Input: The marine polyketide myriaporone 3/4 stalls translation by targeting the elongation phase.

myriaporone 3/4


Input: Myriaporone 3/4, a cytotoxic polyketide, has been reported as an inhibitor of eukaryotic protein synthesis.

Myriaporone 3/4


Input: However, the mechanism by which it inhibits translation was unknown.


Input: Here we show that myriaporone 3/4 stalls protein synthesis in the elongation phase by inducing phosphorylation of eukaryotic elongation factor 2.

myriaporone 3/4


Input: The phosphorylation results from direct binding of myriaporone 3/4 to eukaryotic elongation factor 2 kinase.

myriaporone 3/4


Input: Our study also shows that myriaporone 3/4 in the nanomolar range inhibits in vitro tube formation by endothelial cells without being cytotoxic.

myriaporone 3/4


Input: In general, myriaporone 3/4 was at least 300 times less toxic to primary cells than to tumor cells.

myriaporone 3/4


Input: A Myc-microRNA network promotes exit from quiescence by suppressing the interferon response and cell-cycle arrest genes.


Input: The transition of mammalian cells from quiescence to proliferation is accompanied by the differential expression of several microRNAs (miRNAs) and transcription factors.


Input: However, the interplay between transcription factors and miRNAs in modulating gene regulatory networks involved in human cell proliferation is largely unknown.


Input: Here we show that the miRNA miR-22 promotes proliferation in primary human cells, and through a combination of Argonaute-2 immunoprecipitation and reporter assays, we identified multiple novel targets of miR-22, including several cell-cycle arrest genes that mediate the effects of the tumor-suppressor p53.


Input: In addition, we found that miR-22 suppresses interferon gene expression by directly targeting high mobility group box-1 and interferon regulatory factor (IRF)-5, preventing activation of IRF3 and NF-kappa B, which are activators of interferon genes.


Input: The expression of interferon genes is elevated in quiescent cells and their expression is inhibitory for cell proliferation.


Input: In addition, we find that miR-22 is activated by the transcription factor Myc when quiescent cells enter proliferation and that miR-22 inhibits the Myc transcriptional repressor MXD4, mediating a feed-forward loop to elevate Myc expression levels.


Input: Our results implicate miR-22 in downregulating the anti-proliferative p53 and interferon pathways and reveal a new transcription factor-miRNA network that regulates the transition of primary human cells from quiescence to proliferation.


Input: Space exploration by the promoter of a long human gene during one transcription cycle.


Input: An RNA polymerase has been thought to transcribe by seeking out a promoter, initiating and then tracking down the template.


Input: We add tumor necrosis factor alpha to primary human cells, switch on transcription of a 221-kb gene and monitor promoter position during the ensuing transcription cycle (using RNA fluorescence in situ hybridization coupled to super-resolution localization, chromosome conformation capture and Monte Carlo simulations).


Input: Results are consistent with a polymerase immobilized in a' factory' capturing a promoter and reeling in the template, as the transcript and promoter are extruded.


Input: Initially, the extruded promoter is tethered close to the factory and so likely to re-initiate; later, the tether becomes long enough to allow re-initiation in another factory.


Input: We suggest close tethering underlies enhancer function and transcriptional' bursting'.


Input: Anomalous high mobility in LaAlO3/SrTiO3 nanowires.


Input: Nanoscale control of the metal-insulator transition at the interface between LaAlO (3) and SrTiO (3) provides a pathway for reconfigurable, oxide-based nanoelectronics.

LaAlO (3)

SrTiO (3)


Input: Four-terminal transport measurements of LaAlO (3)/SrTiO (3) nanowires at room temperature (T = 300 K) reveal an equivalent 2D Hall mobility greatly surpassing that of bulk SrTiO (3) and approaching that of n-type Si nanowires of comparable dimensions.

LaAlO (3)

SrTiO (3)

SrTiO (3)

Si


Input: This large enhancement of mobility is relevant for room-temperature device applications.


Input: Enhanced redifferentiation of chondrocytes on microperiodic silk/gelatin scaffolds: toward tailor-made tissue engineering.


Input: Direct-write assembly allows rapid fabrication of complex three-dimensional (3D) architectures, such as scaffolds simulating anatomical shapes, avoiding the need for expensive lithographic masks.


Input: However, proper selection of polymeric ink composition and tailor-made viscoelastic properties are critically important for smooth deposition of ink and shape retention.


Input: Deposition of only silk solution leads to frequent clogging due to shear-induced beta-sheet crystallization, whereas optimized viscoelastic property of silk-gelatin blends facilitate the flow of these blends through microcapillary nozzles of varying diameter.


Input: This study demonstrates that induction of controlled changes in scaffold surface chemistry, by optimizing silk-gelatin ratio, can govern cell proliferation and maintenance of chondrocyte morphology.


Input: Microperiodic silk-gelatin scaffolds can influence postexpansion redifferentiation of goat chondrocytes by enhancing Sox-9 gene expression, aggregation, and driving cartilage matrix production, as evidenced by upregulation of collagen type II and aggrecan expression.


Input: The strategy for optimizing redifferentiation of chondrocytes can offer valuable consideration in scaffold-based cartilage repair strategies.


Input: Anomalous high ionic conductivity of nanoporous beta-Li3PS4.


Input: Lithium-ion-conducting solid electrolytes hold promise for enabling high-energy battery chemistries and circumventing safety issues of conventional lithium batteries.

Lithium

lithium


Input: Achieving the combination of high ionic conductivity and a broad electrochemical window in solid electrolytes is a grand challenge for the synthesis of battery materials.


Input: Herein we show an enhancement of the room-temperature lithium-ion conductivity by 3 orders of magnitude through the creation of nanostructured Li (3) PS (4).

lithium

Li (3) PS (4)


Input: This material has a wide electrochemical window (5 V) and superior chemical stability against lithium metal.

lithium


Input: The nanoporous structure of Li (3) PS (4) reconciles two vital effects that enhance the ionic conductivity: (1) the reduction of the dimensions to a nanometer-sized framework stabilizes the high-conduction beta phase that occurs at elevated temperatures, and (2) the high surface-to-bulk ratio of nanoporous beta-Li (3) PS (4) promotes surface conduction.

Li (3) PS (4)

Li (3) PS (4)


Input: Manipulating the ionic conductivity of solid electrolytes has far-reaching implications for materials design and synthesis in a broad range of applications, including batteries, fuel cells, sensors, photovoltaic systems, and so forth.


Input: Discovery and evaluation of novel inhibitors of mycobacterium protein tyrosine phosphatase B from the 6-Hydroxy-benzofuran-5-carboxylic acid scaffold.

tyrosine

6-Hydroxy-benzofuran-5-carboxylic acid


Input: Mycobacterium tuberculosis (Mtb) protein tyrosine phosphatase B (mPTPB) is a virulence factor secreted by the pathogen and mediates mycobacterial survival in macrophages by targeting host cell immune responses.


Input: Consequently, mPTPB represents an exciting new target to combat tuberculosis (TB) infection.


Input: We describe a medicinal chemistry oriented approach that transforms a benzofuran salicylic acid scaffold into a highly potent (IC (50) = 38 nM) and selective mPTPB inhibitor (> 50 fold against a large panel of PTPs).

benzofuran salicylic acid


Input: Importantly, the inhibitor is capable of reversing the altered host immune responses induced by the bacterial phosphatase and restoring the macrophage' s full capacity to secrete IL-6 and undergo apoptosis in response to interferon-gamma stimulation, validating the concept that chemical inhibition of mPTPB may be therapeutically useful for novel TB treatment.


Input: The study further demonstrates that bicyclic salicylic acid pharmacophores can be used to deliver PTP inhibitors with high potency, selectivity, and cellular efficacy.

salicylic acid


Input: Meroterpenoid pigments from the basidiomycete Albatrellus ovinus.

Meroterpenoid


Input: Eight grifolin derivatives, involving three new monomers, albatrelins A-C (1-3), three novel dimers (meroterpenoid pigments), albatrelins D-F (4-6), and two known ones, 6a, 7, 8, 9, 10, 10a-hexahydro-3, 6, 9-trimethyl-6-(4-methyl-3-penten-1-yl)-1, 9-epoxy-6H-dibenzo [b, d] pyran (7) and confluentin (8), were isolated from Albatrellus ovinus.

grifolin

albatrelins A-C

meroterpenoid

albatrelins D-F

6a, 7, 8, 9, 10, 10a-hexahydro-3, 6, 9-trimethyl-6-(4-methyl-3-penten-1-yl)-1, 9-epoxy-6H-dibenzo [b, d] pyran

confluentin


Input: Their structures were established by extensive spectroscopic analysis.


Input: The absolute configurations of compounds 2-4 were determined as 9R by comparing their optical rotations with data reported in the literature.


Input: Albatrelin F (6) was isolated as a pair of C-2' tautomers with a ratio of 1. 3: 1.

Albatrelin F


Input: Confluentin (8) showed weak cytotoxicity against four human tumor cell lines, HL-60, SMMC-7712, A-549, and MCF-7, in vitro.

Confluentin


Input: Neolignans from leaves of Miliusa mollis.

Neolignans


Input: From the leaves of Miliusa mollis Pierre (Annonaceae), five new dihydrobenzofuran neolignans, namely miliumollin, 7-methoxymiliumollin, 3'-methoxymiliumollin, 4'-O-methylmiliumollin and miliumollinone, and a new 8-O-4' neolignan named miliusamollin were isolated, and their structures were elucidated through analysis of spectroscopic data.

dihydrobenzofuran neolignans

miliumollin

miliumollinone

8-O-4' neolignan

miliusamollin


Input: Miliumollin, 3'-methoxymiliumollin, miliumollinone and decurrenal exhibited weak cytotoxicity against KB, MCF7 and NCI-H187 cells.

Miliumollin

miliumollinone


Input: Miliumollinone possessed weak inhibitory effects against herpes simplex virus types 1 and 2.

Miliumollinone


Input: None of the isolates displayed inhibitory activity against avian influenza H5N1 neuraminidase.


Input: Prophylactic effect of resveratrol against ethinylestradiol-induced liver cholestasis.

resveratrol

ethinylestradiol


Input: Estrogens, and particularly glucuronides such as ethinylestradiol (EE), have been shown to cause cholestasis in animal studies, by reducing bile acid uptake by hepatocytes.

Estrogens

ethinylestradiol

bile acid


Input: The aim of the present article was to investigate anticholestatic activity of resveratrol (RES) against liver cholestasis induced by EE in adult female rats.

resveratrol

RES


Input: The daily oral administration of the RES at a concentration of 25 mg/kg body weight for 15 days to rats treated with EE (100 mu g/kg body weight for 5 days) resulted in a significant protection against EE-induced decrease in both serum cholesterol and bile acid levels as well as against an increase of serum bilirubin concentration.

RES

bile acid

bilirubin


Input: The treatment also resulted in a significant increase in hepatic superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase activities as well as hepatic protein-bound and nonprotein sulfhydryl groups.

superoxide

glutathione

glutathione

sulfhydryl


Input: RES inhibited serum alkaline phosphatase, alanine aminotransferase, pi-glutathione-S-transferase, gamma-glutamyl transpeptidase, and alpha-glutathione-S-transferase activities, as well as reduced serum tumor necrosis factor-alpha, nitric oxide, and hepatic malondialdehyde as compared to EE-treated rats.

RES

alanine

glutathione

S

glutamyl

glutathione

nitric oxide

malondialdehyde


Input: The results clearly suggest that RES has a powerful prophylactic action in cholestasis induced by EE.

RES


Input: Taken together, RES has potential as a preventive and therapeutic agent for cholestasis and deserves clinical trial in the near future as an adjuvant therapy in women treated with estrogen.

RES

estrogen


Input: The first total synthesis and biological evaluation of marine natural products ma' edamines A and B.

ma' edamines A and B


Input: We have developed the first total syntheses of marine natural products ma' edamines A (18) and B (20).

ma' edamines A (18) and B


Input: Structurally, they contain a pyrazine-2-(1H)-one core and were screened for antiproliferative activity on several cancer cell lines.


Input: Out of the six cell lines tested, ma' edamines A and B showed significant cytotoxicity against human colon cancer line COLO 205 (IC (50) 7. 9 and 10. 3 mu M, respectively), breast cancer cell line MCF-7 (IC (50): 6. 9 and 10. 5 mu M, respectively) and human lung adenocarcinoma cell line A549 (IC (50): 12. 2 and 15. 4 mu M, respectively).

ma' edamines A and B


Input: The apoptotic effect of ma' edamines was confirmed by comet assay.

ma' edamines


Input: Hence ma' edamines are likely to be useful as leads for development of a new class of anti-cancer agents.

ma' edamines


Input: Chemical synthesis, docking studies and biological effects of a pan peroxisome proliferator-activated receptor agonist and cyclooxygenase inhibitor.


Input: The compound (5Z)-5-[(5-bromo-1H-indol-3-yl) methylene]-3-(4-chlorobenzyl)-thiazolidine-2, 4-dione (LYSO-7) was synthesised in order to obtain a new type of anti-inflammatory drug, designed with hybrid features to inhibit cyclooxygenase (COX) and also to activate peroxisome proliferator-activated receptor (PPAR).

(5Z)-5-[(5-bromo-1H-indol-3-yl) methylene]-3-(4-chlorobenzyl)-thiazolidine-2, 4-dione


Input: Results obtained from docking (in silico) studies corroborated with experimental data, showing the potential affinity between the studied ligand and targets.


Input: The specificity of LYSO-7 for COX-enzymes was detected by the inhibition of COX-1 and COX-2 activities by 30% and 20%, respectively.


Input: In transactivation reporter gene assays LYSO-07 showed a pan partial agonist effect on the three PPAR subtypes (PPAR gamma, PPAR alpha and PPAR beta/delta).


Input: The agonist action on PPAR gamma was also observed by a pharmacological approach, as the reduction in the Escherichia coli lipopolysaccharide (LPS)-induced interleukin 1 beta (IL-1 beta) secretion and nitric oxide (NO) production by mouse neutrophils was blocked by GW9962, a specific PPAR gamma antagonist.

nitric oxide

NO


Input: Additionally, the in vivo effect was measured by reduced carrageenan-induced neutrophil influx into the subcutaneous tissue of mice.


Input: Taken together, these data show that LYSO-7 displays a potent in vivo anti-inflammatory effect during the innate acute response, which is dependent on its associated COX inhibitory activities and PPAR activation.


Input: A new spatane diterpenoid from the cultured soft coral Sinularia leptoclados.

spatane diterpenoid


Input: A new spatane diterpenoid, leptoclalin A (1), along with two previously reported known norcembranoid diterpenes (2 and 3), were isolated from a cultured soft coral Sinularia leptoclados.

spatane diterpenoid

leptoclalin A

norcembranoid diterpenes


Input: The structures were determined by extensive spectroscopic analyses and by comparison with the spectral data of related known compounds.


Input: Metabolite 1 is rarely found in spatane skeletons reported from soft corals.


Input: In addition, compound 1 exhibited weak cytotoxicity towards human tumor cell lines T-47 D and K-562.


Input: Antibacterial polyketides from the marine alga-derived endophitic Streptomyces sundarbansensis: a study on hydroxypyrone tautomerism.

hydroxypyrone


Input: Polyketide 13 [= 2-hydroxy-5-((6-hydroxy-4-oxo-4H-pyran-2-yl) methyl)-2-propylchroman-4-one] and three related known compounds 7, 9 and 11 were obtained and structurally characterized from Streptomyces sundarbansensis strain, an endophytic actinomycete isolated from the Algerian marine brown algae Fucus sp.

2-hydroxy-5-((6-hydroxy-4-oxo-4H-pyran-2-yl) methyl)-2-propylchroman-4-one


Input: Compound 13 was obtained as the major metabolite from optimized culture conditions, by using Agar state fermentation.


Input: Due to tautomeric equilibrium, 13 in CD (3) OD solution was able to incorporate five deuterium atoms, as deduced by NMR and ESI-MS/MS analysis.

CD (3) OD

deuterium


Input: The 2-hydroxy-gamma-pyrone form was established for these metabolites based on the comparison of their experimental IR spectra with the DFT calculated ones, for both the corresponding 4-hydroxy-alpha-pyrone and 2-hydroxy-gamma-pyrone forms.


Input: During antibacterial evaluation, compound 13 stood out as the most active of the series, showing a selective activity against the gram positive pathogenic methicillin-resistant S. aureus (MRSA, MIC = 6 mu Mu), with a bacteriostatic effect.

methicillin


Input: Verrucarin A enhances TRAIL-induced apoptosis via NF-kappa B-mediated Fas overexpression.

Verrucarin A


Input: We investigated whether verrucarin A (VA) sensitizes HepG2 hepatoma cells to tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis.

verrucarin A


Input: We found that VA alone induces little apoptosis, but when combined with TRAIL (VA/TRAIL), it triggered significant apoptosis, causing little or no toxicity in normal mouse splenocytes.


Input: VA/TRAIL-induced cell death is involved in the loss of mitochondrial transmembrane potential and the consequent activation of caspases.


Input: Because nuclear factor (NF)-kappa B inhibition has been known as a critical target in TRAIL-mediated apoptosis, we also investigated the role of NF-kappa B in VA/TRAIL treatment.


Input: We found that VA upregulated the DNA binding activity of NF-kappa B, but that the antioxidants glutathione and N-acetyl-l-cysteine, as well as NF-kappa B inhibitor MG132, and mutant-I kappa B (m-I kappa B) transfection, significantly downregulated VA/TRAIL-induced cell death by inhibiting caspase-3 and NF-kappa B activities.

glutathione

N-acetyl-l-cysteine


Input: Transfection of mutant-eIF2 alpha also resulted in a decrease in VA/TRAIL-induced cell death by inhibiting of caspase-3, but not NF-kappa B activity.


Input: Although VA/TRAIL treatment led to an increase of DR5 expression, transfection of m-I kappa B had no influence on the DR5 expressional level.


Input: Finally, we showed that NF-kappa B-mediated Fas expression is critical to VA/TRAIL-induced apoptosis.


Input: Taken together, these results indicate that VA/TRAIL sensitizes HepG2 cells to apoptosis via NF-kappa B-mediated overexpression of Fas.


Input: Polyethylene glycol-g-polyvinyl alcohol grafted copolymer: Reproductive toxicity study in Wistar rats.

Polyethylene glycol

polyvinyl alcohol


Input: Polyethylene glycol-g-polyvinyl alcohol (PEG-PVA) grafted copolymer was administered by gavage to groups of 25 male and 25 female young Wistar rats at doses of 0 (vehicle control), 100, 300, or 1000mg/kg bw/day for one generation (F0).

Polyethylene glycol

polyvinyl alcohol

PEG-PVA


Input: The study followed the treated F0 generation through mating, gestation, lactation, and weaning of the F1 generation.


Input: F1 animals were mated and followed to gestation day (GD) 15-17 at which time F2 implants were evaluated.


Input: There were no indications from the various clinical and gross pathological examinations that the oral administration of PEG-PVA grafted copolymer to the F0-parental rats produced any signs of general, reproductive, or developmental toxicity in the F0 or F1 animals or F2 implants.

PEG-PVA


Input: Based on the lack of any dose-related or biologically relevant effects on fertility, reproduction, development, and overall health of rats gavaged with PEG-PVA grafted copolymer and their progeny, the no-observed-adverse effect level (NOAEL) was determined to be the highest dose tested of 1000mg/kg bw/day.

PEG-PVA


Input: Protease-activated receptor (PAR) 1 and PAR4 differentially regulate factor V expression from human platelets.


Input: With the recent interest of protease-activated receptors (PAR) 1 and PAR4 as possible targets for the treatment of thrombotic disorders, we compared the efficacy of protease-activated receptor (PAR) 1 and PAR4 in the generation of procoagulant phenotypes on platelet membranes.


Input: PAR4-activating peptide (AP)-stimulated platelets promoted thrombin generation in plasma up to 5 minutes earlier than PAR1-AP-stimulated platelets.


Input: PAR4-AP-mediated factor V (FV) association with the platelet surface was 1. 6-fold greater than for PAR1-AP.


Input: Moreover, PAR4 stimulation resulted in a 3-fold greater release of microparticles, compared with PAR1 stimulation.


Input: More robust FV secretion and microparticle generation with PAR4-AP was attributable to stronger and more sustained phosphorylation of myosin light chain at serine 19 and threonine 18.

serine

threonine


Input: Inhibition of Rho-kinase reduced PAR4-AP-mediated FV secretion and microparticle generation to PAR1-AP-mediated levels.


Input: Thrombin generation assays measuring prothrombinase complex activity demonstrated 1. 5-fold higher peak thrombin levels on PAR4-AP-stimulated platelets, compared with PAR1-AP-stimulated platelets.


Input: Rho-kinase inhibition reduced PAR4-AP-mediated peak thrombin generation by 25% but had no significant effect on PAR1-AP-mediated thrombin generation.


Input: In conclusion, stimulation of PAR4 on platelets leads to faster and more robust thrombin generation, compared with PAR1 stimulation.


Input: The greater procoagulant potential is related to more efficient FV release from intracellular stores and microparticle production driven by stronger and more sustained myosin light chain phosphorylation.


Input: These data have implications about the role of PAR4 during hemostasis and are clinically relevant in light of recent efforts to develop PAR antagonists to treat thrombotic disorders.


Input: Natalizumab therapy for multiple sclerosis.


Input: The treatment of relapsing remitting multiple sclerosis has witnessed major progress since the first effective disease modifying treatment, beta-interferon, became available in 1993.


Input: One of the most remarkable new treatments has been natalizumab.


Input: This review describes the evolution of this humanized anti-alpha 4 beta 1 monoclonal antibody, from preclinical experimental research through proof-of-concept (phase 1/2) and pivotal (phase 3) clinical trials to the now extensive experience of its use in clinical practice.


Input: The future potential and challenges of natalizumab and oral therapies with a similar mechanism of action are also discussed.


Input: Ambulatory blood pressure monitoring: recent evidence and clinical pharmacy applications.


Input: Conventional office blood pressure readings are a well-established surrogate for the prediction of cardiovascular risk.


Input: It is assumed that these readings reflect an underlying average level of blood pressure exposure occurring in an individual over a period of time.


Input: But because blood pressure is not static, important additional prognostic information about the diurnal blood pressure profile, including within-day and between-day variability, is not easily ascertained from conventional measurements.


Input: Ambulatory blood pressure monitoring provides a more thorough depiction of the underlying blood pressure level and predicts cardiovascular risk more robustly than do conventional blood pressure measurements.


Input: Although the technology has been available for more than 30 years, there has been an expansion of the research base in the past decade supporting its role in the evaluation and management of patients with hypertension and as an important surrogate in research trials.


Input: This review summarizes recent evidence supporting the predictive ability of ambulatory blood pressure monitoring and briefly highlights opportunities for clinical pharmacists to adopt this important clinical and research tool.


Input: Improper Selection of a Pre-specified Primary Dose-Response Analysis Delays Regulatory Drug Approval.


Input: Dose-response analysis is one of the accepted efficacy endpoints to establish effectiveness.


Input: The purpose of this research was to inform selection of an appropriate pre-specified primary dose-response analysis to demonstrate drug efficacy in a registration trial.


Input: The power and the type I error rate of the placebo-corrected (i. e., simply adjusting the observed treatment value by subtracting the placebo mean) and the placebo-anchored (i. e., including the placebo data as dose 0 in the regression) slope analyses were assessed based on regulatory submission data for two antihypertensive drugs and simulated data from hypothetical clinical trials.


Input: In the simulated hypothetical trials, the impact of different dosing strategies (i. e., the fixed dose versus the weight-based per kilogram dose), sample size, and scenarios governing the drug exposure-response relationship (e. g., E max, ED 50, and SD) was also evaluated.


Input: For each scenario, a total 300 replications were simulated.


Input: The placebo-anchored slope analysis is always more powerful to demonstrate effectiveness in all plausible scenarios.


Input: The difference between the placebo-anchored and the placebo-corrected analyses was maximum when the studied doses were too high.


Input: However, the dose-response analysis is not sensitive to the dosing strategies.


Input: Furthermore, the type I error rate of these two methods was also found to be comparable.


Input: The design of dose-response studies should carefully consider these results to justify the inclusion of placebo and the analysis method.


Input: The pharmaceutical industry and the regulatory agencies are equally responsible for using the appropriate methods of primary analysis and providing justification in the protocol.


Input: Fueling open-source drug discovery: 177 small-molecule leads against tuberculosis.


Input: With the aim of fuelling open-source, translational, early-stage drug discovery activities, the results of the recently completed antimycobacterial phenotypic screening campaign against Mycobacterium bovis BCG with hit confirmation in M. tuberculosis H37Rv were made publicly accessible.


Input: A set of 177 potent non-cytotoxic H37Rv hits was identified and will be made available to maximize the potential impact of the compounds toward a chemical genetics/proteomics exercise, while at the same time providing a plethora of potential starting points for new synthetic lead-generation activities.


Input: Two additional drug-discovery-relevant datasets are included: a) a drug-like property analysis reflecting the latest lead-like guidelines and b) an early lead-generation package of the most promising hits within the clusters identified.


Input: Calorie-restricted weight loss reverses high-fat diet-induced ghrelin resistance, which contributes to rebound weight gain in a ghrelin-dependent manner.


Input: Twelve weeks of high-fat diet feeding causes ghrelin resistance in arcuate neuropeptide Y (NPY)/agouti-related protein (AgRP) neurons.


Input: In the current study, we investigated whether diet-induced weight loss could restore NPY/AgRP neuronal responsiveness to ghrelin and whether ghrelin mediates rebound weight gain after calorie-restricted (CR) weight loss.


Input: Diet-induced obese (DIO) mice were allocated to one of two dietary interventions until they reached the weight of age-matched lean controls.


Input: DIO mice received chow diet ad libitum or chow diet with 40% CR.


Input: Chow-fed and high-fat-fed mice served as controls.


Input: Both dietary interventions normalized body weight, glucose tolerance, and plasma insulin.

glucose


Input: We show that diet-induced weight loss with CR increases total plasma ghrelin, restores ghrelin sensitivity, and increases hypothalamic NPY and AgRP mRNA expression.


Input: We propose that long-term DIO creates a higher body weight set-point and that weight loss induced by CR, as seen in the high-fat CR group, provokes the brain to protect the new higher set-point.


Input: This adaptation to weight loss likely contributes to rebound weight gain by increasing peripheral ghrelin concentrations and restoring the function of ghrelin-responsive neuronal populations in the hypothalamic arcuate nucleus.


Input: Indeed, we also show that DIO ghrelin-knockout mice exhibit reduced body weight regain after CR weight loss compared with ghrelin wild-type mice, suggesting ghrelin mediates rebound weight gain after CR weight loss.


Input: Loss and gain of Drosophila TDP-43 impair synaptic efficacy and motor control leading to age-related neurodegeneration by loss-of-function phenotypes.


Input: Cytoplasmic accumulation and nuclear clearance of TDP-43 characterize familial and sporadic forms of amyotrophic lateral sclerosis and frontotemporal lobar degeneration, suggesting that either loss or gain of TDP-43 function, or both, cause disease formation.


Input: Here we have systematically compared loss-and gain-of-function of Drosophila TDP-43, TAR DNA Binding Protein Homolog (TBPH), in synaptic function and morphology, motor control, and age-related neuronal survival.


Input: Both loss and gain of TBPH severely affect development and result in premature lethality.


Input: TBPH dysfunction caused impaired synaptic transmission at the larval neuromuscular junction (NMJ) and in the adult.


Input: Tissue-specific knockdown together with electrophysiological recordings at the larval NMJ also revealed that alterations of TBPH function predominantly affect pre-synaptic efficacy, suggesting that impaired pre-synaptic transmission is one of the earliest events in TDP-43-related pathogenesis.


Input: Prolonged loss and gain of TBPH in adults resulted in synaptic defects and age-related, progressive degeneration of neurons involved in motor control.


Input: Toxic gain of TBPH did not downregulate or mislocalize its own expression, indicating that a dominant-negative effect leads to progressive neurodegeneration also seen with mutational inactivation of TBPH.


Input: Together these data suggest that dysfunction of Drosophila TDP-43 triggers a cascade of events leading to loss-of-function phenotypes whereby impaired synaptic transmission results in defective motor behavior and progressive deconstruction of neuronal connections, ultimately causing age-related neurodegeneration.


Input: Characterization of bundled and individual triple-walled carbon nanotubes by resonant Raman spectroscopy.

carbon


Input: The optical characterization of bundled and individual triple-walled carbon nanotubes was studied for the first time in detail by using resonant Raman spectroscopy.

carbon


Input: In our approach, the outer tube of a triple-walled carbon nanotube system protects the two inner tubes (or equivalently the inner double-walled carbon nanotube) from external environment interactions making them a partially isolated system.

carbon

carbon


Input: Following the spectral changes and line-widths of the radial breathing modes and G-band by performing laser energy dependent Raman spectroscopy, it is possible to extract important information as regards to the electronic and vibrational properties, tube diameters, wall-to-wall distances, radial breathing mode, and G-band resonance evolutions as well as high-curvature intertube interactions in isolated double-and triple-walled carbon nanotube systems.

carbon


Input: Time-resolved single molecule fluorescence spectroscopy of an alpha-chymotrypsin catalyzed reaction.


Input: Single molecule fluorescence spectroscopy offers great potential for studying enzyme kinetics.


Input: A number of fluorescence reporter systems allow for monitoring the sequence of individual reaction events with a confocal microscope.


Input: When using a time-correlated single photon counting (TCSPC) detection scheme, additional information about the fluorescence lifetimes of the fluorophores can be obtained.


Input: We have applied a TCSPC detection scheme for studying the kinetics of alpha-chymotrypsin hydrolyzing a double-substituted rhodamine 110-based fluorogenic substrate in a two-step reaction.


Input: On the basis of the lifetime information, it was possible to discriminate the intermediate and the final product.


Input: At the high substrate concentration used, only the formation of the intermediate was observed.


Input: No rebinding of the intermediate followed by rhodamine 110 formation occurred at these high concentrations.


Input: We have further found no alterations in the fluorescence lifetime of this intermediate that would indicate changes in the local environment of the fluorophore originating from strong interactions with the enzyme.


Input: Our results clearly show the power of using lifetime-resolved measurements for investigating enzymatic reactions at the single molecule level.


Input: Poorly differentiated thyroid carcinoma presenting with gross extrathyroidal extension: 1986-2009 Memorial Sloan-Kettering Cancer Center experience.


Input: To describe the outcome of patients with poorly differentiated thyroid cancer (PDTC) presenting with gross extrathyroidal extension (ETE).


Input: After IRB approval we performed retrospective review of consecutive series of thyroid cancer patients treated by primary surgical resection with or without adjuvant therapy at MSKCC from 1986-2009.


Input: Out of 91 PDTC patients, 27 (30%) had gross ETE (T4a) and they formed the basis of our study.


Input: Of 27 patients, 52% were female.


Input: The median age was 70 (range 27-87).


Input: Ten patients (37%) presented with distant metastases; four to the bone, three to lung and three had both bone and lung metastases.


Input: All patients had extended total thyroidectomy except two who had subtotal thyroidectomy.


Input: 20 patients (74%) had central compartment neck dissection and 11 also had lateral neck dissection.


Input: Four patients had pN0, 6 (30%) pN1a and 10 (50%) pN1b neck disease.


Input: 21 patients (77%) had adjuvant therapy: 15 (55%) RAI only, 3 (11%) postoperative external beam radiation (PORT) only and 3 (11%) had both RAI and PORT.

RAI

RAI


Input: Overall survival (OS), disease specific survival (DSS), local recurrence free survival (LRFS) and regional recurrence free survival (RRFS) were calculated by the Kaplan Meier method.


Input: Median follow-up time was 57 months (range 1-197 months).


Input: The 5 year OS and DSS were 47% and 49% respectively.


Input: This poor outcome was due to distant metastatic disease; 10 patients had distant metastases at presentation and a further 6 developed distant metastases during follow up.


Input: Locoregional control was good with 5 year LRFS and RRFS of 70% and 62% respectively.


Input: Overall, 8 patients (30%) had recurrences: 2 had distant alone, 2 regional, 2 regional and distant, 1 local and distant, and 1 had local, regional and distant recurrence.


Input: Aggressive surgery in patients with PDTC showing gross ETE resulted in satisfactory locoregional control.


Input: Due to the small proportion of patients who received PORT (22%), it is not possible to analyze its benefit on locoregional control.


Input: Of significance is the observation that the majority of patients (60%) who presented with or subsequently developed distant metastases eventually died of distant disease.


Input: New systemic therapies to target distant metastatic disease are required for improvements in outcome.


Input: Phase boundaries, structural characteristics, and NMR spectra of ionic liquid-in-oil microemulsions containing double chain surface active ionic liquid: a comparative study.


Input: A method developed for the first time, to create a huge number of ionic liquid (IL)-in-oil microemulsions has been discussed in our earlier publication (Rao, V. G.; Ghosh, S.; Ghatak, C.; Mandal, S.; Brahmachari, U.; Sarkar, N. J. Phys. Chem. B 2012, 116, 2850-2855).


Input: Here, we present facile methods to adjust the structural parameters of microemulsions using different ionic liquids (ILs) as additives (polar phase).


Input: We have characterized ILs/[C (4) mim] [AOT]/benzene ternary system by performing a phase behavior study, dynamic light scattering (DLS) measurements, and (1) H NMR measurements.

[C (4) mim] [AOT]

benzene

(1) H


Input: The IL loading capacity of microemulsions (area of single phase region) (i) increases with increase in alkyl chain length of cation of ILs and follows the trend [C (6) mim] [TF (2) N] > [C (4) mim] [TF (2) N] > [C (2) mim] [TF (2) N], (ii) increases with decrease in cation anion interaction strength of added ILs and follows the trend [C (4) mim] [TF (2) N] > [C (4) mim] [PF (6)] > [C (4) mim] [BF (4)].

[C (6) mim] [TF (2) N]

[C (4) mim] [TF (2) N]

[C (2) mim] [TF (2) N]

[C (4) mim] [TF (2) N]

[C (4) mim] [PF (6)]

[C (4) mim] [BF (4)]


Input: So depending on the IL used, the amount of IL within the core of microemulsions can be easily manipulated to directly affect the size of aggregates in microemulsions.


Input: The size increase with increasing R value (R value is defined as the molar ratio of RTILs to [C (4) mim] [AOT]) was found to be maximum in the case of [C (2) mim] [TF (2) N]/[C (4) mim] [AOT]/benzene microemulsions and follows the trend [C (2) mim] [TF (2) N] > [C (4) mim] [TF (2) N] > [C (6) mim] [TF (2) N].

[C (4) mim] [AOT]

[C (2) mim] [TF (2) N]

[C (4) mim] [AOT]

benzene

[C (2) mim] [TF (2) N]

[C (4) mim] [TF (2) N]

[C (6) mim] [TF (2) N]


Input: However, the size increase was almost the same with increase in R value in the case of ILs with different anions.


Input: The most promising fact about IL-in-oil microemulsions is their high thermal stability compared to that of aqueous microemulsions, so we investigated the effect of temperature on size of aggregates in microemulsions at R = 1. 0.


Input: It is evident from dynamic light scattering measurements that the aggregates in microemulsions remain monodisperse in nature with increasing temperature, and in all the cases, the size of aggregates in microemulsions decreases with increasing temperature.


Input: The effect of water addition on IL-in-oil (IL/O) microemulsions was also studied in detail.


Input: By far, this is the first report where the effect of water addition on microemulsions containing hydrophobic ILs is being reported and compared with microemulsions containing hydrophilic ILs.


Input: We observed that the added water has a prominent effect on the microstructure of the microemulsions.


Input: In all the cases, (1) H NMR spectra provide more detailed information about intra/intermolecular interactions thus affording a clear picture of locations of (i) the RTILs in RTILs/[C (4) mim] [AOT]/benzene microemulsions and (ii) the added water molecules in microemulsions.

(1) H

[C (4) mim] [AOT]

benzene


Input: Cucumber-like V2O5/poly (3, 4-ethylenedioxythiophene) & MnO2 nanowires with enhanced electrochemical cyclability.

poly (3, 4-ethylenedioxythiophene)


Input: Inspired by the cucumber-like structure, by combining the in situ chemical oxidative polymerization with facile soaking process, we designed the heterostructured nanomaterial with PEDOT as the shell and MnO (2) nanoparticles as the protuberance and synthesized the novel cucumber-like MnO (2) nanoparticles enriched vanadium pentoxide/poly (3, 4-ethylenedioxythiophene) (PEDOT) coaxial nanowires.

PEDOT

MnO (2)

MnO (2)

vanadium pentoxide

poly (3, 4-ethylenedioxythiophene)

PEDOT


Input: This heterostructured nanomaterial exhibits enhanced electrochemical cycling performance with the decreases of capacity fading during 200 cycles from 0. 557 to 0. 173% over V (2) O (5) nanowires at the current density of 100 mA/g.

V (2) O (5)


Input: This method is proven to be an effective technique for improving the electrochemical cycling performance and stability of nanowire electrodes especially at low rate for application in rechargeable lithium batteries.

lithium


Input: Damned if you do, damned if you don' t: the conundrum of adipose tissue vascularization.


Input: The plasticity of adipose tissue requires highly regulated changes in accompanying blood vessels.


Input: In obesity, adipose tissue angiogenesis plays a complex role to support tissue growth and promote metabolic disease.


Input: Emerging research (Sung et al., 2013) indicates that exploiting the mediators of adipose tissue angiogenesis may offer the possibility for therapeutic interventions.


Input: Vascular complications of diabetes: mechanisms of injury and protective factors.


Input: In patients with diabetes, atherosclerosis is the main reason for impaired life expectancy, and diabetic nephropathy and retinopathy are the largest contributors to end-stage renal disease and blindness, respectively.


Input: An improved therapeutic approach to combat diabetic vascular complications might include blocking mechanisms of injury as well as promoting protective or regenerating factors, for example by enhancing the action of insulin-regulated genes in endothelial cells, promoting gene programs leading to induction of antioxidant or anti-inflammatory factors, or improving the sensitivity to vascular cell survival factors.


Input: Such strategies could help prevent complications despite suboptimal metabolic control.


Input: Specific chlorination of isoquinolines by a fungal flavin-dependent halogenase.

isoquinolines

flavin


Input: Rdc2 is the first flavin-dependent halogenase identified from fungi.

flavin


Input: Based on the reported structure of the bacterial halogenase CmlS, we have built a homology model for Rdc2.


Input: The model suggests an open substrate binding site that is capable of binding the natural substrate, monocillin II, and possibly other molecules such as 4-hydroxyisoquinoline (1) and 6-hydroxyisoquinoline (2).

monocillin II


Input: In vitro and in vivo halogenation experiments confirmed that 1 and 2 can be halogenated at the position ortho to the hydroxyl group, leading to the synthesis of the chlorinated isoquinolines 1a and 2a, respectively, which further expands the spectrum of identified substrates of Rdc2.

hydroxyl

isoquinolines


Input: This work revealed that Rdc2 is a useful biocatalyst for the synthesis of various halogenated compounds.


Input: Injectable nanomaterials for drug delivery: Carriers, targeting moieties, and therapeutics.


Input: Therapeutics such as nucleic acids, proteins/peptides, vaccines, anti-cancer, and other drugs have disadvantages of low bio-availability, rapid clearance, and high toxicity.


Input: Thus, there is a significant need for the development of efficient delivery methods and carriers.


Input: Injectable nanocarriers have received much attention due to their vast range of structures and ability to contain multiple functional groups, both within the bulk material and on the surface of the particles.


Input: Nanocarriers may be tailored to control drug release and/or increase selective cell targeting, cellular uptake, drug solubility, and circulation time, all of which lead to a more efficacious delivery and action of therapeutics.


Input: The focus of this review is injectable, targeted nanoparticle drug delivery carriers highlighting the diversity of nanoparticle materials and structures as well as highlighting current therapeutics and targeting moieties.


Input: Structures and materials discussed include liposomes, polymersomes, dendrimers, cyclodextrin-containing polymers (CDPs), carbon nanotubes (CNTs), and gold nanoparticles.

dendrimers

carbon


Input: Additionally, current clinical trial information and details such as trial phase, treatment, active drug, carrier sponsor, and clinical trial identifier for different materials and structures are presented and discussed.


Input: Novel diaryl ureas with efficacy in a mouse model of malaria.

diaryl ureas


Input: Exploration of triclosan analogs has led to novel diaryl ureas with significant potency against in vitro cultures of drug-resistant and drug-sensitive strains of the human malaria parasite Plasmodium falciparum.

diaryl ureas


Input: Compound 18 demonstrated EC (50) values of 37 and 55 nM versus in vitro cultured parasite strains and promising in vivo efficacy in a Plasmodium berghei antimalarial mouse model, with > 50% survival at day 31 post-treatment when administered subcutaneously at 256 mg/kg.


Input: This series of compounds provides a chemical scaffold of novel architecture, as validated by cheminformatics analysis, to pursue antimalarial drug discovery efforts.


Input: Pterostilbene exerts antitumor activity against human osteosarcoma cells by inhibiting the JAK2/STAT3 signaling pathway.

Pterostilbene


Input: Osteosarcoma is a high-grade malignant bone tumor.


Input: Pterostilbene (PTE) is a natural, dimethylated analog of resveratrol with higher bioavailability.

Pterostilbene

PTE

resveratrol


Input: While PTE has been shown to have potent antitumor activity against various types of cancer, the molecular mechanisms underlying the effects of PTE remain largely unknown.

PTE

PTE


Input: The Janus kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) signaling pathway plays a crucial role in tumorigenesis and immune development.


Input: In this study, we assessed the antitumor activity of PTE against human osteosarcoma cells and explored the role of JAK2/STAT3 and apoptosis-related signaling pathways on the activity of PTE.

PTE

PTE


Input: PTE treatment resulted in a dose-and time-dependent inhibition of osteosarcoma cell viability.

PTE


Input: Additionally, PTE exhibited strong antitumor activity, as evidenced not only by reductions in tumor cell adhesion, migration and mitochondrial membrane potential (MMP) but also by increases in the apoptotic index, reactive oxygen species (ROS) and several biochemical parameters.

PTE

oxygen


Input: Furthermore, PTE treatment directly inhibited the phosphorylation of JAK2 at Tyr 1007 and the downstream activation of STAT3.

PTE

Tyr


Input: PTE also down-regulated the expression of STAT3 target genes, including the anti-apoptotic proteins Bcl-xL and Mcl-1, leading to the up-regulation of mitochondrial apoptosis pathway-related proteins (Bax, Bak, cytosolic Cytochrome c, and cleaved Caspase3) and cyclin-dependent kinase inhibitors such as p21 and p27.

PTE


Input: PTE, used in combination with a known JAK2/STAT3 inhibitor, AG490, further decreased the viability of osteosarcoma cells.

PTE


Input: Taken together, PTE is a potent inhibitor of osteosarcoma cell growth that targets the JAK2/STAT3 signaling pathway.

PTE


Input: These data suggest that inhibition of JAK2/STAT3 signaling is a novel mechanism of action for PTE during therapeutic intervention in osteosarcoma cancers.

PTE


Input: The effects of natural disturbances, reef state, and herbivorous fish densities on ciguatera poisoning in Rarotonga, southern Cook Islands.


Input: Ciguatera poisoning is a critical public-health issue among Pacific island nations.


Input: Accurately predicting ciguatera outbreaks has become a priority, particularly in Rarotonga in the southern Cook Islands, which has reported the highest incidence of ciguatera poisoning globally.


Input: Since 2006, however, cases of ciguatera poisoning have declined, and in 2011 ciguatera cases were the lowest in nearly 20 years.


Input: Here we examined the relationships between cases of ciguatera poisoning, from 1994 to 2011, and: (i) coral cover, used as a proxy of reef state, (ii) the densities of herbivorous fishes, and (iii) reef disturbances.


Input: We found that coral cover was not a good predictor of cases of ciguatera poisoning, but high densities of the herbivorous fish Ctenochaetus striatus and reef disturbances were both strong predictors of ciguatera poisoning.


Input: Yet these two predictors were correlated, because the densities of C. striatus increased only after major cyclones had disturbed the reefs.


Input: Since 2006, the number of cyclones has decreased considerably in Rarotonga, because of the climatic shift toward the negative phase of the Pacific Decadal Oscillation.


Input: We suggest that fewer cyclones have led to decreases in both the densities of C. striatus and of the number of reported cases of ciguatera poisoning in Rarotonga.


Input: Preclinical assessment of a polyspecific antivenom against the venoms of Cerrophidion sasai, Porthidium nasutum and Porthidium ophryomegas: Insights from combined antivenomics and neutralization assays.


Input: A polyspecific antivenom is used in Central America for the treatment of envenomings by viperid snakes.


Input: This antivenom is generated in horses hyperimmunized with a mixture of venoms from Bothrops asper, Crotalus simus and Lachesis stenophrys.


Input: The present study analyzed the ability of this antivenom to neutralize the venoms of three Central American viperid species of the' Porthidium group', i. e. Porthidium nasutum, Porthidium ophryomegas and Cerrophidion sasai, formerly classified as Cerrophidion godmani.


Input: In addition, the immunorecognition of the components of these venoms was assessed by immunoaffinity antivenomics.


Input: The antivenom proved effective in neutralizing the lethal, hemorrhagic, myotoxic, phospholipase A (2) (PLA (2)) and proteinase activities of the three venoms, albeit exhibiting quantitative differences in the values of the Median Effective Doses (ED (50)).


Input: Excepting for certain low molecular mass bands corresponding to disintegrins, and some PLA (2) s and PI-metalloproteinases, Western blotting and immunoaffinity chromatography revealed immunorecognition of most Porthidium and Cerrophidion venom proteins.


Input: In agreement with in vivo neutralization assays, immobilized antivenom IgGs showed higher immunocapturing activity of toxins from both Porthidium taxa than from C. sasai.


Input: Overall our results demonstrate a significant paraspecific protection of the Costa Rican polyspecific antivenom against the three venoms sampled.


Input: They also stress the need to search for novel ways to enhance the immune response of horses against several weakly immunogenic venom components.


Input: cDNA cloning of a snake venom metalloproteinase from the eastern diamondback rattlesnake (Crotalus adamanteus), and the expression of its disintegrin domain with anti-platelet effects.


Input: A 5' truncated snake venom metalloproteinase was identified from a cDNA library constructed from venom glands of an eastern diamondback rattlesnake (Crotalus adamanteus).


Input: The 5'-rapid amplification of cDNA ends (RACE) was used to obtain the 1865 bp full-length cDNA sequence of a snake venom metalloproteinase (CamVMPII).


Input: CamVMPII encodes an open reading frame of 488 amino acids, which includes a signal peptide, a pro-domain, a metalloproteinase domain, a spacer, and an RGD-disintegrin domain.

amino acids


Input: The predicted amino acid sequence of CamVMPII showed a 91%, 90%, 83%, and 82% sequence homology to the P-II class enzymes of C. adamanteus metalloproteinase 2, Crotalus atrox CaVMP-II, Gloydius halys agkistin, and Protobothrops jerdonii jerdonitin, respectively.


Input: Disintegrins are potent inhibitors of both platelet aggregation and integrin-dependent cell adhesion.


Input: Therefore, the disintegrin domain (Cam-dis) of CamVMPII was amplified by PCR, cloned into a pET-43. 1a vector, and expressed in Escherichia coli BL21.


Input: Affinity purified recombinantly modified Cam-dis (r-Cam-dis) with a yield of 8. 5 mg/L culture medium was cleaved from the fusion tags by enterokinase cleavage.


Input: r-Cam-dis was further purified by two-step chromatography consisting of HiTrap (TM) Benzamidine FF column, followed by Talon Metal affinity column with a final yield of 1 mg/L culture.


Input: r-Cam-dis was able to inhibit all three processes of platelet thrombus formation including platelet adhesion with an estimated IC (50) of 1 nM, collagen-and ADP-induced platelet aggregation with the estimated IC (50) s of 18 and 6 nM, respectively, and platelet function on clot retraction.

ADP


Input: It is a potent anti-platelet inhibitor, which should be further investigated for drug discovery to treat stroke patients or patients with thrombotic disorders.


Input: Vasorelaxant effects of 1-nitro-2-phenylethane, the main constituent of the essential oil of Aniba canelilla, in superior mesenteric arteries from spontaneously hypertensive rats.


Input: The present study investigated the mechanisms underlying the vasorelaxant effects of the essential oil of Aniba canelilla (EOAC) and its main constituent 1-nitro-2-phenylethane (NP) in isolated superior mesenteric artery from spontaneously hypertensive rats (SHRs).


Input: At 0. 1-1000 mu g/mL, EOAC and NP relaxed SMA preparations pre-contracted with 75 mMKCl with IC (50) (geometric mean [95% confidence interval]) values of 294. 19 [158. 20-94. 64] and 501. 27 [378. 60-624. 00] mu g/mL, respectively); or with phenylephrine (PHE) (IC (50) s = 11. 07 [6. 40-15. 68] and 7. 91 [4. 08-11. 74) mu g/mL, respectively).

mMKCl

phenylephrine

PHE


Input: All these effects were reversible and remained unaltered by vascular endothelium removal.


Input: In preparations maintained under Ca (2 +)-free conditions, EOAC and NP (both at 600 mu g/mL) reduced the PHE-, but not the caffeine-induced contraction.

Ca (2 +)

caffeine


Input: In Ca (2 +)-free and high K (+) (75 mM) medium, the contractions produced by CaCl (2) or BaCl (2) were reduced or even abolished by EOAC and NP at 100 and 600 mu g/mL, respectively.

Ca (2 +)

K (+)

CaCl (2)

BaCl (2)


Input: EOAC and NP (both at 10-1000 mu g/mL) also relaxed the contraction evoked by phorbol dibutyrate (IC (50) = 52. 66 [10. 82-94. 64] and 39. 13 [31. 55-46. 72] mu g/mL, respectively).

phorbol dibutyrate


Input: It is concluded that NP has a myogenic endothelium-independent vasorelaxant effects and appears to be the active principle of the EOAC.


Input: Vasorelaxant effect induced by both EOAC and NP is preferential to receptor-activated pathways and it appears to occur intracellularly more than a superficial action restricted to the membrane environment such as a simple blocking activity on a given receptor or ion channel.


Input: Total synthesis of bicyclic depsipeptides spiruchostatins C and D and investigation of their histone deacetylase inhibitory and antiproliferative activities.

spiruchostatins C and D


Input: The bicyclic depsipeptide histone deacetylase (HDAC) inhibitors spiruchostatins C and D were synthesized for the first time in a highly convergent and unified manner.

spiruchostatins C and D


Input: The method features the amide coupling of a D-leucine-D-cysteine-or D-valine-D-cysteine-containing segment with a D-alanine-or D-valine-containing segment to directly assemble the corresponding seco-acids, key precursors of macrolactonization.

amide

D-leucine-D-cysteine

D-valine-D-cysteine

D-alanine

D-valine


Input: The HDAC inhibitory assay and cell-growth inhibition analysis of the synthesized depsipeptides determined the order of potency of spiruchostatins A-D in comparison with the clinically approved depsipeptide FK228 (romidepsin).

spiruchostatins A-D

romidepsin


Input: Novel aspects of structure-activity relationships (SAR) were revealed.


Input: Design and synthesis of biaryl aryl stilbenes/ethylenes as antimicrotubule agents.

biaryl aryl stilbenes

ethylenes


Input: Two new series of compounds E-2, 3, 4-trimethoxy-6-styrylbiphenyls and 2, 3, 4-trimethoxy-6-(1-phenylvinyl) biphenyls were designed, synthesized and evaluated for antitubulin activity.

E-2, 3, 4-trimethoxy-6-styrylbiphenyls

2, 3, 4-trimethoxy-6-(1-phenylvinyl) biphenyls


Input: A common intermediate 4, 5, 6-trimethoxybiphenyl-2-carbaldehydes was employed to generate the two scaffolds.

4, 5, 6-trimethoxybiphenyl-2-carbaldehydes


Input: Majority of the analogs inhibited cell proliferation and those functionalized with 3, 4-(1, 3-dioxolane) and 3, 4-difluoro groups were identified as effective inhibitors in both the series.

3, 4-(1, 3-dioxolane)

3, 4-difluoro


Input: Treatments with 19b, 19c, 22b and 22c arrested cells at G2/M phase, disrupted microtubule network, accumulated tubulin in the soluble fraction and manifested an increased expression of the G2/M marker, Cyclin B1.


Input: Molecular docking analysis demonstrated the interaction of these compounds at the colchicine binding site of tubulin.

colchicine


Input: Interaction of polyhexamethylene biguanide hydrochloride (PHMB) with phosphatidylcholine containing o/w emulsion and consequences for microbicidal efficacy and cytotoxicity.

polyhexamethylene biguanide hydrochloride

PHMB

phosphatidylcholine


Input: Oil-in-water (o/w) emulsions containing egg yolk phosphatidylcholine (EPC) were combined with aqueous polyhexamethylene biguanide hydrochloride (PHMB).

phosphatidylcholine

polyhexamethylene biguanide hydrochloride

PHMB


Input: The PHMB concentration in the aqueous phase was estimated by filtration centrifugation experiments.

PHMB


Input: In parallel, PHMB concentration was assessed utilizing cytotoxicity assays (neutral red) on cultured murine fibroblasts (L929 cells) and tests of bactericidal efficacy on either Pseudomonas aeruginosa or Staphylococcus aureus.

PHMB

neutral red


Input: Biological tests were performed in cell culture medium.


Input: Filtration centrifugation experiments demonstrated much higher aqueous PHMB concentrations than did the assays for biologically effective PHMB.

PHMB

PHMB


Input: Therefore, biological test systems should preferably be used to verify effective PHMB concentrations.

PHMB


Input: Tests of microbicidal efficacy in which the same 0. 05% PHMB o/w emulsion was re-used 8 times revealed a drug delivery system activated by the presence of test bacteria.

PHMB


Input: Neuroprotective effects of resveratrol on embryonic dorsal root ganglion neurons with neurotoxicity induced by ethanol.

resveratrol

ethanol


Input: Studies have established that ethanol (EtOH) consumption results in damage to the peripheral nervous systems.

ethanol

EtOH


Input: Although the pathobiological mechanism is still unclear, oxidative stress is known to play an important role in EtOH-induced neurotoxicity.

EtOH


Input: Because resveratrol (Res) is attracting increased attention due to its antioxidative properties, we investigated the neuroprotective efficacy of Res in ethanol-treated embryonic dorsal root ganglion (DRG) neurons in vitro.

resveratrol

Res

Res

ethanol


Input: Organotypic DRG explants and a dispersed cell culture model were used to evaluate the effects of Res on EtOH-induced neurotoxicity.

Res

EtOH


Input: Res increased the number of extended nerve fibers and neurons that migrated from the DRG explants.

Res


Input: Hoechst 33342 staining and terminal deoxynucleotidyl-transferase-mediated dUTP nick-end-labeling analysis showed that the EtOH-induced apoptosis was inhibited by Res.

Hoechst 33342

dUTP

EtOH

Res


Input: The effects of Res were blocked by the 5'-adenosine monophosphate-activated protein kinase inhibitor Compound C and the sirtuin 1 inhibitor nicotinamide.

Res

5'-adenosine monophosphate

nicotinamide


Input: The elevation of oxidative/nitrosative stress, as measured by the amount of reactive oxygen species, malondialdehyde, nitrite, glutathione and superoxide dismutase activity, was also attenuated by Res.

oxygen

malondialdehyde

nitrite

glutathione

superoxide

Res


Input: The data from the present study indicate that Res protects DRG neurons from EtOH-induced neurotoxicity.

Res

EtOH


Input: Res and its derivative may be effective for the treatment of diseases characterized by axonopathy and neuron loss induced by EtOH.

Res

EtOH


Input: Specific uptake of folate-decorated triamcinolone-encapsulating nanoparticles by retinal pigment epithelium cells enhances and prolongs antiangiogenic activity.

folate

triamcinolone


Input: We are proposing folate-decorated polymeric nanoparticles as carriers of poorly soluble drug molecules for intracellular and prolonged delivery to retinal pigment epithelium (RPE) cells.

folate


Input: RPE is a monolayer of epithelial cells that forms the outer blood-retinal barrier in the posterior segment of the eye, and is also implicated in the pathology of, such as neovascularization in age-related macular degeneration (AMD).


Input: In this study, folate-functionalized poly (ethylene glycol)-b-polycaprolactone (folate-PEG-b-PCL) were synthesized for assembling into nanoparticles of ~ 130nm.

folate

poly (ethylene glycol)

polycaprolactone

folate

PEG

PCL


Input: These nanoparticles were internalized into ARPE-19 (human RPE cell line) via receptor-mediated endocytosis, and the cellular uptake was significantly higher than particles without folate modification.

folate


Input: Triamcinolone acetonide (TA) was efficiently encapsulated (> 97%) into the folate-decorated nanoparticles and was slowly released over a period of 4 weeks at pH 5. 5 and 8 weeks at pH 7. 4.

Triamcinolone acetonide

folate


Input: The enhanced uptake and controlled release resulted in prolonged anti-angiogenic gene expression of RPE cells.


Input: In cell culture, the down-regulation of vascular endothelial growth factor (VEGF) and up-regulation of pigment epithelium derived factor (PEDF) lasted for at least 3 weeks.


Input: Unlike benzyl alcohol, the surfactant found in commercial formulation, folate-modified nanoparticles were non-toxic.

benzyl alcohol

folate


Input: Furthermore, TA became less cytotoxic by being encapsulated in the nanoparticles.


Input: Our findings suggest that folate-PEG-PCL nanoparticles are promising drug carriers for RPE targeting.

folate

PEG

PCL


Input: Pharmacokinetics of temoporfin-loaded liposome formulations: correlation of liposome and temoporfin blood concentration.

temoporfin

temoporfin


Input: Liposomal formulations of the highly hydrophobic photosensitizer temoporfin were developed in order to overcome solubility-related problems associated with the current therapy scheme.

temoporfin


Input: We have incorporated temoporfin into liposomes of varying membrane composition, cholesterol content, and vesicle size.

temoporfin

cholesterol


Input: Specifically, two phosphatidyl oligoglycerols were compared to PEG2000-DSPE with respect to the ability to prolong circulation half life of the liposomal carrier.


Input: We measured the resulting pharmacokinetic profile of the liposomal carrier and the incorporated temoporfin in a rat model employing a radioactive lipid label and (14) C-temoporfin.

temoporfin

(14) C-temoporfin


Input: The data for the removal of liposomes and temoporfin were analyzed in terms of classical pharmacokinetic theory assuming a two-compartment model.

temoporfin


Input: This model, however, does not allow in a straightforward manner to distinguish between temoporfin eliminated together with the liposomal carrier and temoporfin that is first transferred to other blood components (e. g. plasma proteins) before being eliminated from the blood.

temoporfin

temoporfin


Input: We therefore additionally analyzed the data based on two separate one-compartment models for the liposomes and temoporfin.

temoporfin


Input: The model yields the ratio of the rate constant of temoporfin elimination together with the liposomal carrier and the rate constant of temoporfin elimination following the transfer to e. g. plasma proteins.

temoporfin

temoporfin


Input: Our analysis using this model demonstrates that a fraction of temoporfin is released from the liposomes prior to being eliminated from the blood.

temoporfin


Input: In case of unmodified liposomes this temoporfin release was observed to increase with decreasing bilayer fluidity, indicating an accelerated temoporfin transfer from gel-phase liposomes to e. g. plasma proteins.

temoporfin

temoporfin


Input: Interestingly, liposomes carrying either one of the three investigated surface-modifying agents did not adhere to the tendencies observed for unmodified liposomes.


Input: Although surface-modified liposomes exhibited improved pharmacokinetic properties with regard to the liposomal carrier, an enhanced temoporfin loss and elimination from the PEGylated-liposomes was observed.

temoporfin


Input: This effect was more pronounced for PEGylated liposomes than for the two oligo-glycerols.

glycerols


Input: Our combined experimental-theoretical approach for in vivo plasma re-distribution of liposomal drugs may help to optimize colloidal drug carrier systems.


Input: Inhibition of protein glycation by urea and thiourea derivatives of glycine/proline conjugated benzisoxazole analogue-synthesis and structure-activity studies.

urea

thiourea

glycine

proline

benzisoxazole


Input: Synthesis of a new series of urea/thiourea derivatives of Gly/Pro conjugated benzisoxazole has been reported.

urea

thiourea

Gly

Pro

benzisoxazole


Input: Structure of the compounds was characterized by physical and spectroscopical data and has been screened for their in vitro antiglycation activity.


Input: Several compounds showed promising activity with IC (50) < 5 mu M compared to standard rutin (IC (50) = 41. 9 mu M).

rutin


Input: Further, it was found that compounds containing methoxy and bromine substituents have exerted highly potent activity.

methoxy

bromine


Input: Thus, the title compounds represent novel class of potent antiglycating agents.


Input: Effects of 17 beta-trenbolone on Eastern and Western mosquitofish (Gambusia holbrooki and G. affinis) anal fin growth and gene expression patterns.

17 beta-trenbolone


Input: The Eastern and Western mosquitofish (Gambusia holbrooki and G. affinis) are potential bioindicator organisms for endocrine disruptors.


Input: Male mosquitofish have an elongated anal fin (gonopodium) used for internal fertilization whose formation is driven by androgens.

androgens


Input: Normal female mosquitofish have a normal, rounded anal fin which undergoes elongation into a gonopodium structure when female mosquitofish are exposed to androgenic chemicals.


Input: Significant issues with using mosquitofish as a bioindicator include the lack of knowledge on how anal fin growth in females corresponds to endpoints relevant to biological integrity and the lack of information on the molecular pathways that regulate anal fin growth.


Input: The objectives of this study were to understand how androgen-induced anal fin elongation relates to changes in endpoints related to the female reproductive system and to understand how anal fin elongation occurs in androgen-exposed female mosquitofish.

androgen

androgen


Input: To achieve these objectives, adult female G. holbrooki were exposed to a vehicle control or one of three doses of the androgen 17 beta-trenbolone (TB) at nominal concentrations of 0. 1, 1 or 10 mu g TB/L.

androgen 17 beta-trenbolone


Input: Anal fin measurements were taken and livers were used for quantitative polymerase chain reaction analysis of vitellogenin (vtg) mRNA expression at multiple time points.


Input: 10 mu g TB/L induced anal fin elongation after 7 days of treatment (one-way ANOVA, p < 0. 05) as did 0. 1 and 1 mu g TB/L at later time points (one-way ANOVA, p < 0. 05).


Input: 10 mu g TB/L significantly reduced hepatic vtg gene expression at all time points assessed (one-way ANOVA, p < 0. 05).


Input: There was no correlation between anal fin elongation levels and vtg gene expression (Spearman' s rho, p > 0. 05).


Input: In a separate experiment, female G. holbrooki and G. affinis were exposed to the vehicle control or 1 mu g TB/L.


Input: Anal fins were used for qualitative gene expression analysis of the genes sonic hedgehog (shh), muscle segment homeobox C (msxC), and fibroblast growth factor receptor 1 (fgfr1) by in situ hybridization.


Input: Shh was expressed in the distal tip of the gonopodium while msxC and fgfr1 were more widely expressed along the same anal fin rays during androgen exposure.

androgen


Input: These data provide insight into the molecular pathways involved in anal fin elongation and pave the way for future work toward developing the mosquitofish into a bioindicator organism for endocrine disruptors.


Input: Biochemical and metabolic effects of a short-term exposure to nanoparticles of titanium silicate in tadpoles of Pelophylax perezi (Seoane).

titanium silicate


Input: This study aimed to evaluate sublethal effects of a short-term exposure (96 h) to titanium silicate nanoparticles (TiSiO (4)-NP) on Pelophylax perezi tadpoles.

titanium silicate

TiSiO (4)


Input: Tadpoles were exposed to five concentrations of TiSiO (4)-NP (8. 2, 10. 2, 12. 8, 16 and 20 mg/L) plus a control.

TiSiO (4)


Input: Effect criteria were: mortality, cholinesterases, glutathione S-transferases, lactate dehydrogenase, and catalase activities, and alanine and lactate contents.

glutathione S

lactate

alanine

lactate


Input: Light scattering was used for physical characterization of TiSiO (4)-NP suspensions, revealing a high aggregation state of the NP, consistent with low z-potential values (< 30 mV).

TiSiO (4)


Input: Mortality among TiSiO (4)-NP treatments was < 11%.

TiSiO (4)


Input: Significant differences relatively to the control were observed at the biochemical level (for CAT and LDH) and in lactate and alanine contents, which may end-up in increased oxidative stress.


Input: Overall, some of the monitored endpoints suggest metabolic alterations in TiSiO (4)-NP exposed tadpoles, highlighting the potential of TiSiO (4)-NP long-term effects on these organisms.

TiSiO (4)

TiSiO (4)


Input: Copper induced upregulation of apoptosis related genes in zebrafish (Danio rerio) gill.

Copper


Input: Copper (Cu) is an essential micronutrient that, when present in high concentrations, becomes toxic to aquatic organisms.

Copper

Cu


Input: It is known that Cu toxicity may induce apoptotic cell death.

Cu


Input: However, the precise mechanism and the pathways that are activated, in fish, are still unclear.


Input: Thus, this study aimed to assess which apoptotic pathways are triggered by Cu, in zebrafish (Danio rerio) gill, the main target of waterborne pollutants.

Cu


Input: Fish where exposed to 12. 5 and 100 mu g/L of Cu during 6, 12, 24 and 48 h.

Cu


Input: Fish gills were collected to TUNEL assay and mRNA expression analysis of selected genes by real time PCR.


Input: An approach to different apoptosis pathways was done selecting p53, caspase-8, caspase-9 and apoptosis inducing factor (AIF) genes.


Input: The higher incidence of TUNEL-positive cells, in gill epithelia of the exposed fish, proved that Cu induced apoptosis.

Cu


Input: The results suggest that different apoptosis pathways are triggered by Cu at different time points of the exposure period, as the increase in transcripts was sequential, instead of simultaneous.

Cu


Input: Apoptosis seems to be initiated via intrinsic pathway (caspase-9), through p53 activation; then followed by the extrinsic pathway (caspase-8) and finally by the caspase-independent pathway (AIF).


Input: A possible model for Cu-induce apoptosis pathways is proposed.

Cu


Input: Forming double layer-encapsulated quantum dots for bio-imaging and cell targeting.


Input: We report a simple and effective approach for the preparation of double layer-encapsulated quantum dots (DL-Qdots) composed of alkyl-capping ligands to interdigitate with hydrophobic, protective agents on the surface of AgInS (2)/ZnS quantum dots (Qdots), which allow phase transfer of hydrophobic Qdots from the organic phase into the aqueous phase.

AgInS (2)

ZnS


Input: The alkyl-capping ligands consist of a hydrophobic, aliphatic chain and different functional terminal groups (e. g., carboxyl, amine, hydroxyl, and thiol groups) that can serve as reactive sites to chemically couple with other materials.

carboxyl

amine

hydroxyl

thiol


Input: The resulting DL-Qdots bearing various functional groups retain good fluorescence properties and show excellent solubility as well as stability over a range of pH in the aqueous phase.


Input: Cytotoxicity studies of DL-Qdots bearing carboxyl groups (DL-Qdots-COOH) were carried out against human cervical (HeLa) cancer cells to elicit no apparent toxicity even at high concentrations of 300 mu g mL (-1) and 24 h of incubation.

carboxyl

COOH


Input: To demonstrate their potential biomedical application, DL-Qdots-COOH were further conjugated with folate for staining in HeLa, human liver carcinoma (HepG2), and human breast (MCF-7) cancer cells.

COOH

folate


Input: Confocal imaging characterization revealed that folate-conjugated DL-Qdots could target most specifically and effectively HeLa cells via folate receptor-mediated targeted delivery compared to HepG2 and MCF-7 cells.

folate

folate


Input: The generality and simplicity of this newly developed strategy can possibly be extended to a large variety of hydrophobic Qdots and nanocrystals whose surface protective agents have a long aliphatic chain.


Input: Epigenetic and small RNA regulation of senescence.


Input: Leaf senescence is regulated through a complex regulatory network triggered by internal and external signals for the reprogramming of gene expression.


Input: In plants, the major developmental phase transitions and stress responses are under epigenetic control.


Input: In this review, the underlying molecular mechanisms are briefly discussed and evidence is shown that epigenetic processes are also involved in the regulation of leaf senescence.


Input: Changes in the chromatin structure during senescence, differential histone modifications determining active and inactive sites at senescence-associated genes and DNA methylation are addressed.


Input: In addition, the role of small RNAs in senescence regulation is discussed.


Input: Hypolipidemic effect of fruit fibers in rats fed with high dietary fat.


Input: The hypolipidemic effect of 10% fruit fibers in rats fed with high-fat diet (HFD) was evaluated.


Input: This study was conducted on a total of 50 male Albino rats divided into 10 equal groups fed with different types of dietary fruits.


Input: The feeding period lasted for 24 weeks.


Input: Fasting blood samples were collected and sera separated and subjected to lipid profile assay and atherogenic index.


Input: In addition, total antioxidant activity of different fruits was determined.


Input: The results obtained showed that pomegranate had higher content of antioxidants followed by apple, strawberry and guava compared with other fruits.


Input: Rats fed with 20% coconut oil showed a highly significant elevation in the levels of serum total cholesterol, low-density lipoprotein cholesterol and atherogenic factor while the level of high-density lipoprotein cholesterol was significantly decreased when compared with control rats.

cholesterol

cholesterol

cholesterol


Input: Histological examination revealed that there was a large lipid and cholesterol deposition in the livers of rats fed with HFD.

cholesterol


Input: The potential in lowering the levels of plasma total cholesterol and triglyceride is in the following order: pomegranate > apple > strawberry > guava > papaya > mandarin and orange.

cholesterol

triglyceride


Input: Accumulation of hepatic lipid droplets was diminished when compared with the HFD group.


Input: Also, antiatherogenic is better than the untreated groups.


Input: Accordingly these hypolipidemic effects may be due to high-fiber content and antioxidant activity of these fruits.


Input: Transaldolase deficiency: report of 12 new cases and further delineation of the phenotype.


Input: PURPOSE: Transaldolase deficiency is a recently described inborn error of pentose phosphate pathway.

pentose phosphate


Input: We conducted this study to further delineate the associated phenotype.


Input: METHODS AND RESULTS: We report on 12 new cases representing six families with this metabolic defect that were observed over an 8 year span.


Input: None of these cases received the correct diagnosis initially because of significant overlap in the presenting symptoms (growth retardation, dysmorphic features, cutis laxa, congenital heart disease, hepatosplenomegaly, pancytopenia, and bleeding tendency) with a wide range of genetic disorders.


Input: However, the consanguineous nature of these families allowed us to pursue autozygome analysis, which highlighted TALDO as the likely candidate gene and sequencing confirmed segregation of a novel homozygous mutation with the disease in all the studied families.


Input: Biochemical analysis was also consistent with transaldolase deficiency.


Input: CONCLUSION: This study expands the clinical definition of transaldolase deficiency, and adds to its allelic heterogeneity.


Input: In addition, we emphasize the diagnostic challenge posed by this rare and pleiotropic metabolic disorder.


Input: Effect of the purinergic inhibitor oxidized ATP in a model of islet allograft rejection.

ATP


Input: The lymphocytic ionotropic purinergic P2X receptors (P2X1R-P2X7R, or P2XRs) sense ATP released during cell damage-activation, thus regulating T-cell activation.

ATP


Input: We aim to define the role of P2XRs during islet allograft rejection and to establish a novel anti-P2XRs strategy to achieve long-term islet allograft function.


Input: Our data demonstrate that P2X1R and P2X7R are induced in islet allograft-infiltrating cells, that only P2X7R is increasingly expressed during alloimmune response, and that P2X1R is augmented in both allogeneic and syngeneic transplantation.


Input: In vivo short-term P2X7R targeting (using periodate-oxidized ATP [oATP]) delays islet allograft rejection, reduces the frequency of Th1/Th17 cells, and induces hyporesponsiveness toward donor antigens.

ATP

oATP


Input: oATP-treated mice displayed preserved islet grafts with reduced Th1 transcripts.

oATP


Input: P2X7R targeting and rapamycin synergized in inducing long-term islet function in 80% of transplanted mice and resulted in reshaping of the recipient immune system.

rapamycin


Input: In vitro P2X7R targeting using oATP reduced T-cell activation and diminished Th1/Th17 cytokine production.

oATP


Input: Peripheral blood mononuclear cells obtained from long-term islet-transplanted patients showed an increased percentage of P2X7R (+) CD4 (+) T cells compared with controls.


Input: The beneficial effects of oATP treatment revealed a role for the purinergic system in islet allograft rejection, and the targeting of P2X7R is a novel strategy to induce long-term islet allograft function.

oATP


Input: Low-level domoic acid protects mouse cerebellar granule neurons from acute neurotoxicity: role of glutathione.

domoic acid

glutathione


Input: Domoic acid (DomA) is a potent marine neurotoxin.

Domoic acid

DomA


Input: By activating alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid/kainate receptors, DomA induces oxidative stress-mediated apoptotic cell death in neurons.

alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid

kainate

DomA


Input: The effect of prolonged (10 days) exposure to a low, nontoxic concentration (5nM) of DomA on acute (intermediate concentration) neurotoxicity of this toxin was investigated in cerebellar granule neurons (CGNs) from wild-type mice and mice lacking the glutamate cysteine ligase (GCL) modifier subunit (Gclm (/)).

DomA

glutamate cysteine


Input: CGNs from Gclm (/) mice have very low glutathione (GSH) levels and are very sensitive to DomA toxicity.

glutathione

GSH

DomA


Input: In CGNs from wild-type mice, prolonged exposure to 5nM DomA did not cause any overt toxicity but reduced oxidative stress-mediated apoptotic cell death induced by exposure to an intermediate concentration (100nM for 24h) of DomA.

DomA

DomA


Input: This protection was not observed in CGNs from Gclm (/) mice.


Input: Prolonged DomA exposure increased GSH levels in CGNs of wild-type but not Gclm (/) mice.

DomA

GSH


Input: Levels of GCLC (the catalytic subunit of GCL) protein and mRNA were increased in CGNs of both mouse strains, whereas levels of GCLM protein and mRNA, activity of GCL, and levels of GCL holoenzyme were only increased in CGNs of wild-type mice.


Input: Chronic DomA exposure also protected wild-type CGNs from acute toxicity of other oxidants.

DomA


Input: The results indicate that CGNs from Gclm (/) mice, which are already more sensitive to DomA toxicity, are unable to upregulate their GSH levels.

DomA

GSH


Input: As Gclm (/) mice may represent a model for a common human polymorphism in GCLM, such individuals may be at particular risk for DomA-induced neurotoxicity.

DomA


Input: One-Hour Glucose During an Oral Glucose Challenge Prospectively Predicts beta-Cell Deterioration and Prediabetes in Obese Hispanic Youth.

Glucose

Glucose


Input: OBJECTIVEIn adults, 1-h glucose during an oral glucose tolerance test (OGTT) predicts the development of type 2 diabetes independent of fasting and 2-h glucose concentrations.

glucose

glucose

glucose


Input: The purpose of the current investigation was to examine the utility of elevated 1-h glucose levels to prospectively predict deterioration in beta-cell function and the development of prediabetes in high-risk youth. RESEARCH DESIGN AND METHODSObese Latino youth with a family history of type 2 diabetes (133 male and 100 female; age 11. 1 +/- 1. 7 years) completed a baseline OGTT and were divided into two groups based upon a 1-h glucose threshold of 155 mg/dL (< 155 mg/dL, n = 151, or >= 155 mg/dL, n = 82).

glucose

glucose


Input: Youth were followed annually for up to 8 years for assessment of glucose tolerance, body composition by dual-energy X-ray absorptiometry, and insulin sensitivity, insulin secretion, and the disposition index by the frequently sampled intravenous glucose tolerance test. RESULTSOver time, the >= 155 mg/dL group exhibited a significantly greater decline in beta-cell function compared with youth with a 1-h glucose < 155 mg/dL (beta =-327. 8 +/- 126. 2, P = 0. 01).

glucose

glucose

glucose


Input: Moreover, this decline was independent of fasting or 2-h glucose and body composition.

glucose


Input: When the data were restricted to only participants with normal glucose tolerance at baseline, a 1-h glucose >= 155 mg/dL was independently associated with a 2. 5 times greater likelihood of developing prediabetes during follow-up (95% CI 1. 6-4. 1, P = 0. 0001). CONCLUSIONSThese data suggest that a 1-h glucose >= 155 mg/dL during an OGTT is an independent predictor of beta-cell deterioration and progression to prediabetes among obese Latino youth.

glucose

glucose

glucose


Input: Exciton Dissociation and Charge-Transport Enhancement in Organic Solar Cells with Quantum-Dot/N-doped CNT Hybrid Nanomaterials.


Input: The incorporation of InP quantum-dot/N-doped multiwalled carbon nanotube (QD: NCNT) nanohybrids in the active layer of poly (3-hexylthiophene)/indene-C60 bisadduct (P3HT/ICBA) bulk-heterojuction solar cells enhances VOC and JSC.

InP

N

carbon

poly (3-hexylthiophene)

indene

C60 bisadduct

ICBA


Input: The QDs encourage exciton dissociation by promoting electron transfer, while the NCNTs enhance the transport of the separated electrons and eventual charge collection.


Input: Such a synergistic effect successfully improves the power conversion efficiency (PCE) from 4. 68% (reference cells) to 6. 11%.


Input: N-Boc-protected 1, 2-diphenylethylenediamine-based dendritic organogels with multiple-stimulus-responsive properties.

N-Boc-protected 1, 2-diphenylethylenediamine


Input: A new class of poly (benzyl ether) dendrimers, decorated in their cores with N-Boc-protected 1, 2-diphenylethylenediamine groups, were synthesized and fully characterized.

poly (benzyl ether)

N-Boc-protected 1, 2-diphenylethylenediamine


Input: It was found that the gelation capability of these dendrimers was highly dependent on dendrimer generation, and the second-generation dendrimer (R, R)-G (2) DPENBoc proved to be a highly efficient organogelator.

(R, R)-G (2) DPENBoc


Input: A number of experiments (SEM, TEM, FTIR spectroscopy, (1) H NMR spectroscopy, rheological measurements, UV/Vis absorption spectroscopy, CD, and XRD) revealed that these dendritic molecules self-assembled into elastically interpenetrating one-dimensional nanostructures in organogels.

(1) H


Input: The hydrogen bonding, pi-pi, and solvophobic interactions were found to be the main driving forces for formation of the gels.

hydrogen


Input: Most interestingly, these dendritic organogels exhibited smart multiple-stimulus-responsive behavior upon exposure to environmental stimuli such as temperature, anions, and mechanical stress.


Input: Research resource: tissue-and pathway-specific metabolomic profiles of the steroid receptor coactivator (SRC) family.

steroid


Input: The rapidly growing family of transcriptional coregulators includes coactivators that promote transcription and corepressors that harbor the opposing function.


Input: In recent years, coregulators have emerged as important regulators of metabolic homeostasis, including the p160 steroid receptor coactivator (SRC) family.

steroid


Input: Members of the SRC family have been ascribed important roles in control of gluconeogenesis, fat absorption and storage in the liver, and fatty acid oxidation in skeletal muscle.

fatty acid


Input: To provide a deeper and more granular understanding of the metabolic impact of the SRC family members, we performed targeted metabolomic analyses of key metabolic byproducts of glucose, fatty acid, and amino acid metabolism in mice with global knockouts (KOs) of SRC-1, SRC-2, or SRC-3.

glucose

fatty acid

amino acid


Input: We measured amino acids, acyl carnitines, and organic acids in five tissues with key metabolic functions (liver, heart, skeletal muscle, brain, plasma) isolated from SRC-1,-2, or-3 KO mice and their wild-type littermates under fed and fasted conditions, thereby unveiling unique metabolic functions of each SRC.

amino acids

acyl carnitines


Input: Specifically, SRC-1 ablation revealed the most significant impact on hepatic metabolism, whereas SRC-2 appeared to impact cardiac metabolism.


Input: Conversely, ablation of SRC-3 primarily affected brain and skeletal muscle metabolism.


Input: Surprisingly, we identified very few metabolites that changed universally across the three SRC KO models.


Input: The findings of this Research Resource demonstrate that coactivator function has very limited metabolic redundancy even within the homologous SRC family.


Input: Furthermore, this work also demonstrates the use of metabolomics as a means for identifying novel metabolic regulatory functions of transcriptional coregulators.


Input: The pH Taxis of an Intelligent Catalytic Microbot.


Input: A Pd nanoparticle-containing polymer microsphere moves with increasing speed across a pH gradient, following differential catalytic decomposition of aqueous hydrogen peroxide.

Pd

hydrogen peroxide


Input: The directional motion is akin to the pH taxis of living microorganisms.


Input: The artificial pH taxis exhibits random walk, translation, vertical, hopping, and pulsed motion, when the size of the motor and the imposed pH gradient are modulated.


Input: Gadolinium-and manganite-based contrast agents with fluorescent probes for both magnetic resonance and fluorescence imaging of pancreatic islets: a comparative study.

Gadolinium


Input: Three magnetic resonance (MR)/fluorescence imaging probes were tested for visualization, cellular distribution, and survival of labeled pancreatic islets in vitro and following transplantation.


Input: As T (1) contrast agents (CAs), gadolinium (III) complexes linked to beta-cyclodextrin (Gd-F-beta CD) or bound to titanium dioxide (TiO2 @RhdGd) were tested.

gadolinium (III)

beta-cyclodextrin

Gd-F-beta CD

titanium dioxide


Input: As a T (2) CA, perovskite manganite nanoparticles (LSMO @siF @si) were examined.


Input: Fluorescein or rhodamine was incorporated as a fluorescent marker in all probes.

Fluorescein

rhodamine


Input: Islets labeled with gadolinium (III) CAs were visible as hyperintense spots on MR in vitro, but detection in vivo was inconclusive.

gadolinium (III)


Input: Islets labeled with LSMO @siF @si CA were clearly visible as hypointense spots or areas on MR scans in vitro as well as in vivo.


Input: All CAs were detected inside the islet cells by fluorescence.


Input: Although the vitality and function of the labeled islets was not impaired by any of the tested CAs, results indicate that LSMO @siF @si CA is a superior marker for islet labeling, as it provides better contrast enhancement within a shorter scan time.


Input: Improved quantum efficiency of highly efficient perovskite BaSnO 3-based dye-sensitized solar cells.

perovskite BaSnO 3


Input: Ternary oxides are potential candidates as an electron-transporting material that can replace TiO 2 in dye-sensitized solar cells (DSSCs), as their electronic/optical properties can be easily controlled by manipulating the composition and/or by doping.

oxides

TiO 2


Input: Here, we report a new highly efficient DSSC using perovskite BaSnO 3 (BSO) nanoparticles.

perovskite BaSnO 3

BSO


Input: In addition, the effects of a TiCl 4 treatment on the physical, chemical, and photovoltaic properties of the BSO-based DSSCs are investigated.

TiCl 4

BSO


Input: The TiCl 4 treatment was found to form an ultrathin TiO 2 layer on the BSO surface, the thickness of which increases with the treatment time.

TiCl 4

TiO 2

BSO


Input: The formation of the TiO 2 shell layer improved the charge-collection efficiency by enhancing the charge transport and suppressing the charge recombination.

TiO 2


Input: It was also found that the TiCl 4 treatment significantly reduces the amount of surface OH species, resulting in reduced dye adsorption and reduced light-harvesting efficiency.

TiCl 4

OH


Input: The trade-off effect between the charge-collection and light-harvesting efficiencies resulted in the highest quantum efficiency (i. e., short-circuit photocurrent density), leading to the highest conversion efficiency of 5. 5% after a TiCl 4 treatment of 3 min (cf. 4. 5% for bare BSO).

TiCl 4

BSO


Input: The conversion efficiency could be increased further to 6. 2% by increasing the thickness of the BSO film, which is one of the highest efficiencies from non-TiO 2-based DSSCs.

BSO

TiO 2


Input: Matrix metalloproteinases as drug targets in preeclampsia.


Input: Preeclampsia is an important syndrome complicating pregnancy.


Input: While the pathogenesis of preeclampsia is not entirely known, poor placental perfusion leading to widespread maternal endothelial dysfunction is accepted as a major mechanism.


Input: It has been suggested that altered placental expression of matrix metalloproteinases (MMPs) may cause shallow cytotrophoblastic invasion and incomplete remodeling of the spiral arteries.


Input: MMPs are also thought to link placental ischemia to the cardiovascular alterations of preeclampsia.


Input: In fact, MMPs may promote vasoconstriction and surface receptors cleavage affecting the vasculature.


Input: Therefore, the overall goal of this review article is to provide an overview of the pathophisiology of preeclampsia, more specifically regarding the role of MMPs in the pathogenesis of preeclampsia and the potential of MMP inhibitors as therapeutic options.


Input: Inhibition of matrix metalloproteinases (MMPs) as a potential strategy to ameliorate hypertension-induced cardiovascular alterations.


Input: A group of proteases, the matrix metalloproteinases (MMPs) are well known for their capacity to degrade extracellular matrix (ECM) proteins.


Input: Particularly MMP-2 and MMP-9 contribute to the degradation and reorganization of the ECM components and are involved in the pathophysiology of cardiovascular remodeling.


Input: Imbalanced MMP activity promotes vascular smooth muscle cells and migration and proliferation and endothelial dysfunction, thus resulting in increased cardiovascular stiffness and hypertrophy.


Input: Furthermore, MMP-2 cleaves non-ECM protein substrates including cellular receptors and intracellular proteins, thus causing cardiac and vascular dysfunction.


Input: It is now becoming clear that increased MMP activity promotes long-lasting cardiovascular structural and functional alterations in both experimental and clinical hypertension, and this alteration may contribute to sustained hypertension and its complications.


Input: Other pathogenic mechanisms including activation of the renin-angiotensin-aldosterone system and oxidative stress activate and upregulate MMPs.


Input: Therefore, MMP inhibition may prevent the deleterious consequences of hypertension to the cardiovascular system.


Input: This review article will focus on growing evidence supporting the relevance of MMPs in hypertension and the effects of MMP inhibitors.


Input: Particularly, the effects of doxycycline used as a non selective MMP inhibitor in experimental and clinical studies will be discussed.

doxycycline


Input: Matrix metalloproteinases as drug targets in acute pulmonary embolism.


Input: Acute pulmonary embolism is a critical condition associated with increased mortality.


Input: Lung embolization causes acute pulmonary hypertension and right ventricle afterload.


Input: Global heart ischemia supervenes and may lead to severe shock and death.


Input: In this article, we reviewed current literature supporting the idea that abnormal matrix metalloproteinase (MMP) activity contributes to acute pulmonary embolism-induced hemodynamic changes.


Input: While low MMP levels are usually found in normal lung tissues, it is well known that inflammation and lung injury increase MMP expression and activity.


Input: This is probably due to recruitment and migration of inflammatory cells from the circulation to lung tissues.


Input: In addition, recent studies have shown increased MMP levels and activity in the right ventricle from animals with acute pulmonary embolism.


Input: Such increases in proteolytic activity were associated with increased cardiac troponin I in serum, suggesting a possible role for MMPs in cardiomyocyte injury during acute pulmonary embolism.


Input: These alterations have justified the use of doxycycline as an MMP inhibitor in acute pulmonary embolism.

doxycycline


Input: We review current evidence indicating that MMPs are targets in this critical condition.


Input: MMP inhibition apparently exerts antihypertensive effects and protects against cardiomyocyte injury caused by acute pulmonary embolism.


Input: A Novel Marine Drug, SZ-685C, Induces Apoptosis of MMQ Pituitary Tumor Cells by Downregulating miR-200c.


Input: Objective: We found a novel marine drug, SZ-685C, that was isolated from the secondary metabolites of a mangrove endophytic fungus (No. 1403) collected from the South China Sea, which has been reported to inhibit the proliferation of certain tumor cells.


Input: However, its anticancer mechanism remains unknown.


Input: The aims of this study were to observe the effectiveness of SZ-685C on pituitary adenoma cells and determine the underlying mechanisms of action.


Input: Methods: A rat prolactinoma cell line, MMQ, was used in this study.


Input: A dose escalation of SZ-685C was performed on this cell line, and cell viability was assessed using an MTT assay.

MTT


Input: Hoechst 33342, Annexin V-FITC/PI, TUNEL staining and flow cytometry were used to evaluate the extent of apoptosis at each concentration of SZ-685C.

FITC


Input: The effect of SZ-685C on prolactin expression was also evaluated using RT-PCR and immunoblotting.


Input: Quantitative RT-PCR was used to detect the expression of miR-200c in SZ-685C-stimulated MMQ cells and pituitary adenoma tissues.


Input: This miRNA was then overexpressed in MMQ cells via transfection of a miR-200c mimic to identify the mechanism underling the anti-tumor effect of SZ-685C.


Input: Results: SZ-685C inhibited MMQ cell growth in a dose-dependent manner but showed little toxicity toward rat pituitary cells (RPCs).


Input: The IC50s of SZ-685C in MMQ cells and RPCs were 13. 2 +/- 1. 3 mM and 49. 1 +/- 11. 5 mM, respectively, which was statistically significant.


Input: Increasing numbers of apoptotic cells were observed in response to escalating concentrations of SZ-685C, and the expression level of prolactin (PRL) was inhibited.


Input: Nevertheless, the level of PRL mRNA was unchanged.


Input: Additionally, miR-200c was upregulated in MMQ cells compared with RPCs, and downregulation of miR-200c was observed in SZ-685C-treated MMQ cells.


Input: Furthermore, the overexpression of miR-200c weakened the effect of SZ-685C-induced apoptosis of MMQ cells.


Input: Conclusions: Our results suggest that SZ-685C induces MMQ cell apoptosis in a miR-200c-dependent manner.


Input: Therefore, SZ-685C might be a useful alternative treatment for pituitary adenoma.


Input: JAK inhibitors: pharmacology and clinical activity in chronic myeloprolipherative neoplasms.


Input: The Janus family kinases (JAKs), JAK1, JAK2, JAK3, and TYK2, are involved in cell growth, survival, development, and differentiation of a variety of cells, particularly immune cells and hematopoietic cells.


Input: They form a subgroup of the non-receptor protein tyrosine kinases.

tyrosine


Input: Activating mutations within each of the JAKs is associated with malignant transformations; the most common are mutations of JAK2 in polycythemia vera (PV) and other myeloproliferative neoplasms (MPN).


Input: Identification of the V617F mutation of the JAK2 gene (JAK2 V617F) led to an important breakthrough in the understanding of MPN disease pathogenesis.


Input: The JAK2 V617F mutation is present in the majority of PV patients, and about 50% of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF) are affected.


Input: This mutation leads to hyperactivation of JAK2, cytokine-independent signaling, and subsequent activation of downstream signaling networks.


Input: JAK2 ATP-competitive inhibitors that indirectly inhibit the JAK-STAT pathway are new candidates for the treatment of MPN.

ATP


Input: JAK2 inhibitors in development for the treatment of MPN have demonstrated clinical activity with minimal toxicity.


Input: These agents consistently alleviate constitutional symptoms and reduce spleen size in PMF and other MPN.


Input: However, some of these inhibitors have additional unique effects.


Input: Ruxolitinib causes a significant reduction in the level of pro-inflammatory cytokines.

Ruxolitinib


Input: Another inhibitor, CYT387, improves anemia.


Input: Many other JAK2 inhibitors such as TG101348 or SAR302503, SB1518, CEP701 and LY2784544 are now under investigation for MPN development.