Input: Furthermore, CSEE treatment improved HFD-induced hepatic histological lesions.


Input: CSEE enhanced the phosphorylation of AMP-activated protein kinase (AMPK) and its primary downstream targeting enzyme, acetyl-CoA carboxylase, up-regulated the gene expression of carnitine palmitoyl transferase 1, and down-regulated sterol regulatory element binding protein 1 and fatty acid synthase protein levels in the livers of HFD-fed rats.

AMP

acetyl-CoA

carnitine palmitoyl

sterol

fatty acid


Input: AMPK inhibition by compound C retarded CSEE-induced reduction in triglyceride accumulation in HepG2 cells stimulated by insulin.

triglyceride


Input: Our findings suggest that CSEE may regulate hepatic lipid homeostasis related with an AMPK-dependent signaling pathway.


Input: Targeting AMPK activation with CSEE may represent a promising approach for the prevention and treatment of obesity-related non-alcoholic fatty liver disease.


Input: Light induced nanowire assembly: the electrostatic alignment of semiconductor nanowires into functional macroscopic yarns.


Input: The electrostatic alignment and directed assembly of semiconductor nanowires into macroscopic, centimeter-long yarns is demonstrated.


Input: Different morphologies can be produced, including longitudinally segmented/graded yarns or mixed composition fibers.


Input: Nanowire yarns display long range photoconductivities and open up exciting opportunities for potential use in future nanowire-based textiles or in solar photovoltaics.


Input: Mechanisms in endocrinology.


Input: Role of emotional stress in the pathophysiology of Graves' disease.


Input: The role of stress in the pathophysiology of Graves' disease is suggested by several clinical observations, by recent advances in immunology and by better understanding of autoimmune diseases which provides new insights into potential effects of stress hormones on T helper cell imbalance involved in the pathogenesis of autoimmune diseases.


Input: Stress management should therefore be an important part of the treatment of Graves' disease, as stress reduction may improve the effect of therapy.


Input: However, this field still requires interventional data to support stress management in the treatment of Graves' disease.


Input: Autoinhibition of CYP3A4 leads to important role of CYP2C8 in imatinib metabolism: variability in CYP2C8 activity may alter plasma concentrations and response.

imatinib


Input: Recent data suggest that the role of CYP3A4 in imatinib metabolism is smaller than presumed.

imatinib


Input: This study aimed to evaluate the quantitative importance of different cytochrome P450 (P450) enzymes in imatinib pharmacokinetics.

imatinib


Input: First, the metabolism of imatinib was investigated using recombinant P450 enzymes and human liver microsomes with P450 isoform-selective inhibitors.

imatinib


Input: Thereafter, an in silico model for imatinib was constructed to perform pharmacokinetic simulations to assess the roles of P450 enzymes in imatinib elimination at clinically used imatinib doses.

imatinib

imatinib

imatinib


Input: In vitro, CYP2C8 inhibitors and CYP3A4 inhibitors inhibited the depletion of 0. 1 micro M imatinib by 45 and 80%, respectively, and the formation of the main metabolite of imatinib, N-desmethylimatinib, by > 50%.

imatinib

imatinib

N-desmethylimatinib


Input: Likewise, recombinant CYP2C8 and CYP3A4 metabolized imatinib extensively, whereas other isoforms had minor effect on imatinib concentrations.

imatinib

imatinib


Input: In the beginning of imatinib treatment, the fractions of its hepatic clearance mediated by CYP2C8 and CYP3A4 were predicted to approximate 40 and 60%, respectively.

imatinib


Input: During long-term treatment with imatinib 400 mg once or twice daily, up to 65 or 75% of its hepatic elimination was predicted to occur via CYP2C8, and only about 35 or 25% by CYP3A4, due to dose-and time-dependent autoinactivation of CYP3A4 by imatinib.

imatinib

imatinib


Input: Thus, although CYP2C8 and CYP3A4 are the main enzymes in imatinib metabolism in vitro, in silico predictions indicate that imatinib inhibits its own CYP3A4-mediated metabolism, assigning a key role for CYP2C8.

imatinib

imatinib


Input: During multiple dosing, pharmacogenetic polymorphisms and drug interactions affecting CYP2C8 activity may cause marked interindividual variation in the exposure and response to imatinib.

imatinib


Input: Direct measurement of coherency limits for strain relaxation in heteroepitaxial core/shell nanowires.


Input: The growth of heteroepitaxially strained semiconductors at the nanoscale enables tailoring of material properties for enhanced device performance.


Input: For core/shell nanowires (NWs), theoretical predictions of the coherency limits and the implications they carry remain uncertain without proper identification of the mechanisms by which strains relax.


Input: We present here for the Ge/Si core/shell NW system the first experimental measurement of critical shell thickness for strain relaxation in a semiconductor NW heterostructure and the identification of the relaxation mechanisms.

Ge

Si


Input: Axial and tangential strain relief is initiated by the formation of periodic a/2 < 110 > perfect dislocations via nucleation and glide on {111} slip-planes.


Input: Glide of dislocation segments is directly confirmed by real-time in situ transmission electron microscope observations and by dislocation dynamics simulations.


Input: Further shell growth leads to roughening and grain formation which provides additional strain relief.


Input: As a consequence of core/shell strain sharing in NWs, a 16 nm radius Ge NW with a 3 nm Si shell is shown to accommodate 3% coherent strain at equilibrium, a factor of 3 increase over the 1 nm equilibrium critical thickness for planar Si/Ge heteroepitaxial growth.

Ge

Si

Si

Ge


Input: In vitro metabolism of the 5-hydroxytryptamine1B receptor antagonist elzasonan.

elzasonan


Input: The metabolism of elzasonan has been examined in vitro using hepatic microsomes from human and recombinant heterologously expressed P450 enzymes (rCYP).

elzasonan


Input: Metabolism occurs primarily via oxidative N-demethylation to form M4 and oxidation reactions to form elzasonan N-oxide (M5) and 5-hydroxyelzasonan metabolite (M3).

N

elzasonan N-oxide


Input: Additionally, elzasonan was shown to be metabolized to the novel cyclized indole metabolite (M6) which undergoes subsequent oxidation to form the iminium ion metabolite (M3a).

elzasonan

indole

iminium


Input: The rCYP data was normalized relative to the levels of each CYP form in native human liver microsomes to better assess the contribution of each rCYP in the metabolism of elzasonan.

elzasonan


Input: Results demonstrated the involvement of CYP3A4 in the pathways leading to M3a, M3, M5 and M6 and CYP2C8 in the formation of M4.


Input: Kinetic constants for the formation of M3 were determined and correlation and inhibition studies suggested that CYP3A4 is primarily responsible for the formation of M3 and CYP2C19 plays a very minor role in its formation.


Input: Cytochrome b5 has shown to be an essential component in P450 3A4 catalyzed 5-hydroxyelzasonan formation and provides insights on the disconnect between human liver microsomes data and that of rCYP.


Input: Furthermore, rCYP3A4 containing b5 are useful models for predicting the rates for liver microsomes P450-dependent drug oxidations and should be utilized routinely.


Input: Use of precision-cut renal cortical slices in nephrotoxicity studies.


Input: 1. Unlike cell lines and primary cells in culture, precision-cut tissue slices remain metabolically differentiated for at least 24-48 h and allow to study the effect of xenobiotics during short-term and long-term incubations.


Input: 2. In this article, we illustrate the use of such an experimental model to study the nephrotoxic effects of (i) chloroacetaldehyde, a metabolite of the anticancer drug ifosfamide, (ii) of cobalt chloride, a potential leakage product of the cobalt-containing nanoparticles, and (iii) of valproate, a widely used antiepileptic drug.

chloroacetaldehyde

ifosfamide

cobalt chloride

cobalt

valproate


Input: 3. Since all the latter test compounds, like many toxic compounds, negatively interact with cellular metabolic pathways, we also illustrate our biochemical toxicology approach in which we used not only enzymatic but also carbon 13 NMR measurements and mathematical modelling of metabolic pathways.

carbon 13


Input: 4. This original approach, which can be applied to any tissue, allows to predict the nephrotoxic effects of milligram amounts of test compounds very early during the research and development processes of drugs and chemicals.


Input: This approach, combined with the use of cells that retain their in vivo metabolic properties and, therefore, are predictive, reduces the risk, the time and cost of such processes.


Input: Effective phagocytosis of low Her2 tumor cell lines with engineered, aglycosylated IgG displaying high Fc gamma RIIa affinity and selectivity.


Input: Glycans anchored to residue N297 of the antibody IgG Fc domain are critical in mediating binding toward Fc gamma Rs to direct both adaptive and innate immune responses.


Input: However, using a full length bacterial IgG display system, we have isolated aglycosylated Fc domains with mutations that confer up to a 160-fold increase in the affinity toward the low affinity Fc gamma RIIa-R131 allele as well as high selectivity against binding to the remarkably homologous human inhibitory receptor, Fc gamma RIIb.


Input: The mutant Fc domain (AglycoT-Fc1004) contained a total of 5 amino acid substitutions that conferred an activating to inhibitory ratio of 25 (A/I ratio; FcyRIIa-R131: Fc gamma RIIb).

amino acid


Input: Incorporation of this engineered Fc into trastuzumab, an anti-Her2 antibody, resulted in a 75% increase in tumor cell phagocytosis by macrophages compared to that of the parental glycosylated trastuzumab with both medium and low Her2-expressing cancer cells.


Input: A mathematical model has been developed to help explain how receptor affinity and the A/I ratio relate to improved antibody dependent cell-mediated phagocytosis.


Input: Our model provides guidelines for the future engineering of Fc domains with enhanced effector function.


Input: 8-Hydroxycalamenene isolated from the rhizomes of Reynoutria elliptica exerts neuroprotective effects both in vitro and in vivo.


Input: Retinal ganglion cells (RGCs) death caused by oxidative stress is a common risk factor for glaucoma.


Input: In the present study, 8-hydroxycalamenene was isolated from the hexane fraction of Reynoutria elliptica.

hexane


Input: We showed that 8-hydroxycalamenene attenuated the cell death of transformed RGC-5 cells.


Input: This compound also produced a dose-dependent decrease in the expression of apoptotic proteins (cleaved PARP and caspase-3) induced by l-buthionine-(S, R)-sulfoximine (BSO) plus glutamate and stimulated glutathione and glutathione S-transferase activity.

l-buthionine-(S, R)-sulfoximine

BSO

glutamate

glutathione

glutathione S


Input: Moreover, the addition of 8-hydroxycalamenene to cell cultures restored the reduced mitochondrial membrane potential resulting from glutamate/BSO treatment.

glutamate

BSO


Input: The presence of N-methyl-d-aspartate in the retina of rats affected the thickness of the inner plexiform layer (IPL) and increased the number of TUNEL-positive RGCs.

N-methyl-d-aspartate


Input: However, 8-hydroxycalamenene protected against thinning of the IPL and reduced TUNEL-positive cells in the ganglion cell layer.


Input: Thus, 8-hydroxycalamenene isolated from R. elliptica exerts neuroprotective effects both in vitro and in vivo.


Input: DNA methylation and histone modification profiles of mouse organic anion transporting polypeptides.


Input: Organic anion transporting polypeptides (rodents, Oatps; human, OATPs) are primarily involved in the transmembrane transportation of a wide range of endogenous and exogenous compounds.


Input: Multiple mouse Oatp1 isoforms are closely located on chromosome 6, where each isoform shows distinct tissue distribution; Oatp1b2, Oatp1a6, and Oatp1c1 are expressed exclusively in the liver, kidney, and cerebrum, respectively; Oatp1a1 in the liver and kidney; and Oatp1a4 in the liver and cerebrum.


Input: We have identified tissue-dependent differentially methylated region (T-DMR) around the transcriptional start site (TSS) of Oatp1b2, which correlates with its liver-specific expression.


Input: Bisulfite sequencing also demonstrated the presence of T-DMRs around the TSS in other Oatp1 genes: CpG dinucleotides at + 149 relative to the TSS for Oatp1c1;-48, + 101, and + 356 for Oatp1a4;-572 and-550 for Oatp1a1; and-122 and + 216 for Oatp1a6 were differentially methylated among the liver, kidney, and cerebrum.

Bisulfite


Input: These methylation profiles were largely consistent with the tissue distribution of Oatp1 mRNAs.


Input: Chromatin immunoprecipitation assay revealed that the mRNA expression of Oatp1 genes was accompanied by acetylated histone H3.


Input: Human OATP1B1 and OATP1B3 are located on chromosome 12p12 in the OATP1 cluster; both show predominant expression in the liver.


Input: These genes also contained T-DMRs that were hypomethylated in the liver, compared with kidney cortex:-511,-411, and + 92 relative to the TSS for OATP1B1 and-331, + 70, and + 73 for OATP1B3.


Input: These results suggest that the difference in epigenetic profiles comprising DNA methylation and histone acetylation determines the distinct tissue distribution of Oatp/OATP mRNAs.


Input: Interplay between protein carbonylation and nitrosylation in plants.


Input: ROS and reactive nitrogen species (RNS) are key regulators of redox homeostasis in living organisms including plants.

nitrogen


Input: As control of redox homeostasis plays a central function in plant biology, redox proteomics could help in characterizing the potential roles played by ROS/RNS-induced posttranslational modification in plant cells.


Input: In this review, we focus on two posttranslational modifications: protein carbonylation (a marker of protein oxidation) and protein S-nitrosylation, both of which having recently emerged as important regulatory mechanisms during numerous fundamental biological processes.

S


Input: Here, we describe the recent progress in proteomic analysis of carbonylated and nitrosylated proteins and highlight the achievements made in understanding the physiological basis of these oxy/nitro modifications in plants.

oxy

nitro


Input: In addition, we document the existence of a relationship between ROS-based carbonylation and RNS-based nitrosylation thus supporting the finding that crosstalk between cellular signaling stress pathways induced by ROS and RNS could be mediated by specific protein modifications.


Input: In search of new targets for retinal neuroprotection: is there a role for autophagy?


Input: Autophagy is a highly conserved catabolic pathway in which proteins and organelles are engulfed by vacuoles that are targeted to lysosomes for degradation.


Input: Defects in the autophagic machinery have been described in several neurodegenerative diseases uncovering the tight dependency of neuronal survival on the efficiency of the autophagic process.


Input: Despite the large amount of literature investigating autophagy in a number of pathological conditions our knowledge of its role in glaucoma neurodegeneration is just beginning.


Input: However, recent experimental data revealing that autophagy modulation occurs in retinal ganglion cells (RGCs) under glaucoma-related stressing conditions support the hypothesis that dysfunctional autophagy might underlie the process leading to RGC death.


Input: Although our understanding of the role of autophagy in glaucoma is still developing, there is the possibility that neuroprotection may be achieved by modulating autophagy.


Input: This would be a promising approach as it could lead to the much-sought development of alternative therapeutic strategies to prevent visual loss in glaucoma.


Input: Effect of combining in vitro estrogenicity data with kinetic characteristics of estrogenic compounds on the in vivo predictive value.


Input: With the ultimate aim of increasing the utility of in vitro assays for toxicological risk assessment, a method was developed to calculate in vivo estrogenic potencies from in vitro estrogenic potencies of compounds by taking into account systemic availability.


Input: In vitro estrogenic potencies of three model compounds (bisphenol A, genistein, and 4-nonylphenol) relative to ethinylestradiol (EE2), determined with the estrogen receptor alpha (ER alpha) transcriptional activation assay using hER-HeLa-9903 cells, were taken from literature and used to calculate the EE2 equivalent (EE2EQ) effect doses in the predominantly ER alpha-dependent rat uterotrophic assay.

bisphenol A

genistein

ethinylestradiol

estrogen


Input: Compound-specific differences in hepatic clearance relative to the reference compound EE2 were determined in vitro to examine whether in vivo estrogenic potencies reported in literature could be more accurately estimated.


Input: The EE2EQ doses allowed to predict in vivo uterotrophic responses within a factor of 6-25 and the inclusion of the hepatic clearance further improved the prediction with a factor 1. 6-2. 1 for especially genistein and bisphenol A.

genistein

bisphenol A


Input: Yet, the model compounds still were less potent in vivo than predicted based on their EE2 equivalent estrogenic potency and hepatic clearance.


Input: For further improvement of the in vitro to in vivo predictive value of in vitro assays, the relevance of other kinetic characteristics should be studied, including binding to carrier proteins, oral bioavailability and the formation of estrogenic metabolites.


Input: Simple photosystem II water oxidation centre analogues in visible light oxygen and H + generation.

oxygen

H +


Input: Calcium manganese oxide nanoparticles for application in water oxidation are synthesized by combination with a carboxylated biopolymer stabilizing agent to form very simple but effective analogues of the photosynthetic PSII oxygen evolving complex.

Calcium manganese oxide

oxygen


Input: The relative efficiency of these materials for production of O (2) and protons under visible light-promoted reactions is evaluated and prolonged reaction lifetimes are observed.

O (2)


Input: A calibrated human Y-chromosomal phylogeny based on resequencing.


Input: We have identified variants present in high-coverage complete sequences of 36 diverse human Y chromosomes from Africa, Europe, South Asia, East Asia, and the Americas, representing eight major haplogroups.


Input: After restricting our analysis to 8. 97 Mb of the unique male-specific Y sequence, we identified 6662 high-confidence variants, including single-nucleotide polymorphisms (SNPs), multi-nucleotide polymorphisms (MNPs), and indels.


Input: We constructed phylogenetic trees using these variants, or subsets of them, and recapitulated the known structure of the tree.


Input: Assuming a male mutation rate of 1 x 10 (-9) per base pair per year, the time depth of the tree (haplogroups A3-R) was ~ 101, 000-115, 000 yr, and the lineages found outside Africa dated to 57, 000-74, 000 yr, both as expected.


Input: In addition, we dated a striking Paleolithic male lineage expansion to 41, 000-52, 000 yr ago and the node representing the major European Y lineage, R1b, to 4000-13, 000 yr ago, supporting a Neolithic origin for these modern European Y chromosomes.


Input: In all, we provide a nearly 10-fold increase in the number of Y markers with phylogenetic information, and novel historical insights derived from placing them on a calibrated phylogenetic tree.


Input: Pim kinases in cancer: diagnostic, prognostic and treatment opportunities.


Input: PIM proteins belong to a family of ser/thr kinases composed of 3 members, PIM1, PIM2 and PIM3, with greatly overlapping functions.

ser

thr


Input: PIM kinases are mainly responsible for cell cycle regulation, antiapoptotic activity and the homing and migration of receptor tyrosine kinases mediated via the JAK/STAT pathway.

tyrosine


Input: PIM kinases have been found to be upregulated in many hematological malignancies and solid tumors.


Input: Although these kinases have been described as weak oncogenes, they are heavily targeted for anticancer drug discovery.


Input: The present review summarizes the discoveries made to date regarding PIM kinases as driving oncogenes in the process of tumorigenesis and their validation as drug targets.


Input: Process analytical tools for monitoring, understanding, and control of pharmaceutical fluidized bed granulation: A review.


Input: Fluidized bed granulation is a widely applied wet granulation technique in the pharmaceutical industry to produce solid dosage forms.


Input: The process involves the spraying of a binder liquid onto fluidizing powder particles.


Input: As a result, the (wetted) particles collide with each other and form larger permanent aggregates (granules).


Input: After spraying the required amount of granulation liquid, the wet granules are rapidly dried in the fluid bed granulator.


Input: Since the FDA launched its Process Analytical Technology initiative (and even before), a wide range of analytical process sensors has been used for real-time monitoring and control of fluid bed granulation processes.


Input: By applying various data analysis techniques to the multitude of data collected from the process analyzers implemented in fluid bed granulators, a deeper understanding of the process has been achieved.


Input: This review gives an overview of the process analytical technologies used during fluid bed granulation to monitor and control the process.


Input: The fundamentals of the mechanisms contributing to wet granule growth and the characteristics of fluid bed granulation processing are briefly discussed.


Input: This is followed by a detailed overview of the in-line applied process analyzers, contributing to improved fluid bed granulation understanding, modeling, control, and endpoint detection.


Input: Analysis and modeling tools enabling the extraction of the relevant information from the complex data collected during granulation and the control of the process are highlighted.


Input: Effects of combined treatment with eldecalcitol and alendronate on bone mass, mechanical properties, and bone histomorphometry in ovariectomized rats: a comparison with alfacalcidol and alendronate.

eldecalcitol

alendronate

alfacalcidol

alendronate


Input: Eldecalcitol (ELD), a 2 beta-hydroxypropyloxy derivative of 1 alpha, 25 (OH) 2D3, inhibits bone resorption more potently than alfacalcidol (ALF) while maintaining osteoblastic function in an ovariectomized (OVX) osteoporosis rat model.

Eldecalcitol

ELD

2 beta-hydroxypropyloxy

1 alpha, 25 (OH) 2D3

alfacalcidol

ALF


Input: Alendronate (ALN), which is the most common bisphosphonate used for the treatment of osteoporosis, increases the bone mineral density (BMD) by suppressing bone resorption.

Alendronate

ALN

bisphosphonate


Input: In this study, we investigated the effects of combination treatments with ELD and ALN or with ALF and ALN on bone mass and strength in OVX rats.

ELD

ALN

ALF

ALN


Input: Seventy female rats, 32 weeks old, were assigned to seven groups: (1) a sham-operated control group; (2) an OVX-control group; (3) an ELD group; (4) an ALF group; (5) an ALN group; (6) an ELD + ALN group; and (7) an ALF + ALN group.

ELD

ALF

ALN

ELD

ALN

ALF

ALN


Input: OVX rats were orally treated with ELD (0. 015 mu g/kg), ALF (0. 0375 mu g/kg), or ALN (0. 2mg/kg) daily for 12 weeks.

ELD

ALF

ALN


Input: In both the lumbar spine and the femur, ELD and ALF monotherapy significantly increased the BMD, and ELD + ALN and ALF + ALN significantly increased the BMD, compared with ALN monotherapy, as an additive effect.

ELD

ALF

ELD

ALN

ALF

ALN

ALN


Input: In particular, ELD + ALN resulted in a significantly higher BMD than ALF + ALN in the femur.

ELD

ALN

ALF

ALN


Input: On mechanical testing of the lumbar spine, ELD and ALF monotherapy significantly increased the ultimate load, and ELD + ALN and ALF + ALN significantly increased the ultimate load compared with ALN monotherapy.

ELD

ALF

ELD

ALN

ALF

ALN

ALN


Input: In the femur, ELD, ELD + ALN, and ALF + ALN treatment significantly increased the ultimate load, compared with the OVX-control group, and ELD + ALN resulted in a significantly higher ultimate load than ALN monotherapy.

ELD

ELD

ALN

ALF

ALN

ELD

ALN

ALN


Input: A histomorphometric analysis showed that ELD monotherapy and ELD + ALN combination therapy had a potent inhibitory effect on bone resorption parameters (osteoclast surface and eroded surface), while maintaining bone formation parameters (osteoblast surface and osteoid surface).

ELD

ELD

ALN


Input: By contrast, ALF and ALF + ALN significantly lowered the histological parameters of both bone resorption and formation.

ALF

ALF

ALN


Input: These results suggested that ELD or ALF used in combination with ALN has therapeutic advantages over ALN monotherapy, with ELD + ALN combination treatment producing an especially beneficial anti-osteoporotic effect by inhibiting osteoclastic bone resorption and maintaining osteoblastic function, compared with ALF + ALN combination treatment.

ELD

ALF

ALN

ALN

ELD

ALN

ALF

ALN


Input: Ischemia-induced synaptic plasticity drives sustained expression of calcium-permeable AMPA receptors in the hippocampus.

calcium


Input: Long lasting enhancement of synaptic transmission can be triggered by brief bursts of afferent stimulation, underlying long-term potentiation (LTP), and also by brief ischemia in a process known as i-LTP.


Input: The extent to which LTP and i-LTP rely on comparable cellular mechanisms remains unclear.


Input: Under physiological conditions, LTP induction drives transient expression of calcium-permeable AMPARs (CP-AMPARs) at synapses, whose ability to undergo plasticity is primed by endogenous activation of adenosine A (2A) receptors (A (2A) Rs).

calcium

adenosine


Input: The present work thus addressed the contribution of CP-AMPARs and A (2A) Rs to i-LTP, which was induced in rat hippocampal slices by brief (10 min) oxygen/glucose deprivation (OGD).

oxygen

glucose


Input: The amplitude of afferent-evoked excitatory postsynaptic currents (EPSCs) recorded from CA1 pyramidal neurons was decreased during OGD but gradually recovered toward values significantly above (157 +/- 17%) the baseline (100%) 40-50 min after re-oxygenation.


Input: This i-LTP was precluded by CP-AMPAR blockade (internal spermine (500 mu M) or extracellular NASPM (20 mu M) application) as well as by A (2A) R blockade with a selective antagonist (SCH 58261, 100 nM).

spermine

NASPM

SCH 58261


Input: OGD prompted sustained (> 70 min) facilitation of mEPSC amplitude and frequency, and decreased mEPSC decay time, all of which were prevented by SCH 58261 (100 nM).

SCH 58261


Input: The ability of NASPM (20 mu M) to acutely inhibit EPSCs 1 h after OGD, but not in control conditions nor in OGD-challenged slices when in the presence of SCH 58261 (100 nM), further supports sustained CP-AMPAR recruitment by i-LTP in an A (2A) R-dependent way.

NASPM

SCH 58261


Input: We propose that although i-LTP may initially mimic LTP, failure of auto-regulated CP-AMPAR removal from synapses could constitute an early divergent event between these forms of plasticity.


Input: Salt bridge switching from Arg290/Glu167 to Arg290/ATP promotes the closed-to-open transition of the P2X2 receptor.

ATP


Input: P2X receptors are trimeric adenosine-5'-triphosphate (ATP)-gated cation channels involved in fast signal transduction in many cell types.

ATP


Input: In this study, we used homology modeling of the rat P2X2 receptor with the zebrafish P2X4 X-ray template to determine that the side chains of the Glu167 and Arg290 residues are in close spatial vicinity within the ATP-binding pocket when the rat P2X2 channel is closed.

ATP


Input: Through charge reversal mutation analysis and mutant cycle analysis, we obtained evidence that Glu167 and Arg290 form an electrostatic interaction.


Input: In addition, disulfide trapping indicated the close proximity of Glu167 and Arg290 when the channel is in the closed state, but not in the ATP-bound open state.

disulfide

ATP


Input: Consistent with a gating-induced movement that disrupts the Glu167/Arg290 salt bridge, a comparison of the closed and open rat P2X2 receptor models revealed a significant rearrangement of the protein backbone and the side chains of the Glu167 and Arg290 residues during the closed-to-open transition.


Input: The associated release of the Glu167/Arg290 salt bridge during channel opening allows a strong ionic interaction between Arg290 and a gamma-phosphate oxygen of ATP.

gamma-phosphate oxygen

ATP


Input: We conclude from these results that the state-dependent salt bridge switching from Arg290/Glu167 to Arg290/ATP fulfills a dual role: to destabilize the closed state of the receptor and to promote the ionic coordination of ATP in the ATP-binding pocket.

ATP

ATP

ATP


Input: Sexually dimorphic transcriptomic responses in the teleostean hypothalamus: a case study with the organochlorine pesticide dieldrin.

organochlorine

dieldrin


Input: Organochlorine pesticides (OCPs) such as dieldrin are a persistent class of aquatic pollutants that cause adverse neurological and reproductive effects in vertebrates.

Organochlorine

dieldrin


Input: In this study, female and male largemouth bass (Micropterus salmoides) (LMB) were exposed to 3mg dieldrin/kg feed in a 2 month feeding exposure (August-October) to (1) determine if the hypothalamic transcript responses to dieldrin were conserved between the sexes; (2) characterize cell signaling cascades underlying dieldrin neurotoxicity; and (3) determine whether or not co-feeding with 17 beta-estradiol (E (2)), a hormone with neuroprotective roles, mitigates responses in males to dieldrin.

dieldrin

dieldrin

dieldrin

17 beta-estradiol

dieldrin


Input: Despite also being a weak estrogen, dieldrin treatments did not elicit changes in reproductive endpoints (e. g. gonadosomatic index, vitellogenin, or plasma E (2)).

estrogen

dieldrin


Input: Sub-network (SNEA) and gene set enrichment analysis (GSEA) revealed that neuro-hormone networks, neurotransmitter and nuclear receptor signaling, and the activin signaling network were altered by dieldrin exposure.

dieldrin


Input: Most striking was that the majority of cell pathways identified by the gene set enrichment were significantly increased in females while the majority of cell pathways were significantly decreased in males fed dieldrin.

dieldrin


Input: These data suggest that (1) there are sexually dimorphic responses in the teleost hypothalamus; (2) neurotransmitter systems are a target of dieldrin at the transcriptomics level; and (3) males co-fed dieldrin and E (2) had the fewest numbers of genes and cell pathways altered in the hypothalamus, suggesting that E (2) may mitigate the effects of dieldrin in the central nervous system.

dieldrin

dieldrin

dieldrin


Input: Exposure to valproic acid inhibits chondrogenesis and osteogenesis in mid-organogenesis mouse limbs.

valproic acid


Input: In utero exposure to valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, causes neural tube, heart, and limb defects.

valproic acid

VPA


Input: Valpromide (VPD), the amide derivative of VPA, does not inhibit HDAC activity and is a weak teratogen in vivo.

Valpromide

VPD

amide

VPA


Input: The detailed mechanism of action of VPA as a teratogen is not known.

VPA


Input: The goal of this study was to test the hypothesis that VPA disrupts regulation of the expression of genes that are critical in chondrogenesis and osteogenesis during limb development.

VPA


Input: Murine gestation day-12 embryonic forelimbs were excised and exposed to VPA or VPD in a limb bud culture system.

VPA

VPD


Input: VPA caused a significant concentration-dependent increase in limb abnormalities, which was correlated with its HDAC inhibitory effect.

VPA


Input: The signaling of both Sox9 and Runx2, key regulators of chondrogenesis, was downregulated by VPA.

VPA


Input: In contrast, VPD had little effect on limb morphology and no significant effect on HDAC activity or the expression of marker genes.

VPD


Input: Thus, VPA exposure dysregulated the expression of target genes directly involved in chondrogenesis and osteogenesis in the developing limb.

VPA


Input: Disturbances in these signaling pathways are likely to be a consequence of HDAC inhibition because VPD did not affect their expressions.

VPD


Input: Tumor necrosis factor-alpha potentiates the cytotoxicity of amiodarone in Hepa1c1c7 cells: roles of caspase activation and oxidative stress.

amiodarone


Input: Amiodarone (AMD), a class III antiarrhythmic drug, causes idiosyncratic hepatotoxicity in human patients.

Amiodarone

AMD


Input: We demonstrated previously that tumor necrosis factor-alpha (TNF-alpha) plays an important role in a rat model of AMD-induced hepatotoxicity under inflammatory stress.

AMD


Input: In this study, we developed a model in vitro to study the roles of caspase activation and oxidative stress in TNF potentiation of AMD cytotoxicity.

AMD


Input: AMD caused cell death in Hepa1c1c7 cells, and TNF cotreatment potentiated its toxicity.

AMD


Input: Activation of caspases 9 and 3/7 was observed in AMD/TNF-cotreated cells, and caspase inhibitors provided minor protection from cytotoxicity.

AMD


Input: Intracellular reactive oxygen species (ROS) generation and lipid peroxidation were observed after treatment with AMD and were further elevated by TNF cotreatment.

oxygen

AMD


Input: Adding water-soluble antioxidants (trolox, N-acetylcysteine, glutathione, or ascorbate) produced only minor attenuation of AMD/TNF-induced cytotoxicity and did not influence the effect of AMD alone.

trolox

N-acetylcysteine

glutathione

ascorbate

AMD

AMD


Input: On the other hand, alpha-tocopherol (TOCO), which reduced lipid peroxidation and ROS generation, prevented AMD toxicity and caused pronounced reduction in cytotoxicity from AMD/TNF cotreatment.

alpha-tocopherol

TOCO

AMD

AMD


Input: alpha-TOCO plus a pancaspase inhibitor completely abolished AMD/TNF-induced cytotoxicity.

alpha-TOCO

AMD


Input: In summary, activation of caspases and oxidative stress were observed after AMD/TNF cotreatment, and caspase inhibitors and a lipid-soluble free-radical scavenger attenuated AMD/TNF-induced cytotoxicity.

AMD

AMD


Input: Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment.

Cannabidiol

THC


Input: Community-based studies suggest that cannabis products that are high in Delta 9-tetrahydrocannabinol (THC) but low in cannabidiol (CBD) are particularly hazardous for mental health.

Delta 9-tetrahydrocannabinol

THC

cannabidiol

CBD


Input: Laboratory-based studies are ideal for clarifying this issue because THC and CBD can be administered in pure form, under controlled conditions.

THC

CBD


Input: In a between-subjects design, we tested the hypothesis that pre-treatment with CBD inhibited THC-elicited psychosis and cognitive impairment.

CBD

THC


Input: Healthy participants were randomised to receive oral CBD 600 mg (n = 22) or placebo (n = 26), 210 min ahead of intravenous (IV) THC (1. 5 mg).

CBD

THC


Input: Post-THC, there were lower PANSS positive scores in the CBD group, but this did not reach statistical significance.

THC

CBD


Input: However, clinically significant positive psychotic symptoms (defined a priori as increases >= 3 points) were less likely in the CBD group compared with the placebo group, odds ratio (OR) = 0. 22 (chi (2) = 4. 74, p < 0. 05).

CBD


Input: In agreement, post-THC paranoia, as rated with the State Social Paranoia Scale (SSPS), was less in the CBD group compared with the placebo group (t = 2. 28, p < 0. 05).

THC

CBD


Input: Episodic memory, indexed by scores on the Hopkins Verbal Learning Task-revised (HVLT-R), was poorer, relative to baseline, in the placebo pre-treated group (-10. 6 +/- 18. 9%) compared with the CBD group (-0. 4% +/- 9. 7%) (t = 2. 39, p < 0. 05).

CBD


Input: These findings support the idea that high-THC/low-CBD cannabis products are associated with increased risks for mental health.

THC

CBD


Input: Hydrophobic amino acids in the hinge region of the 5A apolipoprotein mimetic peptide are essential for promoting cholesterol efflux by the ABCA1 transporter.

amino acids

cholesterol


Input: The bihelical apolipoprotein mimetic peptide 5A effluxes cholesterol from cells and reduces inflammation and atherosclerosis in animal models.

cholesterol


Input: We investigated how hydrophobic residues in the hinge region between the two helices are important in the structure and function of this peptide.


Input: By simulated annealing analysis and molecular dynamics modeling, two hydrophobic amino acids, F-18 and W-21, in the hinge region were predicted to be relatively surface-exposed and to interact with the aqueous solvent.

amino acids


Input: Using a series of 5A peptide analogs in which F-18 or W-21 was changed to either F, W, A, or E, only peptides with hydrophobic amino acids in these two positions were able to readily bind and solubilize phospholipid vesicles.

amino acids


Input: Compared with active peptides containing F or W, peptides containing E in either of these two positions were more than 10-fold less effective in effluxing cholesterol by the ABCA1 transporter.

cholesterol


Input: Intravenous injection of 5A in C57BL/6 mice increased plasma-free cholesterol (5A: 89. 9 +/- 13. 6 mg/dl; control: 38. 7 +/- 4. 3 mg/dl (mean +/- S. D.); P < 0. 05) and triglycerides (5A: 887. 0 +/- 172. 0 mg/dl; control: 108. 9 +/- 9. 9 mg/dl; P < 0. 05), whereas the EE peptide containing E in both positions had no effect.

cholesterol

triglycerides


Input: Finally, 5A increased cholesterol efflux approximately 2. 5-fold in vivo from radiolabeled macrophages, whereas the EE peptide was inactive.

cholesterol


Input: These results provide a rationale for future design of therapeutic apolipoprotein mimetic peptides and provide new insights into the interaction of hydrophobic residues on apolipoproteins with phospholipids in the lipid microdomain created by the ABCA1 transporter during the cholesterol efflux process.

cholesterol


Input: Efficacy of the GluK1/AMPA receptor antagonist LY293558 against seizures and neuropathology in a soman-exposure model without pretreatment and its pharmacokinetics after intramuscular administration.

AMPA


Input: Control of brain seizures after exposure to nerve agents is imperative for the prevention of brain damage and death.


Input: Animal models of nerve agent exposure make use of pretreatments, or medication administered within 1 minute after exposure, in order to prevent rapid death from peripheral toxic effects and respiratory failure, which then allows the testing of anticonvulsant compounds.


Input: However, in a real-case scenario of an unexpected attack with nerve agents, pretreatment would not be possible, and medical assistance may not be available immediately.


Input: To determine if control of seizures and survival are still possible without pretreatment or immediate pharmacologic intervention, we studied the anticonvulsant efficacy of the GluK1 (GluR5)/alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist (3S, 4aR, 6R, 8aR)-6-[2-(1 (2) H-tetrazole-5-yl) ethyl] decahydroisoquinoline-3-carboxylic acid (LY293558) in rats that did not receive any treatment until 20 minutes after exposure to the nerve agent soman.

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

AMPA

(3S, 4aR, 6R, 8aR)-6-[2-(1 (2) H-tetrazole-5-yl) ethyl] decahydroisoquinoline-3-carboxylic acid


Input: We injected LY293558 intramuscularly, as this would be the most likely route of administration to humans.


Input: LY293558 (15 mg/kg), injected along with atropine and the oxime HI-6 at 20 minutes after soman exposure, stopped seizures and increased survival rate from 64% to 100%.

oxime HI-6


Input: LY293558 also prevented neuronal loss in the amygdala and hippocampus, and reduced neurodegeneration in a number of brain regions studied 7 days after soman exposure.


Input: Analysis of the LY293558 pharmacokinetics after intramuscular administration showed that this compound readily crosses the blood-brain barrier.


Input: There was good correspondence between the time course of seizure suppression by LY293558 and the brain levels of the compound.


Input: Regulation of a viral proteinase by a peptide and DNA in one-dimensional space: II. adenovirus proteinase is activated in an unusual one-dimensional biochemical reaction.


Input: Late in an adenovirus infection, the viral proteinase (AVP) becomes activated to process virion precursor proteins used in virus assembly.


Input: AVP is activated by two cofactors, the viral DNA and pVIc, an 11-amino acid peptide originating from the C terminus of the precursor protein pVI.

pVIc

amino acid

C


Input: There is a conundrum in the activation of AVP in that AVP and pVI are sequence-independent DNA-binding proteins with nm equilibrium dissociation constants such that in the virus particle, they are predicted to be essentially irreversibly bound to the viral DNA.


Input: Here, we resolve that conundrum by showing that activation of AVP takes place on the one-dimensional contour of DNA.


Input: In vitro, pVI, a substrate, slides on DNA via one-dimensional diffusion, D (1) = 1. 45 x 10 (6) bp (2)/s, until it binds to AVP also on the same DNA molecule.


Input: AVP, partially activated by being bound to DNA, excises pVIc, which binds to the AVP molecule that cut it out.

pVIc


Input: pVIc then forms a disulfide bond with AVP forming the fully active AVP-pVIc complex bound to DNA.

pVIc

disulfide

pVIc


Input: In vivo, in heat-disrupted immature virus, AVP was also activated by pVI in DNA-dependent reactions.


Input: This activation mechanism illustrates a new paradigm for virion maturation and a new way, by sliding on DNA, for bimolecular complexes to form among proteins not involved in DNA metabolism.


Input: Grafting efficiency of synthetic polymers onto biomaterials: a comparative study of grafting-from versus grafting-to.


Input: In the present study, the two grafting techniques grafting-from-by activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP)-and grafting-to-by copper (I)-catalyzed azide-alkyne cycloaddition (CuAAC)-were systematically compared, employing cellulose as a substrate.

copper (I)

azide-alkyne


Input: In order to obtain a meaningful comparison, it is crucial that the graft lengths of the polymers that are grafted from and to the substrates are essentially identical.


Input: Herein, this was achieved by utilizing the free polymer formed in parallel to the grafting-from reaction as the polymer for the grafting-to reaction.


Input: Four graft lengths were investigated, and the molar masses of the four free polymers (21 <= M (n) <= 100 kDa; 1. 07 <= D (M) <= 1. 26), i. e. the polymers subsequently employed in the grafting-to reaction, were shown to be in the same range as the molar masses of the polymers grafted from the surface (23 <= M (n) <= 87 kDa; 1. 08 <= D (M) <= 1. 31).


Input: The molecular weights of the chains grafted from the surface were established after cleavage from the cellulose substrates via size exclusion chromatography (SEC).


Input: High-resolution Fourier transform infrared microscopy (FT-IRM) was employed as an efficient tool to study the spatial distribution of the polymer content on the grafted substrates.


Input: In addition, the functionalized substrates were analyzed by X-ray photoelectron spectroscopy (XPS), contact angle (CA) measurements, and field-emission scanning electron microscopy (FE-SEM).


Input: For cellulose substrates modified via the grafting-from approach, the content of polymer on the surfaces increased with increasing graft length, confirming the possibility to tailor not only the length of the polymer grafts but also the polymeric content on the surface.


Input: In comparison, for the grafting-to reaction, the grafted content could not be controlled by varying the length of the preformed polymer: the polymer content was essentially the same for the four graft lengths.


Input: Consequently, the obtained results, when employing cellulose as a substrate and under these conditions, suggest that the grafting-from approach is superior to the grafting-to technique with respect to controlling the distribution of the polymeric content on the surface.


Input: A temporary decrease in mineral density in perinatal mouse long bones.


Input: Fetal and postnatal bone development in humans is traditionally viewed as a process characterized by progressively increasing mineral density.


Input: Yet, a temporary decrease in mineral density has been described in the long bones of infants in the immediate postnatal period.


Input: The mechanism that underlies this phenomenon, as well as its causes and consequences, remain unclear.


Input: Using daily mu CT scans of murine femora and tibiae during perinatal development, we show that a temporary decrease in tissue mineral density (TMD) is evident in mice.


Input: By monitoring spatial and temporal structural changes during normal growth and in a mouse strain in which osteoclasts are non-functional (Src-null), we show that endosteal bone resorption is the main cause for the perinatal decrease in TMD.


Input: Mechanical testing revealed that this temporary decrease is correlated with reduced stiffness of the bones.


Input: We also show, by administration of a progestational agent to pregnant mice, that the decrease in TMD is not the result of parturition itself.


Input: This study provides a comprehensive view of perinatal long bone development in mice, and describes the process as well as the consequences of density fluctuation during this period.


Input: The early mouse 3D osteocyte network in the presence and absence of mechanical loading.


Input: Osteocytes are considered to act as mechanosensory cells in bone.


Input: They form a functional synctia in which their processes become interconnected to constitute a three-dimensional (3D) network.


Input: Previous studies reported that in mice, the two-dimensional osteocyte network becomes progressively more regular as they grow, although the key factors governing the arrangement of the osteocyte network during bone growth remain unknown.


Input: In this study, we characterized the 3D formation of the osteocyte network during bone growth.


Input: Morphological skeletal changes have been reported to occur in response to mechanical loading and unloading.


Input: In order to evaluate the effect of mechanical unloading on osteocyte network formation, we subjected newborn mice to sciatic neurectomy in order to immobilize their left hind limb as an unloading model.


Input: The osteocyte network was visualized by staining osteocyte cell bodies and processes with fluorescently labeled phalloidin.

phalloidin


Input: First, we compared the osteocyte network in the femora of embryonic and 6-week-old mice in order to understand the morphological changes that occur with normal growth and mechanical loading.


Input: In embryonic mice, the osteocyte network in the femur cortical bone displayed a random cell body distribution, non-directional orientation of cell processes, and irregularly shaped cells.


Input: In 6-week-old mice, the 3D network contained spindle-shaped osteocytes, which were arranged parallel to the longitudinal axis of the femur.


Input: In addition, more and longer cell processes radiated from each osteocyte.


Input: Second, we compared the cortical osteocyte networks of 6-week-old mice that had or had not undergone sciatic neurectomy in order to evaluate the effect of unloading on osteocyte network formation.


Input: The osteocyte network formation in both cortical bone and cancellous bone was affected by mechanical loading.


Input: However, there were differences in the extent of network formation between cortical bone and cancellous bone in response to mechanical loading with regard to the orientation, nuclear shape and branch formation.


Input: Ketamine combinations for the field treatment of soman-induced self-sustaining status epilepticus.

Ketamine

soman


Input: Review of current data and perspectives.


Input: Organophosphorus nerve agents (NA), potent irreversible cholinesterase inhibitors, could induce severe seizures, status epilepticus (SE), seizure-related brain damage (SRBD) and lethality.

Organophosphorus


Input: Despite the lack of data in the case of NA, clinical evidences suggest that SE survivors could suffer from neurological/cognitive deficits and impairments such as spontaneous recurrent seizures (epilepsy) after a latent period of epileptogenesis.


Input: It is beyond doubt that an effective and quick management of the initial seizures and prevention of SRBD are critical to prevent these long-term consequences, explaining why most experimental data are focusing on the 5-40min post-exposure time frame.


Input: However, in field conditions, treatment may be delayed and with the exception of NMDA receptor antagonists, currently no drug provides protection (against lethality, seizures, SRBD and neurological consequences) when seizures are left unabated for one hour or more.

NMDA


Input: Ketamine (KET) is the only NMDA antagonist licensed as an injectable drug in different countries and remains an anesthetic of choice in some difficult field conditions.

Ketamine

KET

NMDA


Input: In this short review paper, after a presentation of some of the key points of the pathophysiology of NA-induced SE and a quick survey of the potential therapeutic avenues in the context of delayed treatment of NA-induced SE, we will review the recent data we obtained showing that KET, in combination with atropine sulfate (AS), with or without a benzodiazepine, considerably reduces soman-induced neuroinflammation, provides neuroprotection, histologically and functionally, and also positively modify soman-induced changes in brain metabolism.

KET

atropine sulfate

benzodiazepine

soman

soman


Input: Finally, we will also mention some results from safety studies including those bringing evidence that, at difference with MK-801, KET does not impair thermoregulation and even seems to reduce AS-induced heat stress.

KET


Input: All in all, KET, in combination, appears a good candidate for the out-of-hospital treatment of severe NA-induced SE.

KET


Input: A cross-linked polymeric micellar delivery system for cisplatin (IV) complex.

cisplatin (IV)


Input: A polymeric cisplatin (IV) prodrug in the form of cross-linked micelles (M (Pt (IV)) was prepared by first constructing MPEG-b-PCL-b-PLL micelles and then attaching a cisplatin (IV) complex with two axial succinic moieties to the lysine residues of the carrier polymer in aqueous medium.

cisplatin (IV)

Pt (IV)

cisplatin (IV)


Input: The micelles obtained were characterized by TEM, DLS, and zeta potential measurement.


Input: Their in vitro release experiments were carried out at pH 7. 4 and 5. 0 or in the presence of 5mM sodium ascorbate (NaAsc).

sodium ascorbate

NaAsc


Input: Results showed that the micelles were sensitive to both acidic hydrolysis and mild reducing agents; in the presence of 5mM NaAsc, cisplatin (II) was directly released and the released cisplatin (II) could chelate with nucleobases; the micelles displayed comparable cytotoxicities to cisplatin; and the micelles were much more efficiently internalized by the cells than cisplatin (II) and cisplatin (IV) counterparts.

cisplatin (II)

cisplatin (II)

nucleobases

cisplatin

cisplatin (II)

cisplatin (IV)


Input: Moreover, in vivo study showed accumulation of more Pt species in the tumor site and lower systematic toxicity compared to free cisplatin (II) and cisplatin (IV).

cisplatin (II)

cisplatin (IV)


Input: This polymeric prodrug of cisplatin is expected to be used more for future study and applications.

cisplatin


Input: Design, synthesis and biological evaluation of benzothiazepinones (BTZs) as novel non-ATP competitive inhibitors of glycogen synthase kinase-3 beta (GSK-3 beta).

benzothiazepinones

BTZs

ATP


Input: Glycogen synthase kinase-3 beta (GSK-3 beta) plays a key role in type II diabetes and Alzheimer' s diseases, to which non-ATP competitive inhibitors represent an effectively therapeutical approach due to their good specificity.

ATP


Input: Herein, a series of small molecules benzothiazepinones (BTZs) as novel non-ATP competitive inhibitors of GSK-3 beta have been designed and synthesized.

benzothiazepinones

BTZs

ATP


Input: The in vitro evaluation performed by luminescent assay showed most BTZ derivatives have inhibitory effects in micromolar scale.

BTZ


Input: Among them compounds 6l, 6t and 6v have the IC50 values of 25. 0 mu M, 27. 8 mu M and 23. 0 mu M, respectively.


Input: Moreover 6v is devoid of any inhibitory activity in the assays to other thirteen protein kinases.


Input: Besides, SAR is analyzed and a hypothetical enzymatic binding mode is proposed by molecular docking study, which would be useful for new candidates design.


Input: The cholinergic and non-cholinergic effects of organophosphates and oximes in cultured human myoblasts.

organophosphates

oximes


Input: Organophosphorus compounds (OPs) and oximes may interfere with other molecules than AChE in the living systems, affecting in this way various cellular processes and underlying mechanisms.

Organophosphorus

oximes


Input: These non-cholinergic effects may contribute to the clinical status in OP poisoning and therefore deserve equal scientific attention.


Input: Here, we investigated the effects of tabun and oxime K048 on the processes known to be involved in muscle response to the environmental factors, like IL-6 release and the regulation of the heat shock proteins (HSPs).

tabun

oxime K048


Input: While IL-6 stimulates muscle regeneration, which follows well known OP-induced myopathy, HSPs have cytoprotective effect against various stress factors including xenobiotics.


Input: All our experiments were carried out on cultured human myoblasts, as the precursors of muscle regeneration.


Input: We found unchanged AChE mRNA level after tabun/K048 treatment meaning that tabun and K048 did not interfere with the transcription or stability of this mRNA in the time period tested, even if AChE catalytic activity was significantly affected.

tabun

tabun


Input: On the other hand, after myoblast exposure to tabun, we observed significant changes in the protein levels of HSP 27 and in the secretion of IL-6.

tabun


Input: Namely, secretion of IL-6 decreased to 53% and the level of HSP 27 increased by 34% compared to the control level.


Input: Both effects were attenuated if myoblasts were pretreated with oxime K048, but not if they were treated with K048 after exposure to tabun.

oxime K048

tabun


Input: The molecular mechanism underlying these effects remains to be elucidated.


Input: However, it seems that these effects could be associated with OPs and oximes as a specific group of compounds rather than as a specific compound itself.

oximes


Input: Overall, the effects of OPs and oximes demonstrated here might play an important role in muscle regeneration which importantly determines the final outcome of OP myotoxicity.

oximes


Input: A versatile multicomponent assembly via beta-cyclodextrin host-guest chemistry on graphene for biomedical applications.

beta-cyclodextrin

graphene


Input: A multi-component nanosystem based on graphene and comprising individual cyclodextrins at its surface is assembled, creating hybrid structures enabling new and important functionalities: optical imaging, drug storage, and cell targeting for medical diagnosis and treatment.

graphene


Input: These nanohybrids are part of a universal system of interchangeable units, capable of mutilple functionalities.


Input: The surface components, made of individual beta-cyclodextrin molecules, are the " hosts " for functional units, which may be used as imaging agents, for anti-cancer drug delivery, and as tumor-specific ligands.

beta-cyclodextrin


Input: Specifically, individual beta-cyclodextrin (beta-CD), with a known capability to host various molecules, is considered a module unit that is assembled onto graphene nanosheet (GNS).

beta-cyclodextrin

beta-CD

graphene


Input: The cyclodextrin-functionalized graphene nanosheet (GNS/beta-CD) enables " host-guest " chemistry between the nanohybrid and functional " payloads ".

graphene

beta-CD


Input: The structure, composition, and morphology of the graphene nanosheet hybrid have been investigated.

graphene


Input: The nanohybrid, GNS/beta-CD, is highly dispersive in various physiological solutions, reflecting the high biostability of cyclodextrin.

beta-CD


Input: Regarding the host capability, the nanohybrid is fully capable of selectively accommodating various biological and functional agents in a controlled fashion, including the antivirus drug amantadine, fluorescent dye [5 (6)-carboxyfluorescein], and Arg-Gly-Asp (RGD) peptide-targeting ligands assisted by an adamantine linker.

amantadine

5 (6)-carboxyfluorescein

Arg-Gly-Asp

adamantine


Input: The loading ratio of 5 (6)-carboxyfluorescein is as high as 110% with a drug concentration of 0. 45 mg mL (-1).

5 (6)-carboxyfluorescein


Input: The cyclic RGD-functionalized nanohybrid exhibits remarkable targeting for HeLa cells.

cyclic RGD


Input: L-BMAA induced ER stress and enhanced caspase 12 cleavage in human neuroblastoma SH-SY5Y cells at low nonexcitotoxic concentrations.

L-BMAA


Input: The cyanobacterial beta-N-methylamino-L-alanine (L-BMAA) is described as a low-potency excitotoxin, possibly a factor in the increased incidence of amyotrophic lateral sclerosis (ALS) and Parkinsonism-dementia complex (PDC) in Guam.

beta-N-methylamino-L-alanine

L-BMAA


Input: The latter association is intensively disputed, as L-BMAA concentrations required for toxic effects exceed those assumed to occur via food.

L-BMAA


Input: The question thus was raised whether L-BMAA leads to neurodegeneration at nonexcitotoxic conditions.

L-BMAA


Input: Using human SH-SY5Y neuroblastoma cells, L-BMAA-transport, incorporation into proteins, and subsequent impairment of cellular protein homeostasis were investigated.

L-BMAA


Input: Binding of L-BMAA to intracellular proteins, but no clear protein incorporation was detected in response to (14) C-L-BMAA exposures.

L-BMAA

(14) C

L-BMAA


Input: Nevertheless, low L-BMAA concentrations (>= 0. 1mM, 48 h) increased protein ubiquitination, 20S proteasomal and caspase 12 activity, expression of the endoplasmic reticulum (ER) stress marker CHOP, and enhanced phosphorylation of elf2 alpha in SH-SY5Y cells.

L-BMAA


Input: In contrast, high L-BMAA concentrations (>= 1mM, 48 h) increased reactive oxygen species and protein oxidization, which were partially ameliorated by coincubation with vitamin E.

L-BMAA

oxygen

vitamin E


Input: L-BMAA-mediated cytotoxicity was observable 48 h following >= 2mM L-BMAA treatment.

L-BMAA

L-BMAA


Input: Consequently, the data presented here suggest that low L-BMAA concentrations result in a dysregulation of the cellular protein homeostasis with ensuing ER stress that is independent from high-concentration effects such as excitotoxicity and oxidative stress.

L-BMAA


Input: Thus, the latter could be a contributing factor in the onset and slow progression of ALS/PDC in Guam.


Input: Ribavirin-induced intracellular GTP depletion activates transcription elongation in coagulation factor VII gene expression.

Ribavirin

GTP


Input: Coagulation FVII (Factor VII) is a vitamin K-dependent glycoprotein synthesized in hepatocytes.

vitamin K


Input: It was reported previously that FVII gene (F7) expression was up-regulated by ribavirin treatment in hepatitis C virus-infected haemophilia patients; however, its precise mechanism is still unknown.

ribavirin


Input: In the present study, we investigated the molecular mechanism of ribavirin-induced up-regulation of F7 expression in HepG2 (human hepatoma cell line).

ribavirin


Input: We found that intracellular GTP depletion by ribavirin as well as other IMPDH (inosine-5'-monophosphate dehydrogenase) inhibitors, such as mycophenolic acid and 6-mercaptopurine, up-regulated F7 expression.

GTP

ribavirin

mycophenolic acid


Input: FVII mRNA transcription was mainly enhanced by accelerated transcription elongation, which was mediated by the P-TEFb (positive-transcription elongation factor b) complex, rather than by promoter activation.


Input: Ribavirin unregulated ELL (eleven-nineteen lysine-rich leukaemia) 3 mRNA expression before F7 up-regulation.

Ribavirin

lysine


Input: We observed that ribavirin enhanced ELL3 recruitment to F7, whereas knockdown of ELL3 diminished ribavirin-induced FVII mRNA up-regulation.

ribavirin

ribavirin


Input: Ribavirin also enhanced recruitment of CDK9 (cyclin-dependent kinase 9) and AFF4 to F7.

Ribavirin


Input: These data suggest that ribavirin-induced intracellular GTP depletion recruits a super elongation complex containing P-TEFb, AFF4 and ELL3, to F7, and modulates FVII mRNA transcription elongation.

ribavirin

GTP


Input: Collectively, we have elucidated a basal mechanism for ribavirin-induced FVII mRNA up-regulation by acceleration of transcription elongation, which may be crucial in understanding its pleiotropic functions in vivo.

ribavirin


Input: Hard-metal (WC-Co) particles trigger a signaling cascade involving p38 MAPK, HIF-1 alpha, HMOX1, and p53 activation in human PBMC.

WC

Co


Input: Hard-metals are made of tungsten carbide (WC) and metallic cobalt (Co) particles and are important industrial materials produced for their extreme hardness and high wear resistance properties.

tungsten carbide

WC

cobalt

Co


Input: While occupational exposure to metallic Co alone is apparently not associated with an increased risk of cancer, the WC-Co particle mixture was shown to increase the risk of lung cancer in exposed workers.

Co

WC

Co


Input: We have previously shown that WC-Co specifically induces a burst of reactive oxygen species (ROS) and in vitro mutagenic/apoptogenic effects in human peripheral blood mononucleated cells (PBMC) used as a validated experimental model.

WC

Co

oxygen


Input: In the present study, PBMCs were treated during a short period (15 min) to focus on the very rapid ROS burst induced by WC-Co.

WC

Co


Input: We investigated by microarray the response to WC-Co versus Co (2 +) ions (CoCl (2)) after 15 min exposure and found that the oxidative stress response HMOX1 gene was highly expressed in WC-Co-treated samples.

WC

Co

Co (2 +)

CoCl (2)

WC

Co


Input: This result was confirmed by qRT-PCR, and western blotting was carried out to analyze translational and post-translational regulation of genes belonging to the HMOX1 pathway.


Input: We show here that WC-Co, and metallic Co particles although with slower kinetics, but not CoCl (2) or WC alone, induced a temporally ordered cascade of events.

WC

Co

Co

CoCl (2)

WC


Input: This cascade implies p38/MAP kinase activation, HIF-1 alpha stabilization, HMOX1 transcriptional activation, and ATM-independent p53 stabilization.


Input: These events, and in particular HIF-1 alpha stabilization, could contribute to the carcinogenic activity of WC-Co dusts.

WC

Co


Input: Neuropeptide Y Y1 receptor knockdown can modify glutathione peroxidase and c-AMP response element-binding protein in phenylpropanolamine-treated rats.

glutathione

c-AMP

phenylpropanolamine


Input: It has been reported that antioxidative enzymes, neuropeptide Y (NPY), and c-AMP response element-binding protein (CREB) are involved in regulating phenylpropanolamine (PPA)-mediated appetite suppression.

c-AMP

phenylpropanolamine

PPA


Input: Here, we investigated whether Y1 receptor (Y1R) might be involved in this regulation.


Input: Rats were daily treated with PPA for 4 days.

PPA


Input: Changes in the contents of NPY, Y1R, glutathione peroxidase (GP), and CREB were assessed and compared.

glutathione


Input: Results showed that Y1R, GP, and CREB increased, with a maximal increase about 100, 200, and 150%, respectively, on Day 2.


Input: By contrast, NPY decreased with a biggest reduction about 48% on Day 2 and the pattern of expression during PPA treatment was opposite to those of Y1R, GP, and CREB.

PPA


Input: Central knockdown (using antisense) or inhibition (using antagonist) of Y1R expression modulated the anorectic response of PPA and the reciprocal regulation between NPY and GP (or CREB), revealing an essential role of Y1R in regulating NPY, GP, and CREB.

PPA


Input: These results suggest that Y1R participates in the reciprocal regulation of NPY, GP, and CREB in the hypothalamus during PPA treatment in conscious rats.

PPA


Input: The present results may aid the therapeutic research of PPA and related antiobesity drugs.

PPA


Input: Enhanced light focusing in self-assembled optoplasmonic clusters with subwavelength dimensions.


Input: Compact metallo-dielectric hybrid clusters with subwavelength dimensions are fabricated by template guided self-assembly.


Input: Elastic and inelastic scattering spectroscopy and electromagnetic simulations reveal that hybrid clusters comprising TiO (2) nanoparticles on top of a cluster of strongly coupled gold nanoparticles harness synergistic electromagnetic interactions between the building blocks.

TiO (2)


Input: This results in a boost of the peak electric field intensity and a redistribution of the field in the ambient medium.


Input: The complex phase landscape in the clusters features optical vortices that enhance the magnetic field.


Input: Alternative copolymerization of a conjugated segment and a flexible segment and fabrication of a fluorescent sensing film for HCl in the vapor phase.

HCl


Input: A novel fluorescently active co-oligomer (P1) was designed and prepared by alternative co-polymerization of oligo (p-phenyleneethynylene) (OPE), possessing two cholesterol-containing side chains, and ethanediamine.

oligo (p-phenyleneethynylene)

OPE

cholesterol

ethanediamine


Input: A control co-oligomer (P2) possessing similar structure to P1 was also prepared, but in this case the OPE bears no side chains.

OPE


Input: P1 and P2 have been used for the fabrication of two fluorescent films, film 1 and film 2, respectively.


Input: Fluorescence studies demonstrated that the emission of film 1 is sensitive and selective to the presence of trace amounts of HCl in air.

HCl


Input: In contrast, film 2 shows no such response.


Input: The quenching has been attributed to the protonation of the imino groups within the oligomer chains, and the difference in the sensing behaviors of the two films was rationalized by supposing the existence of molecular channels in film 1.

imino


Input: The proposed mechanism is supported by the results from additional experiments and theoretical calculations.


Input: Furthermore, the film as fabricated is robust, and thereby it is believed that film 1 has the potential to be developed into a new generation of sensitive and selective HCl sensor.

HCl


Input: Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents.

angiotensin IV


Input: Angiotensin IV (AngIV: VYIHPF)-related peptides have long been recognized as procognitive agents with potential as antidementia therapeutics.

Angiotensin IV

AngIV


Input: Their development as useful therapeutics, however, has been limited by physiochemical properties that make them susceptible to metabolic degradation and impermeable to gut and blood-brain barriers.


Input: A previous study demonstrated that the core structural information required to impart the procognitive activity of the AngIV analog, norleucine (1)-angiotensin IV, resides in its three N-terminal amino acids, Nle-Tyr-Ile.

AngIV

norleucine

angiotensin IV

N

amino acids

Nle-Tyr-Ile


Input: The goal of this project was to chemically modify this tripeptide in such a way to enhance its metabolic stability and barrier permeability to produce a drug candidate with potential clinical utility.

tripeptide


Input: Initial results demonstrated that several N-and C-terminal modifications lead to dramatically improved stability while maintaining the capability to reverse scopolamine-induced deficits in Morris water maze performance and augment hippocampal synaptogenesis.

N

C

scopolamine


Input: Subsequent chemical modifications, which were designed to increase hydrophobicity and decrease hydrogen bonding, yielded an orally active, blood-barrier permeant, metabolically stabilized analog, N-hexanoic-Tyr-Ile-(6) aminohexanoic amide (dihexa), that exhibits excellent antidementia activity in the scopolamine and aged rat models and marked synaptogenic activity.

hydrogen

N-hexanoic-Tyr-Ile-(6) aminohexanoic amide

dihexa

scopolamine


Input: These data suggest that dihexa may have therapeutic potential as a treatment of disorders, such as Alzheimer' s disease, where augmented synaptic connectivity may be beneficial.

dihexa


Input: A new approach to counteract bacteria resistance: a comparative study between moxifloxacin and a new moxifloxacin derivative in different model systems of bacterial membrane.

moxifloxacin

moxifloxacin


Input: New drug design has been one of the major challenges to combat bacterial resistance over the past decade.


Input: Conventional antibiotics act by destroying bacterial cell wall or by blocking biosynthetic pathways necessary for its survival.


Input: Unfortunately, there has been a fast increase in multiresistance, to several conventional antibiotics, in clinical bacterial strains.


Input: Previous studies have shown that metalloantibiotics, ternary complexes of antibiotic-metal-phenanthroline, present an increased potential as antimicrobial agents.

phenanthroline


Input: In this work moxifloxacin, a fourth-generation quinolone, with a broad spectrum of action, and its copper ternary complex (metalloantibiotic) have been study by fluorescence spectroscopy.

moxifloxacin

quinolone

copper


Input: Partition coefficients were determined and showed that while free moxifloxacin exhibits the same behaviour independently of the lipidic system tested, the metalloantibiotic presents higher partition to liposomes, in a lipid composition-dependent way.

moxifloxacin


Input: These significant differences in the interaction of the metalloantibiotic with model bacteria membranes point out for a putative change in its uptake mechanism with increased drug-lipid interaction potentiating metalloantibiotic influx.


Input: A comprehensive study to evaluate the effect of constant low voltage iontophoresis on transungual delivery.


Input: Treatment of nail diseases by topical drug delivery continues to draw much attention in the recent days.


Input: This study aims to systematically investigate the effect of constant voltage iontophoresis in the transungual drug delivery, using ciclopirox as a model drug.

ciclopirox


Input: Preliminary permeation studies were carried out by applying constant voltage (6 V for 24 h) using a gel formulation across the human nail plate in a Franz diffusion cell.


Input: Different protocols have been studied to authenticate the potential of the proposed technique.


Input: Antifungal studies were carried out to assess the pharmacodynamic effect of drug depot formed in the nail plate.


Input: Initial studies revealed that application of constant voltage iontophoresis enhanced the permeation by an order of magnitude (p = 0. 019) and delivered significant amount of drug into the deeper nail layers.


Input: Noticeably higher permeation was observed during the active phase in on-off studies.


Input: Excellent correlation was observed in permeation (r (2) = 0. 98) and drug load (r (2) = 0. 97) with the increase in applied voltage (3-12 V), indicating that the current technique is predictable.


Input: The data observed suggest that any further increase in voltage could eventually lead to increase in the permeation and drug load, as the saturation level is very distant.


Input: Furthermore, the enhancement in permeation with the applied voltage (3-12 V) was found to be 6-20 folds, compared to the passive process.


Input: Results of step up and step down studies substantiated the viability of the current technique.


Input: Zone of inhibition measured during the antifungal studies demonstrated that the drug molecules loaded into the nail plate by low voltage iontophoresis is active and releases over an extended period of time (~ 32 days).


Input: Given the excellent results, the current technique could be used as an effective approach for the delivery of antimycotics, which would localize the drug at the infection site and potentially offer higher patient compliance.


Input: Non-enzymatic proteins from snake venoms: a gold mine of pharmacological tools and drug leads.


Input: Non-enzymatic proteins from snake venoms play important roles in the immobilization of prey, and include some large and well-recognized families of toxins.


Input: The study of such proteins has expanded not only our understanding of venom toxicity, but also the knowledge of normal and disease states in human physiology.


Input: In many cases their characterization has led to the development of powerful research tools, diagnostic techniques, and pharmaceutical drugs.


Input: They have further yielded basic understanding of protein structure-function relationships.


Input: Therefore a number of studies on these non-enzymatic proteins had major impact on several life science and medical fields.


Input: They have led to life-saving therapeutics, the Nobel prize, and development of molecular scalpels for elucidation of ion channel function, vasoconstriction, complement system activity, platelet aggregation, blood coagulation, signal transduction, and blood pressure regulation.


Input: Here, we identify research papers that have had significant impact on the life sciences.


Input: We discuss how these findings have changed the course of science, and have also included the personal recollections of the original authors of these studies.


Input: We expect that this review will provide impetus for even further exciting research on novel toxins yet to be discovered.


Input: The effect of CCL3 and CCR1 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice.


Input: Bone remodeling is affected by mechanical loading and inflammatory mediators, including chemokines.


Input: The chemokine (C-C motif) ligand 3 (CCL3) is involved in bone remodeling by binding to C-C chemokine receptors 1 and 5 (CCR1 and CCR5) expressed on osteoclasts and osteoblasts.


Input: Our group has previously demonstrated that CCR5 down-regulates mechanical loading-induced bone resorption.


Input: Thus, the present study aimed to investigate the role of CCR1 and CCL3 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice.


Input: Our results showed that bone remodeling was significantly decreased in CCL3 (-/-) and CCR1 (-/-) mice and in animals treated with Met-RANTES (an antagonist of CCR5 and CCR1).

Met


Input: mRNA levels of receptor activator of nuclear factor kappa-B (RANK), its ligand RANKL, tumor necrosis factor alpha (TNF-alpha) and RANKL/osteoprotegerin (OPG) ratio were diminished in the periodontium of CCL3 (-/-) mice and in the group treated with Met-RANTES.

Met


Input: Met-RANTES treatment also reduced the levels of cathepsin K and metalloproteinase 13 (MMP13).

Met


Input: The expression of the osteoblast markers runt-related transcription factor 2 (RUNX2) and periostin was decreased, while osteocalcin (OCN) was augmented in CCL3 (-/-) and Met-RANTES-treated mice.

Met


Input: Altogether, these findings show that CCR1 is pivotal for bone remodeling induced by mechanical loading during orthodontic tooth movement and these actions depend, at least in part, on CCL3.


Input: A sensitive H2O2 assay based on dumbbell-like PtPd-Fe3O4 nanoparticles.


Input: Dumbbell-like Pt (48) Pd (52)-Fe (3) O (4) nanoparticles are synthesized and functionalized with oleylamine-polyethyleneglycol to serve as an efficient catalyst for H (2) O (2) reduction and tetramethylbenzidine (TMB) oxidation in biological solutions.

Pt (48) Pd (52)-Fe (3) O (4)

oleylamine

polyethyleneglycol

H (2) O (2)

tetramethylbenzidine

TMB


Input: The Pt (48) Pd (52)-Fe (3) O (4)/TMB kit is even more active than the natural enzyme for H (2) O (2) detection with a detection limit reaching 2 mu M, and is successfully used to quantitatively monitor the extracellular H (2) O (2) generated by neutrophils.

Pt (48) Pd (52)-Fe (3) O (4)

TMB

H (2) O (2)

H (2) O (2)


Input: Organosilicon molecules with medicinal applications.

Organosilicon


Input: The incorporation of silicon and synthesis of organosilicon small molecules provide unique opportunities for medicinal applications.

silicon

organosilicon


Input: The biological investigation of organosilicon small molecules is particularly interesting because of differences in their chemical properties that can contribute to enhanced potency and improved pharmacological attributes.

organosilicon


Input: Applications such as inhibitor design, imaging, drug release technology, and mapping inhibitor binding are discussed.


Input: Menthol--pharmacology of an important naturally medicinal " cool ".

Menthol


Input: Menthol, a natural product of the peppermint plant Mentha x piperita (Lamiaceae), is a monoterpene which is widely used as a natural product in cosmetics, a flavoring agent, and as an intermediate in the production of other compounds.

Menthol

monoterpene


Input: Various extracts from peppermint contain menthol as a major active constituent and have been used for centuries as traditional medicines for a number of ailments including infections, insomnia, and irritable bowel syndrome as well as an insect repellent.

menthol


Input: Menthol' s characteristic cooling sensation is due, in part, to the activation of sensory neurons generally termed transient receptor potential (TRP) channels, in particular transient receptor potential melastatin family member 8 (TRPM8) and transient receptor potential subfamily A, member 1 (TRPA1).

Menthol


Input: Menthol acts upon TRPM8 receptors by rapidly increasing intracellular calcium and mobilizing calcium flux through the channels to induce cold response signals at the application site.

calcium

calcium


Input: Aside from its cold-inducing sensation capabilities, menthol exhibits cytotoxic effects in cancer cells, induces reduction in malignant cell growth, and engages in synergistic excitation of GABA receptors and sodium ion channels resulting in analgesia.

menthol

GABA

sodium


Input: Notwithstanding its plethora of benefits, menthol' s coldsensitivity response mechanism has been shown to inhibit mucosal recognition of nicotine and cigarette toxins common in mentholated cigarette brands thus potentially leading to toxic effects.

menthol

nicotine


Input: Menthol may prove a valuable lead structure for the synthesis of drugs that target multiple receptors involved with a number of pharmacological effects.

Menthol


Input: Biomarkers in marine mussels, Mytilus galloprovincialis, exposed to environmentally relevant levels of the pesticides, chlorpyrifos and penoxsulam.

chlorpyrifos

penoxsulam


Input: The present study examines the influence of environmentally relevant concentrations of two pesticides, chlorpyrifos and penoxsulam on mussel physiological status.

chlorpyrifos

penoxsulam


Input: For this reason, lysosomal membrane stability (LMS), reactive oxygen species (ROS), DNA damage, protein carbonylation (PCC) and antioxidant capacity (TAC) in hemaolymph and hemocytes of the mussels was measured.

oxygen


Input: Mussels were exposed to a range of concentrations of the pesticides chlorpyrifos and penoxsulam and the response of animals to the destabilization of lysosomal membrane in hemocytes (LMS) was studied.

chlorpyrifos

penoxsulam


Input: Subsequently, the half maximal effective concentration (EC50) for both pesticides was calculated.


Input: The animals were subsequently exposed for 0, 1, 3, 5, 7, 15 and 30 days to 10 times less concentration than EC50 of each pesticide (0. 05 mu g/l) and changes in LMS, ROS, DNA damage, protein carbonylation and antioxidant capacity of mussels was evaluated.


Input: Our results showed a significant change in the response of mussels for all parameters tested after 30 days exposure, in relation to the controls.


Input: The pesticides at the environmental concentrations used induced changes to the animal physiology through causing oxidative stress and lysosomal abnormalities and their usage in the agriculture demands great care.


Input: In addition, the results show that ROS, DNA damage, protein carbonylation and antioxidant capacity could constitute, after further investigation, reliable biomarkers for the evaluation of pollution or other environmental stressors.


Input: Two stressors and a community: effects of hydrological disturbance and a toxicant on freshwater zooplankton.


Input: Climate change models predict an increase in the frequency and intensity of extreme fluctuations in water level in aquatic habitats.


Input: Therefore, it is necessary to understand the combined effects of hydrological fluctuations and toxicants on aquatic biological communities.


Input: We investigated the individual and combined effects of the insecticide esfenvalerate and recurring fluctuations in water level on zooplankton communities in a system of 55 outdoor pond microcosms.

esfenvalerate


Input: The communities were exposed to esfenvalerate contamination as a single pulse (at 0. 03, 0. 3, or 3 mu g/L) and gradual removal of water and its subsequent replacement over three cycles and monitored until 84 days after contamination.

esfenvalerate


Input: The results showed that the sensitivities of the community and its constituent populations to the toxicant were increased by the hydrological stress.


Input: Specifically, for both the community structure and abundance of Daphnia spp. the lowest-observed-effect concentrations (LOEC) were 0. 03 and 0. 3 mu g/L for the series with fluctuating and constant water levels, respectively.


Input: Despite these differences in sensitivity, the interactive effects of the two stressors were found to be additive for both the community structure and the abundance of the most affected species.


Input: Presumably, it was not possible to detect synergism due to the strong individual effects of the water level fluctuations.


Input: Recovery times in the series exposed to the highest pesticide concentration were 64 and 55 days under fluctuating and constant water level regimes, respectively.


Input: Competition and water quality are suggested to be the major factors that underlie the observed effects of fluctuations in the water level.


Input: For the ecological risk assessment of toxicants, the present results suggest that (i) community sensitivity may vary substantially, depending on the environmental context, and (ii) this variability can be assessed experimentally to derive safety factors (coefficients used to avoid unexpected effects and define safe concentrations of toxicants) based on empirical findings.


Input: This contrasts with the current approach where such factors are usually defined arbitrarily.


Input: Parental exposure to natural mixtures of POPs reduced embryo production and altered gene transcription in zebrafish embryos.


Input: Determination of toxicity of complex mixtures has been proposed to be one of the most important challenges for modern toxicology.


Input: In this study we performed genome wide transcriptome profiling to assess potential toxicant induced changes in gene regulation in zebrafish embryos following parental exposure to two natural mixtures of persistent organic pollutants (POPs).


Input: The mixtures used were extracted from burbot (Lota lota) liver originating from two lakes (Lake Mj o sa and Lake Losna) belonging to the same freshwater system in Norway.


Input: The dominating groups of contaminants were polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs) and dichlorodiphenyltrichloroethane metabolites (DDTs).

polybrominated diphenyl ethers

PBDEs

polychlorinated biphenyls

PCBs

dichlorodiphenyltrichloroethane


Input: Because both mixtures used in the present study induced similar effects, it is likely that the same toxicants are involved.


Input: The Mj o sa mixture contains high levels of PBDEs while this group of pollutants is low in the Losna mixture.

PBDEs


Input: However, both mixtures contain substantial concentrations of PCB and DDT suggesting these contaminants as the predominant contributors to the toxicity observed.

PCB

DDT


Input: The observed effects included phenotypic traits, like embryo production and survival, and gene transcription changes corresponding with disease and biological functions such as cancer, reproductive system disease, cardiovascular disease, lipid and protein metabolism, small molecule biochemistry and cell cycle.


Input: The changes in gene transcription included genes regulated by HNF4A, insulin, LH, FSH and NF-kappa B which are known to be central regulators of endocrine signaling, metabolism, metabolic homeostasis, immune functions, cancer development and reproduction.


Input: The results suggest that relative low concentrations of the natural mixtures of POPs used in the present study might pose a threat to wild freshwater fish living in the lakes from which the POPs mixtures originated.


Input: Characterisation of the roles of ABCB1, ABCC1, ABCC2 and ABCG2 in the transport and pharmacokinetics of actinomycin D in vitro and in vivo.

actinomycin D


Input: Actinomycin D plays a key role in the successful treatment of Wilms tumour.

Actinomycin D


Input: However, associated liver toxicities remain a drawback to potentially curative treatment.


Input: We have used MDCKII cells over-expressing ABCB1, ABCC1, ABCC2 and ABCG2, alongside knockout mouse models to characterise actinomycin D transport and its impact on pharmacokinetics.

actinomycin D


Input: Growth inhibition, intracellular accumulation and cellular efflux assays were utilised.


Input: A 59-fold difference in GI (50) was observed between MDCKII-WT and MDCKII-ABCB1 cells (12. 7 nM vs. 745 nM, p < 0. 0001).


Input: Reduced sensitivity was also seen in MDCKII-ABCC1 and ABCC2 cells (GI (50) 25. 7 and 40. 4 nM respectively, p < 0. 0001).


Input: Lower intracellular accumulation of actinomycin D was observed in MDCKII-ABCB1 cells as compared to MDCKII-WT (0. 98 nM vs. 0. 1 nM, p < 0. 0001), which was reversed upon ABCB1 inhibition.

actinomycin D


Input: Lower accumulation was also seen in MDCKII-ABCC1 and ABCC2 cells.


Input: Actinomycin D efflux over 2 h was most pronounced in MDCKII-ABCB1 cells, with 5. 5-fold lower intracellular levels compared to WT.

Actinomycin D


Input: In vivo studies showed that actinomycin D plasma concentrations were significantly higher in Abcb1a/1b (-/-) as compared to WT mice following administration of 0. 5 mg/kg actinomycin D (AUC (0-6 h) 242 vs. 152 mu g/Lh respectively).

actinomycin D

actinomycin D


Input: While comparable actinomycin D concentrations were observed in the kidneys and livers of Abcb1a/1b (-/-) and Abcc2 (-/-) mice, concentrations in the brain were significantly higher at 6h following drug administration in Abcb1a/1b (-/-) mice compared to WT.

actinomycin D


Input: Results confirm actinomycin D as a substrate for ABCB1, ABCC1 and ABCC2, and indicate that Abcb1a/1b and Abcc2 can influence the in vivo disposition of actinomycin D.

actinomycin D

actinomycin D


Input: These data have implications for ongoing clinical pharmacology trials involving children treated with actinomycin D.

actinomycin D


Input: Artemisinic acid inhibits melanogenesis through downregulation of C/EBP alpha-dependent expression of HMG-CoA reductase gene.

Artemisinic acid

HMG-CoA


Input: Cholesterol is associated with the regulation of melanogenesis which is the major physiological defense against solar irradiation.

Cholesterol


Input: The present study was designed to determine the effects of artemisinic acid on melanogenesis and its mechanisms of action in human epidermal melanocytes.

artemisinic acid


Input: In this study, we found that artemisinic acid inhibited melanin content.

artemisinic acid


Input: The mRNA levels of microphthalmia-associated transcription factor (MITF) and its downstream genes tyrosinase, tyrosinase-related protein (TRP)-1, and TRP-2 were reduced by artemisinic acid treatment.

artemisinic acid


Input: Additionally, the mRNA levels of melanogenesis-related genes (c-KIT, stem cell factor (SCF), and macrophage migration inhibitory factor (MIF)) were down-regulated by artemisinic acid.

artemisinic acid


Input: Furthermore, cAMP production and protein kinase A (PKA) activity were suppressed by artemisinic acid.

cAMP

artemisinic acid


Input: Moreover, attempts to elucidate a possible mechanism underlying the artemisinic acid-mediated effects revealed that artemisinic acid regulated melanogenesis by inhibiting cholesterol synthesis through downregulation of the hydroxymethylglutaryl CoA (HMG CoA) reductase gene, which was mediated through reduced expression of the CCAAT/enhancer-binding protein (C/EBP) alpha gene.

artemisinic acid

artemisinic acid

cholesterol

hydroxymethylglutaryl CoA

HMG CoA


Input: Taken together, these findings indicate that the inhibition of melanogenesis by artemisinic acid occurs through reduced expression of the HMG CoA reductase gene, which is mediated by C/EBP alpha inhibition and suggest that artemisinic acid may be useful as a hyperpigmentation inhibitor.

artemisinic acid

HMG CoA

artemisinic acid


Input: Herbacetin induces apoptosis in HepG2 cells: Involvements of ROS and PI3K/Akt pathway.

Herbacetin


Input: Herbacetin (HER) is a natural flavonoid compound that can be extracted from Ramose Scouring Rush Herb, and its biological and pharmacological activities lack of corresponding attention.

Herbacetin

HER

flavonoid


Input: In this study, the apoptotic effect of HER against the human hepatoma cell line (HepG2) was investigated.

HER


Input: The results showed that HepG2 cells apoptosis occurred in a dose-dependent manner within 48h incubated with HER, which was confirmed by DNA fragmentation, nuclear shrinkage, and poly (ADP-ribose) polymerase (PARP) cleavage.

HER

poly (ADP-ribose)


Input: HER at 25-100 mu M induced a mitochondria-dependent apoptotic pathway associated with Bcl-2/Bax ratio decrease, mitochondrial membrane potential (Delta Psi) collapse, cytochrome c release, and caspase-3 activation.

HER


Input: Increasing expression of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha) was also observed in HER-treated cells.

HER


Input: Furthermore, the addition of a ROS inhibitor (N-Acetyl-l-cysteine, NAC) significantly attenuated the apoptosis induced by HER and also blocked the expression of PGC-1 alpha protein.

N-Acetyl-l-cysteine

NAC

HER


Input: Additionally, HER effectively inhibited the phosphorylation of Akt and the phosphatidylinositol-3 kinase (PI3K) inhibitor LY294002 increased the inhibition effect of HER on Akt phosphorylation.

HER

phosphatidylinositol

HER


Input: These findings provide evidences that HER induces HepG2 apoptosis in a ROS-mediated mitochondria-dependent manner that correlate with the inactivation of the PI3K/Akt pathway.

HER


Input: Evolutionary dynamism of the primate LRRC37 gene family.


Input: Core duplicons in the human genome represent ancestral duplication modules shared by the majority of intrachromosomal duplication blocks within a given chromosome.


Input: These cores are associated with the emergence of novel gene families in the hominoid lineage, but their genomic organization and gene characterization among other primates are largely unknown.


Input: Here, we investigate the genomic organization and expression of the core duplicon on chromosome 17 that led to the expansion of LRRC37 during primate evolution.


Input: A comparison of the LRRC37 gene family organization in human, orangutan, macaque, marmoset, and lemur genomes shows the presence of both orthologous and species-specific gene copies in all primate lineages.


Input: Expression profiling in mouse, macaque, and human tissues reveals that the ancestral expression of LRRC37 was restricted to the testis.


Input: In the hominid lineage, the pattern of LRRC37 became increasingly ubiquitous, with significantly higher levels of expression in the cerebellum and thymus, and showed a remarkable diversity of alternative splice forms.


Input: Transfection studies in HeLa cells indicate that the human FLAG-tagged recombinant LRRC37 protein is secreted after cleavage of a transmembrane precursor and its overexpression can induce filipodia formation.


Input: Rapid estimation of nuclear magnetic resonance experiment time in low-concentration environmental samples.


Input: Nuclear magnetic resonance (NMR) spectroscopy is an essential tool for studying environmental samples but is often hindered by low sensitivity, especially for the direct detection of nuclei such as (13) C.

(13) C


Input: In very heterogeneous samples with NMR nuclei at low abundance, such as soils, sediments, and air particulates, it can take days to acquire a conventional (13) C spectrum.

(13) C


Input: The present study describes a prescreening method that permits the rapid prediction of experimental run time in natural samples.


Input: The approach focuses the NMR chemical shift dispersion into a single spike, and, even in samples with extremely low carbon content, the spike can be observed in two to three minutes, or less.

carbon


Input: The intensity of the spike is directly proportional to the total concentration of nuclei of interest in the sample.


Input: Consequently, the spike intensity can be used as a powerful prescreening method that answers two key questions: (1) Will this sample produce a conventional NMR spectrum?


Input: (2) How much instrument time is required to record a spectrum with a specific signal-to-noise (S/N) ratio?


Input: The approach identifies samples to avoid (or pretreat) and permits additional NMR experiments to be performed on samples producing high-quality NMR data.


Input: Applications in solid-and liquid-state (13) C NMR are demonstrated, and it is shown that the technique is applicable to a range of nuclei.

(13) C


Input: A novel EPAC-specific inhibitor suppresses pancreatic cancer cell migration and invasion.


Input: Exchange protein directly activated by cAMP (EPAC) and cAMP-dependent protein kinase (PKA) are two intracellular receptors that mediate the effects of the prototypic second messenger cAMP.

cAMP

cAMP

cAMP


Input: Identifying pharmacological probes for selectively modulating EPAC activity represents a significant unmet need within the research field.


Input: Herein, we report the identification and characterization of 3-(5-tert-butyl-isoxazol-3-yl)-2-[(3-chloro-phenyl)-hydrazono]-3-oxo-propionitrile (ESI-09), a novel noncyclic nucleotide EPAC antagonist that is capable of specifically blocking intracellular EPAC-mediated Rap1 activation and Akt phosphorylation, as well as EPAC-mediated insulin secretion in pancreatic beta cells.

3-(5-tert-butyl-isoxazol-3-yl)-2-[(3-chloro-phenyl)-hydrazono]-3-oxo-propionitrile

nucleotide


Input: Using this novel EPAC-specific inhibitor, we have probed the functional roles of overexpression of EPAC1 in pancreatic cancer cells.


Input: Our studies show that EPAC1 plays an important role in pancreatic cancer cell migration and invasion, and thus represents a potential target for developing novel therapeutic strategies for pancreatic cancer.


Input: Two new alkaloids from marine sponge Callyspongia sp.


Input: Two new alkaloids, callylactam A (1) and callyimine A (4), along with three known ones (2, 3 and 5), were isolated from the marine sponge Callyspongia sp.

callylactam A

callyimine A


Input: The structures were determined on the basis of NMR and MS analysis.


Input: Back to the future: can physical models of passive membrane permeability help reduce drug candidate attrition and move us beyond QSPR?


Input: It is widely recognized that adsorption, distribution, metabolism, excretion, and toxicology liabilities kill the majority of drug candidates that progress to clinical trials.


Input: The development of computational models to predict small molecule membrane permeability is therefore of considerable scientific and public health interest.


Input: Empirical qualitative structure permeability relationship models of permeability have been a mainstay in industrial applications, but lack a deep understanding of the underlying biologic physics.


Input: Others and we have shown that implicit solvent models to predict passive permeability for small molecules exhibit mediocre predictive performance when validated across experimental test sets.


Input: Given the vast increase in computer power, more efficient parallelization schemes, and extension of current atomistic simulation codes to general use graphical processing units, the development and application of physical models based on all-atom simulations may now be feasible.


Input: Preliminary results from rigorous free energy calculations using all-atom simulations indicate that performance relative to implicit solvent models may be improved, but many outstanding questions remain.


Input: Here, we review the current state-of-the-art physical models for passive membrane permeability prediction and present a prospective look at promising new directions for all-atom approaches.


Input: Protein-ligand interaction study of CpOGA in complex with GlcNAcstatin.

GlcNAcstatin


Input: The GlcNAcstatin is a potent inhibitor of O-glycoprotein 2-acetamino-2-deoxy-beta-D-glucopyranosidase, which has been related with type II diabetes and neurodegenerative disorders.

GlcNAcstatin


Input: Herein, hybrid quantum mechanics/molecular mechanics, molecular dynamics simulations, and potential of mean force were employed to study the interactions established between GlcNAcstatin and a bacterial O-GlcNAcase enzyme from Clostridium perfringens.

GlcNAcstatin