Input: RESULTS: One milligram per hour, but not 0. 25 mg/h, DP infusion prevented ADE and reduced the total ethanol preference in animals.

ethanol


Input: DP plasma concentrations associated with ADE suppression were around 3-4 mu g/ml, and brain DP levels in these conditions were about 2-3% of those found in plasma.


Input: Intra-pVTA DP administration also suppressed ADE.


Input: CONCLUSION: DP is able to prevent alcohol-relapse-like drinking in rats suggesting that this drug may be a useful new tool in the management of relapse in alcohol-dependent patients.

alcohol

alcohol


Input: Sublethal silver and NaCl toxicity in Daphnia magna: a comparative study of standardized chronic endpoints and progeny phototaxis.

silver

NaCl


Input: Behavioral bioassays with the model freshwater cladoceran Daphnia magna have the potential to serve as nontraditional but sensitive endpoints of sublethal stress.


Input: However, few studies have examined the comparative sensitivity of neonate phototaxis perturbations to standardized endpoints commonly employed in chronic toxicity testing protocols.


Input: Even less understood are the consequences of prenatal exposure on neonate phototactic behavior.


Input: Here, we tested the hypothesis that D. magna neonate phototaxis is a more sensitive endpoint over a chronic study period than mortality and reproduction.


Input: D. magna 21 day studies were conducted with model stressors of sodium chloride and dissolved silver.

sodium chloride

silver


Input: Phototaxis assays of progeny response to relative light changes in small water columns were conducted for each brood.


Input: Significant differences in neonate phototactic behavior were observed among treatment level broods, suggesting that maternal exposure to sublethal levels of NaCl and Ag + impacted offspring.

NaCl

Ag +


Input: In fact, progeny phototactic response was significantly affected at or below 21-day LOEC thresholds for fecundity in broods 2, 3, 5 and 6 of the NaCl experiment and in broods 2, 4, 5 and 6 of the dissolved Ag + study.

NaCl

Ag +


Input: Because neonate phototaxis was generally more sensitive than standardized fecundity thresholds, we suggest employing neonate phototaxis as an ecologically important endpoint in future ecological risk assessments.


Input: Parathyroid Hormone (PTH) and PTH-Related Peptide Domains Contributing to Activation of Different PTH Receptor-Mediated Signaling Pathways.


Input: Parathyroid hormone (PTH) and parathyroid hormone related peptide (PTHrP), acting through the osteoblast PTH1R, play important roles in bone remodeling.


Input: Intermittent administration of PTH (1-34) (teriparatide) leads to bone formation while continuous administration paradoxically leads to bone resorption.


Input: Activation of PTH1R promotes regulation of multiple signaling pathways, including Gs/cAMP/PKA, Gq/calcium/PKC, beta-arrestin recruitment and ERK1/2 phosphorylation as well as receptor internalization but their role in promoting anabolic and catabolic actions of PTH (1-34) are unclear.

cAMP

calcium


Input: In the present investigation, a collection of PTH (1-34) and PTHrP (1-34) peptide analogs were evaluated in orthogonal hPTH1R functional assays capturing Gs-and Gq-signaling, beta-arrestin recruitment, ERK1/2 phosphorylation and receptor internalization to further define patterns of of PTH1R signaling they stimulate and to further establish peptide domains contributing to agonist activity.


Input: Results indicate that both N-and C-terminal domains are critical for activation of signaling pathways.

N

C


Input: However, modifications of both regions leads to more substantial decreases in agonist potency and efficacy to stimulate Gq-signaling, beta-arrestin recruitment, ERK1/2 phosphorylation and receptor internalization than to stimulate Gs.


Input: The substantial contribution of the peptide C-terminal domain in activation of hPTH1R-signaling suggests a role in positioning of the peptide N-terminal region into the receptor J-domain.

C

N


Input: Several PTH and PTHrP peptide analogs evaluated in this study promote different patterns of biased agonist signaling and may serve as useful tools to further elucidate therapeutically relevant PTH1R signaling in osteoblasts.


Input: With a better understanding of therapeutically relevant signaling, novel biased peptides with desired signaling could be designed for safer and more effective treatment of osteoporosis.


Input: Substituted 7-Amino-5-thio-thiazolo [4, 5-d] pyrimidines as Potent and Selective Antagonists of the Fractalkine Receptor (CX3CR1).

7-Amino-5-thio-thiazolo [4, 5-d] pyrimidines


Input: We have developed two parallel series, A and B, of CX3CR1 antagonists for the treatment of multiple sclerosis.


Input: By modifying the substituents on the 7-amino-5-thio-thiazolo [4, 5-d] pyrimidine core structure, we were able to achieve compounds with high selectivity for CX3CR1 over the closely related CXCR2 receptor.

7-amino-5-thio-thiazolo [4, 5-d] pyrimidine


Input: The structure-activity relationships showed that a leucinol moiety attached to the core-structure in the 7-position together with alpha-methyl branched benzyl derivatives in the 5-position displayed promising affinity, and selectivity as well as physicochemical properties, as exemplified by compounds 18a and 24h.

leucinol

alpha-methyl

benzyl


Input: We show the preparation of the first potent and selective orally available CX3CR1 antagonists.


Input: Therapeutic Agents Triggering Nonapoptotic Cancer Cell Death.


Input: It is widely recognized that the evasion of apoptotic cell death is one of the hallmarks of cancer.


Input: For many years cytotoxic agents have been developed to target apoptotic cell death as a main method of treating cancer.


Input: However, the occurrence of cellular defects involving the apoptotic machinery in many cancers has resulted in an acquired resistance to apoptotic cell death, undermining the effectiveness of chemotherapeutic agents.


Input: Over the past decade, research has revealed a growing number of cell death pathways that are not dependent on apoptosis.


Input: In addition, compounds specifically triggering these alternative cell death pathways have been identified and explored as novel cancer treatment options.


Input: These novel anticancer agents are critically discussed by the authors, and therefore, the current Perspective represents a resource for a practicing medicinal chemist looking for new opportunities to combat cancers resistant to the established proapoptotic therapeutic agents.


Input: Constraint Network Analysis (CNA): A Python Software Package for Efficiently Linking Biomacromolecular Structure, Flexibility, (Thermo-) Stability, and Function.


Input: For deriving maximal advantage from information on biomacromolecular flexibility and rigidity, results from rigidity analyses must be linked to biologically relevant characteristics of a structure.


Input: Here, we describe the Python-based software package Constraint Network Analysis (CNA) developed for this task.


Input: CNA functions as a front-and backend to the graph-based rigidity analysis software FIRST.


Input: CNA goes beyond the mere identification of flexible and rigid regions in a biomacromolecule in that it (I) provides a refined modeling of thermal unfolding simulations that also considers the temperature-dependence of hydrophobic tethers, (II) allows performing rigidity analyses on ensembles of network topologies, either generated from structural ensembles or by using the concept of fuzzy noncovalent constraints, and (III) computes a set of global and local indices for quantifying biomacromolecular stability.


Input: This leads to more robust results from rigidity analyses and extends the application domain of rigidity analyses in that phase transition points (" melting points ") and unfolding nuclei (" structural weak spots ") are determined automatically.


Input: Furthermore, CNA robustly handles small-molecule ligands in general.


Input: Such advancements are important for applying rigidity analysis to data-driven protein engineering and for estimating the influence of ligand molecules on biomacromolecular stability.


Input: CNA maintains the efficiency of FIRST such that the analysis of a single protein structure takes a few seconds for systems of several hundred residues on a single core.


Input: These features make CNA an interesting tool for linking biomacromolecular structure, flexibility, (thermo-) stability, and function.


Input: CNA is available from http://cpclab. uni-duesseldorf. de/software for nonprofit organizations.


Input: Novel Plasmodium falciparum Maurer' s clefts protein families implicated in the release of infectious merozoites.


Input: The pathogenicity of the most deadly human malaria parasite, Plasmodium falciparum, relies on the export of virulence factors to the surface of infected erythrocytes.


Input: A novel membrane compartment, referred to as Maurer' s clefts, is transposed to the host erythrocyte, acting as a marshal platform in the red blood cell cytoplasm, for exported parasite proteins addressed to the host cell plasma membrane.


Input: We report here the characterization of three new P. falciparum multigene families organized in 9 highly conserved clusters with the Pfmc-2tm genes in the subtelomeric regions of parasite' s chromosomes and expressed at early trophozoite stages.


Input: Like the PfMC-2TM proteins, the PfEPF1, 3 and 4 proteins encoded by these families are exported to the Maurer' s clefts, as peripheral or integral proteins of the Maurer' s cleft membrane and largely exposed to the red cell cytosolic face of this membrane.


Input: A promoter titration approach was used to question the biological roles of these P. falciparum-specific exported proteins.


Input: Using the Pfepf1 family promoter, we observed the specific downregulation of all four families, correlating with the inefficient release of merozoites while the parasite intra-erythrocytic maturation and Maurer' s clefts morphology were not impacted.


Input: Ultrafast Spectroscopy of Quantum Confined States in a Single CdSe Nanowire.

CdSe


Input: We measure for the first time transient absorption spectra of individual CdSe nanowires with about 10 nm diameter.

CdSe


Input: Confinement of the carrier wave functions leads to discrete states which can be described by a six-band effective mass model.


Input: Combining transient absorption and luminescence spectroscopy allows us to track the excitation dynamics in the visible and near-infrared spectral range.


Input: About 10% of all absorbed photons lead to an excitation of the lowest energy state.


Input: Of these excitations, less than 1% lead to a photon in the optical far-field.


Input: Almost all emission is reabsorbed by other parts of the nanowire.


Input: These findings might explain the low overall quantum efficiency of CdSe nanowires.

CdSe


Input: 1, 4, 2-Benzo/pyridodithiazine 1, 1-Dioxides Structurally Related to the ATP-Sensitive Potassium Channel Openers 1, 2, 4-Benzo/pyridothiadiazine 1, 1-Dioxides Exert a Myorelaxant Activity Linked to a Distinct Mechanism of Action.

1, 4, 2-Benzo/pyridodithiazine 1, 1-Dioxides

ATP

Potassium

1, 2, 4-Benzo/pyridothiadiazine 1, 1-Dioxides


Input: The synthesis of diversely substituted 3-alkyl/aralkyl/arylamino-1, 4, 2-benzodithiazine 1, 1-dioxides and 3-alkylaminopyrido [4, 3-e]-1, 4, 2-dithiazine 1, 1-dioxides is described.

3-alkyl/aralkyl/arylamino-1, 4, 2-benzodithiazine 1, 1-dioxides

3-alkylaminopyrido [4, 3-e]-1, 4, 2-dithiazine 1, 1-dioxides


Input: Their biological activities on pancreatic beta-cells and on smooth muscle cells were compared to those of the reference ATP-sensitive potassium channel (KATP channel) openers diazoxide and 7-chloro-3-isopropylamino-4H-1, 2, 4-benzothiadiazine 1, 1-dioxide.

ATP

potassium

diazoxide

7-chloro-3-isopropylamino-4H-1, 2, 4-benzothiadiazine 1, 1-dioxide


Input: The aim was to assess the impact on biological activities of the replacement of the 1, 2, 4-thiadiazine ring by an isosteric 1, 4, 2-dithiazine ring.

1, 2, 4-thiadiazine

1, 4, 2-dithiazine


Input: Most of the dithiazine analogues were found to be inactive on the pancreatic tissue, although some compounds bearing a 1-phenylethylamino side chain at the 3-position exerted a marked myorelaxant activity.

dithiazine


Input: Such an effect did not appear to be related to the opening of KATP channels but rather reflected a mechanism of action similar to that of calcium channel blockers.

calcium


Input: Tightly related 3-(1-phenylethyl) sulfanyl-4H-1, 2, 4-benzothiadiazine 1, 1-dioxides were also found to exert a pronounced myorelaxant activity, resulting from both a KATP channel activation and a calcium channel blocker mechanism.

3-(1-phenylethyl) sulfanyl-4H-1, 2, 4-benzothiadiazine 1, 1-dioxides

calcium


Input: The present work highlights the critical importance of an intracyclic NH group at the 4-position, as well as an exocyclic NH group linked to the 3-position of the benzo-and pyridothiadiazine dioxides, for activity on KATP channels.

NH

NH

benzo-and pyridothiadiazine dioxides


Input: Discovery of 3, 3'-diindolylmethanes as potent antileishmanial agents.

3, 3'-diindolylmethanes


Input: An efficient protocol for synthesis of 3, 3'-diindolylmethanes using recyclable Fe-pillared interlayered clay (Fe-PILC) catalyst under aqueous medium has been developed.

3, 3'-diindolylmethanes

Fe

Fe


Input: All synthesized 3, 3'-diindolylmethanes showed promising antileishmanial activity against Leishmania donovani promastigotes as well as axenic amastigotes.

3, 3'-diindolylmethanes


Input: Structure-activity relationship analysis revealed that nitroaryl substituted diindolylmethanes showed potent antileishmanial activity.

nitroaryl substituted diindolylmethanes


Input: The 4-nitrophenyl linked 3, 3'-diindolylmethane 8g was found to be the most potent antileishmanial analog showing IC50 values of 7. 88 and 8. 37 mu M against both L. donovani promastigotes and amastigotes, respectively.

4-nitrophenyl linked 3, 3'-diindolylmethane


Input: Further, a pharmacophore based QSAR model was established to understand the crucial molecular features of 3, 3'-diindolylmethanes essential for potent antileishmanial activity.

3, 3'-diindolylmethanes


Input: These compounds also exhibited promising antifungal activity against Cryptococcus neoformans, wherein fluorophenyl substituted 3, 3'-diindolylmethanes were found to be most potent antifungal agents.

fluorophenyl substituted 3, 3'-diindolylmethanes


Input: Developed synthetic protocol will be useful for economical and eco-friendly synthesis of potent antileishmanial and antifungal 3, 3'-diindolylmethane class of compounds.

3, 3'-diindolylmethane


Input: Synthesis and selected immunological properties of substituted quino [3, 2-b] benzo [1, 4] thiazines.

quino [3, 2-b] benzo [1, 4] thiazines


Input: A new type of azaphenothiazines-tetracyclic quino [3, 2-b] benzo [1, 4] thiazines, possessing common substituents (H, CH3, Cl, Br, F, CF3, SCH3) in positions 8-10 and pharmacophoric aminoalkyl substituents in position 6, were obtained from diquinodithiin and 2, 2'-dichloro-3, 3'-diquinolinyl disulfide in several-step syntheses.

azaphenothiazines

tetracyclic quino [3, 2-b] benzo [1, 4] thiazines

H

Cl

Br

F

aminoalkyl

diquinodithiin

2, 2'-dichloro-3, 3'-diquinolinyl disulfide


Input: Sixty one compounds, grouped as the 6H, 6-dialkylaminoalkyl, 6-acylaminoalkyl and sulfonylaminoalkyl derivatives, were tested for cytotoxicity, their effects on phytohemagglutin A (PHA)-induced proliferative response of human peripheral blood mononuclear cells (PBMC) and lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-alpha) production by these cells.

sulfonylaminoalkyl


Input: The compounds exhibited differential inhibitory activities in these tests and significantly varied in terms of cytotoxicity.


Input: The most promising compounds were tested for growth inhibition of leukemia L-1210 cells, colon cancer SV-948 cells and epidermal carcinoma A-341 cells.


Input: The most active compounds exhibited anticancer activity against these cell lines comparable to that of cisplatin.

cisplatin


Input: The structure-activity relationship of the compounds were discussed.


Input: Fisetin regulates obesity by targeting mTORC1 signaling.

Fisetin


Input: Fisetin, a flavonol present in vegetables and fruits, possesses antioxidative and anti-inflammatory properties.

Fisetin

flavonol


Input: In this study, we have demonstrated that fisetin prevents diet-induced obesity through regulation of the signaling of mammalian target of rapamycin complex 1 (mTORC1), a central mediator of cellular growth, cellular proliferation and lipid biosynthesis.

fisetin

rapamycin


Input: To evaluate whether fisetin regulates mTORC1 signaling, we investigated the phosphorylation and kinase activity of the 70-kDa ribosomal protein S6 kinase 1 (S6K1) and mTORC1 in 3T3-L1 preadipocytes.

fisetin


Input: Fisetin treatment of preadipocytes reduced the phosphorylation of S6K1 and mTORC1 in a time-and concentration-dependent manner.

Fisetin


Input: To further our understanding of how fisetin negatively regulates mTORC1 signaling, we analyzed the phosphorylation of S6K1, mTOR and Akt in fisetin-treated TSC2-knockdown cells.

fisetin

fisetin


Input: The results suggested that fisetin treatment inhibits mTORC1 activity in an Akt-dependent manner.

fisetin


Input: Recent studies have shown that adipocyte differentiation is dependent on mTORC1 activity.


Input: Fisetin treatment inhibited adipocyte differentiation, consistent with the negative effect of fisetin on mTOR.

Fisetin

fisetin


Input: The inhibitory effect of fisetin on adipogenesis is dependent of mTOR activity, suggesting that fisetin inhibits adipogenesis and the accumulation of intracellular triglycerides during adipocyte differentiation by targeting mTORC1 signaling.

fisetin

fisetin

triglycerides


Input: Fisetin supplementation in mice fed a high-fat diet (HFD) significantly attenuated HFD-induced increases in body weight and white adipose tissue.

Fisetin


Input: We also observed that fisetin efficiently suppressed the phosphorylation of Akt, S6K1 and mTORC1 in adipose tissue.

fisetin


Input: Collectively, these results suggest that inhibition of mTORC1 signaling by fisetin prevents adipocyte differentiation of 3T3-L1 preadipocytes and obesity in HFD-fed mice.

fisetin


Input: Therefore, fisetin may be a useful phytochemical agent for attenuating diet-induced obesity.

fisetin


Input: Structural elucidation of possible lutein oxidation products mediated through peroxyl radical inducer 2, 2'-Azobis (2-methylpropionamidine) dihydrochloride: Antioxidant and cytotoxic influence of oxidized lutein in HeLa cells.

lutein

peroxyl

2, 2'-Azobis (2-methylpropionamidine) dihydrochloride

lutein


Input: Aim of this study was to elucidate lutein oxidation products mediated through peroxyl radical inducer 2, 2'-Azobis (2-methylpropionamidine) dihydrochloride (AAPH) and to study antioxidant and cytotoxic effects of oxidized lutein using liposome and HeLa cells.

lutein

peroxyl

2, 2'-Azobis (2-methylpropionamidine) dihydrochloride

AAPH

oxidized lutein


Input: Lutein (20 mu mol) with AAPH (5mM) in liposome' s was incubated at 37 degrees C in dark for 3h, oxidized lutein products were characterized by LC-MS (APCI (+)) and studied for their free radical scavenging activity and cytotoxic effects in terms of cell viability, cellular glutathione, and malondialdehyde levels.

Lutein

AAPH

oxidized lutein

glutathione

malondialdehyde


Input: AAPH mediated lutein fragmented ions were identified as 551 (M (+) + H (+)-H2O), 391 (M (+) + H (+) + O2-C22H32O) and 276 (M (+) + H (+) + O2-C12H20O) and its isomers as 13-Z lutein, 13-Z zeaxanthin, 13'-Z zeaxanthin and all-E zeaxanthin.

AAPH

lutein

H (+)

H (+)

H (+)

13-Z lutein

13-Z zeaxanthin

13'-Z zeaxanthin

all-E zeaxanthin


Input: Free radical scavenging activity of oxidized lutein was higher by 32. 7% (IC50, 2. 64 mu g) than lutein (IC50, 5. 28 mu g).

oxidized lutein

lutein


Input: Oxidized lutein lowered the lipid peroxidation (21%), HeLa cells viability (22%) and glutathione levels (32%) than lutein.

Oxidized lutein

glutathione

lutein


Input: To conclude, the oxidized lutein may be highly reactive, since oxidation by AAPH results in peroxyl radical ions, which can react with conjugated polyene chain of lutein that could lead to higher antioxidant and cytotoxic effects on HeLa cells.

oxidized lutein

AAPH

peroxyl

polyene

lutein


Input: Tricyclic thiazoles are a new class of angiogenesis inhibitors.

Tricyclic thiazoles


Input: Tricyclic thiazoleamine derivatives that were identified as hits in a screen against human umbilical vein endothelial cell proliferation were subjected to a structure-activity relationship study.

Tricyclic thiazoleamine


Input: Two structurally superimposable scaffolds-4H-thiochromeno [4, 3-d] thiazol-2-amine and 5, 6-dihydro-4H-benzo [6, 7] cyclohepta [1, 2-d] thiazol-2-amine derivatives-yielded low-micromolar inhibitors, and two among them 37 and 43 also exhibited antiangiogenic activity in an endothelial tube formation assay.

4H-thiochromeno [4, 3-d] thiazol-2-amine

5, 6-dihydro-4H-benzo [6, 7] cyclohepta [1, 2-d] thiazol-2-amine


Input: Thus, 37 and 43 can serve as leads to develop a novel class of antiangiogenic agents.


Input: Neuroprotective effect of sulforaphane in 6-hydroxydopamine-lesioned mouse model of Parkinson' s disease.

sulforaphane


Input: Parkinson' s disease (PD) is characterized by the selective loss of dopaminergic nigrostriatal neurons, which leads to disabling motor disturbances.


Input: Sulforaphane (SFN), found in cruciferous vegetables, is a potent indirect antioxidant and recent advances have shown its neuroprotective activity in various experimental models of neurodegeneration.

Sulforaphane

SFN


Input: This study was undertaken to examine the effects of SFN on behavioral changes and dopaminergic neurotoxicity in mice exposed to 6-hydroxydopamine (6-OHDA).

SFN


Input: For this purpose, mice were treated with SFN (5mg/kg twice a week) for four weeks after the unilateral intrastriatal injection of 6-OHDA.

SFN


Input: The increase in 6-OHDA-induced rotations and deficits in motor coordination were ameliorated significantly by SFN treatment.

SFN


Input: In addition, SFN protected 6-OHDA-induced apoptosis via blocking DNA fragmentation and caspase-3 activation.

SFN


Input: These results were further supported by immunohistochemical findings in the substantia nigra that showed that SFN protected neurons from neurotoxic effects of 6-OHDA.

SFN


Input: The neuroprotective effect of SFN may be attributed to its ability to enhance glutathione levels and its dependent enzymes (glutathione-S-transferase and glutathione reductase) and to modulate neuronal survival pathways, such as ERK1/2, in the brain of mice.

SFN

glutathione

glutathione

S

glutathione


Input: These results suggest that SFN may potentially be effective in slowing down the progression of idiopathic PD by the modulation of oxidative stress and apoptotic machinery.

SFN


Input: Oxidative DNA damage corresponds to the long term survival of human cells treated with silver nanoparticles.

silver


Input: We examined the relation between DNA damage and the clonogenic potential of 3 human cell lines, HepG2, HT29 and A549, treated with bare 20nm or 200nm silver nanoparticles (AgNPs).

silver


Input: The endpoints examined were the DNA breakage estimated by the comet assay, the oxidative base damage recognized by formamido-pyrimidine glycosylase (FPG) and estimated with the FPG + comet assay, and the frequencies of histone gamma H2AX foci and micronuclei.

formamido-pyrimidine


Input: Each cell line studied had a different pattern of DNA breakage and base damage versus the NPs concentration and time of treatment.


Input: The overall pattern of DNA breakage and base damage induction corresponded to the intracellular generation of reactive oxygen species.

oxygen


Input: There was no increase in the frequencies of histone gamma H2AX foci and micronuclei as compared to those in the untreated cells.


Input: The reported experiments suggest that only the oxidative DNA damage corresponds to the loss of the clonogenic ability of cells treated with AgNPs.


Input: Detecting genome-wide gene transcription profiles associated with high pollution burden in the critically endangered European eel.


Input: The European eel illustrates an example of a critically endangered fish species strongly affected by human stressors throughout its life cycle, in which pollution is considered to be one of the factors responsible for the decline of the stock.


Input: The objective of our study was to better understand the transcriptional response of European eels chronically exposed to pollutants in their natural environment.


Input: A total of 42 pre-migrating (silver) female eels from lowly, highly and extremely polluted environments in Belgium and, for comparative purposes, a lowly polluted habitat in Italy were measured for polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs) and brominated flame retardants (BFRs).

polychlorinated biphenyls

PCBs

organochlorine


Input: Multipollutant level of bioaccumulation was linked to their genome-wide gene transcription using an eel-specific array of 14, 913 annotated cDNAs.


Input: Shared responses to pollutant exposure were observed when comparing the highly polluted site in Belgium with the relatively clean sites in Belgium and Italy.


Input: First, an altered pattern of transcription of genes was associated with detoxification, with a novel European eel CYP3A gene and gluthatione S-transferase transcriptionally up-regulated.

gluthatione S


Input: Second, an altered pattern of transcription of genes associated with the oxidative phosphorylation pathway, with the following genes involved in the generation of ATP being transcriptionally down-regulated in individuals from the highly polluted site: NADH dehydrogenase, succinate dehydrogenase, ubiquinol-cytochrome c reductase, cytochrome c oxidase and ATP synthase.

ATP

NADH

succinate

ubiquinol

ATP


Input: Although we did not measure metabolism directly, seeing that the transcription level of many genes encoding enzymes involved in the mitochondrial respiratory chain and oxidative phosphorylation were down-regulated in the highly polluted site suggests that pollutants may have a significant effect on energy metabolism in these fish.


Input: Large-scale synthesis and in situ functionalization of Zn3P2 and Zn4Sb3 nanowire powders.


Input: A simple method for the large-scale synthesis of gram quantities of compound semiconductor nanowires without the need for any external catalysts or templates is presented.


Input: This method is demonstrated using zinc phosphide (Zn3P2) and zinc antimonide (beta-Zn4Sb3) nanowires as example systems.

zinc phosphide

zinc antimonide


Input: Large-scale synthesis of Zn3P2 and Zn4Sb3 nanowire powders was accomplished using a hot-walled chemical vapor deposition chamber by transporting phosphorus and antimony, respectively, via the vapor phase onto heated zinc foils.

phosphorus

antimony

zinc


Input: The zinc foils were rolled concentrically into coils to maximize the substrate surface area, and consequently, the nanowire yield.

zinc


Input: Using this method, 250 mg of Zn3P2 nanowires were obtained on 480 cm (2) of zinc foil in a span of 45 minutes.

zinc


Input: Furthermore, a process of exposing the synthesized nanowires to a vapor of organic functional molecules immediately after their synthesis and before their removal from the vacuum chamber was developed to obtain large quantities of surface functionalized nanowire powders.


Input: This in situ vapor-phase functionalization procedure passivated the nanowire surfaces without adversely affecting their morphology or dimensions.


Input: Our studies revealed that both 4-aminothiophenol and 3-propanedithiol functionalized Zn3P2 nanowires were stable over a 120 day duration without any agglomeration or degradation.


Input: This method of mass producing nanowires can also be extended to other binary semiconductors.


Input: Loss of Survivin influences liver regeneration and is associated with impaired Aurora B function.


Input: The chromosomal passenger complex (CPC) acts as a key regulator of mitosis, preventing asymmetric segregation of chromosomal material into daughter cells.


Input: The CPC is composed of three non-enzymatic components termed Survivin, the inner centromere protein (INCENP) and Borealin, and an enzymatic component, Aurora B kinase.


Input: Survivin is necessary for the appropriate separation of sister chromatids during mitosis and is involved in liver regeneration, but its role in regenerative processes is incompletely elucidated.


Input: Whether Survivin, which is classified as an inhibitor of apoptosis protein (IAP) based on domain composition, also has a role in apoptosis is controversial.


Input: The present study examined the in vivo effects of Survivin ablation in the liver and during liver regeneration after 70% hepatectomy in a hepatocyte-specific knockout mouse model.


Input: The absence of Survivin caused a reduction in the number of hepatocytes in the liver, together with an increase in cell volume, macronucleation and polyploidy, but no changes in apoptosis.


Input: During liver regeneration, mitosis of hepatocytes was associated with mislocalization of the members of the CPC, which were no longer detectable at the centromere despite an unchanged protein amount.


Input: Furthermore, the loss of survivin in regenerating hepatocytes was associated with reduced levels of phosphorylated Histone H3 at serine 28 and abolished phosphorylation of CENP-A and Hec1 at serine 55, which is a consequence of decreased Aurora B kinase activity.

serine

serine


Input: These data indicate that Survivin expression determines hepatocyte number during liver development and liver regeneration.


Input: Lack of Survivin causes mislocalization of the CPC members in combination with reduced Aurora B activity, leading to impaired phosphorylation of its centromeric target proteins and inappropriate cytokinesis.


Input: Predictive factors of sensitivity to elisidepsin, a novel kahalalide f-derived marine compound.

elisidepsin

kahalalide f


Input: Elisidepsin (PM02734, Irvalec (R)) is a synthetic marine-derived cyclic peptide of the Kahalalide F family currently in phase II clinical development.

Elisidepsin

Irvalec

Kahalalide F


Input: Elisidepsin was shown to induce rapid oncosis in ErbB3-expressing cells.

Elisidepsin


Input: Other predictive factors of elisidepsin sensitivity remained unknown.

elisidepsin


Input: A panel of 23 cancer cell lines of different origin was assessed for elisidepsin cytotoxicity and correlated with mutational state, mRNA and protein expression of selected genes.

elisidepsin


Input: Elisidepsin showed potent and broad cytotoxic effects in our cancer cell line panel, being active at concentrations ranging from 0. 4 to 2 mu M that may be relevant for clinical settings.

Elisidepsin


Input: We have shown that elisidepsin is more active in cells harboring epithelial phenotype with high E-cadherin and low vimentin expression.

elisidepsin


Input: In addition, high ErbB3 and Muc1 expression was correlated with sensitivity to elisidepsin, whereas the presence of KRAS activating mutations was associated with resistance.

elisidepsin


Input: In DU-PM cells with acquired resistance to elisidepsin, ErbB3 expression was decreased, while Bcl2 was increased.

elisidepsin


Input: DU-PM cells displayed higher sensitivity to ErbB1-inhibitors suggesting possible cross-talk of ErbB1 and ErbB3 signaling pathways.


Input: Combinations of elisidepsin with lapatinib and several chemotherapies including 5-FU and oxaliplatin resulted in synergistic effects that offer the potential of clinical use of elisidepsin in combination settings.

elisidepsin

lapatinib

oxaliplatin

elisidepsin


Input: Gold nanoparticle-enhanced luminescence of silicon quantum dots co-encapsulated in polymer nanoparticles.

silicon


Input: The preparation of two-component polymer composite nanoparticles encapsulating both Si quantum dots (SiQDs) and Au nanoparticles (AuNPs) by a single step miniemulsion polymerization of divinylbenzene is described.

Si

Au

divinylbenzene


Input: This simple and robust method affords well-defined polymer composite nanoparticles with mean diameters in a range of 100-200 nm and with narrow polydispersity indices as determined by dynamic light scattering and transmission electron microscopy.


Input: The successful encapsulation of AuNPs within poly (divinylbenzene) was confirmed by UV-visible spectroscopy and from TEM images.

poly (divinylbenzene)


Input: Plasmon-enhanced fluorescence of the luminescence of the SiQDs by AuNPs encapsulated within the polymer composite nanoparticles was evaluated by confocal microspectroscopy, and luminescence enhancements of up to 15 times were observed.


Input: These observations indicate that the luminescence of the SiQDs is enhanced by the proximity of the AuNPs.


Input: The polymer composite nanoparticles were successfully ink-jet printed onto a glass substrate, which demonstrates that these composites are processable in printing applications.


Input: Novel Phosphorylation and Ubiquitination Sites Regulate Reactive Oxygen Species-dependent Degradation of Anti-apoptotic c-FLIP Protein.

Oxygen


Input: The cytosolic protein c-FLIP (cellular Fas-associated death domain-like interleukin 1 beta-converting enzyme inhibitory protein) is an inhibitor of death receptor-mediated apoptosis that is up-regulated in a variety of cancers, contributing to apoptosis resistance.


Input: Several compounds found to restore sensitivity of cancer cells to TRAIL, a TNF family death ligand with promising therapeutic potential, act by targeting c-FLIP ubiquitination and degradation by the proteasome.


Input: The generation of reactive oxygen species (ROS) has been implicated in c-FLIP protein degradation.

oxygen


Input: However, the mechanism by which ROS post-transcriptionally regulate c-FLIP protein levels is not well understood.


Input: We show here that treatment of prostate cancer PPC-1 cells with the superoxide generators menadione, paraquat, or buthionine sulfoximine down-regulates c-FLIP long (c-FLIPL) protein levels, which is prevented by the proteasome inhibitor MG132.

superoxide

menadione

paraquat

buthionine sulfoximine


Input: Furthermore, pretreatment of PPC-1 cells with a ROS scavenger prevented ubiquitination and loss of c-FLIPL protein induced by menadione or paraquat.

menadione

paraquat


Input: We identified lysine 167 as a novel ubiquitination site of c-FLIPL important for ROS-dependent degradation.

lysine


Input: We also identified threonine 166 as a novel phosphorylation site and demonstrate that Thr-166 phosphorylation is required for ROS-induced Lys-167 ubiquitination.

threonine

Thr

Lys


Input: The mutation of either Thr-166 or Lys-167 was sufficient to stabilize c-FLIP protein levels in PPC-1, HEK293T, and HeLa cancer cells treated with menadione or paraquat.

Thr

Lys

menadione

paraquat


Input: Accordingly, expression of c-FLIP T166A or K167R mutants protected cells from ROS-mediated sensitization to TRAIL-induced cell death.


Input: Our findings reveal novel ROS-dependent post-translational modifications of the c-FLIP protein that regulate its stability, thus impacting sensitivity of cancer cells to TRAIL.


Input: Nicotine-, tobacco particulate matter-and methamphetamine-produced locomotor sensitisation in rats.

Nicotine

methamphetamine


Input: RATIONALE: Repeated nicotine exposure produces a weak and transient sensitised locomotor response in rats.

nicotine


Input: Since tobacco smoke contains thousands of non-nicotine chemical constituents, these could alter the sensitised response.

nicotine


Input: OBJECTIVES: This study aims to compare the magnitude, persistence and spatial distribution of locomotor sensitisation produced by repeated doses of nicotine, aqueous tobacco particulate matter (TPM) and a positive methamphetamine control.

nicotine

methamphetamine


Input: METHODS: Male Sprague-Dawley rats received five nicotine (0. 0, 0. 2 or 0. 4 mg/kg), TPM (containing 0. 2 or 0. 4 mg/kg nicotine) or methamphetamine (0. 5 mg/kg) injections every second day, followed by a 4-day withdrawal before the first challenge (Challenge 1, C1).

nicotine

nicotine

methamphetamine


Input: The animals were re-challenged again at 15 days post C1 to test for the persistence of sensitisation (Challenge 2, C2).


Input: RESULTS: There were no major differences in sensitisation profile between nicotine and TPM.

nicotine


Input: At the lowest 0. 2 mg/kg nicotine/TPM dose, however, small differences emerged on select test days.

nicotine


Input: CONCLUSIONS: The results indicated that the non-nicotinic agents in TPM did not greatly impact the nicotine-produced locomotor-sensitised response.

nicotine


Input: These findings might suggest that the differential pharmacological properties of TPM do not have major clinical significance.


Input: Alternatively, the locomotor model might not expose effects of non-nicotinic constituents, and furthermore, might not closely relate to human tobacco dependence.


Input: Different reward-related behavioural models should also be utilised to assess potential effects of non-nicotinic constituents before a role in dependence is discounted.


Input: Treatment of Primary Chronic Glomerulonephritis with Rehmannia Glutinosa Acteosides in Combination with the Angiotensin Receptor Blocker Irbesartan: A Randomized Controlled Trial.

Acteosides

Irbesartan


Input: This study aims to assess the efficacy and safety of Rehmannia glutinosa acteosides used in combination with the angiotensin receptor blocker irbesartan to treat primary chronic glomerulonephritis.

acteosides

irbesartan


Input: A total of 479 patients diagnosed with primary chronic glomerulonephritis were recruited from outpatient clinics and were randomly assigned to the treatment group (Rehmannia glutinosa acteosides, two 200-mg capsules, bid; and irbesartan, one 150-mg tablet, qd) or the control group (irbesartan, one 150-mg tablet, qd).

acteosides

irbesartan

irbesartan


Input: The primary outcome was 24-h urinary protein.


Input: Secondary outcome measures included blood pressure, estimated glomerular filtration rate, erythrocyturia, serum alanine aminotransferase, aspartate transaminase and electrolytes.

alanine

aspartate


Input: After 8 weeks of treatment, the treatment group showed a mean reduction in 24-h proteinuria of 36. 42% compared to baseline, which was significantly higher than the mean reduction from baseline of 27. 97% in the control group (P = 0. 0278). Adverse drug reactions occurred at a similarly low rate in the treatment group (0. 4%) and control group (1. 2%, P = 0. 3724).


Input: In the treatment of chronic glomerulonephritis, the combination of Rehmannia glutinosa acteosides and irbesartan can reduce proteinuria more effectively than irbesartan alone.

acteosides

irbesartan

irbesartan


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


Input: 6-Gingerol Inhibits Rosiglitazone-Induced Adipogenesis in 3T3-L1 Adipocytes.

Rosiglitazone


Input: We investigated the effects of 6-gingerol ((S)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-3-decanone) on the inhibition of rosiglitazone (RGZ)-induced adipogenesis in 3T3-L1 cells.

(S)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-3-decanone

rosiglitazone

RGZ


Input: The morphological changes were photographed based on staining lipid accumulation by Oil-Red O in RGZ (1 micro mol/l)-treated 3T3-L1 cells without or with various concentrations of 6-gingerol on differentiation day 8.

Oil-Red O

RGZ


Input: Quantitation of triglycerides content was performed in cells on day 8 after differentiation induction.

triglycerides


Input: Differentiated cells were lysed to detect mRNA and protein levels of adipocyte-specific transcription factors by real-time reverse transcription-polymerase chain reaction and Western blot analysis, respectively.


Input: 6-gingerol (50 micro mol/l) effectively suppressed oil droplet accumulation and reduced the sizes of the droplets in RGZ-induced adipocyte differentiation in 3T3-L1 cells.

RGZ


Input: The triglyceride accumulation induced by RGZ in differentiated 3T3-L1 cells was also reduced by 6-gingerol (50 micro mol/l).

triglyceride

RGZ


Input: Treatment of differentiated 3T3-L1 cells with 6-gingerol (50 micro mol/l) antagonized RGZ-induced gene expression of peroxisome proliferator-activated receptor (PPAR) gamma and CCAAT/enhancer-binding protein alpha.

RGZ


Input: Additionally, the increased levels of mRNA and protein in adipocyte-specific fatty acid binding protein 4 and fatty acid synthase induced by RGZ in 3T3-L1 cells were decreased upon treatment with 6-gingerol.

fatty acid

fatty acid

RGZ


Input: Our data suggests that 6-gingerol may be beneficial in obesity, by reducing adipogenesis partly through the down-regulating PPAR gamma activity.


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


Input: Multisite quantitative ultrasound for the prediction of fractures over five years of follow-up: The Canadian Multicentre Osteoporosis Study.


Input: This study assessed the ability of multisite quantitative ultrasound (mQUS) to predict fracture over a five-year follow-up.


Input: Participants were a subset of the Canadian Multicentre Osteoporosis Study.


Input: mQUS-assessed speed of sound (SOS in m/s) at three sites (distal radius, tibia and phalanx) and extensive questionnaires were completed, after which participants were followed for five years and incident fractures recorded.


Input: Two survival analyses were completed for each site-a univariate analysis and an adjusted multivariate analysis controlling for age, anti-resorptive use, femoral neck bone mineral density, number of diseases, previous fractures, BMI, parental history of hip fracture, current smoking, current alcoholic drinks > 3 per day, current using glucocorticoids, and rheumatoid arthritis diagnosis (variables from the FRAX 10-year fracture risk assessment tool).

alcoholic


Input: The unit of change for regression analyses was one standard deviation for all measurement sites, specific to site and sex.


Input: Separate analyses were completed for all clinical fractures, non-vertebral fractures and hip fractures by sex.


Input: There were 2633 women and 1108 men included and they experienced 204 incident fractures over five years (5. 5% fractured).


Input: Univariate models revealed statistically significant (p < 0. 05) predictive ability of mQUS for all three measurement sites for women alone for all three fracture types (one standard deviation decrease in SOS was associated with a 52-130% increase in the risk of fracture), but not for the men' s group.


Input: The adjusted model found that measures at the distal radius and tibia in the women' s group could significantly (p < 0. 05) predict all clinical fractures and non-vertebral fractures within the next five years (one standard deviation decrease in SOS was associated with a 25-31% increase in the risk of fracture).


Input: mQUS provided significant five-year clinical fracture prediction in women, independent of bone mineral density and other significant risk factors for fracture, when measured at the distal radius and tibia sites.


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


Input: Library construction and biological evaluation of enmein-type diterpenoid analogues as potential anticancer agents.

enmein

diterpenoid


Input: A library of promising enmein-type 14-O-diterpenoid derivatives was constructed from a commercially available kaurene-type oridonin by practical and efficient synthetic methods.

enmein

kaurene

oridonin


Input: These synthetic derivatives were evaluated for their antiproliferative activities against a set of four human cancer cell lines.


Input: The IC50 values are similar to or improved over those of the parent molecule and paclitaxel, the latter of which was used as a positive control.

paclitaxel


Input: Compound 29 was further investigated for its apoptotic properties against human hepatocarcinoma Bel-7402 cells to better understand its mode of action.


Input: Moreover, compound 29 was shown to have potent antitumor activity in vivo in studies with a murine model of gastric cancer (MGC-803 mice).


Input: These results warrant further preclinical investigations of these diterpenoid-based analogues as potential novel anticancer chemotherapeutics.

diterpenoid


Input: PHARMACODYNAMIC EFFECTS OF A D-AMINO ACID OXIDASE INHIBITOR INDICATE A SPINAL SITE OF ACTION IN RAT MODELS OF NEUROPATHIC PAIN.

D-AMINO ACID


Input: Inhibition of D-amino acid oxidase (DAAO) activity is a potential target for the treatment of chronic pain.

D-amino acid


Input: Here we characterized the effects of systemic administration of the DAAO inhibitor 4H-furo [3, 2-b] pyrrole-5-carboxylic acid (SUN) in rat models of neuropathic and inflammatory pain.

4H-furo [3, 2-b] pyrrole-5-carboxylic acid

SUN


Input: Oral administration of SUN dose-dependently attenuated tactile allodynia induced by ligation of the L5 spinal nerve (SNL), and similarly reversed thermal hyperalgesia produced by chronic constriction injury (CCI).

SUN


Input: In addition, SUN was efficacious against Complete Freund' s Adjuvant (CFA)-induced thermal hyperalgesia.

SUN


Input: In these models, maximal reversal of pain-related behaviors corresponded with maximum rates-of-increase in brain and plasma D-serine concentrations, indicative of full inhibition of DAAO activity.

D-serine


Input: To investigate the possible site (s) of action, we recorded spontaneous nerve activity and mechanically-evoked responses of central spinal cord dorsal horn neurons and compared these to spontaneous activity of peripheral dorsal root filaments in anesthetized SNL model animals.


Input: Oral SUN reduced spontaneous activity in both central and peripheral recordings at doses and pretreatment times that corresponded to reduced mechanical allodynia in behavioral experiments.

SUN


Input: Following i. v. administration of SUN, the onset of action for this central effect was rapid (maximal effects within 30 minutes), but was abolished by severing afferent inputs to the dorsal horn.

SUN


Input: Overall, these results indicate that inhibition of DAAO in peripheral afferent-spinal circuits reduced spontaneous neuronal activity to attenuate pain-related behaviors in rat models of neuropathic and inflammatory pain.


Input: Synthesis and Structure-Activity Relationships of 5, 6, 7-Substituted Pyrazolopyrimidines: Discovery of a Novel TSPO PET Ligand for Cancer Imaging.

5, 6, 7-Substituted Pyrazolopyrimidines


Input: Focused library synthesis and structure-activity relationship development of 5, 6, 7-substituted pyrazolopyrimidines led to the discovery of 2-(5, 7-diethyl-2-(4-(2-fluoroethoxy) phenyl) pyrazolo [1, 5-a] pyrimidin-3-yl)-N, N-diethylacetamide (6b), a novel translocator protein (TSPO) ligand exhibiting a 36-fold enhancement in affinity compared to another pyrazolopyrimidine-based TSPO ligand, 6a (DPA-714).

5, 6, 7-substituted pyrazolopyrimidines

2-(5, 7-diethyl-2-(4-(2-fluoroethoxy) phenyl) pyrazolo [1, 5-a] pyrimidin-3-yl)-N, N-diethylacetamide

pyrazolopyrimidine


Input: Radiolabeling with fluorine-18 ((18) F) facilitated production of 2-(5, 7-diethyl-2-(4-(2-[(18) F] fluoroethoxy) phenyl) pyrazolo [1, 5-a] pyrimidin-3-yl)-N, N-diethylacetamide ((18) F-6b) in high radiochemical yield and specific activity.

(18) F

2-(5, 7-diethyl-2-(4-(2-[(18) F] fluoroethoxy) phenyl) pyrazolo [1, 5-a] pyrimidin-3-yl)-N, N-diethylacetamide

(18) F


Input: In vivo studies of (18) F-6b were performed which illuminated this agent as an improved probe for molecular imaging of TSPO-expressing cancers.

(18) F


Input: A new sesquiterpene from the mangrove endophytic fungus Aspergillus terreus (No. GX7-3B).

sesquiterpene


Input: A new compound 1 (named botryosphaerin F), along with other three known compounds 2 (13, 14, 15, 16-tetranorlabd-7-ene-19, 6b: 12, 17-diolide), 3 (botryosphaerin B) and 4 (LL-Z1271 beta), has been isolated from the mangrove fungus Aspergillus terreus (No. GX7-3B).

botryosphaerin F

13, 14, 15, 16-tetranorlabd-7-ene-19, 6b: 12, 17-diolide

botryosphaerin B

LL-Z1271 beta


Input: The structure of the new compound was established by analysis of spectroscopic data.


Input: The hypothetical biogenic relationship of four sesquiterpene analogues was also described in this paper.

sesquiterpene


Input: Furthermore, in the cytotoxicity assays, compound 1 showed potent inhibiting activity towards MCF-7 and HL-60 cancer cell lines with 50% inhibition of cell growth (IC50) values of 4. 49 and 3. 43 mu M, respectively, and compound 4 exhibited promising activity against HL-60 cell line with an IC50 value of 0. 6 mu M.


Input: Comparison of transcriptomic signature of post-Chernobyl and post-radiotherapy thyroid tumors.


Input: Background: We previously identified two highly discriminating and predictive radiation-induced transcriptomic signatures by comparing series of sporadic and post-radiotherapy thyroid tumors (322-gene signature), and by re-analyzing a previously published dataset of sporadic and post-Chernobyl thyroid tumors (106-gene signature).


Input: The aim of the present work was 1) to compare the two signatures in terms of gene expression deregulations and molecular features/pathways and 2) to test the capacity of the post-radiotherapy signature in classifying the post-Chernobyl series of tumors and reciprocally of the post Chernobyl signature in classifying the post-radiotherapy induced tumors.


Input: Methods: We now explored if post-radiotherapy and post-Chernobyl thyroid papillary carcinomas (PTC) display common molecular features by comparing molecular pathways deregulated in the two tumor series and test the potential of gene subsets of the post-radiotherapy signature to classify the post-Chernobyl series (14 sporadic and 12 post-Chernobyl PTC), and reciprocally of gene subsets of the post-Chernobyl signature to classify the post-radiotherapy series (15 sporadic and 12 post-radiotherapy PTC), by using conventional Principal Component Analysis.


Input: Results: We found that the 5 genes common to the two signatures classified the learning/training tumors (used to search these signatures) of both the post-radiotherapy (7 PTC) and the post-Chernobyl (6 PTC) thyroid tumor series as compared with the sporadic tumors (7 sporadic PTC in each series).


Input: Importantly, these 5 genes were also effective for classifying independent series of post-radiotherapy (5 PTC) and post-Chernobyl (6 PTC) tumors compared to independent series of sporadic tumors (8 PTC and 6 PTC, respectively) (testing tumors) Moreover, part of each post-radiotherapy (32 genes) and post-Chernobyl signature (16 genes) cross-classified the respective series of thyroid tumors.


Input: Finally, several molecular pathways deregulated in post-Chernobyl tumors matched those found to be deregulated in post-radiotherapy tumors.


Input: Conclusions Overall, our data suggest that thyroid tumors that developed following either external exposure or internal 131I contamination shared common molecular features, related to DNA repair, oxidative and endoplasmic reticulum stresses, allowing their classification as radiation-induced tumors in comparison with sporadic counterparts, independently of doses and dose rates, which suggests there may be a " general " radiation-induced signature of thyroid tumors.


Input: Baeckein E, a new bioactive C-methylated biflavonoid from the roots of Baeckea frutescens.

Baeckein E

C-methylated biflavonoid


Input: A phytochemical study of Baeckea frutescens afforded a new biflavonoid named as baeckein E (1), along with four known C-methylated flavonols, baeckeins A (2) and B (3), 6-methylquercetin (6) and 6-methylquercetin-4'-O-beta-d-glucopyranoside (7), and two known biflavonoids baeckeins C (4) and D (5).

biflavonoid

baeckein E

C-methylated flavonols

baeckeins A

6-methylquercetin-4'-O-beta-d-glucopyranoside

baeckeins C


Input: The structure of compound 1 was elucidated on the basis of spectroscopic analysis, including HR-ESI-MS, 1D and 2D NMR spectra, and the absolute configurations of C-2 and C-3 for compound 1 were assigned by circular dichroism spectrometry combined with quantum chemical calculations.


Input: The antioxidant and cytoprotective activities of compounds 1-7 were also investigated.


Input: Controlled Assembly of Gold Nanoparticles through Antibody Recognition: Study and Utilizing the Effect of Particle Size on Interparticle Distance.


Input: An assembly of gold nanoparticle through the recognition of unmodified antibody was developed.


Input: The use of peptide (Cys-Ala-Leu-Asn-Asn) as ligands to stabilize and functionalize gold nanoparticles provides technical and operational convenience.

Cys-Ala-Leu-Asn-Asn


Input: These peptide-capped particles in different sizes are recognized by antibody and assembly to form dimers and expanded hybrid material by controlling the conditions.


Input: The interparticle spacing of these assemblies was well studied with small-angle X-ray scattering measurements, and it was found that the interparticle spacing is inversely dependent on the particle size.


Input: This relationship of interparticle spacing and particle size is closely related to the structure of antibody linker.


Input: Therefore, analyzing the interparticle spacing of assemblies can reveal the equilibrium configuration of IgG.


Input: Based on the investigation, the Fab-Fab angle of IgG is obtained to be =~ 102 degrees and the Fab arms are =~ 7. 8 nm.


Input: These results provide new experimental data on the structure of flexible IgG.


Input: Time-split cross-validation as a method for estimating the goodness of prospective prediction.


Input: Cross-validation is a common method to validate a QSAR model.


Input: In cross-validation, some compounds are held out as a test set, while the remaining compounds form a training set.


Input: A model is built from the training set, and the test set compounds are predicted on that model.


Input: The agreement of the predicted and observed activity values of the test set (measured by, say, R (2)) is an estimate of the self-consistency of the model and is sometimes taken as an indication of the predictivity of the model.


Input: This estimate of predictivity can be optimistic or pessimistic compared to true prospective prediction, depending how compounds in the test set are selected.


Input: Here, we show that time-split selection gives an R (2) that is more like that of true prospective prediction than the R (2) from random selection (too optimistic) or from our analog of leave-class-out selection (too pessimistic).


Input: Time-split selection should be used in addition to random selection as a standard for cross-validation in QSAR model building.


Input: Discovery of oxysterol-derived pharmacological chaperones for NPC1: implication for the existence of second sterol-binding site.

oxysterol

sterol


Input: Niemann-Pick type C1 (NPC1) is a polytopic endosomal membrane protein required for efflux of LDL-derived cholesterol from endosomes, and mutations of this protein are associated with Niemann-Pick disease type C, a fatal neurodegenerative disease.

cholesterol


Input: At least one prevalent mutation (I1061T) has been shown to cause a folding defect, which results in failure of endosomal localization, leading to a loss-of-function phenotype.


Input: Here, we show that several oxysterols and their derivatives act as pharmacological chaperones; binding of these compounds to I1061T NPC1 corrects the localization/maturation defect of the mutant protein.

oxysterols


Input: Further, these compounds alleviate intracellular cholesterol accumulation in patient-derived fibroblasts, suggesting that they may have therapeutic potential.

cholesterol


Input: These oxysterol derivatives bind to a domain of NPC1 that is different from the known N-terminal sterol-binding domain; i. e., there is an additional sterol-binding site on NPC1.

oxysterol

sterol

sterol


Input: Mouse DNA polymerase kappa has a functional role in the repair of DNA strand breaks.


Input: The Y-family of DNA polymerases support of translesion DNA synthesis (TLS) associated with stalled DNA replication by DNA damage.


Input: Recently, a number of studies suggest that some specialized TLS polymerases also support other aspects of DNA metabolism beyond TLS in vivo.


Input: Here we show that mouse polymerase kappa (Pol kappa) could accumulate at laser-induced sites of damage in vivo resembling polymerases eta and iota.


Input: The recruitment was mediated through Pol kappa C-terminus which contains the PCNA-interacting peptide, ubiquitin zinc finger motif 2 and nuclear localization signal.

C

zinc


Input: Interestingly, this recruitment was significantly reduced in MSH2-deficient LoVo cells and Rad18-depleted cells.


Input: We further observed that Pol kappa-deficient mouse embryo fibroblasts were abnormally sensitive to H2O2 treatment and displayed defects in both single-strand break repair and double-strand break repair.


Input: We speculate that Pol kappa may have an important role in strand break repair following oxidative stress in vivo.


Input: In silico identification of poly (ADP-ribose) polymerase-1 inhibitors and their chemosensitizing effects against cisplatin-resistant human gastric cancer cells.

poly (ADP-ribose)

cisplatin


Input: Poly (ADP-ribose) polymerase-1 (PARP-1) enzyme is involved in the repair of DNA damages made by certain anticancer agents.

Poly (ADP-ribose)


Input: It is suggested that PARP-1 inhibitors potentiate the cytotoxic effects and circumvent the resistance of DNA-modifying anticancer agents such as cisplatin.

cisplatin


Input: In this study, we conducted virtual screening of Korea Chemical Bank database targeting PARP-1 and identified several potent PARP-1 inhibitors with submicromolar IC50 values (77-79nM).


Input: We then examined the chemosensitization of cisplatin by pre-treatment of PARP-1 inhibitors in cisplatin-resistant human gastric cancer cells.

cisplatin

cisplatin


Input: Our results show that PARP-1 inhibitors suppress the formation of poly (ADP-ribose) and enhance the cytotoxicity of cisplatin.

poly (ADP-ribose)

cisplatin


Input: Activation of PPAR gamma is required for hydroxysafflor yellow A of Carthamus tinctorius to attenuate hepatic fibrosis induced by oxidative stress.

hydroxysafflor yellow A


Input: Oxidative stress caused hepatic fibrosis by activating hepatic stellate cells (HSCs), which were implemented by depressing PPAR gamma activation.


Input: Hydroxysafflor yellow A (HSYA) as a nature active ingredient with antioxidant capacity was able to effectively attenuate oxidative stress mediated injury.

Hydroxysafflor yellow A

HSYA


Input: So it will be very interesting to study effect of HSYA on HSCs activation and liver fibrosis, and reveal the role of PPAR gamma. CCl4 and H2O2 were used to mimic oxidative stress mediated hepatic injury in vitro and in vivo respectively.

HSYA


Input: The anti-fibrosis effects of HSYA were evaluated and its mechanisms were disclosed by applying western blot, histopathological analysis, flow cytometry, RT-PCR and ELISA.

HSYA


Input: Our results showed that HSCs activation and proliferation could be induced by oxidative stress, and the expressive levels of TGF-beta 1 and TIMP-1, the serum levels of ALT, AST, HA, LN, III-C and IV-C were also enhanced by oxidative stress, which is correlated with liver fibrosis (p < 0. 05 or p < 0. 01).


Input: HSYA was able to effectively inhibit oxidative stress mediated hepatic injury by increasing the activities of antioxidant enzymes, up regulating the expression of PPAR gamma and MMP-2, and down regulating the expression of TGF-beta 1 and TIMP-1, and reducing alpha-SMA level.

HSYA


Input: The protective effect of HSYA can be significantly attenuated by GW9662 via blocking PPAR gamma (p < 0. 05 or p < 0. 01).

HSYA


Input: Taken together, these results demonstrate that HSYA is able to significantly protect the liver from oxidative stress, which requires for HSYA to stimulate PPAR gamma activity, reduce cell proliferation and suppress ECM synthesis.

HSYA

HSYA


Input: Targeting kinases: a new approach to treating inflammatory rheumatic diseases.


Input: After two decades of research and development activity focussed on orally active kinase inhibitors, the first such drug (the JAK inhibitor Xeljanz, tofacitinib) was approved by the FDA in November 2012 for the treatment of rheumatoid arthritis (RA).

Xeljanz

tofacitinib


Input: There is an intense activity in many companies both on expanding the utility of JAK inhibitors in other auto-immune indications and in discovering inhibitors of the JAK family with different and more selective profiles.


Input: Progress is also being made with orally active Syk inhibitors.


Input: One such inhibitor (fostamatinib) is currently in large-scale phase 3 trials, and there are others in clinical development.

fostamatinib


Input: The last two to three years have been transformative for kinase inhibitors in auto-immune diseases, as several inhibitors have finally progressed beyond phase 2 trials after so many failures on other targets.


Input: Thus, there are new treatment options for RA patients beyond existing oral DMARDs and parenteral biologics.


Input: An Ancient Transcription Factor Initiates the Burst of piRNA Production during Early Meiosis in Mouse Testes.


Input: Animal germ cells produce PIWI-interacting RNAs (piRNAs), small silencing RNAs that suppress transposons and enable gamete maturation.


Input: Mammalian transposon-silencing piRNAs accumulate early in spermatogenesis, whereas pachytene piRNAs are produced later during postnatal spermatogenesis and account for > 95% of all piRNAs in the adult mouse testis.


Input: Mutants defective for pachytene piRNA pathway proteins fail to produce mature sperm, but neither the piRNA precursor transcripts nor the trigger for pachytene piRNA production is known.


Input: Here, we show that the transcription factor A-MYB initiates pachytene piRNA production.


Input: A-MYB drives transcription of both pachytene piRNA precursor RNAs and the mRNAs for core piRNA biogenesis factors including MIWI, the protein through which pachytene piRNAs function.


Input: A-MYB regulation of piRNA pathway proteins and piRNA genes creates a coherent feedforward loop that ensures the robust accumulation of pachytene piRNAs.


Input: This regulatory circuit, which can be detected in rooster testes, likely predates the divergence of birds and mammals.


Input: Structure of the Polycomb Group Protein PCGF1 in Complex with BCOR Reveals Basis for Binding Selectivity of PCGF Homologs.


Input: Polycomb-group RING finger homologs (PCGF1, PCGF2, PCGF3, PCGF4, PCGF5, and PCGF6) are critical components in the assembly of distinct Polycomb repression complex 1 (PRC1)-related complexes.


Input: Here, we identify a protein interaction domain in BCL6 corepressor, BCOR, which binds the RING finger-and WD40-associated ubiquitin-like (RAWUL) domain of PCGF1 (NSPC1) and PCGF3 but not of PCGF2 (MEL18) or PCGF4 (BMI1).


Input: Because of the selective binding, we have named this domain PCGF Ub-like fold discriminator (PUFD).


Input: The structure of BCOR PUFD bound to PCGF1 reveals that (1) PUFD binds to the same surfaces as observed for a different Polycomb group RAWUL domain and (2) the ability of PUFD to discriminate among RAWULs stems from the identity of specific residues within these interaction surfaces.


Input: These data show the molecular basis for determining the binding preference for a PCGF homolog, which ultimately helps determine the identity of the larger PRC1-like assembly.


Input: Characterization of the first K (+) channel blockers from the venom of the Moroccan scorpion Buthus occitanus Paris.

K (+)


Input: The availability of a large variety of specific blockers, which inhibit different K (+) currents, would help to elucidate their differences in physiological function.

K (+)


Input: Short peptide toxins isolated from scorpion venoms are able to block voltage-dependent or Ca (2 +)-activated K (+) channels.

Ca (2 +)

K (+)


Input: Here, we have studied the venom of the Moroccan scorpion Buthus occitanus Paris (BoP) in order to find new peptides, which could enlarge our structure-function relationship knowledge on the Kv1. 3 blocker Kaliotoxin (KTX) that belongs to the alpha-KTx3. 1 family.


Input: Indeed and since more a decade, KTX is widely used by international investigators because it exhibits a quite sharp specificity and a high-affinity for the Kv1. 3 channel, which is not only a neuronal channel but also a therapeutic target for diverse autoimmune diseases such as multiple sclerosis, type 1 diabetes, and rheumatoid arthritis.


Input: The BoP venom was first investigated using HPLC and MALDI-TOF/MS.


Input: Further, the HPLC fractions were screened by ELISA with antibodies raised against KTX.


Input: These antibodies recognized at least three components toxic in mice by intracerebroventricular injection.


Input: They were further pharmacologically characterized by competition using (125) I-KTX bound to its specific binding sites on rat brain synaptosomes.

(125) I


Input: A single component (4161 Da) inhibited totally the (125) I-KTX binding and with high-affinity (IC50 = 0. 1 nM), while the two other components poorly competed with (IC50 > 100 nM).

(125) I


Input: These toxins were sequenced in full by Edman' s degradation.


Input: The high-affinity ligand (BoPKTX) shares 86% sequence identity with KTX and was classified as toxin alpha-KTx3. 17.


Input: The two others peptides (BoP1 and BoP2, 4093 Da and 4121 Da, respectively) only differ by a Lys/Arg mutation.

Lys

Arg


Input: Their amino acid sequences were related to Martentoxin, which has been characterized from the Chinese scorpion Buthus martenzi Karch and described as both a BKCa and Kv1. 3 blocker.

amino acid


Input: Accordingly, they belong to the alpha-KTx16 family.


Input: Towards the bioequivalence of pressurised metered dose inhalers 1: Design and characterisation of aerodynamically equivalent beclomethasone dipropionate inhalers with and without glycerol as a non-volatile excipient.

beclomethasone dipropionate

glycerol


Input: A series of semi-empirical equations were utilised to design two solution based pressurised metered dose inhaler (pMDI) formulations, with equivalent aerosol performance but different physicochemical properties.


Input: Both inhaler formulations contained the drug, beclomethasone dipropionate (BDP), a volatile mixture of ethanol co-solvent and propellant (hydrofluoroalkane-HFA).

beclomethasone dipropionate

BDP

ethanol

hydrofluoroalkane

HFA


Input: However, one formulation was designed such that the emitted aerosol particles contained BDP and glycerol, a common inhalation particle modifying excipient, in a 1: 1 mass ratio.

BDP

glycerol


Input: By modifying the formulation parameters, including actuator orifice, HFA and metering volumes, it was possible to produce two formulations (glycerol-free and glycerol-containing) which had identical mass median aerodynamic diameters (2. 4 mu m +/- 0. 1 and 2. 5 mu m +/- 0. 2), fine particle dose (>= 5 mu m; 66 mu g +/- 6 and 68 mu g +/- 2) and fine particle fractions (28% +/- 2% and 30% +/- 1%), respectively.

HFA

glycerol

glycerol


Input: These observations demonstrate that it is possible to engineer formulations that generate aerosol particles with very different compositions to have similar emitted dose and in vitro deposition profiles, thus making them equivalent in terms of aerosol performance.


Input: Analysis of the physicochemical properties of each formulation identified significant differences in terms of morphology, thermal properties and drug dissolution of emitted particles.


Input: The particles produced from both formulations were amorphous; however, the formulation containing glycerol generated particles with a porous structure, while the glycerol-free formulation generated particles with a primarily spherical morphology.

glycerol

glycerol


Input: Furthermore, the glycerol-containing particles had a significantly lower dissolution rate (7. 8% +/- 2. 1%, over 180min) compared to the glycerol-free particles (58. 0% +/- 2. 9%, over 60min) when measured using a Franz diffusion cell.

glycerol

glycerol


Input: It is hypothesised that the presence of glycerol in the emitted aerosol particles altered solubility and drug transport, which may have implications for BDP pharmacokinetics after deposition in the respiratory tract.

glycerol

BDP


Input: 5-HT1A receptors direct the orientation of plasticity in layer 5 pyramidal neurons of the mouse prefrontal cortex.


Input: Several psychiatric disorders involving the prefrontal cortex (PFC) are associated with a dysfunction of 5-HT1A receptors (5-HT1AR).


Input: These receptors, located on interneurons and pyramidal neurons, may influence neuronal excitability through a regulation of the balance between excitation (E) and inhibition (I).


Input: Patch-clamp recordings in mouse cortical slices were performed to determine the modulatory role of 5-HT1AR on the excitability and the synaptic plasticity of layer 5 pyramidal neurons (L5PyNs) of the PFC.


Input: This was done by a comparison of postsynaptic currents evoked by electrical stimulation in layer 2/3 of 5-HT1AR-KO and wild-type (WT) mice.


Input: We observed that the E-I balance was significantly changed from 20% E-80% I in WT mice to 23% E-77% I in 5-HT1AR-KO mice, demonstrating that 5-HT1ARs contribute to the control of the balance between excitation and inhibition.


Input: Furthermore, we show that interfering with 5-HT1AR reduced the magnitude of the long term potentiation of excitation (eLTP) (induced by high frequency stimulation).


Input: In addition, we show that 5-HT1ARs determine the orientation of the synaptic plasticity towards LTP or LTD or no plasticity through the modulation of NMDAR-mediated currents.


Input: Our data point out to a unique role of 5-HT1A postsynaptic receptors in PFC to adapt the functional plasticity of L5PyNs towards LTP, LTD or no plasticity.


Input: This brings a new way to intervene on neuronal networks of the PFC in anxiety disorders and schizophrenia.


Input: Baicalein attenuates bleomycin-induced pulmonary fibrosis in rats through inhibition of miR-21.

Baicalein

bleomycin


Input: Currently, there is no satisfactory treatment for pulmonary fibrosis, and effective agents urgently need to be developed.


Input: The aim of the present study was to investigate the effects of baicalein on bleomycin-induced pulmonary fibrosis, and the novel mechanisms involved in the anti-fibrosis effects.

baicalein

bleomycin


Input: Pulmonary fibrosis was induced by a single intratracheal instillation of 5 mg/kg bleomycin.

bleomycin


Input: Two bleomycin-treated groups were orally administered daily with 50 and 100 mg/kg of baicalein from day 1 to 28.

bleomycin

baicalein


Input: The results showed baicalein decreased hydroxyproline content and alpha-SMA levels and increased lung index.

baicalein

hydroxyproline


Input: Histopathological examinations demonstrated baicalein could obviously lower the degree of alveolitis and lung fibrosis.

baicalein


Input: The total antioxidant capacity in bleomycin-treated rats with baicalein was also remarkably higher than in those without baicalein.

bleomycin

baicalein

baicalein


Input: Baicalein remarkably decreased miR-21 levels and inhibited the increased expression of TGF-beta 1 and p-Smad-2/3 in bleomycin-treated rats.

Baicalein

bleomycin


Input: Baicalein can attenuate bleomycin-induced pulmonary fibrosis.

Baicalein

bleomycin


Input: The attenuation is partly achieved by improving antioxidant activity, alleviating inflammation, repressing miR-21, and inhibiting TGF-beta/Smad signaling.


Input: Quercetin and epigallocatechin-3-gallate effect on the anisotropy of model membranes with cholesterol.

Quercetin

cholesterol


Input: Cell membrane fluidity, which can be altered by oxidative stress, plays an important role in the cell physiology.


Input: Flavonoids are among the most studied food substances that prevent and/or reduce oxidative stress, but their action mechanisms are far from being understood.

Flavonoids


Input: We performed a study on the effect of quercetin and epigallocatechin-3-gallate on 2-Dimyristoyl-sn-glycero-3-phosphocholine small unilamellar vesicles (SUVs) with different amounts of cholesterol, using Laurdan as a fluorescent probe, to put into evidence the perturbations of the phospholipid membrane fluidity and local lipid order in an attempt to decipher the action mechanism of the flavonoids at the cell membrane level.

quercetin

2-Dimyristoyl-sn-glycero-3-phosphocholine

cholesterol

Laurdan

flavonoids


Input: Results indicate that polyphenols modulate the transition from the gel phase to the liquid crystalline phase of SUVs in all studied membranes.

polyphenols


Input: SUVs with cholesterol have by themselves higher phase transition temperature and the presence of polyphenols stabilizes further the membrane.

cholesterol

polyphenols


Input: Quercetin has a dose-dependent effect on the fluidity and local order of the lipid membranes, whilst epigallocatechin-3-gallate action is not dose-dependent, the differences being attributable to the hydrophobic/hydrophilic character of the substances.

Quercetin


Input: The findings are discussed within the frame of earlier reports on the effect of polyphenols on artificial membranes.

polyphenols


Input: Cytotoxic mechanism of Piper gaudichaudianum Kunth essential oil and its major compound nerolidol.

nerolidol


Input: Piper gaudichaudianum Kunth is used in popular medicine as anti-inflamatory and against liver disorders.


Input: One of the most studied components of the plant is the essential oil for which chemical analysis revealed (E)-nerolidol as major compound.

(E)-nerolidol


Input: Recently, we have shown that P. gaudichaudianum essential oil possesses strong cytotoxic effects in mammalian V79 cells.


Input: The aim of this study was to analyze the cytotoxicity and mutagenicity of P. gaudichaudianum essential oil and nerolidol using Saccharomyces cerevisiae as model study.

nerolidol


Input: Treatment of the XV185-14c and N123 strains with essential oil and nerolidol led to cytotoxicity but did not induce mutagenicity.

nerolidol


Input: Our results revealed an important role of base excision repair (BER) as the ntg1, ntg2, apn1 and apn2 mutants showed pronounced sensitivity to essential oil and nerolidol.

nerolidol


Input: In the absence of superoxide dismutase (in sod1 Delta mutant strain) sensitivity to the essential oil and nerolidol increased indicating that this oil and nerolidol are generating reactive oxygen species (ROS).

superoxide

nerolidol

nerolidol

oxygen


Input: The ROS production was confirmed by DCF-DA probing assay in Sod-deficient strains.

DCF-DA


Input: From this, we conclude that the observed cytotoxicity to P. gaudichaudianum essential oil and nerolidol is mainly related to ROS and DNA single strand breaks generated by the presence of oxidative lesions.

nerolidol


Input: Differential effects of acute and chronic zinc (Zn) exposure on hepatic lipid deposition and metabolism in yellow catfish Pelteobagrus fulvidraco.

zinc

Zn


Input: The present study is conducted to determine the potential mechanisms of Zn on hepatic lipid deposition and metabolism for yellow catfish Pelteobagrus fulvidraco with 8-week chronic exposure to low Zn levels (Zn levels: 0. 05, 0. 35 and 0. 86mg/l Zn, respectively) and 96-h acute exposure to a high Zn level (Zn level: 4. 71mg/l Zn, respectively).

Zn

Zn

Zn

Zn

Zn

Zn

Zn


Input: For that purpose, hepatic lipid deposition and Zn accumulation, hepatic carnitine palmitoyltransferase I (CPT I) and lipoprotein lipase (LPL) activities, and the hepatic mRNA expression of ten genes involved in lipid metabolism are determined.

Zn

carnitine


Input: Chronic (8 weeks) exposure to low Zn levels apparently increases hepatic lipid content, hepatosomatic index (HSI) (P < 0. 05) and LPL activity, and reduces hepatic CPT I activity.

Zn


Input: In contrast, the acute (96h) exposure to high Zn level reduces hepatic lipid content, HSI and LPL activity, and increases CPT I activity.

Zn


Input: The change of mRNA levels of genes related to lipid metabolism is Zn concentration-dependent.

Zn


Input: Pearson correlations among mRNA expression levels, lipid content, CPT I and LPL activities in liver are also observed in yellow catfish with the 8-week chronic Zn exposure.

Zn


Input: For the first time, our study demonstrates the effect of waterborne Zn exposure on lipid metabolism at the molecular levels in fish, which may contribute to understanding the mechanism of Zn-induced hepatic toxicity in fish.

Zn

Zn


Input: The force of the spontaneously contracting zebrafish heart, in the assessment of cardiovascular toxicity: Application on adriamycin.

adriamycin


Input: The heart of the zebrafish has been used extensively to assess the cardiotoxic effect of compounds, using the frequency of heart contractions as the main index of cardiac response to drugs.


Input: In this study, the force and the frequency generated by the spontaneously contracting zebrafish heart, isolated in saline, were found to be 0. 87 +/- 0. 05mN and 1. 54 +/- 0. 03Hz (n = 6) respectively within the first hour of recording.


Input: Both values of force and frequency remained constant for over 8h.


Input: The advantage of prolonged vitality in the assessment of cardiovascular toxicity was shown using the well-known anticancer drug adriamycin, which has severe cardiotoxic side effects.

adriamycin


Input: At 10. 0 mu M there was a 21. 05 +/- 4. 42% (p = 0. 02, n = 4) decrease in the force of contraction, while the frequency was not affected after 3h treatment (p > 0. 05).


Input: At 50. 0 and 100. 0 mu M there was a 33. 24 +/- 3. 0 and 46. 6 +/- 4. 80% irreversible decrease in force (p < 0. 05, n = 4), while a 18. 02 +/- 4. 07% and 16. 16 +/- 4. 07% reversible increase was observed in the frequency (p = 0. 02, n = 4).


Input: These contradictory positive chronotropic and negative inotropic responses indicate the strong inhibitory effect of adriamycin on ventricular cardiomyocytes and its excitatory effects on auto-rhythmical pacemaker cells.

adriamycin


Input: If heart frequency was the only parameter used to assess the cardiotoxic effect of adriamycin, at the above range of concentrations, this compound would have been classified as non-cardiotoxic.

adriamycin


Input: Potentiation of morphine-induced mechanical antinociception by sigma 1 receptor inhibition: Role of peripheral sigma 1 receptors.

morphine


Input: We studied the modulation of morphine-induced mechanical antinociception and side effects by sigma 1 receptor inhibition.

morphine


Input: Both wild-type (WT) and sigma 1 receptor knockout (sigma 1-KO) mice showed similar responses to paw pressure (100-600 g).


Input: The systemic (subcutaneous) or local (intraplantar) administration of sigma 1 antagonists (BD-1063, BD-1047, NE-100 and S1RA) was devoid of antinociceptive effects in WT mice.


Input: However, sigma 1-KO mice exhibited an enhanced mechanical antinociception in response to systemic morphine (1-16 mg/kg).

morphine


Input: Similarly, systemic treatment of WT mice with sigma 1 antagonists markedly potentiated morphine-induced antinociception, and its effects were reversed by the selective sigma 1 agonist PRE-084.

morphine


Input: Although the local administration of morphine (50-200 mu g) was devoid of antinociceptive effects in WT mice, it induced dose-dependent antinociception in sigma 1-KO mice.

morphine


Input: This effect was limited to the injected paw.


Input: Enhancement of peripheral morphine antinociception was replicated in WT mice locally co-administered with sigma 1 antagonists and the opioid.

morphine


Input: None of the sigma 1 antagonists tested enhanced morphine-antinociception in sigma 1-KO mice, confirming a sigma 1-mediated action.

morphine


Input: Morphine-induced side-effects (hyperlocomotion and inhibition of gastrointestinal transit) were unaltered in sigma 1-KO mice.

Morphine


Input: These results cannot be explained by a direct interaction of sigma 1 ligands with mu-opioid receptors or adaptive changes of mu-receptors in sigma 1-KO mice, given that [(3) H] DAMGO binding in forebrain, spinal cord, and hind-paw skin membranes was unaltered in mutant mice, and none of the sigma 1 drugs tested bound to mu-opioid receptors.

[(3) H] DAMGO


Input: These results show that sigma 1 receptor inhibition potentiates morphine-induced mechanical analgesia but not its acute side effects, and that this enhanced analgesia can be induced at peripheral level.

morphine


Input: Accumulation of phenolic compounds in in vitro cultures and wild plants of Lavandula viridis L' H e r and their antioxidant and anti-cholinesterase potential.

phenolic


Input: In this study, we evaluated the phenolic profile, antioxidant and anti-cholinesterase potential of different extracts from wild plants and in vitro cultures of Lavandula viridis L' H e r.


Input: The HPLC-DAD analysis allowed the identification and quantification of 3-O-caffeoylquinic, 4-O-caffeoylquinic, 5-O-caffeoylquinic and rosmarinic acids, and luteolin and pinocembrin.

3-O-caffeoylquinic, 4-O-caffeoylquinic, 5-O-caffeoylquinic and rosmarinic acids

luteolin

pinocembrin


Input: Water/ethanol extract from in vitro cultures contained the highest amount of the identified phenolic compounds (51652. 92mg/kg).

ethanol

phenolic


Input: To investigate the antioxidant activity we used Trolox equivalent antioxidant capacity, oxygen radical absorbance capacity, Fe (2 +) chelation activity and the inhibition of Fe (2 +)-induced lipid peroxidation in mouse brain homogenates (in vitro).

Trolox

oxygen

Fe (2 +)

Fe (2 +)


Input: Overall, all the extracts from both wild plants and in vitro cultures exhibited ability to scavenge free radicals, to chelate Fe (2 +) and to protect against lipid peroxidation.

Fe (2 +)


Input: In addition, the extracts from L. viridis were active in inhibiting both acetylcholinesterase and butyrylcholinesterase (Ellman' s method).


Input: Our findings suggest that L. viridis in vitro cultures represent a promising alternative for the production of active metabolites with antioxidant and anti-cholinesterase activity.


Input: Hypocholesterolemic effect of daily fisetin supplementation in high fat fed Sprague-Dawley rats.

fisetin


Input: We aimed to test whether fisetin could modulate cholesterol homeostasis in rats with diet-induced hypercholesterolemia, and further investigated the underlying mechanisms by which fisetin exerts its cholesterol lowering effect.

fisetin

cholesterol

fisetin

cholesterol


Input: Blood lipid profile, hepatic cholesterol content, as well as gene expressions in cholesterol metabolism were examined.

cholesterol

cholesterol


Input: Elevated levels of total cholesterol and LDL-cholesterol, along with hepatic cholesterol content in a high fat group were found to be significantly reduced by fisetin.

cholesterol

cholesterol

cholesterol

fisetin


Input: The high fat diet significantly decreased hepatic mRNA levels of LDLR, SREBP2, HMGCR and PCSK9 in comparison to the control diet, however, fisetin did not further elicit any changes in mRNA levels of the same genes.

fisetin


Input: The high fat diet dramatically increased the transcript levels of CYP7A1, which was subsequently reversed by the fisetin.

fisetin


Input: In HepG2 cells, fisetin was found to increase the levels of a nuclear form of SREBP2 and LDLR.

fisetin


Input: In conclusion, fisetin supplementation displayed hypocholesterolemic effects by modulating the expression of genes associated with cholesterol and bile acid metabolism.

fisetin

bile acid


Input: Phenolic compounds from Jacaranda caroba (Vell.) A.

Phenolic


Input: DC.: Approaches to neurodegenerative disorders.


Input: Diseases affecting the central nervous system are spread throughout the world.


Input: As so, more efficient and safe neuroprotective drugs are required.


Input: The present study describes, for the first time, the phenolic composition and bioactivity of Jacaranda caroba (Vell.) A.

phenolic


Input: DC, a species whose infusion is consumed as traditional medicine.


Input: The HPLC-DAD-ESI/MS (n) analysis revealed the presence of four dicaffeoyl acid derivatives and nine flavonoids, comprising quercetin, kaempferol and isorhamnetin derivatives.

dicaffeoyl acid

flavonoids

quercetin

kaempferol

isorhamnetin


Input: Twelve compounds are described for the first time in Jacaranda genus.


Input: Although isorhamnetin-3-O-rhmanoside-7, 4'-di-O-glucoside and quercetin-3-O-(2-pentosyl) hexoside are the main metabolites in both aqueous and hydromethanolic extracts, qualitative and quantitative differences were found between them.

isorhamnetin-3-O-rhmanoside-7, 4'-di-O-glucoside

quercetin-3-O-(2-pentosyl) hexoside


Input: Aqueous extract is richer in dicaffeoyl acid derivatives.

dicaffeoyl acid


Input: Both extracts proved to be strong radicals' scavengers and effective monoamine-oxidase A inhibitors, but showed weak protection against cholinesterases' activity.

monoamine


Input: The results highlight the value of J. caroba as a source of health-promoting antioxidants and antidepressant compounds.


Input: The mycotoxin T-2 inhibits hepatic cytochrome P4503A activity in pigs.

mycotoxin T-2


Input: Mycotoxins are toxic metabolites produced by fungi that readily colonize crops.


Input: After ingestion, these mycotoxins can compromise intestinal health, and once entering the blood stream, even affect the liver and its metabolizing enzymes.


Input: It was therefore the aim of the present study to investigate the effect of T-2 toxin, an emerging and potent Fusarium mycotoxin, on the enzymatic activity of cytochrome P4503A (CYP3A) metabolizing enzymes in the liver of pigs.

T-2 toxin


Input: In addition, a yeast-derived feed additive that claims to bind T-2 toxin was included in the study to evaluate its efficacy.

T-2 toxin


Input: Our results demonstrated that a 14-days intake of T-2 toxin contaminated feed at a dose of 903 mu g/kg feed, whether or not combined with the mycotoxin binder, results in a substantial inhibition of the CYP3A activity in the liver of pigs.

T-2 toxin


Input: This result may be of importance for animal health, the pharmacokinetics and the withdrawal time of drugs that are substrate of CYP3A enzymes, and consequently can be a threat for public health with respect to tissue residues of these drugs.


Input: Metabolism Studies of Unformulated Internally [3H]-labeled siRNAs in Mice.


Input: Absorption, distribution, metabolism, and excretion properties of two unformulated model siRNAs were determined using a single internal [(3) H]-radiolabeling procedure, where the full-length oligonucleotides were radiolabeled by Br/(3) H-exchange.

(3) H

Br

(3) H


Input: Tissue distribution, excretion, and mass balance of radioactivity were investigated in male CD-1 mice, following a single intravenous administration of the [(3) H]-siRNAs, at a target dose level of 5 mg/kg.

(3) H


Input: Quantitative whole-body autoradiography (QWBA) and liquid scintillation counting techniques were used to determine tissue distribution.


Input: Radiochromatogram profiles were determined in plasma, tissue extracts and urine.


Input: Metabolites were separated by liquid chromatography and identified by radiodetection and high-resolution accurate mass spectrometry.


Input: In general, there was little difference in the distribution of total radiolabeled components after administration of the two unformulated [(3) H]-siRNAs.

(3) H


Input: The radioactivity was rapidly and widely distributed throughout the body, and remained detectable in all tissues investigated at later time points (24 and 48 hours for [(3) H]-MRP4 and [(3) H]-SSB siRNA, respectively).

(3) H

(3) H


Input: After an initial rapid decline, concentrations of total radiolabeled components in dried blood declined at a much slower rate.


Input: A nearly complete mass balance was obtained for the [(3) H]-SSB siRNA and renal excretion was the main route of elimination (38%).

(3) H


Input: The metabolism of the two model siRNAs was rapid and extensive.


Input: Five minutes after administration, no parent compound could be detected in plasma.


Input: Instead, radiolabeled nucleosides resulting from nuclease hydrolysis were observed.

nucleosides


Input: In the metabolism profiles obtained from various tissues only radiolabeled nucleosides were found, suggesting that siRNAs are rapidly metabolized and that the distribution pattern of total radiolabeled components can be ascribed to small molecular weight metabolites.

nucleosides


Input: Enhanced broadband and omnidirectional performance of Cu (In, Ga) Se2 solar cells with ZnO functional nanotree arrays.

Cu (In, Ga) Se2

ZnO


Input: An effective approach is demonstrated for enhancing photoelectric conversion of Cu (In, Ga) Se2 (CIGS) solar cells with three-dimensional ZnO nanotree arrays.

Cu (In, Ga) Se2

CIGS

ZnO


Input: Under a simulated one-sun condition, cells with ZnO nanotree arrays enhance the short-circuit current density by 10. 62%.

ZnO


Input: The omnidirectional anti-reflection of CIGS solar cells with various ZnO nanostructures is also investigated.

CIGS

ZnO


Input: The solar-spectrum weighted reflectance is approximately less than 5% for incident angles of up to 60 degrees and for the wavelengths primarily from 400 nm to 1000 nm.


Input: This enhancement in light harvesting is attributable to the gradual refractive index profile between the ZnO nanostructures and air.

ZnO


Input: Serotonergic hallucinogens differentially modify gamma and high frequency oscillations in the rat nucleus accumbens.


Input: RATIONALE: The nucleus accumbens (NAc) is a site critical for the actions of many drugs of abuse.


Input: Psychoactive compounds, such as N-methyl-D-aspartate receptor (NMDAR) antagonists, modify gamma (40-90) and high frequency oscillations (HFO, 130-180 Hz) in local field potentials (LFPs) recorded in the NAc.

N-methyl-D-aspartate


Input: Lysergic acid diethylamide (LSD) and 2, 5-dimethoxy-4-iodoamphetamine (DOI) are serotonergic hallucinogens and activation of 5HT2A receptors likely underlies their hallucinogenic effects.

Lysergic acid diethylamide

LSD

2, 5-dimethoxy-4-iodoamphetamine

DOI


Input: Whether these compounds can also modulate LFP oscillations in the NAc is unclear.


Input: OBJECTIVE: This study aims to examine the effect of serotonergic hallucinogens on gamma and HFO recorded in the NAc and to test whether 5HT2A receptors mediate the effects observed.


Input: METHODS: LFPs were recorded from the NAc of freely moving rats.


Input: Drugs were administered intraperitoneally.


Input: RESULTS: LSD (0. 03-0. 3 mg/kg) and DOI (0. 5-2. 0 mg/kg) increased the power and reduced the frequency of HFO.

LSD

DOI


Input: In contrast, the hallucinogens produced a robust reduction in the power of low (40-60 Hz), but not high gamma oscillations (70-90 Hz).


Input: MDL 11939 (1. 0 mg/kg), a 5HT2A receptor antagonist, fully reversed the changes induced by DOI on HFO but only partially for the low gamma band.

MDL 11939

DOI


Input: Equivalent increases in HFO power were observed after TCB-2 (5HT2A receptor agonist, 0. 1-1. 5 mg/kg), but not CP 809101 (5H2C receptor agonist, 0. 1-3 mg/kg).

CP 809101


Input: Notably, hallucinogen-induced increases in HFO power were smaller than those produced by ketamine (25 mg/kg).

ketamine


Input: CONCLUSIONS: Serotonergic hallucinogen-induced changes in HFO and gamma are mediated, at least in part, by stimulation of 5HT2A receptors.


Input: Comparison of the oscillatory changes produced by serotonergic hallucinogens and NMDAR antagonists are also discussed.


Input: Inhibition of Ebola Virus Infection: Identification of Niemann-Pick C1 as the Target by Optimization of a Chemical Probe.


Input: A high throughput screen identified adamantane dipeptide 1 as an inhibitor of Ebola virus (EboV) infection.

adamantane


Input: Hit-to-lead optimization to determine the structure-activity relationship (SAR) identified the more potent EboV inhibitor 2 and a photoaffinity labeling agent 3.


Input: These anti-viral compounds were employed to identify the target as Niemann-Pick C1 (NPC1), a host protein that binds the EboV glycoprotein and is essential for infection.


Input: These studies establish NPC1 as a promising target for anti-viral therapy.


Input: The Arf GAP AGAP2 Interacts with beta Arrestin2 and Regulates beta 2-Adrenergic Receptor Recycling and Erk Activation.


Input: AGAP2 is a multidomain Arf GAP (ADP ribosylation factor-directed GTPase-activating protein) that was shown to promote the fast-recycling of transferrin receptors.

ADP


Input: Here, we tested the hypothesis that AGAP2 regulates trafficking of beta 2-adrenergic receptors.


Input: We found that AGAP2 formed a complex with beta Arrestin1 and beta Arrestin2, proteins that are known to regulate beta 2-adrenergic receptor signaling and trafficking.


Input: AGAP2 colocalized with beta Arrestin2 on the plasma membrane, and knockdown of AGAP2 expression reduced plasma membrane association of beta Arrestin2 upon beta 2-adrenergic receptor activation.


Input: AGAP2 also colocalized with internalized beta 2-adrenergic receptors on endosomes, and overexpression of AGAP2 slowed accumulation of beta 2-adrenergic receptor in the perinuclear recycling endosomes.


Input: On the contrary, knockdown of AGAP2 expression prevented recycling of beta 2-adrenergic receptor back to the plasma membrane.


Input: In addition, AGAP2 formed a complex with endogenous Erk and overexpression of AGAP2 potentiated Erk phosphorylation induced by beta 2-adrenergic receptors.


Input: Taken together, these results support the hypothesis that AGAP2 plays a role in the signaling and recycling of beta 2-adrenergic receptors.


Input: Identification of the first synthetic inhibitors of the type II transmembrane serine protease TMPRSS2 suitable for inhibition of influenza virus activation.

serine


Input: TMPRSS2 is a multidomain type II transmembrane serine protease that cleaves the surface glycoprotein hemagglutinin (HA) of influenza viruses with monobasic cleavage site, which is a prerequisite for virus fusion and propagation.

serine


Input: Furthermore, it activates the fusion protein F of the human metapneumovirus and the spike protein S of the SARS coronavirus.


Input: Increased TMPRSS2 expression was also described in several tumor entities.


Input: Therefore, TMPRSS2 emerged as a potential target for drug design.


Input: The catalytic domain of TMPRSS2 was expressed in E. coli and used for an inhibitor screen with previously synthesized inhibitors of various trypsin-like serine proteases.

serine


Input: Two inhibitor types were identified, which inhibit TMPRSS2 in the nanomolar range.


Input: The first series comprises substrate analogue inhibitors containing a 4-amidinobenzylamide moiety in P1 position, whereby some of these analogues possess inhibition constants around 20 nM.


Input: An improved potency was found for second type derived from sulfonylated 3-amindinophenylalanylamide derivates.

sulfonylated 3-amindinophenylalanylamide


Input: The most potent derivative of this series inhibits TMPRSS2 with a Ki value of 0. 9 nM and showed an efficient blockage of influenza virus propagation in human airway epithelial cells.


Input: Based on the inhibitor studies a series of new fluorogenic substrates containing a d-arginine residue in P3 position was synthesized, some of them were efficiently cleaved by TMPRSS2.

d-arginine


Input: Broken Symmetry Quantum Hall States in Dual-Gated ABA Trilayer Graphene.

Graphene


Input: ABA-stacked trilayer graphene is a unique 2D electron system with mirror reflection symmetry and unconventional quantum Hall effect.

graphene


Input: We present low-temperature transport measurements on dual-gated suspended trilayer graphene in the quantum Hall (QH) regime.

graphene


Input: We observe QH plateaus at filling factors nu =-8,-2, 2, 6, and 10, which is in agreement with the full-parameter tight binding calculations.


Input: In high magnetic fields, odd-integer plateaus are also resolved, indicating almost complete lifting of the 12-fold degeneracy of the lowest Landau level (LL).


Input: Under an out-of-plane electric field E _|_, we observe degeneracy breaking and transitions between QH plateaus.


Input: Interestingly, depending on its direction, E _|_ selectively breaks the LL degeneracies in the electron-doped or hole-doped regimes.


Input: Our results underscore the rich interaction-induced phenomena in trilayer graphene.

graphene


Input: Coarse-grained model for predicting RNA folding thermodynamics.


Input: We present a thermodynamically robust coarse-grained model to simulate folding of RNA in monovalent salt solutions.


Input: The model includes stacking, hydrogen bond, and electrostatic interactions as fundamental components in describing the stability of RNA structures.

hydrogen


Input: The stacking interactions are parametrized using a set of nucleotide-specific parameters, which were calibrated against the thermodynamic measurements for single-base stacks and base-pair stacks.

nucleotide


Input: All hydrogen bonds are assumed to have the same strength, regardless of their context in the RNA structure.

hydrogen


Input: The ionic buffer is modeled implicitly, using the concept of counterion condensation and the Debye-H u ckel theory.


Input: The three adjustable parameters in the model were determined by fitting the experimental data for two RNA hairpins and a pseudoknot.


Input: A single set of parameters provides good agreement with thermodynamic data for the three RNA molecules over a wide range of temperatures and salt concentrations.


Input: In the process of calibrating the model, we establish the extent of counterion condensation onto the single-stranded RNA backbone.


Input: The reduced backbone charge is independent of the ionic strength and is 60% of the RNA bare charge at 37 degrees C.


Input: Our model can be used to predict the folding thermodynamics for any RNA molecule in the presence of monovalent ions.


Input: Supramolecular Structure of TTBC J-Aggregates in Solution and on Surface.

TTBC