Input: The methanol extract of the tubers of Polygonum perfoliatum L. afforded a new lignan: 8-oxo-pinoresinol (1), and five known compounds 3', 5-dihydroxy-3, 4', 5', 7-tetramethoxy-flavone (2), catechin (3), quercetin (4), quercetin-3-O-beta-D-glucuronide (5) and rutin (6).

methanol

lignan

3', 5-dihydroxy-3, 4', 5', 7-tetramethoxy-flavone

catechin

quercetin

rutin


Input: Their structures were established by MS, one-and two-dimensional NMR experiments.


Input: Compound 1 showed cytotoxicity against human mammary carcinoma (Bcap-37), human colon carcinoma (RKO), human hepatocellular carcinoma (SMMC-7721), human prostate carcinoma (PC3) and human erythroleukaemia (K562) cells.


Input: Tonic GABA (A) receptor-mediated signalling in temporal lobe epilepsy.

GABA


Input: The tonic activation of extrasynaptic GABAA receptors by extracellular GABA provides a powerful means of regulating neuronal excitability.

GABAA


Input: A consistent finding from studies that have used various models of temporal lobe epilepsy is that tonic GABAA receptor-mediated conductances are largely preserved in epileptic brain (in contrast to synaptic inhibition which is often reduced).


Input: Tonic inhibition is therefore an attractive target for antiepileptic drugs.


Input: However, the network consequences of a commonly used approach to augment tonic GABAA receptor-mediated conductances by global manipulation of extracellular GABA are difficult to predict without understanding how epileptogenesis alters the pharmacology and GABA sensitivity of tonic inhibition, and how manipulation of tonic conductances modulates the output of individual neurons.

GABAA

GABA


Input: Here we review the current literature on epilepsy-associated changes in tonic GABAA receptor-mediated signalling, and speculate about possible effects they have at the network level.


Input: This article is part of the Special Issue entitled' New Targets and Approaches to the Treatment of Epilepsy'.


Input: Metabotropic glutamate 7 (mGlu7) receptor: a target for medication development for the treatment of cocaine dependence.

glutamate

cocaine


Input: Brain glutamate has been shown to play an important role in reinstatement to drug seeking, a behavior considered to be of relevance to relapse to drug taking in humans.

glutamate


Input: Therefore, glutamate receptors, in particular metabotropic glutamate (mGlu) receptors, have become important targets for medication development for the treatment of drug dependence.

glutamate

glutamate


Input: In this review article, we focus on the mGlu7 receptor subtype, and discuss recent findings with AMN082, a selective mGlu7 receptor allosteric agonist, in animal models with relevance to drug dependence.


Input: Systemic or local administration of AMN082 into the nucleus accumbens (NAc), a critical brain region involved in reward and drug dependence processes, inhibited the reinforcing and motivational effects of cocaine, heroin and ethanol, as assessed by the intravenous drug self-administration procedure.

cocaine

heroin

ethanol


Input: In addition, AMN082 inhibited the reward-enhancing effects induced by cocaine, as assessed in the intracranial self-stimulation procedure, and cocaine-or cue-induced reinstatement of drug-seeking behavior.

cocaine

cocaine


Input: In vivo microdialysis studies indicated that systemic or intra-NAc administration of AMN082 significantly decreased extracellular gamma-aminobutyric acid (GABA) and elevated extracellular glutamate, but had no effect on extracellular dopamine in the NAc, suggesting that a non-dopaminergic mechanism underlies the effects of AMN082 on the actions of cocaine.

gamma-aminobutyric acid

GABA

glutamate

dopamine

cocaine


Input: Further, data indicated that AMN082-induced changes in glutamate were the net effect of two actions: one is the direct inhibition of glutamate release by activation of mGlu7 receptors on glutamatergic neurons; another is the indirect increases of glutamate release mediated by decreases in GABA transmission.

glutamate

glutamate

glutamatergic

GABA


Input: These increases in extracellular glutamate functionally antagonized cocaine-induced inhibition of NAc-ventral pallidum GABAergic neurotransmission, and therefore, the rewarding effects of cocaine.

glutamate

cocaine

pallidum

cocaine


Input: In addition, elevated extracellular glutamate activated presynaptic mGlu2/3 autoreceptors which in turn inhibited cocaine priming-or cue-induced enhancement of glutamate release and reinstatement of drug-seeking behavior.

glutamate

cocaine

glutamate


Input: Taken together, these findings suggest that the mGlu7 receptor is an important target for medication development for the treatment of drug dependence.


Input: AMN082 or other mGlu7 receptor allosteric agonists may have potential as novel pharmacotherapies for cocaine addiction.

cocaine


Input: This article is part of a Special Issue entitled' Metabotropic Glutamate Receptors'.

Glutamate


Input: The synergistic apoptotic interaction of panaxadiol and epigallocatechin gallate in human colorectal cancer cells.

panaxadiol

epigallocatechin gallate


Input: Panaxadiol (PD) is a purified sapogenin of ginseng saponins, which exhibits anticancer activity.

Panaxadiol

sapogenin

saponins


Input: Epigallocatechin gallate (EGCG), a major catechin in green tea, is a strong botanical antioxidant.

Epigallocatechin gallate

EGCG

catechin


Input: In this study, we investigated the possible synergistic anticancer effects of PD and EGCG on human colorectal cancer cells and explored the potential role of apoptosis in the synergistic activities.

EGCG


Input: Effects of selected compounds on HCT-116 and SW-480 human colorectal cancer cells were evaluated by a modified trichrome stain cell proliferation analysis.


Input: Cell cycle distribution and apoptotic effects were analyzed by flow cytometry after staining with PI/RNase or annexin V/PI.


Input: Cell growth was suppressed after treatment with PD (10 and 20 micro m) for 48 h.


Input: When PD (10 and 20 micro m) was combined with EGCG (10, 20, and 30 micro m), significantly enhanced antiproliferative effects were observed in both cell lines.

EGCG


Input: Combining 20 micro m of PD with 20 and 30 micro m of EGCG significantly decreased S-phase fractions of cells.

EGCG


Input: In the apoptotic assay, the combination of PD and EGCG significantly increased the percentage of apoptotic cells compared with PD alone (p < 0. 01).

EGCG


Input: The synergistic apoptotic effects were also supported by docking analysis, which demonstrated that PD and EGCG bound in two different sites of the annexin V protein.

EGCG


Input: Data from this study suggested that apoptosis might play an important role in the EGCG-enhanced antiproliferative effects of PD on human colorectal cancer cells.

EGCG


Input: HPLC analysis of Stephania rotunda extracts and correlation with antiplasmodial activity.


Input: Stephania rotunda (Menispermaceae), a creeper commonly found in the mountainous areas of Cambodia, has been mainly used for the treatment of fever and malaria.


Input: Thus, the aim of this study is to investigate the chemical composition and antiplasmodial activity of different samples of S. rotunda and compare their antiplasmodial activity with their alkaloid content.


Input: Sixteen samples from different parts (roots, stem, and tuber) of S. rotunda were collected from four regions of Cambodia (Battambang, Pailin, Siem Reap, and Kampot).


Input: Reversed-phase HPLC was used to determine the content of three bioactive alkaloids (cepharanthine, tetrahydropalmatine, and xylopinine).

cepharanthine

tetrahydropalmatine

xylopinine


Input: These three alkaloids have been found in all samples from Battambang and Pailin (samples I-IX), whereas only tetrahydropalmatine was present in samples from Siem Reap and Kampot (samples X-XVI).

tetrahydropalmatine


Input: The analyzed extracts were evaluated for their antiplasmodial activity on W2 strain of Plasmodium falciparum.


Input: Among them, 13 extracts were significantly active with inhibitory concentration 50 (IC (50)) from 1. 2 to 3. 7 micro g/mL and 2 extracts were moderately active (IC (50) = 6. 1 and 10 micro g/mL, respectively), whereas sample XI was not active (IC (50) = 19. 6 micro g/mL).


Input: A comparison between antiplasmodial activity and concentration of the three bioactive alkaloids in S. rotunda extracts has been realized.


Input: Preventive effects of North American ginseng (Panax quinquefolius) on diabetic retinopathy and cardiomyopathy.


Input: Ginseng (Araliaceae) has multiple pharmacological actions because of its diverse phytochemical constituents.


Input: The aims of the present study are to evaluate the preventive effects of North American ginseng on diabetic retinopathy and cardiomyopathy and to delineate the underlying mechanisms of such effects.


Input: Models of both type 1 (C57BL/6 mice with streptozotocin-induced diabetes) and type 2 diabetes (db/db mice) and age-matched and sex-matched controls were examined.

streptozotocin


Input: Alcoholic ginseng root (200 mg/kg body weight, daily oral gavage) extract was administered to groups of both type 1 and type 2 diabetic mice for 2 or 4 months.


Input: Dysmetabolic state in the diabetic mice was significantly improved by ginseng treatment.


Input: In both the heart and retina of diabetic animals, ginseng treatment significantly prevented oxidative stress and diabetes-induced upregulations of extracellular matrix proteins and vasoactive factors.


Input: Ginseng treatment in the diabetic animals resulted in enhancement of stroke volume, ejection fraction, cardiac output, and left ventricle pressure during systole and diastole and diminution of stroke work.


Input: In addition, mRNA expressions of atrial natriuretic factor and brain natriuretic factor (molecular markers for cardiac hypertrophy) were significantly diminished in ginseng-treated diabetic mice.


Input: These data indicate that North American ginseng prevents the diabetes-induced retinal and cardiac biochemical and functional changes probably through inhibition of oxidative stress.


Input: Evaluation of food-drug interaction of guava leaf tea.


Input: Guava leaf tea (GLT) contains guava leaf polyphenol (Gvpp), which regulates the absorption of dietary carbohydrate from the intestines.

polyphenol

carbohydrate


Input: Borderline diabetics, who are at high risk of development of diabetes, take GLT to suppress a rapid increase of blood sugar level after meals.

sugar


Input: However, patients with diabetes in whom diabetic drugs or warfarin as a blood thinner are prescribed also take GLT with the expectation of glycemic control.

warfarin


Input: Therefore, we studied whether GLT had potential for inhibition or induction of cytochrome P450 (CYP) and an influence on the action of warfarin.

warfarin


Input: Extract of guava leaf (GvEx) consists of carbohydrate and polyphenols, which are Gvpp, quercetin, and ellagic acid.

carbohydrate

polyphenols

quercetin

ellagic acid


Input: These polyphenols, but not GvEx, showed a certain level of inhibition of human-cDNA-expressed CYPs.

polyphenols


Input: In a comparison of GLT and grapefruit juice, GLT showed weaker inhibition of CYP activities and of midazolam 1'-hydroxylation than grapefruit juice.

midazolam


Input: Furthermore, neither liver weight nor CYP3A expression in the liver was changed in rats that received GvEx for 90 days compared with the control group.


Input: When rats were concomitantly treated with GLT and warfarin, the prolongation of clotting time of blood by warfarin was not influenced.

warfarin

warfarin


Input: These data suggest that GLT is unlikely to interact with drugs.


Input: A new phenylethanoid glucoside from Plantago depressa Willd.

phenylethanoid glucoside


Input: Chemical research of Plantago depressa Willd. led to one new phenylethanoid glucoside with alpha-L-rhamnosyl (1 --> 2)-beta-D-glucose structure, together with four known compounds.

phenylethanoid glucoside

alpha-L-rhamnosyl (1 --> 2)-beta-D-glucose


Input: These five compounds (1-5) were isolated from the family Plantaginaceae for the first time; the chemotaxonomic significance of cerebrosides was also discussed.

cerebrosides


Input: Chemical composition of essential oil from Calligonum polygonoides Linn.


Input: The essential oil from air dried buds and roots of Calligonum polygonoides Linn., has been extracted from dry steam distillation and analysed for chemical composition by gas chromatography-mass spectrometry.


Input: In total, 27 and 10 compounds were analysed qualitatively and quantitatively, accounting for 68. 42% and 82. 12% total contents of the essential oils of buds and roots, respectively.


Input: It contains a complex mixture of terpenoids, hydrocarbons, phenolic compounds, acid derivatives and ketones.

terpenoids

hydrocarbons

phenolic

ketones


Input: The main component of essential oil was ethyl homovanillate (11. 79%) in buds and drimenol (29. 42%) in roots.

ethyl homovanillate

drimenol


Input: The effects of temperature and salinity on 17-alpha-ethynylestradiol uptake and its relationship to oxygen consumption in the model euryhaline teleost (Fundulus heteroclitus).

oxygen


Input: The synthetic estrogen 17-alpha-ethynylestradiol (EE2), a component of birth control and hormone replacement therapy, is discharged into the environment via wastewater treatment plant (WWTP) effluents.

estrogen 17-alpha-ethynylestradiol


Input: The present study employed radiolabeled EE2 to examine impacts of temperature and salinity on EE2 uptake in male killifish (Fundulus heteroclitus).


Input: Fish were exposed to a nominal concentration of 100ng/L EE2 for 2h.


Input: The rate of EE2 uptake was constant over the 2h period.


Input: Oxygen consumption rates (MO (2)), whole body uptake rates, and tissue-specific EE2 distribution were determined.

Oxygen


Input: In killifish acclimated to 18 degrees C at 16ppt (50% sea water), MO (2) and EE2 uptake were both lower after 24h exposure to 10 degrees C and 4 degrees C, and increased after 24h exposure to 26 degrees C.


Input: Transfer to fresh water (FW) for 24h lowered EE2 uptake rate, and long-term acclimation to fresh water reduced it by 70%.


Input: Both long-term acclimation to 100% sea water (32ppt) and a 24h transfer to 100% sea water also reduced EE2 uptake rate by 50% relative to 16ppt.


Input: Tissue-specific accumulation of EE2 was highest (40-60% of the total) in the liver plus gall bladder across all exposures, and the vast majority of this was in the bile at 2h, regardless of temperature or salinity.


Input: The carcass was the next highest accumulator (30-40%), followed by the gut (10-20%) with only small amounts in gill and spleen.


Input: Killifish chronically exposed (15 days) to 100ng/L EE2 displayed no difference in EE2 uptake rate or tissue-specific distribution.


Input: Drinking rate, measured with radiolabeled polyethylene glycol-4000, was about 25 times greater in 16ppt-acclimated killifish relative to FW-acclimated animals.

polyethylene glycol-4000


Input: However, drinking accounted for less than 30% of gut accumulation, and therefore a negligible percentage of whole body EE2 uptake rates.


Input: In general, there were strong positive relationships between EE2 uptake rates and MO (2), suggesting similar uptake pathways of these lipophilic molecules across the gills.


Input: These data will be useful in developing a predictive model of how key environmental parameter variations (salinity, temperature, dissolved oxygen) affect EE2 uptake in estuarine fish, to determine optimal timing and location of WWTP discharges.

oxygen


Input: One new antitumour cassane-type diterpene from Caesalpinia crista.

cassane

diterpene


Input: 1 alpha-acetoxy-5 alpha, 7 beta-dihydroxycassa-11, 13 (15)-diene-16, 12-lactone, a new cassane-type diterpene was isolated from Caesalpinia crista.

1 alpha-acetoxy-5 alpha, 7 beta-dihydroxycassa-11, 13 (15)-diene-16, 12-lactone

cassane

diterpene


Input: The structure of this compound was elucidated by analysis of NMR spectra, and the relative configuration was established by NOE experiment.


Input: The new compound was evaluated for antitumour activity against T47D, DU145 and showed significant inhibitory activities.


Input: MUC1-C oncoprotein as a target in breast cancer: activation of signaling pathways and therapeutic approaches.


Input: Mucin 1 (MUC1) is a heterodimeric protein formed by two subunits that is aberrantly overexpressed in human breast cancer and other cancers.


Input: Historically, much of the early work on MUC1 focused on the shed mucin subunit.


Input: However, more recent studies have been directed at the transmembrane MUC1-C-terminal subunit (MUC1-C) that functions as an oncoprotein.


Input: MUC1-C interacts with EGFR (epidermal growth factor receptor), ErbB2 and other receptor tyrosine kinases at the cell membrane and contributes to activation of the PI3K <E232> AKT and mitogen-activated protein kinase kinase (MEK) <E232> extracellular signal-regulated kinase (ERK) pathways.

tyrosine


Input: MUC1-C also localizes to the nucleus where it activates the Wnt/beta-catenin, signal transducer and activator of transcription (STAT) and NF (nuclear factor)-kappa B RelA pathways.


Input: These findings and the demonstration that MUC1-C is a druggable target have provided the experimental basis for designing agents that block MUC1-C function.


Input: Notably, inhibitors of the MUC1-C subunit have been developed that directly block its oncogenic function and induce death of breast cancer cells in vitro and in xenograft models.


Input: On the basis of these findings, a first-in-class MUC1-C inhibitor has entered phase I evaluation as a potential agent for the treatment of patients with breast cancers who express this oncoprotein.


Input: beta-Eudesmol induces JNK-dependent apoptosis through the mitochondrial pathway in HL60 cells.

beta-Eudesmol


Input: beta-eudesmol, a natural sesquiterpenol present in a variety of Chinese herbs, is known to inhibit the proliferation of human tumor cells.

beta-eudesmol

sesquiterpenol


Input: However, the molecular mechanisms of the effect of beta-eudesmol on human tumor cells are unknown.

beta-eudesmol


Input: In the present study, we report the cytotoxic effect of beta-eudesmol on the human leukemia HL60 cells and its molecular mechanisms.

beta-eudesmol


Input: The cytotoxic effect of beta-eudesmol on HL60 cells was associated with apoptosis, which was characterized by the presence of DNA fragmentation.

beta-eudesmol


Input: beta-eudesmol-induced apoptosis was accompanied by cleavage of caspase-3, caspase-9, and poly (ADP-ribose) polymerase; downregulation of Bcl-2 expression; release of cytochrome c from mitochondria; and decrease in mitochondrial membrane potential (MMP).

beta-eudesmol

poly (ADP-ribose)


Input: Activation of c-Jun N-terminal kinases (JNK) mitogen-activated protein kinases was observed in beta-eudesmol-treated HL60 cells, and the inhibitor of JNK blocked the beta-eudesmol-induced apoptosis, downregulation of Bcl-2, and the loss of MMP.

N

beta-eudesmol

beta-eudesmol


Input: These data suggest that beta-eudesmol induces apoptosis in HL60 cells via the mitochondrial apoptotic pathway, which is controlled through JNK signaling.

beta-eudesmol


Input: Copyright (c) 2012 John Wiley & Sons, Ltd.


Input: A new triterpenoid saponin from Glinus oppositifolius with alpha-glucosidase inhibitory activity.

triterpenoid saponin


Input: Evaluation of alpha-glucosidase inhibitory activity led to the isolation of six triterpene saponins from the aerial parts of Glinus oppositifolius including one new and five known constituents.

triterpene saponins


Input: The structure of the new saponin, glinoside C (1), was established as 16-O-(beta-D-glucopyranosyl)-3 beta, 12 beta, 16 beta, 21 alpha, 22-pentahydroxy hopane by extensive use of 1-D, 2-D NMR and mass spectral techniques.

saponin

glinoside C

16-O-(beta-D-glucopyranosyl)-3 beta, 12 beta, 16 beta, 21 alpha, 22-pentahydroxy hopane


Input: The other constituents identified were 3-O-(beta-D-xylopyranosyl)-spergulagenin A (2), spergulacin (3), spergulin A (4), spergulacin A (5) and spergulin B (6).

3-O-(beta-D-xylopyranosyl)-spergulagenin A

spergulacin

spergulin A

spergulacin A

spergulin B


Input: Compound 1 exhibited the greatest inhibition of the enzyme with IC50 of 127 +/- 30 micro M.


Input: Kinetics study for the compound 1 demonstrated mixed type of inhibition (Ki = 157. 9 micro M).


Input: Optimization of PLGA nanoparticles formulation containing L-DOPA by applying the central composite design.

PLGA

L-DOPA


Input: The aim of this work was to prepare L-DOPA loaded poly (D, L-lactide-co-glycolide) (PLGA) nanoparticles by a modified water-in-oil-in-water (W (1)/O/W (2)) emulsification solvent evaporation method.

L-DOPA

poly (D, L-lactide-co-glycolide)

PLGA


Input: A central composite design was applied for optimization of the formulation parameters and for studying the effects of three independent variables: PLGA concentration, polyvinyl alcohol (PVA) concentration and organic solvent removal rate on the particle size and the entrapment efficiency (response variables).

PLGA

polyvinyl alcohol

PVA


Input: Second-order models were obtained to adequately describe the influence of the independent variables on the selected responses.


Input: The analysis of variance showed that the three independent variables had significant effects (p < 0. 05) on the responses.


Input: The experimental results were in perfect accordance with the predictions estimated by the models.


Input: Using the desirability approach and overlay contour plots, the optimal preparation area can be highlighted.


Input: It was found that the optimum values of the responses could be obtained at higher concentration of PLGA (5%, w/v) and PVA (6%, w/v); and faster organic solvent removal rate (700 rpm).

PLGA

PVA


Input: The corresponding particle size was 256. 2 nm and the entrapment efficiency was 62. 19%.


Input: FTIR investigation confirmed that the L-DOPA and PLGA polymer maintained its backbone structure in the fabrication of nanoparticles.

L-DOPA

PLGA


Input: The scanning electron microscopic images of nanoparticles showed that all particles had spherical shape with porous outer skin.


Input: The results suggested that PLGA nanoparticles might represent a promising formulation for brain delivery of L-DOPA.

PLGA

L-DOPA


Input: The preparation of L-DOPA loaded PLGA nanoparticles can be optimized by the central composite design.

L-DOPA

PLGA


Input: Impact of early-life stress, on group III mGlu receptor levels in the rat hippocampus: effects of ketamine, electroconvulsive shock therapy and fluoxetine treatment.

ketamine

fluoxetine


Input: The glutamatergic system is increasingly being viewed as a promising target for the development of novel treatments for depression.


Input: The group III metabotropic glutamate (mGlu) receptors (mGlu (4, 7) and (8) receptors) in particular are beginning to show promise in this respect.

glutamate


Input: It remains unclear how antidepressant medications modulate mGlu receptors.


Input: In this study we investigated the effects of three antidepressant treatments (fluoxetine, ketamine and electroconvulsive shock therapy (ECT)).

fluoxetine

ketamine


Input: Ketamine is an NMDA receptor antagonist which possess a rapid antidepressant therapeutic profile and moreover is effective in cases of treatment-resistant depression.

Ketamine

NMDA


Input: Furthermore, ECT is also a therapeutic strategy possessing increased efficacy compared to conventional monoamine based therapies.

monoamine


Input: The effect these two highly efficacious treatments have on hippocampal group III mGlu receptors remains completely unexplored.


Input: To redress this deficit we investigated the effects these treatments and the prototypical selective serotonin reuptake inhibitor (SSRI) fluoxetine would have on hippocampal group III mGlu receptor mRNA levels in na i ve Sprague-Dawley rats and rats which had undergone early-life stress in the form of the maternal separation (MS) procedure.

serotonin

fluoxetine


Input: We found MS significantly reduced mGlu (4) receptor expression and fluoxetine reversed this MS induced change.

fluoxetine


Input: ECT and ketamine treatment significantly reduced mGlu (4) receptor expression in non-separated (NS) animals while having no effect in MS animals.

ketamine


Input: Fluoxetine and ECT significantly increased mGlu (7) receptor expression in NS animals.

Fluoxetine


Input: This work demonstrates changes to mGlu (4) receptor expression may be a lasting molecular change which occurs due to early-life stress.


Input: Taken together our data shows there are selective changes to group III mGlu receptors under basal and early-life stress conditions.


Input: This article is part of a Special Issue entitled' Metabotropic Glutamate Receptors'.

Glutamate


Input: In vitro biomonitoring of the genotoxic and oxidative potentials of two commonly eaten insects in southwestern Nigeria.


Input: In this study, the cytogenetic and oxidative effects of water soluble extracts of two commonly eaten insects, Zonocerus variegatus (Orthoptera: Pyrgomorphidae) and Oryctes boas (Solanales: Solanaceae), in southwestern Nigeria were evaluated on cultured human blood cells.


Input: The extracts were added to the cultures at various concentrations (0-2000 ppm).


Input: The chromosome aberration and micronucleus tests were used to find out the DNA and chromosomal damage potentials in vitro by aqueous insect extracts.


Input: To assess the oxidative effects of these insect extracts, total antioxidant capacity (TAC) and total oxidant status (TOS) levels were also measured.


Input: Our results indicated that these extracts did not show genotoxic effects at the tested concentrations.


Input: However, the extracts caused dose-dependent alterations in both TAC and TOS levels.


Input: Based on the findings, it was concluded that the studied insects can be consumed safely, but it is necessary to consider the cellular damages that are likely to appear depending on the oxidative stress.


Input: We also suggest that this in vitro approach for oxidative and genotoxicity assessments may be useful to compare the potential health risks of edible insects.


Input: The role of diallyl sulfides and dipropyl sulfides in the in vitro antimicrobial activity of the essential oil of garlic, Allium sativum L., and Leek, Allium porrum L.

diallyl sulfides

dipropyl sulfides


Input: The in vitro antibacterial activity of essential oils (EOs) obtained from fresh bulbs of garlic, Allium sativum L., and leek, Allium porrum L.


Input: (Alliaceae), was studied.


Input: A. sativum (garlic) EO showed a good antimicrobial activity against Staphylococcus aureus (inhibition zone 14. 8 mm), Pseudomonas aeruginosa (inhibition zone 21. 1 mm), and Escherichia coli (inhibition zone 11. 0 mm), whereas the EO of A. porrum (leek) had no antimicrobial activity.


Input: The main constituents of the garlic EO were diallyl monosulfide, diallyl disulfide (DADS), diallyl trisulfide, and diallyl tetrasulfide.

diallyl monosulfide

diallyl disulfide

DADS

diallyl trisulfide

diallyl tetrasulfide


Input: The EO of A. porrum was characterized by the presence of dipropyl disulfide (DPDS), dipropyl trisulfide, and dipropyl tetrasulfide.

dipropyl disulfide

DPDS

dipropyl trisulfide

dipropyl tetrasulfide


Input: The antimicrobial activities of the DADS and DPDS were also studied.

DADS

DPDS


Input: The results obtained suggest that the presence of the allyl group is fundamental for the antimicrobial activity of these sulfide derivatives when they are present in Allium or in other species (DADS inhibition zone on S. aureus 15. 9 mm, P. aeruginosa 21. 9 mm, E. coli 11. 4 mm).

allyl

sulfide

DADS


Input: Copyright (c) 2012 John Wiley & Sons, Ltd.


Input: MicroRNA-7 functions as an anti-metastatic microRNA in gastric cancer by targeting insulin-like growth factor-1 receptor.


Input: Metastasis is a major clinical obstacle in the treatment of gastric cancer (GC) and it accounts for the majority of cancer-related mortality.


Input: MicroRNAs have recently emerged as regulators of metastasis by acting on multiple signaling pathways.


Input: In this study, we found that miR-7 is significantly downregulated in highly metastatic GC cell lines and metastatic tissues.


Input: Both gain-of-function and loss-of-function experiments showed that increased miR-7 expression significantly reduced GC cell migration and invasion, whereas decreased miR-7 expression dramatically enhanced cell migration and invasion.


Input: In vivo metastasis assays also demonstrated that overexpression of miR-7 markedly inhibited GC metastasis.


Input: Moreover, the insulin-like growth factor-1 receptor (IGF1R) oncogene, which is often mutated or amplified in human cancers and functions as an important regulator of cell growth and tumor invasion, was identified as a direct target of miR-7.


Input: Silencing of IGF1R using small interefering RNA (siRNA) recapitulated the anti-metastatic function of miR-7, whereas restoring the IGF1R expression attenuated the function of miR-7 in GC cells.


Input: Furthermore, we found that suppression of Snail by miR-7, through targeting IGF1R, increased E-cadherin expression and partially reversed the epithelial-mesenchymal transition (EMT).


Input: Finally, analyses of miR-7 and IGF1R levels in human primary GC with matched lymph node metastasis tissue arrays revealed that miR-7 is inversely correlated with IGF1R expression.


Input: The present study provides insight into the specific biological behavior of miR-7 in EMT and tumor metastasis.


Input: Targeting this novel miR-7/IGF1R/Snail axis would be helpful as a therapeutic approach to block GC metastasis.


Input: Flavonoids and saponins from Zizyphus incurva.

Flavonoids

saponins


Input: A new flavonol triglycoside, myricetin-3-O-[beta-xylopyranosyl-(1-2)-alpha-rhamnopyranoside]-4'-O-alpha-rhamnopyranoside, named as bayarin (1), was isolated from the aerial parts of Zizyphus incurva Roxb.

flavonol triglycoside

myricetin-3-O-[beta-xylopyranosyl-(1-2)-alpha-rhamnopyranoside]-4'-O-alpha-rhamnopyranoside

bayarin


Input: (Rhamnaceae) along with eight known compounds: six flavonoids and two saponins.

flavonoids

saponins


Input: All of these compounds were isolated for the first time from this plant.


Input: Structures of these compounds were elucidated on the basis of spectroscopic data.


Input: Rapid characterisation of flavonoids from Sophora alopecuroides L. by HPLC/DAD/ESI-MSn.

flavonoids


Input: An HPLC/DAD/ESI-MSn method was established to characterise flavonoids in the seeds of Sophora alopecuroides L.

flavonoids


Input: All the flavonoids exhibited abundant [M-H]-ions, which triggered data-dependent multistage mass spectrometry fragmentations.

flavonoids

H


Input: Characteristic UV spectra were used to confirm flavonoid subtypes.

flavonoid


Input: In total, 22 flavonoids and two phenolic compounds were detected and identified.

flavonoids

phenolic


Input: Five of them were identified by comparing with reference standards, and the others were characterised based on the retention behaviour, multistage fragmentation feature and UV absorption.


Input: A total of 19 compounds were reported from S. alopecuroides for the first time.


Input: This method accomplished rapid profiling of flavonoid constituents in S. alopecuroides L.

flavonoid


Input: cAMP regulation of airway smooth muscle function.

cAMP


Input: Agonists activating beta (2)-adrenoceptors (beta (2) ARs) on airway smooth muscle (ASM) are the drug of choice for rescue from acute bronchoconstriction in patients with both asthma and chronic obstructive pulmonary disease (COPD).


Input: Moreover, the use of long-acting beta-agonists combined with inhaled corticosteroids constitutes an important maintenance therapy for these diseases.

corticosteroids


Input: beta-Agonists are effective bronchodilators due primarily to their ability to antagonize ASM contraction.


Input: The presumed cellular mechanism of action involves the generation of intracellular cAMP, which in turn can activate the effector molecules cAMP-dependent protein kinase (PKA) and Epac.

cAMP

cAMP


Input: Other agents such as prostaglandin E (2) and phosphodiesterase inhibitors that also increase intracellular cAMP levels in ASM, can also antagonize ASM contraction, and inhibit other ASM functions including proliferation and migration.

prostaglandin E (2)

cAMP


Input: Therefore, beta (2) ARs and cAMP are key players in combating the pathophysiology of airway narrowing and remodeling.

cAMP


Input: However, limitations of beta-agonist therapy due to drug tachyphylaxis related to beta (2) AR desensitization, and recent findings regarding the manner in which beta (2) ARs and cAMP signal, have raised new and interesting questions about these well-studied molecules.

cAMP


Input: In this review we discuss current concepts regarding beta (2) ARs and cAMP in the regulation of ASM cell functions and their therapeutic roles in asthma and COPD.

cAMP


Input: Anxiolytic-but not antidepressant-like activity of Lu AF21934, a novel, selective positive allosteric modulator of the mGlu 4 receptor.

Lu AF21934


Input: Previous studies demonstrated that the Group III mGlu receptor-selective orthosteric agonist, LSP1-2111 produced anxiolytic-but not antidepressant-like effects upon peripheral administration.


Input: Herein, we report the pharmacological actions of Lu AF21934, a novel, selective, and brain-penetrant positive allosteric modulator (PAM) of the mGlu (4) receptor in the stress-induced hyperthermia (SIH), four-plate, marble-burying and Vogel' s conflict tests.

Lu AF21934


Input: In all models, except Vogel' s conflict test, a dose-dependent anxiolytic-like effect was seen.


Input: The anti-hyperthermic effect of Lu AF21934 (5 mg/kg) in the SIH test was inhibited by the benzodiazepine receptor antagonist flumazenil (10 mg/kg) and was not serotonin-dependent, as it persisted in serotonin-deficient mice and upon blockade of either 5-HT (1A) receptors by WAY100635, or 5-HT (2A/2C) receptors by ritanserin.

Lu AF21934

benzodiazepine

flumazenil

serotonin

serotonin

ritanserin


Input: These results suggest that the GABAergic system, but not the serotonergic system, is involved in the mechanism of the anxiolytic-like phenotype of Lu AF21934 in rodents.

Lu AF21934


Input: Lu AF21934 did not produce antidepressant-like effects in the tail suspension test (TST) in mice; however, it decreased the basal locomotor activity of mice that were not habituated to activity cages.

Lu AF21934


Input: This article is part of a Special Issue entitled' Metabotropic Glutamate Receptors'.

Glutamate


Input: Intraspecific variability of the essential oil of Calamintha nepeta subsp. nepeta from Southern Italy (Apulia).


Input: The essential oil of 46 spontaneous plants of Calamintha nepeta (L.) Savi subsp. nepeta growing wild in Sud, Italy (Salento, Apulia), were investigated by GC/MS.


Input: Fifty-seven components were identified in the oil representing over the 98% of the total oil composition.


Input: Four chemotypes were identified: piperitone oxide, piperitenone oxide, piperitone-menthone and pulegone.

piperitone oxide

piperitenone oxide

piperitone

menthone

pulegone


Input: Screening of venezuelan medicinal plant extracts for cytostatic and cytotoxic activity against tumor cell lines.


Input: There are estimated to be more than 20, 000 species of plants in Venezuela, of which more than 1500 are used for medicinal purposes by indigenous and local communities.


Input: Only a relatively small proportion of these have been evaluated in terms of their potential as antitumor agents.


Input: In this study, we screened 308 extracts from 102 species for cytostatic and cytotoxic activity against a panel of six tumor cell lines using a 24-h sulphorhodamine B assay.

sulphorhodamine B


Input: Extracts from Clavija lancifolia, Hamelia patens, Piper san-vicentense, Physalis cordata, Jacaranda copaia, Heliotropium indicum, and Annona squamosa were the most cytotoxic, whereas other extracts from Calotropis gigantea, Hyptis dilatata, Chromolaena odorata, Siparuna guianensis, Jacaranda obtusifolia, Tapirira guianensis, Xylopia aromatica, Protium heptaphyllum, and Piper arboreum showed the greatest cytostatic activity.


Input: These results confirm previous reports on the cytotoxic activities of the abovementioned plants as well as prompting further studies on others such as C. lancifolia and H. dilatata that have not been so extensively studied.


Input: Copyright (c) 2012 John Wiley & Sons, Ltd.


Input: The interaction between mGluR1 and the calcium channel Cav 2. 1 preserves coupling in the presence of long Homer proteins.

calcium


Input: Group I metabotropic glutamate receptors (mGluR1 and 5) are G protein coupled receptors that regulate neuronal activity in a number of ways.

glutamate


Input: Some of the most well studied functions of group I mGluRs, such as initiation of multiple forms of mGluR-dependent long-term depression, require receptor localization near the post-synaptic density (PSD).


Input: This localization is in turn dependent on the Homer family of scaffolding proteins which bind to a small motif on the distal C-termini of mGluR1 and 5, localize the receptors near the PSD, strengthen coupling to post-synaptic effectors and simultaneously uncouple the mGluRs from extra-synaptic effectors such as voltage dependent ion channels.

C


Input: Here the selectivity of this uncoupling process was examined by testing the ability of Homer-2b to uncouple mGluR1 from multiple voltage dependent calcium channels including Ca (V2. 2) (N-type), Ca (V3. 2) (T-type), and Ca (V2. 1) (P/Q-type) expressed in rat sympathetic neurons from the superior cervical ganglion (SCG).

calcium

Ca

Ca

Ca


Input: Of these, only the mGluR1-Ca (V2. 1) modulatory pathway was insensitive to Homer-2b expression.


Input: Uncoupling from this channel was achieved by co-expression of an mGluR1 C-terminal protein designed to disrupt a previously described direct interaction between these two proteins, suggesting that this interaction allows incorporation of Ca (V2. 1) into the mGluR1/Homer signaling complex, thereby preserving modulation in the presence of scaffolding Homer proteins.

C

Ca


Input: This article is part of a Special Issue entitled' Metabotropic Glutamate Receptors'.

Glutamate


Input: Pharmacological profiling of native group II metabotropic glutamate receptors in primary cortical neuronal cultures using a FLIPR.

glutamate


Input: The group II metabotropic glutamate (mGlu) receptors comprised of the mGlu2 and mGlu3 receptor subtypes have gained recognition in recent years as potential targets for psychiatric disorders, including anxiety and schizophrenia.

glutamate


Input: In addition to studies already indicating which subtype mediates the anxiolytic and anti-psychotic effects observed in disease models, studies to help further define the preferred properties of selective group II mGlu receptor ligands will be essential.


Input: Comparison of the in vitro properties of these ligands to their in vivo efficacy and tolerance profiles may help provide these additional insights.


Input: We have developed a relatively high-throughput native group II mGlu receptor functional assay to aid this characterisation.


Input: We have utilised dissociated primary cortical neuronal cultures, which after 7 days in vitro have formed functional synaptic connections and display periodic and spontaneous synchronised calcium (Ca (2 +)) oscillations in response to intrinsic action potential bursts.

calcium

Ca (2 +)


Input: We herein demonstrate that in addition to non-selective group II mGlu receptor agonists, (2R, 4R)-APDC, LY379268 and DCG-IV, a selective mGlu2 agonist, LY541850, and mGlu2 positive allosteric modulators, BINA and CBiPES, inhibit the frequency of synchronised Ca (2 +) oscillations in primary cultures of rat and mouse cortical neurons.

(2R, 4R)-APDC

DCG-IV

Ca (2 +)


Input: Use of cultures from wild-type, mGlu2 (-/-), mGlu3 (-/-) and mGlu2/3 (-/-) mice allowed us to further probe the contribution of mGlu2 and mGlu3, and revealed LY541850 to be a partial mGlu2 agonist and a full mGlu3 antagonist.


Input: Overnight pre-treatment of cultures with these ligands revealed a preferred desensitisation profile after treatment with a positive allosteric modulator.


Input: This article is part of a Special Issue entitled' Metabotropic Glutamate Receptors'.

Glutamate


Input: Glycine release is regulated by metabotropic glutamate receptors sensitive to mGluR2/3 ligands and activated by N-acetylaspartylglutamate (NAAG).

Glycine

glutamate

N-acetylaspartylglutamate

NAAG


Input: The presence of metabotropic glutamate receptors (mGluRs) of group II modulating glycine exocytosis from glycinergic nerve endings of mouse spinal cord was investigated.

glutamate

glycine


Input: Purified synaptosomes were selectively prelabeled with [(3) H] glycine through the neuronal transporter GlyT2 and subsequently depolarized by superfusion with 12 mM KCl.

[(3) H] glycine

KCl


Input: The selective mGluR2/3 agonist LY379268 inhibited the K (+)-evoked overflow of [(3) H] glycine in a concentration-dependent manner (EC (50) about 0. 2 nM).

K (+)

[(3) H] glycine


Input: The effect of LY379268 was prevented by the selective mGluR2/3 antagonist LY341495 (IC (50) about 1 nM).


Input: N-acetylaspartylglutamate (NAAG) inhibited [(3) H] glycine overflow with extraordinary potency (EC (50) about 50 fmol).

N-acetylaspartylglutamate

NAAG

[(3) H] glycine


Input: In contrast, glutamate was ineffective up to 0. 1 nM, excluding that glutamate contamination of commercial NAAG samples is responsible for the reported activity of NAAG at mGluR3.

glutamate

glutamate

NAAG

NAAG


Input: LY341495 antagonized the NAAG inhibition of [(3) H] glycine release.

NAAG

[(3) H] glycine


Input: The effect of a combination of maximally effective concentrations of LY379268 and NAAG exhibited no additivity.

NAAG


Input: The non-hydrolysable NAAG analogue N-acetylaspartyl-beta-linked glutamate (beta-NAAG) antagonized NAAG and LY379268.

NAAG

N-acetylaspartyl-beta-linked glutamate

beta-NAAG

NAAG


Input: In conclusion, our results show that glycinergic nerve endings in spinal cord are endowed with group II mGluRs mediating inhibition of glycine exocytosis.

glycinergic


Input: NAAG can activate these presynaptic receptors with extremely high affinity and with characteristics compatible with the reported mGluR3 pharmacology.

NAAG


Input: This article is part of a Special Issue entitled' Metabotropic Glutamate Receptors'.

Glutamate


Input: Attenuation of methamphetamine seeking by the mGluR2/3 agonist LY379268 in rats with histories of restricted and escalated self-administration.

methamphetamine


Input: Recent findings implicate group II metabotropic glutamate receptors (mGluR (2/3)) in the reinforcing effects of psychostimulants and have identified these receptors as potential treatment targets for drug addiction.

glutamate


Input: Here, we investigated the effects of mGluR (2/3) stimulation on cue-and drug-primed reinstatement in rats with different histories of methamphetamine (METH) self-administration training, under two conditions: 16 daily sessions of short access (90 min/day, ShA), or 8 daily sessions of short access followed by 8 sessions of long access (6 h/day, LgA).

methamphetamine

METH


Input: Following self-administration and subsequent extinction training, rats were pretreated with the selective mGluR (2/3) agonist LY379268 (variable dose, 0-3 mg/kg), exposed to METH-paired cues or a priming injection of METH (1 mg/kg), and tested for reinstatement of METH-seeking behavior.

METH

METH

METH


Input: LgA rats self-administered greater amounts of METH during the second half of training, but when pretreated with vehicle, ShA and LgA rats showed cue-and drug-primed reinstatement at equivalent response rates.

METH


Input: However, LgA rats demonstrated greater sensitivity to mGluR (2/3) stimulation with attenuated responding during cue-induced reinstatement after 0. 3 mg/kg and higher doses of LY379268, whereas ShA rats decreased cue-induced reinstatement behavior following 1. 0 mg/kg and 3. 0 mg/kg LY379268.


Input: Additionally, both LgA and ShA rats exhibited decreased METH-primed reinstatement behavior following 0. 3 mg/kg and higher doses of LY379268.

METH


Input: A separate group of control rats was trained to self-administer sucrose pellets, and demonstrated attenuated cue-induced sucrose-seeking behavior following 1. 0 and 3. 0 mg/kg LY379268.


Input: Together, the results indicate that LY379268 has differential attenuating effects on cue-induced reinstatement behavior in rats with different histories of METH intake.

METH


Input: This article is part of a Special Issue entitled' Metabotropic Glutamate Receptors'.

Glutamate


Input: Stathmin 1 is a potential novel oncogene in melanoma.


Input: In previous studies, we demonstrated that miR-193b expression is reduced in melanoma relative to benign nevi, and also that miR-193b represses cyclin D1 and Mcl-1 expression.


Input: We suggested that stathmin 1 (STMN1) might be a target of miR-193b.


Input: STMN1 normally regulates microtubule dynamics either by sequestering free tubulin heterodimers or by promoting microtubule catastrophe.


Input: Increased expression of STMN1 has been observed in a variety of human malignancies, but its association with melanoma is unknown.


Input: We now report that STMN1 is upregulated during the progression of melanoma relative to benign nevi, and that STMN1 is directly regulated by miR-193b.


Input: Using an experimental cell culture approach, overexpression of miR-193b using synthetic microRNAs repressed STMN1 expression, whereas inhibition of miR-193b with anti-miR oligos increased STMN1 expression in melanoma cells.


Input: The use of a luciferase reporter assay confirmed that miR-193b directly regulates STMN1 by targeting the 3'-untranslated region of STMN1 mRNA.


Input: We further demonstrated that STMN1 is overexpressed in malignant melanoma compared with nevi in two independent melanoma cohorts, and that its level is inversely correlated with miR-193b expression.


Input: However, STMN1 expression was not significantly associated with patient survival, Breslow depth, mitotic count or patient age.


Input: STMN1 knockdown by small-interfering RNA in melanoma cells drastically repressed cell proliferation and migration potential, whereas ectopic expression of STMN1 using lentivirus increased cell proliferation and migration rates.


Input: Subsequent gene expression analysis indicated that interconnected cytoskeletal networks are directly affected following STMN1 knockdown.


Input: In addition, we identified deregulated genes associated with proliferation and migration, and revealed that p21 (Cip1/Waf1) and p27 (Kip) could be downstream effectors of STMN1 signaling.


Input: Taken together, our study suggests that downregulation of miR-193b may contribute to increased STMN1 expression in melanoma, which consequently promotes migration and proliferation of tumor cells.


Input: The p44/wdr77-dependent cellular proliferation process during lung development is reactivated in lung cancer.


Input: During lung development, cells proliferate for a defined length of time before they begin to differentiate.


Input: Factors that control this proliferative process and how this growth process is related to lung cancer are currently unknown.


Input: Here, we found that the WD40-containing protein (p44/wdr77) was expressed in growing epithelial cells at the early stages of lung development.


Input: In contrast, p44/wdr77 expression was diminished in fully differentiated epithelial cells in the adult lung.


Input: Loss of p44/wdr77 gene expression led to cell growth arrest and differentiation.


Input: Re-expression of p44/wdr77 caused terminally differentiated cells to re-enter the cell cycle.


Input: Our findings suggest that p44/wdr77 is essential and sufficient for proliferation of lung epithelial cells.


Input: P44/Wdr77 was re-expressed in lung cancer, and silencing p44/wdr77 expression strongly inhibited growth of lung adenocarcinoma cells in tissue culture and abolished growth of lung adenocarcinoma tumor xenografts in mice.


Input: The growth arrest induced by loss of p44/wdr77 expression was partially through the p21-Rb signaling.


Input: Our results suggest that p44/wdr77 controls cellular proliferation during lung development, and this growth process is reactivated during lung tumorigenesis.


Input: Two new phenolic glycosides from Inula cappa DC.

phenolic glycosides


Input: Two new phenolic glycosides were isolated from the ethanol extract of the roots of Inula cappa DC.

phenolic glycosides

ethanol


Input: Their structures were defined as 4-[(6-O-(E)-caffeoyl)-beta-D-glucopyranosyl] vanillic acid (1) and 3-O-[beta-D-apiofurarnosyl-(1-6)-beta-D-glucopyranoxy]-6-hydroxy-p-cymene (2) on the basis of spectral analysis.

4-[(6-O-(E)-caffeoyl)-beta-D-glucopyranosyl] vanillic acid

3-O-[beta-D-apiofurarnosyl-(1-6)-beta-D-glucopyranoxy]-6-hydroxy-p-cymene


Input: In vitro characterization of organophosphorus compound hydrolysis by native and recombinant human prolidase.

organophosphorus


Input: Human prolidase is a binuclear metalloenzyme, which can potentially function as a catalytic bioscavenger for organophosphorus (OP) nerve agents.

organophosphorus


Input: Although the biochemical properties of native prolidase purified from human erythrocytes, liver, kidney, and fibroblast cells are well known, it is very poorly characterized with regard to its OP hydrolyzing activity.


Input: Also, the high cost of purification of large quantities of native enzyme limits its use as a bioscavenger.


Input: Thus, recombinant human prolidase with similar biochemical properties to those of native enzyme would be more suitable as a catalytic bioscavenger.


Input: In this study, we established an Escherichia coli expression system, which produced a large amount of tagged human liver prolidase that was purified to over 95% purity from the soluble fraction of cell lysate by affinity chromatography on Streptavidin-agarose resin.


Input: The catalytic properties of the recombinant enzyme were compared in vitro with those of highly purified prolidase I isolated from human erythrocytes.


Input: The catalytic properties of recombinant prolidase overlap with those of the erythrocyte-derived native enzyme.


Input: Both enzymes efficiently hydrolyzed diisopropylfluorophosphate, sarin, soman, tabun and cyclosarin, but were much less efficient at hydrolyzing paraoxon and methyl paraoxon.

diisopropylfluorophosphate

sarin

soman

tabun

cyclosarin

paraoxon

methyl paraoxon


Input: These results suggest that human prolidase expressed in E. coli is suitable for further development as a catalytic bioscavenger for OP nerve agents.


Input: Theoretical study of the pH-dependent antioxidant properties of vitamin C.

vitamin C


Input: Molecules acting as antioxidants capable of scavenging reactive oxygen species (ROS) are of utmost importance in the living cell.

oxygen


Input: Vitamin C is known to be one of these molecules.

Vitamin C


Input: In this study we have analyzed the reactivity of vitamin C toward the [Formula: see text] and [Formula: see text] ROS species, in all acidic, neutral and basic media.

vitamin C


Input: In order to do so, density functional theory (DFT) have been used.


Input: More concretely, the meta-GGA functional MPW1B95 have been used.


Input: Two reaction types have been studied in each case: addition to the ring atoms, and hydrogen/proton abstraction.

hydrogen


Input: Our results show that [Formula: see text] is the most reactive species, while [Formula: see text] displays low reactivity.


Input: In all three media, vitamin C reactions with two hydroxyl radicals show a wide variety of possible products.

vitamin C

hydroxyl


Input: Cooperation between p53 and the telomere-protecting shelterin component Pot1a in endometrial carcinogenesis.


Input: Type II endometrial cancer (EMCA) represents only 10% of all EMCAs, but accounts for 40% of EMCA-related mortality.


Input: Previous studies of human tumors have shown an association between Type II tumors and damaged telomeres.


Input: We hypothesized that the lack of murine Type II EMCA models is due to the extremely long telomeres in laboratory mouse strains.


Input: We previously showed that telomerase-null mice with critically short telomeres developed endometrial lesions histologically resembling endometrial intraepithelial carcinoma (EIC), the accepted precursor for Type II EMCA.


Input: However, these mice did not develop invasive endometrial adenocarcinoma, and instead succumbed prematurely to multi-organ failure.


Input: Here, we modeled critical telomere attrition by conditionally inactivating Pot1a, a component of the shelterin complex that stabilizes telomeres, within endometrial epithelium.


Input: Inactivation of Pot1a by itself did not stimulate endometrial carcinogenesis, and did not result in detectable DNA damage or apoptosis in endometrium.


Input: However, simultaneous inactivation of Pot1a and p53 resulted in EIC-like lesions by 9 months indistinguishable from those seen in late generation telomerase-null mice.


Input: These lesions progressed to invasive endometrial adenocarcinomas as early as 9 months of age with metastatic disease in 100% of the animals by 15 months.


Input: These tumors were poorly differentiated endometrial adenocarcinomas with prominent nuclear atypia, resembling human Type II cancers.


Input: Furthermore, these tumors were aneuploid with double-stranded DNA breaks and end-to-end telomere fusions and most were tetraploid or near-tetraploid.


Input: These studies lend further support to the hypothesis that telomeric instability has a critical role in Type II endometrial carcinogenesis and provides an intriguing in-vivo correlate to recent studies implicating telomere-dependent tetraploidization as an important mechanism in carcinogenesis.


Input: Hyperinakin, a new anti-inflammatory phloroglucinol derivative from Hypericum nakamurai.

Hyperinakin

phloroglucinol


Input: Phytochemical investigation of Hypericum nakamurai (Masamune) Robson has led to the isolation of three phloroglucinol derivatives 1-3.

phloroglucinol


Input: The structures of these compounds were determined by the analysis of their spectroscopic data (IR, mass and UV), and by the application of 1-D and 2-D-NMR techniques.


Input: Hyperinakin (1) is a new compound.

Hyperinakin


Input: The anti-inflammatory activities of compounds 1-3 were also tested and evaluated.


Input: A biogenetic pathway for compounds 1-3 was also proposed.


Input: Recurrent gene deletions and the evolution of adaptive cyanogenesis polymorphisms in white clover (Trifolium repens L.).


Input: Understanding the molecular evolution of genes that underlie intraspecific polymorphisms can provide insights into the process of adaptive evolution.


Input: For adaptive polymorphisms characterized by gene presence/absence (P/A) variation, underlying loci commonly show signatures of long-term balancing selection, with gene-presence and gene-absence alleles maintained as two divergent lineages.


Input: We examined the molecular evolution of two unlinked P/A polymorphisms that underlie a well-documented adaptive polymorphism for cyanogenesis (hydrogen cyanide release with tissue damage) in white clover.

hydrogen cyanide


Input: Both cyanogenic and acyanogenic plants occur in this species, and the ecological forces that maintain this chemical defence polymorphism have been studied for several decades.


Input: Using a sample of 65 plants, we investigated the molecular evolution of sequences flanking the two underlying cyanogenesis genes: Ac/ac (controlling the presence/absence of cyanogenic glucosides) and Li/li (controlling the presence/absence of their hydrolysing enzyme, linamarase).

cyanogenic glucosides


Input: A combination of genome walking, PCR assays, DNA sequence analysis and Southern blotting was used to test whether these adaptive P/A polymorphisms show evidence of long-term balancing selection, or whether gene-absence alleles have evolved repeatedly through independent deletion events.


Input: For both loci, we detect no signatures of balancing selection in the closest flanking genomic sequences.


Input: Instead, we find evidence for variation in the size of the deletions characterizing gene-absence alleles.


Input: These observations strongly suggest that both of these polymorphisms have been evolving through recurrent gene deletions over time.


Input: We discuss the genetic mechanisms that could account for this surprising pattern and the implications of these findings for mechanisms of rapid adaptive evolution in white clover.


Input: Regulation of gene expression in human prostate cancer cells with artificially constructed promoters that are activated in response to ultrasound stimulation.


Input: We chose promoters responsive to sonication in LNCap cells, a prostate cancer cell line, out of a library composed of DNA fragments constructed by linking the TATA box sequence to randomly combined cis-acting elements of transcription factors activated in response to radiation in prostate cancer cells.


Input: When a plasmid containing the luciferase gene under control of a promoter was transfected into LNCap cells and sonicated with 1 MHz ultrasound at 0. 5 W/cm (2), 10% DF for 60s, 13 promoters showed more than 10-fold enhancement compared with their counterparts without sonication 12h after sonication.


Input: As to their responsiveness to sonication, the best two promoters were then compared to clone 880-8, a derivative from clone 880 that was created by random introduction of point mutations and was shown to have an improved response to X-ray irradiation.


Input: We then took clone 880-8 for further analyses since it showed the highest enhancement to sonication, though not statistically significant from the others.


Input: Next, we employed a retrovirus vector and stably introduced the luciferase gene under control of clone 880-8 into LNCap cells to establish a cell line.


Input: When the cell line was sonicated with 1 MHz ultrasound at 0. 5 W/cm (2), 10% DF for 60s, luciferase expression was enhanced up to 14. 8-fold 12h after sonication.


Input: We then established another cell line by replacing the luciferase gene with the fcy:: fur gene, a suicide gene, and when the cell line was sonicated with 1 MHz ultrasound at 0. 5 W/cm (2), 10% DF for 60s, expression of the gene was enhanced, showing the maximum expression 12-24h after sonication.


Input: When the cells were incubated in medium containing 5-fluorocytosine, cell survival ratio decreased dose dependently with 5-fluorocytosine only after sonication treatment, suggesting this promoter could be utilized for gene expression control with ultrasound.


Input: Genetic determinants of neuronal vulnerability to apoptosis.


Input: Apoptosis is a common mode of cell death that contributes to neuronal loss associated with neurodegeneration.


Input: Single-nucleotide polymorphisms (SNPs) in chromosomal DNA are contributing factors dictating natural susceptibility of humans to disease.

nucleotide


Input: Here, the most common SNPs affecting neuronal vulnerability to apoptosis are reviewed in the context of neurological disorders.


Input: Polymorphic variants in genes encoding apoptotic proteins, either from the extrinsic (FAS, TNF-alpha, CASP8) or the intrinsic (BAX, BCL2, CASP3, CASP9) pathways could be highly valuable in the diagnosis of neurodegenerative diseases and stroke.


Input: Interestingly, the Arg72Pro SNP in TP53, the gene encoding tumor suppressor p53, was recently revealed a biomarker of poor prognosis in stroke due to its ability to modulate neuronal apoptotic death.


Input: Search for new SNPs responsible for genetic variability to apoptosis will ensure the implementation of novel diagnostic and prognostic tools, as well as therapeutic strategies against neurological diseases.


Input: Dissolved gas and ultrasonic cavitation--a review.


Input: The physics and chemistry of nonlinearly oscillating acoustic cavitation bubbles are strongly influenced by the dissolved gas in the surrounding liquid.


Input: Changing the gas alters among others the luminescence spectrum, and the radical production of the collapsing bubbles.


Input: An overview of experiments with various gas types and concentration described in literature is given and is compared to mechanisms that lead to the observed changes in luminescence spectra and radical production.


Input: The dissolved gas type changes the bubble adiabatic ratio, thermal conductivity, and the liquid surface tension, and consequently the hot spot temperature.


Input: The gas can also participate in chemical reactions, which can enhance radical production or luminescence of a cavitation bubble.


Input: With this knowledge, the gas content in cavitation can be tailored to obtain the desired output.


Input: Towards an understanding and control of cavitation activity in 1 MHz ultrasound fields.


Input: Various industrial processes such as sonochemical processing and ultrasonic cleaning strongly rely on the phenomenon of acoustic cavitation.


Input: As the occurrence of acoustic cavitation is incorporating a multitude of interdependent effects, the amount of cavitation activity in a vessel is strongly depending on the ultrasonic process conditions.


Input: It is therefore crucial to quantify cavitation activity as a function of the process parameters.


Input: At 1 MHz, the active cavitation bubbles are so small that it is becoming difficult to observe them in a direct way.


Input: Hence, another metrology based on secondary effects of acoustic cavitation is more suitable to study cavitation activity.


Input: In this paper we present a detailed analysis of acoustic cavitation phenomena at 1 MHz ultrasound by means of time-resolved measurements of sonoluminescence, cavitation noise, and synchronized high-speed stroboscopic Schlieren imaging.


Input: It is shown that a correlation exists between sonoluminescence, and the ultraharmonic and broadband signals extracted from the cavitation noise spectra.


Input: The signals can be utilized to characterize different regimes of cavitation activity at different acoustic power densities.


Input: When cavitation activity sets on, the aforementioned signals correlate to fluctuations in the Schlieren contrast as well as the number of nucleated bubbles extracted from the Schlieren Images.


Input: This additionally proves that signals extracted from cavitation noise spectra truly represent a measure for cavitation activity.


Input: The cyclic behavior of cavitation activity is investigated and related to the evolution of the bubble populations in the ultrasonic tank.


Input: It is shown that cavitation activity is strongly linked to the occurrence of fast-moving bubbles.


Input: The origin of this " bubble streamers " is investigated and their role in the initialization and propagation of cavitation activity throughout the sonicated liquid is discussed.


Input: Finally, it is shown that bubble activity can be stabilized and enhanced by the use of pulsed ultrasound by conserving and recycling active bubbles between subsequent pulsing cycles.


Input: The potential of nicotinic enhancement of cognitive remediation training in schizophrenia.


Input: Cognitive deficits in schizophrenia are critically important predictors of long-term psychosocial outcome and are not significantly ameliorated by currently available medications.


Input: Cognitive remediation training has shown promise for alleviating cognitive symptoms of schizophrenia, but the clinical significance has often been limited by small effect sizes.


Input: Approaches that achieve larger improvement involve time requirements that can be cost-prohibitive within the current clinical care system.


Input: This mini-review evaluates the theoretical potential of a pharmacological enhancement strategy of cognitive remediation training with nicotinic acetylcholine receptor (nAChR) agonists.

acetylcholine


Input: nAChR agonists can facilitate sensory processing, alertness, attention, learning and memory.


Input: While these effects may be too subtle and short-lasting to be of clinical relevance as a primary treatment of cognitive deficits, they constitute an ideal effects profile for enhancing training benefits.


Input: Several mechanisms are described through which repeated coupling of cognitive training challenges with nAChR stimulation may enhance and accelerate cognitive remediation training effects, advancing such interventions into more effective and practicable treatments of some of the most debilitating symptoms of schizophrenia.


Input: This article is part of a Special Issue entitled' Cognitive Enhancers'.


Input: Enhanced mGlu5-receptor dependent long-term depression at the Schaffer collateral-CA1 synapse of congenitally learned helpless rats.


Input: Alterations of the glutamatergic system have been implicated in the pathophysiology and treatment of major depression.


Input: In order to investigate the expression and function of mGlu5 receptors in an animal model for treatment-resistant depression we used rats bred for congenital learned helplessness (cLH) and the control strain, bred for resistance against inescapable stress, congenitally. not learned helpless rats (cNLH).


Input: Western blot analysis showed an increased expression of mGlu5 (but not mGlu1a) receptors in the hippocampus of cLH rats, as compared with control cNLH rats.


Input: We also examined mGlu1/5 receptor signaling by in vivo measurement of DHPG-stimulated polyphosphoinositides hydrolysis.

DHPG

polyphosphoinositides


Input: Stimulation of (3) H-inositolmonophosphate formation induced by i. c. v. injection of DHPG was enhanced by about 50% in the hippocampus of cLH rats.

(3) H-inositolmonophosphate

DHPG


Input: Correspondingly, DHPG-induced long-term depression (LTD) at Schaffer collateral/CA1 pyramidal cell synapses was amplified in hippocampal slices of cLH rats, whereas LTD induced by low frequency stimulation of the Schaffer collaterals did not change.

DHPG


Input: Moreover, these effects were associated with decreased basal dendritic spine density of CA1 pyramidal cell in cLH rats.


Input: These data raise the attractive possibility that changes in the expression and function of mGlu5 receptors in the hippocampus might underlie the changes in synaptic plasticity associated with the depressive-like phenotype of cLH rats.


Input: However, chronic treatment of cLH rats with MPEP did not reverse learned helplessness, indicating that the enhanced mGlu5 receptor function is not the only player in the behavioral phenotype of this genetic model of depression.

MPEP


Input: This article is part of a Special Issue entitled' Metabotropic Glutamate Receptors'.

Glutamate


Input: A variant in the carboxyl-terminus of connexin 40 alters GAP junctions and increases risk for tetralogy of Fallot.

carboxyl


Input: GJA5 gene (MIM no. 121013), localized at 1q21. 1, encodes for the cardiac gap junction protein connexin 40.


Input: In humans, copy number variants of chromosome 1q21. 1 have been associated with variable phenotypes comprising congenital heart disease (CHD), including isolated TOF.


Input: In mice, the deletion of Gja5 can cause a variety of complex CHDs, in particular of the cardiac outflow tract, corresponding to TOF in many cases.


Input: In the present study, we screened for mutations in the GJA5 gene 178 unrelated probands with isolated TOF.


Input: A heterozygous nucleotide change (c. 793C > T) in exon 2 of the gene leading to the p. Pro265Ser variant at the carboxyl-terminus of the protein was found in two unrelated sporadic patients, one with classic anatomy and one with pulmonary atresia.

nucleotide

carboxyl


Input: This GJA5 missense substitution was not observed in 1568 ethnically-matched control chromosomes.


Input: Immunofluorescent staining and confocal microscopy revealed that cells expressing the mutant protein form sparse or no visible gap-junction plaques in the region of cell-cell contact.


Input: Moreover, analysis of the transfer of the gap junction permanent tracer lucifer yellow showed that cells expressing the mutant protein have a reduced rate of dye transfer compared with wild-type cells.


Input: Finally, use of a zebrafish model revealed that microinjection of the GJA5-p. Pro265Ser mutant disrupts overall morphology of the heart tube in the 37% (22/60) of embryos, compared with the 6% (4/66) of the GJA5 wild-type-injected embryos.


Input: These findings implicate GJA5 gene as a novel susceptibility gene for TOF.


Input: A newly identified locus for benign adult familial myoclonic epilepsy on chromosome 3q26. 32-3q28.


Input: Benign Adult Familial Myoclonic Epilepsy (BAFME) is an autosomal dominant disorder characterized by adult-onset cortical tremor or action myoclonus predominantly in the upper limbs, and generalized seizures.


Input: We investigated a Thai BAFME family.


Input: Clinical and electrophysiological studies revealed that 13 were affected with BAFME.


Input: There were a total of 24 individuals studied.


Input: Genetic analysis by genome-wide linkage study (GWLS) was performed using 400 microsatellite markers and excluded linkage of the previous BAFME loci, 8q23. 3-q24. 1, and 2p11. 1-q12. 2.


Input: GWLS showed that the disease-associated region in our Thai family was linked to a newly identified locus on chromosome 3q26. 32-3q28.


Input: This locus represents the fourth chromosomal region for BAFME.


Input: Sonoluminescence quenching and cavitation bubble temperature measurements in an ionic liquid.


Input: A comparison between the temperatures within imploding acoustic cavitation bubbles and the extent of sonoluminescence (SL) quenching by C (1)-C (5) aliphatic alcohols in 1-ethyl-3-methylimidazolium ethylsulfate ([EMIM] [EtSO (4)], a well known imidazolium based room temperature ionic liquid (RTIL)), has been made at an ultrasound frequency of 213 kHz.

aliphatic alcohols

1-ethyl-3-methylimidazolium ethylsulfate

[EMIM] [EtSO (4)]

imidazolium


Input: The temperatures obtained ranged from 3500 +/- 200K, in neat [EMIM] [EtSO (4)], to about 3200 +/- 200K in RTIL-alcohol containing solutions.

[EMIM] [EtSO (4)]

alcohol


Input: It was also found that the SL intensity decreased with increasing concentration (up to 1M) of the alcohols to a greater extent compared with the relative changes to the bubble temperatures.

alcohols


Input: Both the extent of the reduction in the bubble temperatures and the SL quenching were much smaller than those obtained in comparable aqueous solutions containing aliphatic alcohols.

aliphatic alcohols


Input: Possible reasons for the differences in the observed trends between water/alcohol and [EMIM] [EtSO (4)]/alcohol systems under sonication at 213 kHz are discussed.

alcohol

[EMIM] [EtSO (4)]

alcohol


Input: GABAergic activity in autism spectrum disorders: an investigation of cortical inhibition via transcranial magnetic stimulation.


Input: Mounting evidence suggests a possible role for gamma-aminobutyric acid (GABA) in the neuropathophysiology of autism spectrum disorders (ASD), but the extent of this impairment is unclear.

gamma-aminobutyric acid

GABA


Input: A non-invasive, in vivo measure of GABA involves transcranial magnetic stimulation (TMS) of the primary motor cortex to probe cortical inhibition.

GABA


Input: Individuals diagnosed with ASD (high-functioning autism or Asperger' s disorder) (n = 36 [28 male]; mean age: 26. 00 years) and a group of healthy individuals (n = 34 [23 male]; mean age: 26. 21 years) (matched for age, gender, and cognitive function) were administered motor cortical TMS paradigms putatively measuring activity at GABAA and GABAB receptors (i. e., short and long interval paired pulse TMS, cortical silent period).


Input: All cortical inhibition paradigms yielded no difference between ASD and control groups.


Input: There was, however, evidence for short interval cortical inhibition (SICI) deficits among those ASD participants who had experienced early language delay, suggesting that GABA may be implicated in an ASD subtype.

GABA


Input: The current findings do not support a broad role for GABA in the neuropathophysiology of ASD, but provide further indication that GABAA could be involved in ASD where there is a delay in language acquisition.

GABA


Input: This article is part of the Special Issue entitled' Neurodevelopmental Disorders'.


Input: Pharmacological treatment of tic disorders and Tourette Syndrome.


Input: The present review gives an overview of current pharmacological treatment options of tic disorders and Tourette Syndrome (TS).


Input: After a short summary on phenomenology, clinical course and comorbid conditions we review indications for pharmacological treatment in detail.


Input: Unfortunately, standardized and large enough drug trials in TS patients fulfilling evidence based medicine standards are still scarce.


Input: Treatment decisions are often guided by individual needs and personal experience of treating clinicians.


Input: The present recommendations for pharmacological tic treatment are therefore based on both scientific evidence and expert opinion.


Input: As first-line treatment of tics risperidone (best evidence level for atypical antipsychotics) or tiapride (largest clinical experience in Europe and low rate of adverse reactions) are recommended.

risperidone

tiapride


Input: Aripiprazole (still limited but promising data with low risk for adverse reactions) and pimozide (best evidence of the typical antipsychotics) are agents of second choice.

Aripiprazole

pimozide


Input: In TS patients with comorbid attention deficit hyperactivity disorder (ADHD) atomoxetine, stimulants or clonidine should be considered, or, if tics are severe, a combination of stimulants and risperidone.

atomoxetine

clonidine

risperidone


Input: When mild to moderate tics are associated with obsessive-compulsive symptoms, depression or anxiety sulpiride monotherapy can be helpful.

sulpiride


Input: In more severe cases the combination of risperidone and a selective serotonin reuptake inhibitor should be given.

risperidone

serotonin


Input: In summary, further studies, particularly randomized, double-blind, placebo-controlled trials including larger and/or more homogenous patient groups over longer periods are urgently needed to enhance the scientific basis for drug treatment in tic disorders.


Input: This article is part of the Special Issue entitled' Neurodevelopmental Disorders'.


Input: Cognitive enhancement as a treatment for drug addictions.


Input: Drug addiction continues to be an important public health problem, with an estimated 22. 6 million current illicit drug users in the United States alone.


Input: For many addictions, including cocaine, methamphetamine, and marijuana addiction, there are no approved pharmacological treatments.

cocaine

methamphetamine


Input: Behavioral treatments are effective but effects vary widely across individuals.


Input: Treatments that are effective across multiple addictions are greatly needed, and accumulating evidence suggests that one such approach may be pharmacological or behavioral interventions that enhance executive inhibitory control in addicts.


Input: Current evidence indicates that most forms of chronic drug use may be associated with significant cognitive impairments, especially in attention, working memory, and response inhibition functions.


Input: In some studies, these impairments predict poor treatment retention and outcome.


Input: A number of cognitive enhancing agents, including galantamine, modafinil, atomoxetine, methylphenidate, and guanfacine, have shown promising findings in human studies.

galantamine

modafinil

atomoxetine

methylphenidate

guanfacine


Input: Specific behavioral interventions, including cognitive remediation, also show promise.


Input: However, whether improvement of selective cognitive functions reduces drug use behavior remains to be determined.


Input: Cognitive enhancement to improve treatment outcomes is a novel strategy worthy of future research, as are related questions such as whether these approaches may be broadly beneficial to most addicts or best reserved for substance users with specific demonstrated cognitive impairments.


Input: This article is part of a Special Issue entitled' Cognitive Enhancers'.


Input: Pinosylvin Induces Cell Survival, Migration and Anti-Adhesiveness of Endothelial Cells via Nitric Oxide Production.

Pinosylvin

Nitric Oxide


Input: Pinosylvin is a phenolic compound mainly found in the Pinus species.

Pinosylvin

phenolic


Input: To determine the vascular functions of pinosylvin, we first examined both proliferation and apoptosis of bovine aortic endothelial cells (BAECs) in the presence of pinosylvin.

pinosylvin

pinosylvin


Input: When BAECs were treated with pinosylvin, etoposide-or starvation-induced apoptosis was shown to be significantly reduced.

pinosylvin

etoposide


Input: The anti-apoptotic effect of pinosylvin was mediated by inhibition of caspase-3.

pinosylvin


Input: Moreover, pinosylvin was shown to activate endothelial nitric oxide synthetase (eNOS).

pinosylvin

nitric oxide


Input: At 1 pM, pinosylvin appeared to have a cell-proliferative effect in the endothelial cell.

pinosylvin


Input: The pinosylvin-induced cell proliferation was declined by treatment with L-NAME, an eNOS inhibitor.

pinosylvin

L-NAME


Input: Then, we found that pinosylvin had a stimulatory effect on cell migration and tube formation.

pinosylvin


Input: These stimulatory effects suggest that pinosylvin is likely to act as a pro-angiogenic factor.

pinosylvin


Input: Yet another effect of pinosylvin was inhibition of lipopolysaccharide-induced THP-1 cell adhesion to endothelial cells.

pinosylvin


Input: Altogether, we propose that pinosylvin may be utilized as a phytotherapic agent for the prevention of cardiovascular inflammatory diseases.

pinosylvin


Input: Copyright (c) 2012 John Wiley & Sons, Ltd.


Input: Dihydroxy-Isosteviol Methyl Ester from Pulsatilla nigricans Induces Apoptosis in HeLa Cells: Its Cytoxicity and Interaction with Calf Thymus DNA.

Dihydroxy-Isosteviol Methyl Ester


Input: Dihydroxy-isosteviol methyl ester (DIME), the principal biological compound isolated from the medicinal plant Pulsatilla nigricans (Fam: Ranunculaceae) having the molecular formula of C21 H34 O3 (molecular weight 334. 25), was administered to cervical cancer cells (HeLa) in vitro to evaluate its possible apoptotic (anti-cancer) potentials.

Dihydroxy-isosteviol methyl ester

DIME

C21 H34 O3


Input: We analyzed the expression of p53, Bax, Bcl2, Apaf and caspase 3 signal proteins and analyzed the early apoptotic events in HeLa cells induced by DIME using protocols like Annexin V-FITC and PI staining.

DIME


Input: DIME caused a significant decrease in cell viability, induced nuclear condensation and inter-nucleosomal DNA fragmentation.

DIME


Input: We further studied the interaction of DIME with calf thymus DNA as target through circular-dichroism spectra.

DIME


Input: Results showed that DIME interacted with DNA, bringing indiscernible changes in structure and conformation.

DIME


Input: Thus, DIME showed its capability to induce apoptosis in cancer cells, signifying its utility in drug design as a possible candidate for chemoprevention.

DIME


Input: Copyright (c) 2012 John Wiley & Sons, Ltd.


Input: Genome-wide patterns of standing genetic variation in a marine population of three-spined sticklebacks.


Input: Since the end of the Pleistocene, the three-spined stickleback (Gasterosteus aculeatus) has repeatedly colonized and adapted to various freshwater habitats probably originating from ancestral marine populations.


Input: Standing genetic variation and the underlying genomic architecture both have been speculated to contribute to recent adaptive radiations of sticklebacks.


Input: Here, we expand on the current genomic resources of this fish by providing extensive genome-wide variation data from six individuals from a marine (North Sea) stickleback population.


Input: Using next-generation sequencing and a combination of paired-end and mate-pair libraries, we detected a wide size range of genetic variation.


Input: Among the six individuals, we found more than 7% of the genome is polymorphic, consisting of 2599111 SNPs, 233464 indels and structural variation (SV) (> 50 bp) such as 1054 copy-number variable regions (deletions and duplications) and 48 inversions.


Input: Many of these polymorphisms affect gene and coding sequences.


Input: Based on SNP diversity, we determined outlier regions concordant with signatures expected under adaptive evolution.


Input: As some of these outliers overlap with pronounced regions of copy-number variation, we propose the consideration of such SV when analysing SNP data from re-sequencing approaches.


Input: We further discuss the value of this resource on genome-wide variation for further investigation upon the relative contribution of standing variation on the parallel evolution of sticklebacks and the importance of the genomic architecture in adaptive radiation.


Input: Structure-based optimization of oxadiazole-based GSK-3 inhibitors.

oxadiazole


Input: Inhibition of glycogen synthase kinase-3 (GSK-3) induces neuroprotective effects, e. g. decreases beta-amyloid production and reduces tau hyperphosphorylation, which are both associated with Alzheimer' s disease (AD).


Input: The two isoforms of GSK-3 in mammalians are GSK-3 alpha and beta, which share 98% homology in their catalytic domains.


Input: We investigated GSK-3 inhibitors based on 2 different scaffolds in order to elucidate the demands of the ATP-binding pocket [1].

ATP


Input: Particularly, the oxadiazole scaffold provided potent and selective GSK-3 inhibitors.

oxadiazole


Input: For example, the most potent inhibitor of the present series, the acetamide 26d, is characterized by an IC50 of 2 nM for GSK-3 alpha and 17 nM for GSK-3 beta.

acetamide


Input: In addition, the benzodioxane 8g showed up to 27-fold selectivity for GSK-3 alpha over GSK-3 beta, with an IC50 of 35 nM for GSK-3 alpha.

benzodioxane


Input: Two GSK-3 inhibitors were further profiled for efficacy and toxicity in the wild-type (wt) zebrafish embryo assay to evaluate simultaneously permeability and safety.


Input: Dual inhibitor of PDE7 and GSK-3-VP1. 15 acts as antipsychotic and cognitive enhancer in C57BL/6J mice.


Input: Cognitive deficit is a core of schizophrenia and it is not effectively treated by the available antipsychotic drugs, hence new and more effective therapy is needed.


Input: Schizophrenia is considered as a pathway disorder where Disrupted-In-Schizophrenia-1 (DISC1) is important molecular player that regulates multiple cellular cascades.


Input: We recently reported synergistic action between phosphodiesterase-4 (PDE4) and glycogen synthase kinase-3 (GSK-3) as DISC1 interacting proteins.


Input: In the current study we characterized behavioural effects of a newly developed compound, VP1. 15 that inhibits both PDE7 and GSK-3 with main focus on its antipsychotic and cognitive capacities.


Input: VP1. 15 reduced ambulation in C57BL/6J mice in a dose-dependent manner (7. 5 mg/kg and 3 mg/kg, respectively) and, hence, lower dose was chosen for the further analysis.


Input: VP1. 1. 5 facilitated pre-pulse inhibition (PPI), reversed amphetamine-but not MK-801-induced PPI deficit.

amphetamine


Input: The drug was able to ameliorate the disrupted latent inhibition (LI) induced by the increased number of conditioning trials and reversed amphetamine-induced LI deficit, supporting further its antipsychotic effects.

amphetamine


Input: The drug also significantly improved episodic memory in the spatial object recognition test, facilitated working memory in Y-maze and enhanced cued fear memory, but had no effect on executive function in the Puzzle box and contextual fear conditioning.


Input: Taken together, VP1. 15 elicited antipsychotic effects and also facilitated cognitive domains in mice, suggesting that multitarget drugs, affecting molecular substrates from the same pathway, perhaps could be antipsychotics of new-generation that open a new possibilities in drug discoveries.


Input: This article is part of a Special Issue entitled' Cognitive Enhancers'.


Input: The novel phosphodiesterase 10A inhibitor THPP-1 has antipsychotic-like effects in rat and improves cognition in rat and rhesus monkey.


Input: Phosphodiesterase 10A (PDE10A) is a novel target for the treatment of schizophrenia that may address multiple symptomatic domains associated with this disorder.


Input: PDE10A is highly expressed in the brain and functions to metabolically inactivate the important second messengers cAMP and cGMP.

cAMP

cGMP


Input: Here we describe effects of a potent and orally bioavailable PDE10A inhibitor [2-(6-chloropyridin-3-yl)-4-(2-methoxyethoxy)-7, 8-dihydropyrido [4, 3-d] pyrimidin-6 (5H)-yl] (imidazo [1, 5-a] pyridin-1-yl) methanone] (THPP-1) on striatal signaling pathways, in behavioral tests that predict antipsychotic potential, and assays that measure episodic-like memory in rat and executive function in rhesus monkey.

2-(6-chloropyridin-3-yl)-4-(2-methoxyethoxy)-7, 8-dihydropyrido [4, 3-d] pyrimidin-6 (5H)-yl] (imidazo [1, 5-a] pyridin-1-yl) methanone


Input: THPP-1 exhibits nanomolar potency on the PDE10A enzyme, demonstrates excellent pharmacokinetic properties in multiple preclinical animal species, and is selective for PDE10A over other PDE families of enzymes.


Input: THPP-1 significantly increased phosphorylation of proteins in the striatum involved in synaptic plasticity, including the a-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor (AMPA) GluR1 subunit, extracellular receptor kinase (ERK), and cAMP-response element binding protein (CREB).

a-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid

AMPA

cAMP


Input: THPP-1 produced dose-dependent effects in preclinical assays predictive of antipsychotic activity including attenuation of MK-801-induced psychomotor activation and condition avoidance responding in rats.


Input: At similar plasma exposures, THPP-1 significantly increased object recognition memory in rat and attenuated a ketamine-induced deficit in the object retrieval detour task in rhesus monkey.

ketamine


Input: These findings suggest that PDE10A inhibitors have the potential to impact multiple symptomatic domains of schizophrenia including positive symptoms and cognitive impairment.


Input: This article is part of a Special Issue entitled' Cognitive Enhancers'.


Input: Quetiapine ameliorates stress-induced cognitive inflexibility in rats.

Quetiapine


Input: The antidepressant action of quetiapine has been demonstrated in clinical and preclinical studies.

quetiapine


Input: Nevertheless, little is known about its effectiveness in the treatment of frontal-like cognitive disturbances that may be associated with stress-related disorder.


Input: Therefore, the aim of the present study was to investigate whether quetiapine would prevent and/or reverse stress-induced cognitive impairments in a rat model of prefrontal cortex (PFC)-dependent attentional set-shifting task (ASST).

quetiapine


Input: Because quetiapine augmentation to selective serotonin reuptake inhibitors (SSRIs) has recently been proven to be beneficial in neuropsychiatric disorders, a separate experiment was designed to assess the impact of combined administration of inactive doses of quetiapine and escitalopram on ASST performance in rats.

quetiapine

serotonin

quetiapine

escitalopram


Input: According to our previous studies, 1 h daily exposure to restraint stress for 7 days significantly and specifically impaired extra-dimensional (ED) set-shifting ability of rats.


Input: Quetiapine (2. 5 mg/kg, PO) given to rats prior to the restraint sessions completely prevented this stress-induced cognitive inflexibility.

Quetiapine


Input: Similar effect was demonstrated after pretreatment with the alpha 1-adrenoceptor antagonist, prazosin (1 mg/kg, IP).

prazosin


Input: Moreover, acute administration of quetiapine before the test reversed set-shifting deficits in stressed rats (0. 63, 1. 25 and 2. 5 mg/kg, PO) and improved ED performance of cognitively unimpaired control animals (1. 25 and 2. 5 mg/kg, PO).

quetiapine


Input: Finally, the combined administration of inactive doses of quetiapine (0. 63 and 0. 3 mg/kg in control and stressed rats, respectively) and escitalopram (0. 3 mg/kg, IP) facilitated set-shifting performance in either control or stressed rats.

quetiapine

escitalopram


Input: In conclusion, quetiapine administration either prevented or reversed stress-induced cognitive inflexibility in rats.

quetiapine


Input: In addition to promoting of set-shifting by itself, quetiapine also enhanced the procognitive efficacy of escitalopram.

quetiapine

escitalopram


Input: The potential contribution of the antagonism at alpha 1-adrenoceptors to the mechanisms underlying the protective action of quetiapine requires further evaluation.

quetiapine


Input: These findings may have therapeutic implications for the treatment of frontal-like disturbances, particularly cognitive inflexibility, in stress-related psychiatric disorders.


Input: This article is part of a Special Issue entitled' Cognitive Enhancers'.


Input: Modified-release prednisone decreases complaints and fatigue compared to standard prednisolone in patients with adrenal insufficiency.

prednisone

prednisolone


Input: Patients with adrenal insufficiency (AI) receive first glucocorticoid replacement dose after waking, resulting in a 3-5 h delay compared to physiological secretion.


Input: Impaired quality of life (QoL) and fatigue might be due to this delayed dose scheme.


Input: Modified-release glucocorticoid preparations might have therapeutic advantages.


Input: Exploratory pilot study including 14 patients with AI was conducted in a single university center.


Input: Patients on morning dose prednisolone (5 mg) were included, switched to modified-release prednisone (5 mg) at 10 PM for 3 months, and then switched back on standard prednisolone.

prednisolone

prednisone

prednisolone


Input: 3 standardized questionnaires (GBB-24, MFI, and AddiQoL) investigating complaints and fatigue were completed at baseline, after 3, and 6 months.


Input: Data regarding clinical and hormonal parameters were assessed.


Input: Modified-release prednisone showed significant improvement in one of 4 scales of GBB-24 and positive trends to better scores in 3 of 4 scales.

prednisone


Input: The global score of discomfort improved significantly.


Input: The MFI showed also significant improvement in 3 of 5 scales and positive trend to better scores in 2 scales.


Input: Significant changes to better scores were seen in 4 out of 30 items of the AddiQoL.


Input: Modified-release prednisone showed decreased complaints and fatigue compared to standard prednisolone indicating importance of glucocorticoid increase in early morning hours before waking.

prednisone

prednisolone


Input: Bioactivity of Diosmetin Glycosides Isolated from the Epicarp of Date Fruits, Phoenix dactylifera, on the Biochemical Profile of Alloxan Diabetic Male Rats.

Diosmetin Glycosides

Alloxan


Input: The new natural flavonoid compounds-diosmetin 7-O-beta-L-arabinofuranosyl (1 --> 2) beta-D-apiofuranoside (1) and diosmetin 7-O-beta-D-apiofuranoside (2)-were isolated from the acetone extract of date fruits epicarp belonging to family Arecaceae (Palmae).

flavonoid

diosmetin 7-O-beta-L-arabinofuranosyl (1 --> 2) beta-D-apiofuranoside

diosmetin 7-O-beta-D-apiofuranoside

acetone


Input: Elucidation of their chemical structures was determined by different spectroscopic methods in addition to the chemical and physical methods of analysis.


Input: These compounds were assessed for their biological activity on alloxan diabetic rats.

alloxan


Input: A dose of 1. 5 ml of (1) and (2) suspensions/100 gm b.


Input: wt were orally administrated to alloxan diabetic rats for 30 days.

alloxan


Input: The treatment of diabetic rats with these compounds resulted in marked improvement of the different biochemical results, i. e. the serum glucose level (highly significant, from 330 + 5. 5 mg/dL to 140 + 1. 2 mg/dL) treated with (1); liver functions markedly developed both by AST and ALT levels, (reduced significantly from 68. 3 + 4. 8 mu/L to 54 + 5. 5 mu/L and from 61. 0 + 3. 6 mu/L to 40. 1 + 3. 6 mu/L, respectively) treated with (2), accompanying with mild decrease in both cholesterol and triglycerides levels with (1) or (2).

glucose

cholesterol

triglycerides


Input: Decrease of TBARS level was observed in whole blood when treated with (1) or (2), while levels of glutathione peroxidase and superoxide dismutase were increased in liver.

glutathione

superoxide


Input: Serum testosterone level was highly significantly increased (from 705. 1 + 3. 6 mg/100 ml to 720 + 4. 7 mg/100 ml), total acid phosphatase and prostate acid phosphatase activities were highly significantly decreased (from 16. 9 + 0. 28 mu/L to 10. 7 + 1. 2 mu/L and from 9. 7 + 0. 7 mu/L to 6. 5 + 1 mu/L, respectively) for compound (1).

testosterone


Input: Copyright (c) 2012 John Wiley & Sons, Ltd.


Input: Haplotype analysis of the 185delAG BRCA1 mutation in ethnically diverse populations.


Input: The 185delAG * BRCA1 mutation is encountered primarily in Jewish Ashkenazi and Iraqi individuals, and sporadically in non-Jews.


Input: Previous studies estimated that this is a founder mutation in Jewish mutation carriers that arose before the dispersion of Jews in the Diaspora ~ 2500 years ago.


Input: The aim of this study was to assess the haplotype in ethnically diverse 185delAG * BRCA1 mutation carriers, and to estimate the age at which the mutation arose.


Input: Ethnically diverse Jewish and non-Jewish 185delAG * BRCA1 mutation carriers and their relatives were genotyped using 15 microsatellite markers and three SNPs spanning 12. 5 MB, encompassing the BRCA1 gene locus.


Input: Estimation of mutation age was based on a subset of 11 markers spanning a region of ~ 5 MB, using a previously developed algorithm applying the maximum likelihood method.


Input: Overall, 188 participants (154 carriers and 34 noncarriers) from 115 families were included: Ashkenazi, Iraq, Kuchin-Indians, Syria, Turkey, Iran, Tunisia, Bulgaria, non-Jewish English, non-Jewish Malaysian, and Hispanics.


Input: Haplotype analysis indicated that the 185delAG mutation arose 750-1500 years ago.


Input: In Ashkenazim, it is a founder mutation that arose 61 generations ago, and with a small group of founder mutations was introduced into the Hispanic population (conversos) ~ 650 years ago, and into the Iraqi-Jewish community ~ 450 years ago.


Input: The 185delAG mutation in the non-Jewish populations in Malaysia and the UK arose at least twice independently.


Input: We conclude that the 185delAG * BRCA1 mutation resides on a common haplotype among Ashkenazi Jews, and arose about 61 generations ago and arose independently at least twice in non-Jews.


Input: Role of AMPK in pancreatic beta cell function.


Input: Pharmacological activation of AMP activated kinase (AMPK) by metformin has proven to be a beneficial therapeutic approach for the treatment of type II diabetes.

metformin


Input: Despite improved glucose regulation achieved by administration of small molecule activators of AMPK, the potential negative impact of enhanced AMPK activity on insulin secretion by the pancreatic beta cell is an important consideration.

glucose


Input: In this review, we discuss our current understanding of the role of AMPK in central functions of the pancreatic beta cell, including glucose-stimulated insulin secretion (GSIS), proliferation, and survival.

glucose


Input: In addition we discuss the controversy surrounding the role of AMPK in insulin secretion, underscoring the merits and caveats of methods used to date.


Input: Enhancement of cognitive function in models of brain disease through environmental enrichment and physical activity.


Input: This review will provide an overview of the non-drug based approaches that have been demonstrated to enhance cognitive function of the compromised brain, primarily focussed on the two most widely adopted paradigms of environmental enrichment and enhanced physical exercise.


Input: Environmental enrichment involves the generation of novelty and complexity in animal housing conditions which facilitates enhanced sensory and cognitive stimulation as well as physical activity.


Input: In a wide variety of animal models of brain disorders, environmental enrichment and exercise have been found to have beneficial effects, including cognitive enhancement, delayed disease onset, enhanced cellular plasticity and associated molecular processes.


Input: Potential cellular and molecular mechanisms will also be discussed, which have relevance for the future development of' enviromimetics', drugs which could mimic or enhance the beneficial effects of environmental stimulation.


Input: This article is part of a Special Issue entitled' Cognitive Enhancers'.


Input: Human neuronal coenzyme Q10 deficiency results in global loss of mitochondrial respiratory chain activity, increased mitochondrial oxidative stress and reversal of ATP synthase activity: implications for pathogenesis and treatment.

coenzyme Q10

ATP


Input: Disorders of coenzyme Q (10) (CoQ (10)) biosynthesis represent the most treatable subgroup of mitochondrial diseases.

coenzyme Q (10)

CoQ (10)


Input: Neurological involvement is frequently observed in CoQ (10) deficiency, typically presenting as cerebellar ataxia and/or seizures.

CoQ (10)


Input: The aetiology of the neurological presentation of CoQ (10) deficiency has yet to be fully elucidated and therefore in order to investigate these phenomena we have established a neuronal cell model of CoQ (10) deficiency by treatment of neuronal SH-SY5Y cell line with para-aminobenzoic acid (PABA).

CoQ (10)

CoQ (10)

para-aminobenzoic acid

PABA


Input: PABA is a competitive inhibitor of the CoQ (10) biosynthetic pathway enzyme, COQ2.

PABA

CoQ (10)


Input: PABA treatment (1 mM) resulted in a 54% decrease (46% residual CoQ (10)) decrease in neuronal CoQ (10) status (p < 0. 01).

PABA

CoQ (10)

CoQ (10)