands, both agonists and antagonists as potential novel therapeutics for inflammatory and neuropathic pain syndromes.


Input: The safety profile of these agents, in particular their impact on thermosensation, is also discussed below.


Input: Photoactive analogs of farnesyl diphosphate and related isoprenoids: design and applications in studies of medicinally important isoprenoid-utilizing enzymes.

farnesyl diphosphate

isoprenoids

isoprenoid


Input: Farnesyl diphosphate (FPP) is an important metabolic intermediate in the biosynthesis of a variety of molecules including sesquiterpenes and the side chains of a number of cofactors.

Farnesyl diphosphate

FPP

sesquiterpenes


Input: FPP is also the source of isoprenoid side chains found attached to proteins.

FPP

isoprenoid


Input: Enzymes that employ FPP as a substrate are of interest because they are involved in the semisynthesis of drugs as well as targets for drug design.

FPP


Input: Photoactive analogs of FPP have been useful for identifying enzymes that use this molecule as a substrate.

FPP


Input: A variety of photocrosslinking groups have been employed to prepare FPP analogs for use in such experiments including aryl azides, diazotrifluoropropionates and benzophenones.

FPP

aryl azides

diazotrifluoropropionates

benzophenones


Input: In this review, the design of these probes is described along with an examination of how they have been used in crosslinking experiments.


Input: Impact of quaternary structure dynamics on allosteric drug discovery.


Input: The morpheein model of allosteric regulation draws attention to proteins that can exist as an equilibrium of functionally distinct assemblies where: one subunit conformation assembles into one multimer; a different subunit conformation assembles into a different multimer; and the various multimers are in a dynamic equilibrium whose position can be modulated by ligands that bind to a multimer-specific ligand binding site.


Input: The case study of porphobilinogen synthase (PBGS) illustrates how such an equilibrium holds lessons for disease mechanisms, drug discovery, understanding drug side effects, and identifying proteins wherein drug discovery efforts might focus on quaternary structure dynamics.

porphobilinogen


Input: The morpheein model of allostery has been proposed as applicable for a wide assortment of disease-associated proteins (Selwood, T., Jaffe, E., (2012) Arch. Bioch. Biophys, 519: 131-143).


Input: Herein we discuss quaternary structure dynamics aspects to drug discovery for the disease-associated putative morpheeins phenylalanine hydroxylase, HIV integrase, pyruvate kinase, and tumor necrosis factor alpha.

phenylalanine

pyruvate


Input: Also highlighted is the quaternary structure equilibrium of transthyretin and successful drug discovery efforts focused on controlling its quaternary structure dynamics.


Input: Mechanistic insights into water-protein interactions of filamentous bacteriophage.


Input: Water plays a major structural and functional role around proteins.


Input: In an attempt to explore this mechanistic structural aspect of proteins, we present site-specific interaction of hydration water with the major coat protein subunit of filamentous virus Pf1 by magic angle spinning (MAS) solid-state NMR.


Input: The interaction of surrounding water with 36 MDa Pf1 virion is investigated in uniformly (13) C, (15) N isotopically labeled; polyethylene glycol precipitated fully hydrated samples by solid-state nuclear magnetic resonance spectroscopy.

(13) C

(15) N

polyethylene glycol


Input: Dipolar edited two-dimensional (2D) (1) H-(15) N heteronuclear correlation (HETCOR) experiments lead to unambiguous assignments of cross-peaks originating exclusively from (1) H resonances of water molecules correlating to the protein amide nitrogen.

(1) H

(15) N

(1) H

amide nitrogen


Input: An enhanced resolved (1) H chemical shift dimension in these experiments also precludes the need of perdeuteration.

(1) H


Input: We report seven residues spanning the 40-residue continuous alpha-helical conformation assembly of Pf1 interacting with surrounding water.


Input: It shows a highly hydrated inner core inside this viral filamentous assembly.


Input: The results obtained also suggest the first evidence of a water-mediated interface cluster formed at the site of Arg44 with the single-stranded DNA genome of the filamentous phage supramolecular assembly.


Input: Multifunctional carboxymethyl cellulose-based magnetic nanovector as a theragnostic system for folate receptor targeted chemotherapy, imaging, and hyperthermia against cancer.

carboxymethyl

folate


Input: A multifunctional biocompatible nanovector based on magnetic nanoparticle and carboxymethyl cellulose (CMC) was developed.

carboxymethyl


Input: The nanoparticles have been characterized using TEM, SEM, DLS, FT-IR spectra, VSM, and TGA studies.


Input: We found that the synthesized carboxymethyl cellulose magnetic nanoparticles (CMC MNPs) were spherical in shape with an average size of 150 nm having low aggregation and superparamagnetic properties.

carboxymethyl


Input: We found that the folate-tagged CMC MNPs were delivered to cancer cells by a folate-receptor-mediated endocytosis mechanism.

folate

folate


Input: 5-FU was encapsulated as a model drug for delivering cytotoxicity, and we could demonstrate the sustained release of 5-FU.


Input: It was also observed that the FITC-labeled CMC MNPs could effectively enter cells, and the fate of nanoparticles was tracked with Lysotracker.

FITC


Input: The CMC MNPs could induce significant cell death when an alternating magnetic field was applied.


Input: These results indicate that the multifunctional CMC MNPs possess a high drug loading efficiency and high biocompatibility and with low cell cytotoxicity and can be considered to be promising candidates for CMC-based targeted drug delivery, cellular imaging, and magnetic hyperthermia (MHT).


Input: Rotational dynamics of metal azide ion pairs in dimethylsulfoxide solutions.

metal azide

dimethylsulfoxide


Input: Azide ion is an excellent vibrational probe for studying ion-ion and ion-dipole interactions in solutions because its frequency is sensitively dependent on its local environments.

Azide


Input: When azide ion forms contact ion pairs with cations in dimethylsulfoxide (DMSO), free azide ion and contact ion pairs are spectrally well distinguished in FTIR spectra.

azide

dimethylsulfoxide

DMSO

azide


Input: Here, we investigated vibrational population relaxation, P (t), and orientational relaxation dynamics, r (t), of free azide ion and contact ion pairs (LiN3, NaN3, NH4N3, MgN3 (+), and CaN3 (+)) in DMSO by IR pump-probe spectroscopy.

azide

MgN3 (+)

CaN3 (+)

DMSO


Input: For metal azide ion pairs, the metal ion slowed down the vibrational relaxation of azide ion by acting like a thermal insulator.

metal azide

azide


Input: Biexponential behavior of r (t) was analyzed in the wobbling-in-a-cone model.


Input: The long time component of r (t) of free azide ion was found to be viscosity-dependent.

azide


Input: The wobbling motion of azide ion within the frame of metal azide ion pairs was weakly dependent on the countercation.

azide

metal azide


Input: When the overall orientational relaxation of metal azide ion pairs was analyzed by the extended Debye-Stokes-Einstein equation, it was well described under stick or superstick boundary conditions due to a strong interaction between the metal ion and DMSO molecules.

metal azide

DMSO


Input: Our experimental results provide important insight in understanding the rotational dynamics of small ionic species in polar solvents when the size of the ionic species is smaller than or comparable to that of the solvent molecule.


Input: The metalloproteases meprin alpha and meprin beta: unique enzymes in inflammation, neurodegeneration, cancer and fibrosis.


Input: The metalloproteases meprin alpha and meprin beta exhibit structural and functional features that are unique among all extracellular proteases.


Input: Although meprins were discovered more than 30 years ago, their precise substrates and physiological roles have been elusive.


Input: Both enzymes were originally found to be highly expressed in kidney and intestine, which focused research on these particular tissues and associated pathologies.


Input: Only recently it has become evident that meprins exhibit a much broader expression pattern, implicating functions in angiogenesis, cancer, inflammation, fibrosis and neurodegenerative diseases.


Input: Different animal models, as well as proteomics approaches for the identification of protease substrates, have helped to reveal more precise molecular signalling events mediated by meprin activity, such as activation and release of pro-inflammatory cytokines.


Input: APP (amyloid precursor protein) is cleaved by meprin beta in vivo, reminiscent of the beta-secretase BACE1 (beta-site APP-cleaving enzyme 1).


Input: The subsequent release of A beta (amyloid beta) peptides is thought to be the major cause of the neurodegenerative Alzheimer' s disease.


Input: On the other hand, ADAM10 (a disintegrin and metalloprotease domain 10), which is the constitutive alpha-secretase, was shown to be activated by meprin beta, which is itself shed from the cell surface by ADAM10.


Input: In skin, both meprins are overexpressed in fibrotic tumours, characterized by massive accumulation of fibrillar collagens.


Input: Indeed, procollagen III is processed to its mature form by meprin alpha and meprin beta, an essential step in collagen fibril assembly.


Input: The recently solved crystal structure of meprin beta and the unique cleavage specificity of these proteases identified by proteomics will help to generate specific inhibitors that could be used as therapeutics to target meprins under certain pathological conditions.


Input: Isolation and structures of axistatins 1-3 from the Republic of Palau marine sponge Agelas axifera Hentschel.

axistatins 1-3


Input: An investigation begun in 1979 directed at the Republic of Palau marine sponge Agelas axifera Hentschel for cancer cell growth inhibitory constituents subsequently led to the isolation of three new pyrimidine diterpenes designated axistatins 1 (1), 2 (2), and 3 (3), together with the previously reported formamides 4, 5, and agelasine F (6).

pyrimidine diterpenes

axistatins 1 (1), 2 (2), and 3 (3)

formamides

agelasine F


Input: The structures were elucidated by analysis of 2D-NMR spectra and by HRMS.


Input: All of the isolated compounds were found to be moderate inhibitors of cancer cell growth.


Input: Axistatins 1-3 (1-3), formamide 4, and agelasine F (6) also exhibited antimicrobial activity.

Axistatins 1-3

formamide

agelasine F


Input: Toward a physically based quantitative modeling of impact sensitivities.


Input: Among the subsequent steps leading from impact to explosive decomposition in nitro compounds, the ability of early exothermic reactions to trigger the decomposition of neighboring molecules before the released energy has dissipated away is assumed to be critical.

nitro


Input: The rate of this process is roughly estimated using as inputs the energy content and the dissociation energy of the weakest X-NO2 bonds.


Input: While the sensitivity index thus obtained was previously shown to exhibit striking correlations with gap test pressures, its correlation with drop weight impact test data is poorer.


Input: Nevertheless, considering four different subsets of molecules depending on the environment of the most labile nitro groups, straightforward regressions against this sensitivity index yield a practical method to estimate impact sensitivity, whose combination of fair performance and generality is provided by no alternative approach, except purely empirical models based on extensive parametrization.

nitro


Input: Insight into the medicinal chemistry of the endocannabinoid hydrolase inhibitors.


Input: Endocannabinoid hydrolases are nowadays increasingly considered as potential therapeutic targets for treating several pathological states.


Input: So far, numerous classes of endocannabinoid hydrolase inhibitors have been described.


Input: We herein review the medicinal chemistry of these inhibitors with a particular emphasis on the basis of their design, chemical structure, structure-activity relationships, and inhibition mechanisms.


Input: The economics of polypharmacology: fixed dose combinations and drug cocktails.


Input: The history of Fixed Dose Combination (FDC) oral drug products has been tumultuous over its history.


Input: Some FDCs were prepared for marketing purposes and others for clinical improvements.


Input: Often, the products prepared for marketing advantage ended up causing negative outcomes.


Input: However, in recent years, there has been a resurgence of FDCs as clinicians have found them adventitious for treatment of AIDS/HIV and for oral contraceptives, just to name two examples.


Input: International regulatory Agencies and most major drug regulatory agencies have established guidelines along with regulations concerning preparation, labeling and marketing for FDCs.


Input: The advantages of FDCs are said to be in the clinical realm where simplified therapy regimens are thought to enhance patient' s medication taking compliance.


Input: On the financial side, health insurers and other payers normally save money from a decreased number of dispensing fees, the use of fewer bottles, labels, etc., and from the possible situation where the price of the FDC is less than the medication price of the two separate ingredients dispensed individually.


Input: Overall, there is a great deal of evidence in favor of appropriate FDCs.


Input: Polypharmacology in a single drug: multitarget drugs.


Input: Polypharmacology offers a model for the way drug discovery must evolve to develop therapies most suited to treating currently incurable diseases.


Input: It is driven by a worldwide demand for safer, more effective, and affordable medicines against the most complex diseases, and by the failures of modern drug discovery to provide these.


Input: Polypharmacology can involve combinations and/or multitarget drugs (MTD).


Input: Although not mutually exclusive, my premise is that MTDs have inherent advantages over combinations.


Input: This review article focuses on MTDs from a medicinal chemistry perspective.


Input: I will explore their use in current clinical practice, their likely application in the future, and the challenges to be overcome to achieve this goal.


Input: Multi-target compounds acting in the central nervous system designed from natural products.


Input: Modern medicinal chemistry has come to its bottleneck and is full of challenges, specially when facing with long-term central nervous system (CNS) disorders induced by several factors, such as Alzheimer' s disease (AD) or Parkinson' s disease (PD).


Input: In order to probe these challenges, multi-target directed ligands (MTDLs) design has been applied recently by medicinal scientists trying to get single compounds that can simultaneously modulate multiple targets.


Input: In addition, natural products have drawn the attention of drug developers again in recent years, as they have been used by human race for thousands of years and are full of diversity with their concomitant high potential to exhibit biological activities.


Input: We hereby review some of the research within the last few years focusing on multiple-target compounds acting in the CNS using natural products as lead resources.


Input: The target compounds obtained and described here represent bioactive hybrids either covalently connected or obtained by fusion of different bioactive moieties with at least one part derived from or representing directly natural products, along with some natural compounds themselves showing multiple pharmacological activities.


Input: We describe suitable ways to connect the drug components chemically, how to use the approach to enhance biological activity and selectivity, as well as potential drawbacks of the hybrid approach.


Input: This review will also show the rationale that these MTDLs are more than just the sum of their components but in many cases should be considered as new pharmacological entities in their own respect.


Input: Rationally designed multitarget anticancer agents.


Input: Balanced modulation of multiple targets is an attractive therapeutic strategy in treating complex diseases including cancer.


Input: Comparing with drugs combination, single molecule modulating desirable multiple targets has advantages in pharmacokinetic and pharmacodynamics.


Input: Different from previous reviews, we provided an overview of reported multitarget antitumor agents from the viewpoint of pharmacophores.


Input: These multitarget antitumor agents were designed by combination of pharmacophores or by high-throughput screening plus structural modification, which were exemplified by the privileged pharmacophore quinazoline and several other popular pharmacophores, including phenylaminopyrimidine, anthracycline and naphthalimide.

phenylaminopyrimidine

anthracycline

naphthalimide


Input: Previous research demonstrated the importance of in-depth validation against multiple targets not only in cell-free system, but also in cancer cells.


Input: Furthermore, the multitarget compounds were also effective for resistance cell lines which highlighted their antitumor potency in the era of increasing drug resistance in cancer patients.


Input: Recent developments in rationally designed multitarget antiprotozoan agents.


Input: Protozoan infections are the leading cause of morbidity and mortality among parasitic infections of humans, accounting for approximately 800 thousand mortalities and a loss of more than 30 million disability-adjusted life years annually.


Input: The major protozoan infections of humans, namely malaria, Chagas disease, human African trypanosomiasis, and leishmaniasis, are primarily centered in the tropics, with a reach into some subtropical regions of the world.


Input: Though globally massive in their impact, these diseases mostly afflict the least economically endowed and geographically marginalized populations in low-income countries.


Input: As such, there is no sufficient market incentive for industrial businessdriven antiprotozoal drug discovery due to poor marketing prospects and low returns on investment.


Input: Consequently, the pharmacopoeia for majority of these diseases, composed mainly of agents with poor efficacy and unsatisfactory safety profiles, has essentially remained unchanged for decades, creating a compelling need for more efficacious and better tolerated medicines.


Input: The policy makers and the scientific community are seeking effective ways to meet this need.


Input: So far, two approaches have emerged promising in this regard: combination chemotherapy and drug repositioning.


Input: Molecular hybridization has been cited as a potential third approach that could be used to deliver new antiprotozoal chemical entities.


Input: In this review article, recent applications of this novel strategy in antimalarial, antichagasic, antitrypanosomal, and antileishmanial drug discovery research and development over the last five years will be presented and discussed.


Input: Rationally Designed Multitarget Anti-HIV Agents.


Input: Multitarget-directed ligands (MTDLs), an emerging and appealing drug discovery strategy, utilizing a single chemical entity to inhibit multitargets, was confirmed to be effective in reducing the likelihood of drug resistance, diminishing problems of dosing complexity, drug-drug interactions and toxicities, as well as improving patient compliance.


Input: The exploration of MTDL strategy should be valuable in anti-HIV drug discovery.


Input: In this article, current knowledge and strategies for the rational design of the multitarget and selective anti-HIV agents are described and a number of illustrative examples are given.


Input: Moreover, the challenges, limitations and outlook of such novel drug design strategies are also presented, with a goal to highlight the representative paradigms in the rational design of MTDLs, and to help medicinal chemists discover the next generation of multitarget anti-HIV agents.


Input: Design of multifunctional compounds for cardiovascular disease: from natural scaffolds to " classical " multitarget approach.


Input: Cardiovascular disease represents the main cause of death worldwide.


Input: Novel therapies to reduce elevated blood pressure and treat resistant hypertension, to consequently reduce the associated cardiovascular risk factors, are still required.


Input: Among the different strategies commonly used in medicinal chemistry to develop new molecules, the synthesis of multitarget/hybrid compounds combining two or more pharmacophore groups targeting simultaneously selected factors involved in cardiovascular diseases, has gained increasing interest.


Input: This review will focus on the most recent literature on multifunctional cardiovascular drugs, paying particular attention on hybrid compounds bearing natural scaffolds, considering that compounds derived from medicinal extracts are generally appealing for the medicinal chemist as they often bear the so-called " privileged structures ".


Input: Moreover, taking into account many excellent reviews dealing with multitarget cardiovascular drugs published in the last few years, mainly devoted to RAAS inhibition and/or NO donors hybrid drugs, herein the most significant results obtained and the benefits and limitations of these approaches will be highlighted.


Input: Rationally designed multitarget agents against inflammation and pain.


Input: Arachidonic acid (ARA) undergoes enzyme-mediated oxidative metabolism, resulting in the formation of a number of biologically active metabolites.

Arachidonic acid

ARA


Input: For over a century, these biochemical transformations have been the target of numerous pharmacological drugs for inflammation and pain.


Input: In particular, non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) selective inhibitors (coxibs) are widely used in the treatment of inflammation and pain.


Input: However, gastrointestinal (GI) and cardiovascular adverse effects of NSAIDs and coxibs, and recent findings demonstrating that there are significant risks from the disruption of oxylipin levels when pharmacologically inhibiting a single ARA cascade metabolic pathway, have led to studies involving the simultaneous inhibition of multiple pathways in ARA cascade.

oxylipin

ARA

ARA


Input: These studies suggest that multitarget inhibition represents a new and valuable option to enhance efficacy or reduce side-effects in the treatment of inflammation and pain.


Input: This review focuses on the crosstalk within the three pathways of the ARA cascade (cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450)), and summarizes the current and future approaches of multitarget inhibitors for the treatment of eicosanoid driven inflammation and pain.

ARA

eicosanoid


Input: Time series analysis of oxidative stress response patterns in HepG2: A toxicogenomics approach.


Input: Oxidative stress plays an important role in chemically induced liver injury, however, our insight into molecular responses to different oxygen radicals is fragmentary.

oxygen


Input: Since these cellular responses will differ over time, examining time-dependent changes in gene expression, and correlating these with markers for oxidative stress, may provide new insights into responses to oxidants.


Input: We used the human hepatoma cell line HepG2 to investigate the effects of oxidative stress on the transcriptome level by micro-arrays at seven time points (0. 5, 1, 2, 4, 6, 8 and 24h) following exposure to the oxidants menadione, hydrogen peroxide and tert-butyl hydroperoxide including the effects on cell cycle and apoptosis by flow cytometry, protein carbonyl formation by spectrophotometry and oxidative DNA damage by FPG-comet.

menadione

hydrogen peroxide

tert-butyl hydroperoxide

carbonyl


Input: In total, 3429 genes were differentially expressed, including 136 genes that were significantly modified by all oxidants.


Input: Time-dependent biological pathway analysis showed that these genes were particularly involved in inflammatory responses, cell cycle processes and glutathione signaling.

glutathione


Input: These responses were confirmed and supported by phenotypic anchoring to the different cellular endpoints.


Input: In addition, using an innovative temporal analysis we established an oxidative stress-related gene expression time cluster.


Input: Altogether, this study provides new insights in temporal oxidative stress mechanisms and demonstrates sequential cellular responses that may contribute to a better hazard identification and the mechanisms of toxicological responses in the liver induced by oxidative stress.


Input: Association of nephrolithiasis with metabolic syndrome and its components.


Input: OBJECTIVE: Both metabolic syndrome (MetS) and nephrolithiasis (NL) are common and clinically important disorders.


Input: Therefore, we conducted this study to assess the association of MetS and NL.


Input: MATERIALS/METHODS: Data were obtained from 116, 536 individuals who underwent health screening tests between January 2010 and December 2010 at a health promotion center in Seoul, Korea.


Input: All subjects were asked to respond to a questionnaire including medical history of each subject.


Input: Anthropometric and biochemical measurements were applied to each subject.


Input: Presence of NL was evaluated by an abdominal ultrasonography.


Input: The subjects were classified into MetS and non-MetS group according to the criteria for MetS (National Cholesterol Education Program Adult Treatment Panel III).

Cholesterol


Input: Compared to the non-MetS group, we estimated the Odds Ratios (ORs) and 95% Confidence Intervals (CIs) of the presence of NL in the MetS group adjusting for age, serum levels of creatinine and uric acid, and past medical history of NL based on the multivariate logistic regression analysis.

creatinine

uric acid


Input: RESULTS: The prevalence of MetS was 15. 9% (N = 1129/7107) in the NL group, and 11. 2% (N = 12, 287/109, 429) in the non-NL group, respectively.


Input: After adjusting for the potential confounding factors, male MetS patients had a higher presence of NL than non-MetS subjects (OR 1. 11; 95% CI 1. 02-1. 20; p = 0. 01).


Input: Of MetS components, only high blood pressure (BP) was a significantly related factor to the presence of NL (male; OR 1. 08; 95% CI 1. 01-1. 15; p = 0. 043, female; OR 1. 24; 95% CI 1. 08-1. 42; p = 0. 002).


Input: As the number MetS components increased, the presence of NL was significantly higher in male subjects (P for trend < 0. 001), but not in female subjects (P for trend = 0. 961).


Input: CONCLUSIONS: We found that NL was associated with MetS and high BP.


Input: Arylglycine derivatives as potent transient receptor potential melastatin 8 (TRPM8) antagonists.

Arylglycine


Input: A series of arylglycine-based analogs was synthesized and tested for TRPM8 antagonism in a cell-based functional assay.

arylglycine


Input: Following structure-activity relationship studies in vitro, a number of compounds were identified as potent TRPM8 antagonists and were subsequently evaluated in an in vivo pharmacodynamic assay of icilin-induced' wet-dog' shaking in which compound 12 was fully effective.

icilin


Input: TRPM8 antagonists of the type described here may be useful in treating pain conditions wherein cold hypersensitivity is a dominant feature.


Input: Design, synthesis and structure-activity relationship of rhenium 2-arylbenzothiazoles as beta-amyloid plaque binding agents.

rhenium 2-arylbenzothiazoles


Input: To continue our efforts toward the development of (99m) Tc PiB analogs, we have synthesized 24 neutral and lipophilic Re (as a surrogate of (99m) Tc) 2-arylbenzothiazoles, and explored their structure-activity relationship for binding to A beta 1-40 fibrils.

(99m) Tc

Re

(99m) Tc


Input: These Re complexes were designed and synthesized via the integrated approach, so their (99m) Tc analogs would have a greater chance of crossing the blood-brain barrier.

Re

(99m) Tc


Input: While the lipophilicities (logPC18 = 1. 59-3. 53) of these Re 2-arylbenzothiazoles were all within suitable range, their binding affinities (Ki = 30-617nM) to A beta 1-40 fibrils varied widely depending on the selection and integration of the tetradentate chelator into the 2-phenylbenzothiazole pharmacophore.

Re 2-arylbenzothiazoles


Input: For potential clinical applications, further refinement to obtain Re 2-arylbenzothiazoles with better binding affinities (< 10nM) will likely be needed.

Re 2-arylbenzothiazoles


Input: The integrated approach reported here to generate compact, neutral and lipophilic Re 2-arylbenzothiazoles could be applied to other potent pharmacophores as well to convert other current A beta PET tracers to their (99m) Tc analogs for more widespread application via the use of SPECT scanners.

Re 2-arylbenzothiazoles

(99m) Tc


Input: Steroidal constituents from the leaves of Hosta longipes and their inhibitory effects on nitric oxide production.

Steroidal

nitric oxide


Input: Hosta longipes (FR. et SAV.) MATSUMURA (Liliaceae) is an edible vegetable in Korea.


Input: This study was conducted with the aim of evaluating the potential of H. longipes as a functional food for the treatment of neurodegenerative diseases such as Alzheimer' s disease and Parkinson' s disease.


Input: In this respect, the study resulted in the identification of three new steroidal compounds, longipenane (1), longipenane 26-O-beta-d-glucopyranoside (2) and neogitogenin 3-O-alpha-l-rhamnopyranosyl-(1 --> 2)-O-[beta-d-glucopyranosyl-(1 --> 4)]-beta-d-galactopyranoside (3), along with two known steroidal saponins (4 and 5).

steroidal

longipenane

longipenane 26-O-beta-d-glucopyranoside

neogitogenin 3-O-alpha-l-rhamnopyranosyl-(1 --> 2)-O-[beta-d-glucopyranosyl-(1 --> 4)]-beta-d-galactopyranoside

steroidal saponins


Input: The identification and structural elucidation of these compounds were based on 1D and 2D NMR measurements, high-resolution FAB mass spectroscopy (HR-FAB-MS), and chemical methods.


Input: A proinflammatory mediator, nitric oxide (NO), in murine microglial BV-2 cells was used to assess the anti-neuroinflammatory effect of the isolated compounds from H. longipes.

nitric oxide

NO


Input: Among them, compounds 4 and 5 showed strong inhibitory effects on NO production without high cell toxicity in lipopolysaccharide-activated BV-2 cells (IC50 = 17. 66 and 13. 16 mu M, respectively).

NO


Input: Complexation of Hypocrellin A with Al3 + in water solution and the photodynamic therapy study.

Hypocrellin A

Al3 +


Input: The complex of Hypocrellin A with Al (3 +) is prepared in water solution by a facile method.

Hypocrellin A

Al (3 +)


Input: The water-solubility and stability of complexes are improved.


Input: Irradiation of Al (3 +)-HA complex results in higher efficient generation of singlet oxygen ((1) O2) and photocleavage ability to CT DNA than HA.

Al (3 +)

oxygen

(1) O2


Input: In vitro studies have illustrated that the Al (3 +)-HA complex has anti-cancer activity.

Al (3 +)


Input: Development of the simple and sensitive method for lipoxygenase assay in AOT/isooctane reversed micelles.

AOT

isooctane


Input: In this study, we investigated the possibility of reversed micelles, widely used as an enzyme reactor for lipases, for the determination of lipoxygenase activity.


Input: Although it is rapid and simple, reversed micelles have some limitations, such as interference by UV-absorbing materials and surfactant.


Input: Lipoxygenase activity in the reversed micelles was determined by reading the absorbance of the lipid hydroperoxidation product (conjugated diene) at 234 nm.

diene


Input: Among surfactants and organic media, AOT and isooctane were most effective for the dioxygenation of linoleic acid in reversed micelles.

AOT

isooctane

linoleic acid


Input: The strong absorbance of AOT in the UV region is a major obstacle for the direct application of the AOT/isooctane reversed micelles to lipoxygenase activity determination.

AOT

AOT

isooctane


Input: To prevent interference by AOT, we added an AOT removal step in the procedure for lipoxygenase activity determination in reversed micelles.

AOT

AOT


Input: The lipoxygenase activity was dependent on water content, and maximum activity was obtained at an R-value of 10.


Input: Nutritional and antinutritional evaluation of raw and processed Australian wattle (Acacia saligna) seeds.


Input: Raw and processed (soaked, soaked/boiled, roasted) wattle, Acacia saligna subspecies (subsp.) saligna, pruinescens, stolonifera and lindleyi, seeds were analysed for nutritional and antinutritional qualities.


Input: Whole wattle seeds mainly comprised proteins (27. 6-32. 6%) and carbohydrates (30. 2-36. 4%), which had approximately 12. 0-14. 0% fat and 13. 0-15. 0% crude fibre.

carbohydrates


Input: Palmitic (9. 6%), stearic (2. 0%), oleic (20. 0%) and linoleic (64. 3%) acids were identified by gas chromatography (GC) analysis.

Palmitic

stearic

oleic

linoleic


Input: Phenolic (~ 0. 2%), oxalate (2. 2-3. 4%) and saponin (2. 6-3. 0%) contents were fairly high; phytate content was low.

oxalate

saponin

phytate


Input: All untreated samples contained a high level of trypsin inhibitor (2474. 3-3271. 4 trypsin inhibitor units per gramme (TIU/g) of flour) and low level of alpha-chymotrypsin inhibitor (120. 4-150. 6 CIU/g).


Input: Soaking overnight following with 2-min boiling led to a significant reduction of protease inhibitor activity.


Input: Roasting at 2 min or longer was sufficient to reduce both trypsin and alpha-chymotrypsin inhibitors to negligible values, also to reduce phytate, oxalate and saponin contents, simultaneously enhanced the nutritional values of wattle seeds.

phytate

oxalate

saponin


Input: Interaction and digestibility of phaseolin/polyphenol in the common bean.

polyphenol


Input: The polyphenols and phaseolin interaction in common bean varieties was studied.

polyphenols


Input: Raw beans of three different colours were analysed: black (BRS Supremo), brown (BRS Pontal) and white (WAF-75).


Input: Based on the phaseolin digestibility in vitro and phaseolin-polyphenol complexation obtained by SDS-PAGE on a 10% polyacrylamide gel, it was observed that the polyphenols interfere with the digestibility of beans by decreasing the hydrolysis of phaseolin, especially in the darker ones.

polyphenol

polyacrylamide

polyphenols


Input: Furthermore it was possible to verify a difference in the electrophoretic pattern of phaseolin, indicating an interaction between phaseolin and polyphenols.

polyphenols


Input: Influence of seasonality on the chemical composition of oysters (Crassostrea rhizophorae).


Input: This paper aimed to evaluate the influence of seasonality on the chemical composition of oysters (Crassostrea rhizophorae).


Input: Samples were collected during summer and winter from the estuary and lagoon complex of the municipality of Barra de S a o Miguel, Alagoas, Brazil.


Input: Statistical differences (p < 0. 05) between summer and winter were observed in relation to chemical composition.


Input: The oysters cultivated in the winter presented some nutritional advantages because of the higher levels of proteins and functional nutrients, such as the eicosapentaenoic-docosahexaenoic acid combination and percentages of polyunsaturated fatty acids (n-3 and n-6), and the lower levels of saturated fatty acids.

eicosapentaenoic-docosahexaenoic acid

polyunsaturated fatty acids

saturated fatty acids


Input: Therefore, the animals in winter presented a higher content of cholesterol oxides.

cholesterol oxides


Input: The levels of cholesterol oxides found in these products during winter may encourage researchers to investigate the composition of oysters cultivated in different climates all over the world.

cholesterol oxides


Input: Simultaneous determination of 2-naphthol and 1-hydroxypyrene in fish and shellfish contaminated with crude oil by gas chromatography-mass spectrometry.


Input: This paper describes a gas chromatography-mass spectrometric method of l-hydroxypyrene (1-HOP) and 2-naphthol (2-NAP) in fish and shellfish.

l-hydroxypyrene


Input: Alkali hydrolysis method in this study was chosen and optimized to the reaction condition for 90 min at 90 degrees C in a 2. 0M KOH solution.

KOH


Input: For five independent determinations at 0. 2 and 1. 0 mu g/kg, the coefficient of variation was less than 5. 1%.


Input: This method was used to assess the long-term influence of spilled crude oil on marine ecosystems and analyze fifty-two shellfish samples taken in the near of the accident region of the Hebei Spirit oil spill.


Input: 2-NAP and 1-HOP were detected in the mean concentration range of 0. 09-12. 42 and 0. 03-0. 06 mu g/kg, respectively.


Input: 2-NAP was detected in a high concentration range in shellfishes gathered in 2 months after the accident and it decreased rapidly to 6 months after that.


Input: The results showed that 2-NAP might be an important biomarker in biota contaminated with crude oil.


Input: In vitro biological activity of essential oils and isolated furanosesquiterpenes from the neglected vegetable Smyrnium olusatrum L.

furanosesquiterpenes


Input: (Apiaceae).


Input: Smyrnium olusatrum, better known as Alexanders or wild celery, is a biennal herb used in cuisine for many centuries by Romans in many dishes, where it has now been replaced by celery.


Input: In order to provide additional evidences so that this forgotten vegetable can be reconsidered in the human diet, as well as in pharmaceutics, the essential oils obtained from different parts and its main isolated furanosesquiterpenes were in vitro biologically assayed for antiproliferative activity on human tumor cell lines by MTT assay, for antioxidant potential by DPPH, ABTS and FRAP assays, and for antimicrobial activity by the agar disc diffusion method.

furanosesquiterpenes

MTT

DPPH

ABTS


Input: The essential oils showed cytotoxic effects on tested human tumor cell lines, related to the furanosesquiterpenoid content; the IC (50) values on colon carcinoma, glioblastoma, and breast adenocarcinoma cells were 8. 51, 13. 35, and 14. 81 mu g/ml, respectively.


Input: Isofuranodiene and 1 beta-acetoxyfuranoeudesm-4 (15)-ene resulted the most active constituents.

Isofuranodiene

1 beta-acetoxyfuranoeudesm-4 (15)-ene


Input: The essential oils possessed also radical scavenging activity.


Input: Quantification of organic acids using voltammetric tongues.


Input: Recently, electronic tongues (ET) have appeared as an excellent alternative to traditional techniques for the evaluation of food quality and processes.


Input: ET systems are based on arrays of low selectivity sensors that are simultaneously sensitive to several components in a measured sample (cross-sensitivity).


Input: The aim of this study was to determine the ability of an ET based on pulse voltammetry to quantify organic acids (ascorbic, citric and malic acids) in simple (SS) and binary solutions (BS) using different electrodes.

ascorbic, citric and malic acids


Input: The most significant electrodes for ascorbic acid prediction were Ni and Ag for SS, and Ag and Ir for BS where positive pulses were more suitable than negative ones.

ascorbic acid

Ni

Ag

Ag

Ir


Input: The prediction of citric and malic acids in SS and BS were suitable using Ir, Rh, Pt, Ag and Cu electrodes, using both positive and negative pulses.

citric and malic acids

Ir

Rh

Pt

Ag

Cu


Input: Quality enhancement in refrigerated red drum (Sciaenops ocellatus) fillets using chitosan coatings containing natural preservatives.


Input: The present work was undertaken to examine the influence of grape seed extract (GS) and tea polyphenols (TP), as natural preservatives, combined with chitosan (Ch), on the quality of red drum (Sciaenops ocellatus) fillets during refrigerated storage.

polyphenols


Input: Two different treatments (Ch + GS and Ch + TP) and a control were prepared.


Input: The samples were stored (4 +/- 1 degrees C) for 20 days and the sampling was done at 0, 4, 8, 12, 16, 20 days.


Input: Microbiological, physicochemical and sensory attributes were periodically assessed.


Input: The results indicated that the two pretreatments could more effectively maintain quality and could extend the shelf life by 6-8 days compared with the control group during refrigerated storage.


Input: Multi-class method for determination of veterinary drug residues and other contaminants in infant formula by ultra performance liquid chromatography-tandem mass spectrometry.


Input: A rapid, simple and generic analytical method which was able to simultaneously determine 220 undesirable chemical residues in infant formula had been developed.


Input: The method comprised of extraction with acetonitrile, clean-up by low temperature and water precipitation, and analysis by ultra performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (UPLC-ESI-MS-MS) using multiple reaction monitoring (MRM) mode.

acetonitrile


Input: Most fat materials in acetonitrile extract were eliminated by low temperature clean-up.

acetonitrile


Input: The water precipitation, providing a necessary and supplementary cleanup, could avoid losses of hydrophobic analytes (avermectins, ionophores).

avermectins


Input: Average recoveries for spiked infant formula were in the range from 57% to 147% with associated RSD values between 1% and 28%.


Input: For over 80% of the analytes, the recoveries were between 70% and 120% with RSD values in the range of 1-15%.


Input: The limits of quantification (LOQs) were from 0. 01 to 5 mu g/kg, which were usually sufficient to verify the compliance of products with legal tolerances.


Input: Application of this method in routine monitoring programs would imply a drastic reduction of both effort and time.


Input: Comparative analysis of nutritional compositions of transgenic high iron rice with its non-transgenic counterpart.

iron


Input: Iron is an essential micronutrient for human nutrition and polished rice contains very low amount of iron.

Iron

iron


Input: Rice with high iron content in seed endosperm has been developed by insertion of soybean ferritin gene under the control of the endosperm specific glutelin promoter into the genome of indica rice line IR68144.

iron


Input: The nutritional composition of the brown and milled rice grain has been compared with that of the non-transgenic rice of the same variety.


Input: In this study, the nutritional components, as well as the anti-nutrient levels, were measured.


Input: Our studies established that apart from the increased level of iron and zinc in transgenic seeds, the nutritional quality of both the brown and milled rice grains from the transgenic line was substantially equivalent to that of the non-transgenic rice plants.

iron

zinc


Input: The result clearly shows that the measured amounts of the nutritional components are well within the range of values reported for other commercial lines.