Input: Regarding this latter aspect, drugs and environmental pollutants have been reported to affect plasma membrane characteristics which may further affect cell fate.


Input: Changes in membrane fluidity or in composition and function of specialized membrane microdomains (plasma membrane remodeling) have been proven to be involved in the regulation of many important physiological signaling pathways, including cell death.


Input: Furthermore, it has been suggested that a crosstalk between chemical-induced cellular membrane effects and other organelles may be of vital importance to explain the final outcome of chemical exposure.


Input: Here, we review the effects of plasma membrane remodeling on cell survival and cell death; we describe how the cell signaling pathways activated by changes in plasma membrane characteristics may influence cell fate.


Input: Since plasma membrane function plays an important role in the regulation of a number of cellular responses, it has been implicated in the development or progress of several diseases.


Input: A better knowledge of the effects of various chemicals on plasma membrane remodeling may be important for understanding the pathogenesis of major diseases, and may assist in developing new therapeutic strategies.


Input: Inhibition of T-type calcium channels disrupts Akt signaling and promotes apoptosis in glioblastoma cells.

calcium


Input: Glioblastoma multiforme (GBM) are brain tumors that are exceptionally resistant to both radio-and chemotherapy regimens and novel approaches to treatment are needed.


Input: T-type calcium channels are one type of low voltage-gated channel (LVCC) involved in embryonic cell proliferation and differentiation; however they are often over-expressed in tumors, including GBM.

calcium


Input: In this study, we found that inhibition of T-type Ca (2 +) channels in GBM cells significantly reduced their survival and resistance to therapy.

Ca (2 +)


Input: Moreover, either T-type selective antagonists, such as mibefradil, or siRNA-mediated knockdown of the T-type channel alpha subunits not only reduced cell viability and clonogenic potential, but also induced apoptosis.


Input: In response to channel blockade or ablation, we observed reduced phosphorylation of Akt and Rictor, suggesting inhibition of the mTORC2/Akt pathway.


Input: This was followed by reduction in phosphorylation of anti-apoptotic Bad and caspases activation.


Input: The apoptotic response was specific for T-type Ca (2 +) channels, as inhibition of L-type Ca (2 +) channels did not induce similar effects.

Ca (2 +)

Ca (2 +)


Input: Our results implicate T-type Ca (2 +) channels as distinct entities for survival signaling in GBM cells and suggest that they are a novel molecular target for tumor therapy.

Ca (2 +)


Input: Differential anti-ischemic efficacy and therapeutic time window of trans-and cis-hinokiresinols: Stereo-specific antioxidant and anti-inflammatory activities.

trans-and cis-hinokiresinols


Input: During cerebral ischemia, neurons are injured by various mechanisms including excitotoxicity, oxidative stress, and inflammatory responses.


Input: Thus, pharmacological manipulation of multiple cytotoxic pathways has been pursued for the treatment of ischemic injury.


Input: Cis-hinokiresinol, a naturally occurring phenylpropanoid, was previously reported to possess anti-oxidant, anti-inflammatory and estrogen-like activities.

Cis-hinokiresinol

phenylpropanoid

estrogen


Input: In the present study, we investigated anti-ischemic effects of trans-and cis-hinokiresinols using in vitro as well as in vivo experimental models.

trans-and cis-hinokiresinols


Input: The ORAC and DPPH assays showed that two isomers had similar free radical scavenging activities.

DPPH


Input: However, only trans-hinokiresinol significantly decreased neuronal injury in cultured cortical neurons exposed to oxygen-glucose deprivation (75 min) followed by re-oxygenation (9 h).

trans-hinokiresinol

oxygen

glucose


Input: The differential neuroprotective effect could be due to the stereo-specific augmentation of Cu/Zn-SOD activity by trans-hinokiresinol, when compared with cis-hinokiresinol.

Cu

Zn

trans-hinokiresinol

cis-hinokiresinol


Input: Similarly, in rats subjected to transient middle cerebral artery occlusion (1. 5 h) followed by 24-h reperfusion, pre-ischemic treatment with trans-hinokiresinol, but not with cis-isomer, reduced cerebral infarct volume.

trans-hinokiresinol


Input: Interestingly, however, post-ischemic treatment with both hinokiresinols (2 and 7 h after onset of ischemia) significantly reduced cerebral infarct.

hinokiresinols


Input: When administered after onset of ischemia, trans-hinokiresinol, but not its cis-isomer reduced nitrotyrosine immunoreactivity in ischemic regions.

trans-hinokiresinol

nitrotyrosine


Input: In contrast, both hinokiresinols suppressed neutrophil infiltration and IL-1 beta release to a similar extent.

hinokiresinols


Input: The observed differential anti-oxidant, but comparable anti-inflammatory, activities may explain the stereo-specific anti-ischemic activities and different therapeutic time windows of the hinokiresinols examined.

hinokiresinols


Input: More detailed delineation of the anti-ischemic mechanism (s) of hinokiresinols may provide a better strategy for development of efficacious regimens for cerebral ischemic stroke.

hinokiresinols


Input: Sunset yellow FCF, a permitted food dye, alters functional responses of splenocytes at non-cytotoxic dose.

Sunset yellow FCF


Input: Sunset yellow FCF (SY), a permitted food color, is extensively used in various food preparations and quite often exceeds the permissible levels (100-200 mg/kg).

Sunset yellow FCF


Input: Several toxicity studies on SY are reported, however immunomodulatory properties have not been explored yet.


Input: To investigate the immunotoxic properties of SY, splenocytes were isolated, cultured and subjected to mitogen stimulated proliferation assay (lipopolysaccharide, LPS or concanavalin A, Con A), mixed lymphocyte reaction (MLR) assay, immunophenotypic analysis of cell surface receptor expression and assay for cytokines release in the culture supernatants were performed in the presence of SY.


Input: Since SY did not exhibit any cytotoxicity up to 250 mu g/ml, this dose was used for further studies.


Input: It was observed that SY (250 mu g/ml) significantly (p < 0. 05) suppressed the mitogen induced proliferation of splenocytes and MLR response.


Input: Further, immunophenotypic analysis revealed that SY alters the relative expression of CD3e/CD4/CD8 in T cells and CD19 in B-cells.


Input: Consistent with the suppression of T-cell and B-cell responses and altered surface receptor expression, SY also lowered the expression of IL2, IL4, IL6, IL-17, IFN-gamma and TNF-alpha cytokines.


Input: These results suggest that non-cytotoxic dose of SY may have immunomodulatory effects.


Input: Trypsin and chymotrypsin inhibitor peptides from the venom of Chinese Daboia russellii siamensis.


Input: Two trypsin inhibitors and one chymotrypsin inhibitor from Chinese Daboia russellii siamensis venom, denoted as CBPTI-1, CBPTI-2 and CBPTI-3 were purified, characterized and cloned from lyophilized venom-derived cDNA libraries.


Input: The N-terminus of CBPTI-1 was modified and not amenable to Edman degradation sequencing, however an internal partial sequence was found to be SGRCRGHLRRIYYNPDSNKCE.

N


Input: The N-termini of CBPTI-2 and CBPTI-3 were unmodified and their partial sequences were established as HDRPTFCNLAPESGRCRAH and HDRPKFCYLPADPGECMAYIRSFYYDS respectively.

N


Input: From cloning studies CBPTI-1 was found to consist of 66 amino acid residues, while CBPTI-2 and CBPTI-3 precursors consist of 60 amino acid residues, including 6 cysteine residues.

amino acid

amino acid

cysteine


Input: Another cDNA sequence (CBPTI-4) was also obtained.


Input: Alignment of cDNA sequences showed that CBPTI-3 exhibited similar sequence homology to CBPTI-4 cDNA except for an 8 nucleotide deletion in the open-reading frame.

nucleotide


Input: CBPTI-1 and CBPTI-2 were demonstrated to be potent trypsin inhibitors, but were also shown to be effectively potent in chymotrypsin inhibition.


Input: The K (i) values of CBPTI-1 and CBPTI-2 for trypsin inhibition were 4. 07 x 10 (-7) M and 6. 66 x 10 (-7) M, respectively, and they were non-competitive in their activity.


Input: CBPTI-3 showed chymotrypsin inhibition activity with a K (i) value of 2. 55 x 10 (-9) M, but did not show trypsin inhibitor activity.


Input: Marked toxicity of Albizia bernieri extracts on embryo-larval development in the medaka fish (Oryzias latipes).


Input: Previous phytochemical studies have shown that the plants of the Albizia genus (Fabaceae) contain bioactive saponins, lignans, spermine alkaloids, flavonoids, glycosides phenols and pyridoxine derivatives.

saponins

lignans

spermine alkaloids

flavonoids

glycosides phenols

pyridoxine


Input: Their extracts sometimes display medical properties, but can have also toxic effects.


Input: The purpose of our study was to determine the in vivo toxicity of Albizia bernieri seeds in the experimental model of the medaka fish embryo, which is recommended for use in toxicity studies.


Input: Our results show clearly that incubating the embryos or larvae of the medaka fish in a medium containing A. bernieri extracts caused a dose-dependent reduction in embryo or larvae survival.


Input: Embryos exposed to an extract of A. bernieri displayed cerebral lesions, such as cell lysis and the emergence of lysosomes in the glial tissue.


Input: We conclude that when comparing with data obtained with different plant extracts tested on medaka development in our laboratory, A. bernieri displays an unusually high toxicity.


Input: Focussing on the cerebral target as well as the fish behaviour could bring more specific informations.


Input: Remarkable stabilization of antiparallel DNA triplexes by strong stacking effects of consecutively modified nucleobases containing thiocarbonyl groups.

thiocarbonyl


Input: The consecutive arrangement of 2'-deoxy-6-thioguanosines (s (6) Gs) and 4-thiothymidines (s (4) Ts) in antiparallel triplex-forming oligonucleotides (TFOs) considerably stabilized the resulting antiparallel triplexes with high base recognition ability by the strong stacking effects of thiocarbonyl groups.

s (6) Gs

s (4) Ts

thiocarbonyl


Input: This result was remarkable because chemical modifications of the sugar moieties and nucleobases of antiparallel TFOs generally destabilize triplex structures.

sugar


Input: Moreover, in comparison with unmodified TFOs, it was found that TFOs containing s (6) Gs and s (4) Ts could selectively bind to the complementary DNA duplex but not to mismatched DNA duplexes or single-stranded RNA.

s (6) Gs

s (4) Ts


Input: Influence of DNA repair on nonlinear dose-responses for mutation.


Input: Recent evidence has challenged the default assumption that all DNA-reactive alkylating agents exhibit a linear dose-response.


Input: Emerging evidence suggests that the model alkylating agents methyl-and ethylmethanesulfonate and methylnitrosourea (MNU) and ethylnitrosourea observe a nonlinear dose-response with a no observed genotoxic effect level (NOGEL).

methyl

ethylmethanesulfonate

methylnitrosourea

MNU

ethylnitrosourea


Input: Follow-up mechanistic studies are essential to understand the mechanism of cellular tolerance and biological relevance of such NOGELs.


Input: MNU is one of the most mutagenic simple alkylators.

MNU


Input: Therefore, understanding the mechanism of mutation induction, following low-dose MNU treatment, sets precedence for weaker mutagenic alkylating agents.

MNU


Input: Here, we tested MNU at 10-fold lower concentrations than a previous study and report a NOGEL of 0. 0075 micro g/ml (72. 8nM) in human lymphoblastoid cells, quantified through the hypoxanthine (guanine) phosphoribosyltransferase assay (OECD 476).

MNU

hypoxanthine

guanine


Input: Mechanistic studies reveal that the NOGEL is dependent upon repair of O (6)-methylguanine (O (6) MeG) by the suicide enzyme O (6) MeG-DNA methyltransferase (MGMT).

O (6)-methylguanine

O (6) MeG

O (6) MeG


Input: Inactivation of MGMT sensitizes cells to MNU-induced mutagenesis and shifts the NOGEL to the left on the dose axis.

MNU


Input: An animal model of marginal iodine deficiency during development: the thyroid axis and neurodevelopmental outcome.

iodine


Input: Thyroid hormones (THs) are essential for brain development, and iodine is required for TH synthesis.

iodine


Input: Environmental chemicals that perturb the thyroid axis result in modest reductions in TH, yet there is a paucity of data on the extent of neurological impairments associated with low-level TH disruption.


Input: This study examined the dose-response characteristics of marginal iodine deficiency (ID) on parameters of thyroid function and neurodevelopment.

iodine


Input: Diets deficient in iodine were prepared by adding 975, 200, 125, 25, or 0 micro g/kg potassium iodate to the base casein diet to produce five nominal iodine levels ranging from ample (Diet 1: 1000 mu g iodine/kg chow, D1) to deficient (Diet 5: 25 micro g iodine/kg chow, D5).

iodine

potassium iodate

iodine

iodine

iodine


Input: Female Long Evans rats were maintained on these diets beginning 7 weeks prior to breeding until the end of lactation.


Input: Dams were sacrificed on gestational days 16 and 20, or when pups were weaned on postnatal day (PN) 21.


Input: Fetal tissue was harvested from the dams, and pups were sacrificed on PN14 and PN21.


Input: Blood, thyroid gland, and brain were collected for analysis of iodine, TH, and TH precursors and metabolites.

iodine


Input: Serum and thyroid gland iodine and TH were reduced in animals receiving two diets that were most deficient in iodine.

iodine

iodine


Input: T4 was reduced in the fetal brain but was not altered in the neonatal brain.


Input: Neurobehavior, assessed by acoustic startle, water maze learning, and fear conditioning, was unchanged in adult offspring, but excitatory synaptic transmission was impaired in the dentate gyrus in animals receiving two diets that were most deficient in iodine.

iodine


Input: A 15% reduction in cortical T4 in the fetal brain was sufficient to induce permanent reductions in synaptic function in adults.


Input: These findings have implications for regulation of TH-disrupting chemicals and suggest that standard behavioral assays do not readily detect neurotoxicity induced by modest developmental TH disruption.


Input: Sunitinib, a tyrosine kinase inhibitor, induces cytochrome P450 1A1 gene in human breast cancer MCF7 cells through ligand-independent aryl hydrocarbon receptor activation.

Sunitinib

tyrosine

aryl hydrocarbon


Input: Sunitinib (SUN) is a new multi-targeted oral tyrosine kinase inhibitor that has both anti-angiogenic and anti-tumor activities.

Sunitinib

SUN

tyrosine


Input: However, information reported in the literature on the effects of SUN on the constitutive expression of cytochrome P450 1A1 (CYP1A1) gene in cells from mammalian species remains unclear.

SUN


Input: Therefore, the main objectives of the current work were to investigate the potentiality of SUN to induce CYP1A1 gene expression in human breast cancer MCF7 cells and to explore the molecular mechanisms involved.

SUN


Input: Our results showed that SUN induced the CYP1A1 mRNA, protein, and activity levels in a concentration-dependent manner in MCF7 cells.

SUN


Input: The increase in CYP1A1 mRNA by SUN was completely blocked by the transcriptional inhibitor, actinomycin D; implying that SUN increased de novo RNA synthesis.

SUN

actinomycin D

SUN


Input: Furthermore, the ability of SUN to increase luciferase reporter gene expression suggests an aryl hydrocarbon receptor (AhR)-dependent transcriptional control and excludes the possibility of any posttranscriptional mechanisms.

SUN

aryl hydrocarbon


Input: In addition, blocking of AhR activation by resveratrol, a well-known AhR antagonist, prevented the SUN-induced CYP1A1 gene expression, further confirms the involvement of AhR.

SUN


Input: Interestingly, this was associated with the inability of SUN to directly bind to and induce transformation of cytosolic AhR to its DNA-binding form in vitro, suggesting that the effect of SUN does not involve direct binding to AhR.

SUN

SUN


Input: The current manuscript provides the first evidence for the ability of SUN to induce CYP1A1 gene expression in MCF7 cells through AhR ligand-independent mechanisms.

SUN


Input: Drug repositioning by structure-based virtual screening.


Input: Approved drugs have favourable or validated pharmacokinetic properties and toxicological profiles, and the repositioning of existing drugs for new indications can potentially avoid expensive costs associated with early-stage testing of the hit compounds.


Input: In recent years, technological advances in virtual screening methodologies have allowed medicinal chemists to rapidly screen drug libraries for therapeutic activity against new biomolecular targets in a cost-effective manner.


Input: This review article outlines the basic principles and recent advances in structure-based virtual screening and highlights the powerful synergy of in silico techniques in drug repositioning as demonstrated in several recent reports.


Input: Pharmacokinetic profile of artemisinin derivatives and companion drugs used in artemisinin-based combination therapies for the treatment of Plasmodium falciparum malaria in children.

artemisinin

artemisinin


Input: Malaria is one of the most common parasitic infections worldwide.


Input: Plasmodium falciparum is the most prevalent strain in Africa and also the most fatal.


Input: The disease especially affects children, with those under age 5 years accounting for approximately 86% of malaria deaths in 2010.


Input: The objectives of this review are to summarize and evaluate published literature reporting the pharmacokinetic parameters of artemisinin-based combinations used to treat P. falciparum in paediatric populations and to identify and discuss controversies regarding pharmacokinetics of these agents in children.

artemisinin


Input: A search of MEDLINE (1948-September 2012), EMBASE (1980-September 2012), International Pharmaceutical Abstracts (1970-September 2012), Google and Google Scholar was conducted for articles describing pharmacokinetics of antimalarials in children.


Input: Our search produced 30 articles, of which 23 were included in the review: artemisinin compounds, 12 articles; lumefantrine, four articles; amodiaquine, five articles; sulfadoxine, six articles; pyrimethamine, one article; mefloquine, three articles; and piperaquine, two articles.

artemisinin

lumefantrine

amodiaquine

sulfadoxine

pyrimethamine

mefloquine

piperaquine


Input: Studies were summarized based on comparison groups and major findings.


Input: Many controversies were identified, including pharmacokinetic equivalence of novel dosage forms, altered pharmacokinetic parameters in children versus adults, effect of drug interactions, and association of pharmacokinetic changes with clinical outcomes.


Input: A large variation in pharmacokinetic parameters of many antimalarial agents was shown, which may be a consequence of the wide range of ages and/or bodyweights of each paediatric cohort.


Input: These studies may mask important associations with age and bodyweight and produce mean data that do not adequately represent the paediatric population as a whole.


Input: In order to properly assess the clinical implications of such pharmacokinetic changes and recommend safe and effective dosage regimens, there is an urgent need for dose-optimization studies for all recommended first-and second-line agents, along with the different drug formulations, used in paediatric populations with P. falciparum.


Input: Regiospecificity and stereospecificity of human UDP-glucuronosyltransferases in the glucuronidation of estriol, 16-epiestriol, 17-epiestriol, and 13-epiestradiol.

UDP

estriol


Input: The glucuronidation of estriol, 16-epiestriol, and 17-epiestriol by the human UDP-glucuronosyltransferases (UGTs) of subfamilies 1A, 2A, and 2B was examined.

estriol

UDP


Input: UGT1A10 is highly active in the conjugation of the 3-OH in all these estriols, whereas UGT2B7 is the most active UGT toward one of the ring D hydroxyls, the 16-OH in estriol and 16-epiestriol, but the 17-OH in 17-epiestriol.

estriols

estriol


Input: Kinetic analyses indicated that the 17-OH configuration plays a major role in the affinity of UGT2B7 for estrogens.

estrogens


Input: The glucuronidation of the different estriols by the human liver and intestine microsomes reflects the activity of UGT1A10 and UGT2B7 in combination with the tissues' difference in UGT1A10 expression.

estriols


Input: The UGT1A10 mutant 1A10-F93G exhibited much higher V (max) values than UGT1A10 in estriol and 17-epiestriol glucuronidation, but a significantly lower value in 16-epiestriol glucuronidation.

estriol


Input: To this study on estriol glucuronidation we have added experiments with 13-epiestradiol, a synthetic estradiol in which the spatial arrangement of the methyl on C18 and the hydroxyl on C17 is significantly different than in other estrogens.

estriol

estradiol

methyl

hydroxyl

estrogens


Input: In comparison with estradiol glucuronidation, the C13 configuration change decreases the turnover of UGTs that conjugate the 3-OH, but increases it in UGTs that primarily conjugate the 17-OH.

estradiol


Input: Unexpectedly, UGT2B17 exhibited similar conjugation rates of both the 17-OH and 3-OH of 13-espiestradiol.


Input: The combined results reveal the strong preference of UGT1A10 for the 3-OH of physiologic estrogens and the equivalently strong preference of UGT2B7 and UGT2B17 for the hydroxyls on ring D of such steroid hormones.

estrogens

hydroxyls

steroid hormones


Input: Induced expression of cytochrome P450 1A and NAD (P) H: quinone oxidoreductase determined at mRNA, protein, and enzyme activity levels in rats exposed to the carcinogenic azo dye 1-phenylazo-2-naphthol (Sudan I).

NAD (P) H

quinone

azo

Sudan I


Input: Sudan I (1-phenylazo-2-hydroxynaphthol) is a suspected human carcinogen causing tumors in the livers and urinary bladders of rats, mice, and rabbits.

Sudan I


Input: Here, we investigated for the first time the influence of Sudan I exposure on the expression of several biotransformation enzymes in the livers, kidneys, and lungs of rats concomitantly at the mRNA and protein levels and assayed their enzymatic activities.

Sudan I


Input: We also studied its effect on the formation of Sudan I-derived DNA adducts in vitro.

Sudan I


Input: Sudan I increased the total amounts of cytochrome P450 (P450) in all organs tested.

Sudan I


Input: Western blots using antibodies raised against various P450s, NADPH: P450 reductase, and NAD (P) H: quinone oxidoreductase 1 (NQO1) showed that the expression of P450 1A1 and NQO1 was induced in the liver, kidney, and lung of rats treated with Sudan I.

NADPH

NAD (P) H

quinone

Sudan I


Input: The higher protein levels correlated with increased enzyme activities of P450 1A1/2 and NQO1.


Input: Furthermore, 9. 9-, 5. 9-, and 2. 8-fold increases in the formation of Sudan I oxidative metabolites catalyzed by microsomes isolated from the liver, kidney, and lung, respectively, of rats treated with Sudan I were found.

Sudan I

Sudan I


Input: The relative amounts of P450 1A and NQO1 mRNA, measured by real-time polymerase chain reaction (RT-PCR) analysis, demonstrated that Sudan I induced the expression of P450 1A1 and NQO1 mRNA in the liver, kidney, and lung, and of P450 1A2 mRNA in kidney and lung.

Sudan I


Input: Finally, microsomes isolated from livers, kidneys, and lungs of Sudan I exposed rats more effectively catalyzed the formation of Sudan I-DNA adducts than microsomes from organs of control rats.

Sudan I

Sudan I


Input: This was attributable to the higher P450 1A1 expression.


Input: Because P450 1A1 is playing a major role in the bioactivation of Sudan I in rat and human systems, its induction by Sudan I may have a profound effect on cancer risk by this azo dye.

Sudan I

Sudan I

azo


Input: In addition, the induction of P450 1A1/2 and NQO1 enzymes can influence individual human susceptibility to other environmental carcinogens and have an effect on cancer risk.


Input: A beta interacts with both the iron center and the porphyrin ring of heme: mechanism of heme' s action on A beta aggregation and disaggregation.

iron

porphyrin

heme

heme


Input: Amyloid beta peptide (A beta) aggregation is a pathological hallmark of Alzheimer' s disease (AD).


Input: Modulation of the self-assembly processes, therefore, is thought to be an attractive strategy for the prevention and treatment of AD.


Input: Interestingly, heme has been found to inhibit A beta aggregation and even dismantle A beta aggregates.

heme


Input: However, the mechanism remains unresolved.


Input: Recent research has shown that heme binds preferentially to the His (13) residue of A beta with the iron center, while the hydrophobic domain of A beta is also able to bind to heme.

heme

His

iron

heme


Input: Herein, absorption spectrometric, Thioflavin T fluorescence, and circular dichroism spectroscopic and transmission electron microscopic measurements revealed that the iron center is not required for the inhibition of A beta aggregation but do influence the binding affinity of heme toward A beta and the dismantlement rate and degree of the A beta aggregates.

Thioflavin T

iron

heme


Input: By studying the interaction of different truncated or mutated A beta peptides with heme or protoporphyrin, we further found that the porphyrin ring of heme is implicated to interact preferentially with the Phe (19) residue, facilitating the binding of heme to A beta and disturbing the interstrand aromatic interaction between the Phe residues, which is crucial for A beta fibrillation.

heme

protoporphyrin

porphyrin

heme

Phe

heme

Phe


Input: These findings open new avenues in the understanding of the interaction between the heme and A beta and the pathways for modulation of A beta aggregation and disaggregation, which would be helpful in designing therapeutic strategies against AD.

heme


Input: Antimutagenic effect of aqueous extract from Agaricus brasiliensis on culture of human lymphocytes.


Input: The mushroom Agaricus brasiliensis (sun mushroom), native from the southeast of Brazil, is well known by its medicinal properties that include effects on diabetes, cholesterol levels, and osteoporosis.

cholesterol


Input: The antimutagenic effects of A. brasiliensis has been investigated recently and revealed some controversial results depending on the temperature by which the A. brasiliensis tea is obtained.


Input: In the present study, we evaluated the effect of the A. brasiliensis extract prepared in two different temperatures, 4 degrees C and 25 degrees C, on the doxorubicin-induced DNA strand breaks and chromosomal aberrations (CAs) in human lymphocytes.

doxorubicin


Input: The results demonstrated that A. brasiliensis was able to reduce the DXR-induced DNA damage in both temperatures; however, the CA test was more sensitive to demonstrate a better reduction when the cells were treated with an extract obtained at 25 degrees C.


Input: A. brasiliensis extract obtained in different temperatures exhibited antigenotoxic and anticlastogenic effects in human lymphocytes.


Input: A new strategy for intracellular delivery of enzyme using mesoporous silica nanoparticles: superoxide dismutase.

silica

superoxide


Input: We developed mesoporous silica nanoparticle (MSN) as a multifunctional vehicle for enzyme delivery.

silica


Input: Enhanced transmembrane delivery of a superoxide dismutase (SOD) enzyme embedded in MSN was demonstrated.

superoxide


Input: Conjugation of the cell-penetrating peptide derived from the human immunodeficiency virus 1 (HIV) transactivator protein (TAT) to mesoporous silica nanoparticle is shown to be an effective way to enhance transmembrane delivery of nanoparticles for intracellular and molecular therapy.

silica


Input: Cu, Zn-superoxide dismutase (SOD) is a key antioxidant enzyme that detoxifies intracellular reactive oxygen species, ROS, thereby protecting cells from oxidative damage.

Cu

Zn

superoxide

oxygen


Input: In this study, we fused a human Cu, Zn-SOD gene with TAT in a bacterial expression vector to produce a genetic in-frame His-tagged TAT-SOD fusion protein.

Cu

Zn


Input: The His-tagged TAT-SOD fusion protein was expressed in E. coli using IPTG induction and purified using FMSN-Ni-NTA.

Ni


Input: The purified TAT-SOD was conjugated to FITC-MSN forming FMSN-TAT-SOD.


Input: The effectiveness of FMSN-TAT-SOD as an agent against ROS was investigated, which included the level of ROS and apoptosis after free radicals induction and functional recovery after ROS damage.


Input: Confocal microscopy on live unfixed cells and flow cytometry analysis showed characteristic nonendosomal distribution of FMSN-TAT-SOD.


Input: Results suggested that FMSN-TAT-SOD may provide a strategy for the therapeutic delivery of antioxidant enzymes that protect cells from ROS damage.


Input: Neuron-type specific cannabinoid-mediated G protein signalling in mouse hippocampus.


Input: Type 1 cannabinoid receptor (CB1) is expressed in different neuronal populations in the mammalian brain.


Input: In particular, CB1 on GABAergic or glutamatergic neurons exerts different functions and display different pharmacological properties in vivo.


Input: This suggests the existence of neuron-type specific signalling pathways activated by different subpopulations of CB1.


Input: In this study, we analysed CB1 expression, binding and signalling in the hippocampus of conditional mutant mice, bearing CB1 deletion in GABAergic (GABA-CB1-KO mice) or cortical glutamatergic neurons (Glu-CB1-KO mice).

Glu


Input: Compared to their wild-type littermates, Glu-CB1-KO displayed a small decrease of CB1 mRNA amount, immunoreactivity and [(3) H] CP55, 940 binding.

Glu

[(3) H] CP55, 940


Input: Conversely, GABA-CB1-KO mice showed a drastic reduction of these parameters, confirming that CB1 is present at much higher density on hippocampal GABAergic interneurons than glutamatergic neurons.

GABA


Input: Surprisingly, however, saturation analysis of HU210-stimulated [(35) S] GTP gamma S binding demonstrated that' glutamatergic' CB1 is more efficiently coupled to G protein signalling than' GABAergic' CB1.

[(35) S] GTP gamma S


Input: Thus, the minority of CB1 on glutamatergic neurons is paradoxically several fold more strongly coupled to G protein signalling than' GABAergic' CB1.


Input: This selective signalling mechanism raises the possibility of designing novel cannabinoid ligands that differentially activate only a subset of physiological effects of CB1 stimulation, thereby optimizing therapeutic action.


Input: Class III phosphatidylinositol 3-kinase and its catalytic product PtdIns3P in regulation of endocytic membrane traffic.

phosphatidylinositol


Input: Endocytosis and subsequent membrane traffic through endosomes are cellular processes that are integral to eukaryotic evolution, and numerous human diseases are associated with their dysfunction.


Input: Consequently, it is important to untangle the molecular machineries that regulate membrane dynamics and protein flow in the endocytic pathway.


Input: Central in this context is class III phosphatidylinositol 3-kinase, an evolutionarily conserved enzyme complex that phosphorylates phosphatidylinositol into phosphatidylinositol 3-phosphate.

phosphatidylinositol

phosphatidylinositol

phosphatidylinositol 3-phosphate


Input: Phosphatidylinositol 3-phosphate recruits specific effector proteins, most of which contain FYVE or PX domains, to promote endocytosis, endosome fusion, endosome motility and endosome maturation, as well as cargo sorting to lysosomes, the biosynthetic pathway or the plasma membrane.

Phosphatidylinositol 3-phosphate


Input: Here we review the functions of key phosphatidylinositol 3-phosphate effectors in regulation of endocytic membrane dynamics and protein sorting.

phosphatidylinositol 3-phosphate


Input: Design, synthesis, characterization and biological evaluation of novel pyrazole integrated benzophenones.

pyrazole

benzophenones


Input: A series of novel pyrazole integrated benzophenones (9a-j) have been designed, synthesized from 1-methyl-5-(2, 4, 6-trimethoxy-phenyl)-1H-pyrazole 6.

pyrazole

benzophenones

1-methyl-5-(2, 4, 6-trimethoxy-phenyl)-1H-pyrazole


Input: The structures of the regioisomers 6 and 7 were determined by 2D (1) H-(1) H COSY, (1) H-(13) C HSQC and (1) H-(13) C HMBC experiments.

(1) H

(1) H

(1) H

(13) C

(1) H

(13) C


Input: The newly synthesized compounds (9a-j) were evaluated for in vivo anti-inflammatory activity by carrageenan paw edema in rats and in vitro COX-1/COX-2 inhibition and antioxidant potential.


Input: Among the synthesized compounds, compounds 9b, 9d and 9f, were found to be active anti-inflammatory agents in addition to having potent antioxidant activity.


Input: Inhibition of HIV-1 replication by a tricyclic coumarin GUT-70 in acutely and chronically infected cells.

tricyclic coumarin GUT-70


Input: The anti-HIV-1 activity of GUT-70, a natural product derived from the stem bark of Chlophyllum brasiliense, was evaluated.


Input: GUT-70 inhibited HIV-1 replication in both acutely and chronically infected cells through suppression of NF-kappa B.


Input: Our results strengthen the idea that NF-kappa B pathway is one of the potential targets to control HIV-1 replication and that GUT-70 could serve as a lead compound to develop novel therapeutic agents against HIV-1 infection.


Input: Risk factors for atherosclerosis in patients with chronic kidney disease: recognition and management.


Input: Heart disease is the most common cause of death in patients with chronic kidney disease (CKD), particularly in those receiving dialysis.


Input: Atherosclerosic cardiovascular (CV) disease (CVD) accounts for a large number of these deaths.


Input: Atherosclerosis is accelerated in patients with CKD due predominantly to the high prevalence of traditional CVD risk factors in the CKD population.


Input: CKD aggravates pre-existent traditional risk factors such as hypertension and dyslipidemia due to secondary renal parenchymal hypertension and secondary dyslipidemia.


Input: In addition, a variety of non-traditional risk factors that occur commonly in CKD patients contribute to CV risk.


Input: Recent studies suggest that CKD itself may be an independent risk factor for CVD, particularly coronary heart disease (CHD).


Input: Many therapies aimed at CV risk factor modification that have been successful in reducing CV risk in the general population are less effective or ineffective in favorably modifying CV risk in CKD.


Input: Biophysical characterization of the drug-membrane interactions: The case of propranolol and acebutolol.

propranolol

acebutolol


Input: The interaction of propranolol and acebutolol with biological membranes was assessed in the present work by using a range of biophysical techniques and liposomes, as membrane mimetic models.

propranolol

acebutolol


Input: Liposomes were made of zwitterionic phosphatidylcholines and experiments were performed at physiologic pH and at various membrane physical states (gel, ripple and fluid phases).

phosphatidylcholines


Input: Fluorescence techniques were used to study the partition coefficient of beta-blockers, the influence of drugs on membrane fluidity and the drugs-membrane binding.


Input: Moreover, small and wide angle X-ray scattering techniques were used to evaluate the beta-blockers effect on long range bilayer order and hydrocarbon chain packing.

hydrocarbon


Input: The gathered results highlighted the importance of electrostatic interactions between propranolol and acebutolol with membranes.

propranolol

acebutolol


Input: Furthermore, both beta-blockers exhibited a membrane-fluidizing effect and the capacity to disturb the membrane organization.


Input: In general, propranolol unveiled a more pronounced effect on membrane fluidity and structure than acebutolol.

propranolol

acebutolol


Input: In the current study, the obtained results were also correlated with the cardioprotective properties of the beta-blockers studied.


Input: Cholinesterase and carboxylesterase inhibition in Planorbarius corneus exposed to binary mixtures of azinphos-methyl and chlorpyrifos.

azinphos-methyl

chlorpyrifos


Input: Though pesticide mixtures are commonly encountered in fresh water systems, the knowledge of their effects on non-target aquatic species is scarce.


Input: The present investigation was undertaken to explore the in vivo inhibition of the freshwater gastropod snail Planorbarius corneus cholinesterase (ChE) and carboxylesterases (CES) activities by the organophosphorus pesticides azinphos-methyl (AZM) and chlorpyrifos (CPF).

organophosphorus

azinphos-methyl

AZM

chlorpyrifos

CPF


Input: To this end, snails were exposed for 48 h to different concentrations of AZM and CPF in single-chemical and binary-mixture studies, and ChE and CES activities were measured in the whole soft body tissues and hemolymph.

AZM

CPF


Input: ChE activity was measured with acetylthiocholine as substrate and CES activity was measured with four substrates: p-nitrophenyl acetate, p-nitrophenyl butyrate, 1-and 2-naphthyl acetate.

acetylthiocholine

p-nitrophenyl acetate

p-nitrophenyl butyrate

1-and 2-naphthyl acetate


Input: Single-chemical experiments showed that CPF was a more potent inhibitor of ChE activity than AZM (350 and 27 times for the whole soft tissue and hemolymph, respectively).

CPF

AZM


Input: CES were 15 times more sensitive than ChE when the activities were measured in the whole soft tissue of the animals exposed to AZM.

AZM


Input: Based on a default assumption of concentration addition, P. corneus snails were exposed to mixtures of AZM + CPF designed to yield predicted soft tissue ChE inhibitions of 31% (mixture 1), 50% (mixture 2) and 61% (mixture 3).

AZM

CPF


Input: Results showed that ChE inhibition produced by mixture 1 followed a model of concentration addition.


Input: In contrast, the other mixtures showed synergism, both in whole soft tissue and hemolymph.


Input: In addition, results obtained when the snails were exposed sequentially to the pesticides showed that the sequence AZM/CPF produced at 48 h a higher ChE inhibition than the sequence CPF/CPF.

AZM

CPF

CPF

CPF


Input: A range of metabolic pathways and responses associated with bioactivation or detoxification may play important roles in organophosphorus interactions.

organophosphorus


Input: In particular, the data presented in the present study indicate that CES enzymes would be important factors in determining the effects of the mixtures of OPs on P. corneus ChE activity.

OPs


Input: Sub-lethal coral stress: detecting molecular responses of coral populations to environmental conditions over space and time.


Input: In order for sessile organisms to survive environmental fluctuations and exposures to pollutants, molecular mechanisms (i. e. stress responses) are elicited.


Input: Previously, detrimental effects of natural and anthropogenic stressors on coral health could not be ascertained until significant physiological responses resulted in visible signs of stress (e. g. tissue necrosis, bleaching).


Input: In this study, a focused anthozoan holobiont microarray was used to detect early and sub-lethal effects of spatial and temporal environmental changes on gene expression patterns in the scleractinian coral, Montastraea cavernosa, on south Florida reefs.


Input: Although all colonies appeared healthy (i. e. no visible tissue necrosis or bleaching), corals were differentially physiologically compensating for exposure to stressors that varied over time.


Input: Corals near the Port of Miami inlet experienced significant changes in expression of stress responsive and symbiont (zooxanthella)-specific genes after periods of heavy precipitation.


Input: In contrast, coral populations did not demonstrate stress responses during periods of increased water temperature (up to 29 degrees C).


Input: Specific acute and long-term localized responses to other stressors were also evident.


Input: A correlation between stress response genes and symbiont-specific genes was also observed, possibly indicating early processes involved in the maintenance or disruption of the coral-zooxanthella symbiosis.


Input: This is the first study to reveal spatially-and temporally-related variation in gene expression in response to different stressors of in situ coral populations, and demonstrates that microarray technology can be used to detect specific sub-lethal physiological responses to specific environmental conditions that are not visually detectable.


Input: In vitro study of intestinal transport of fluoride using the Caco-2 cell line.

fluoride


Input: Water and food are the main sources of fluoride exposure and therefore it is necessary to study intestinal absorption in order to make a correct evaluation of the risk/benefit associated with exposure to fluoride.

fluoride

fluoride


Input: The present study characterizes intestinal transport of fluoride, using the Caco-2 cell line as a model of the intestinal epithelium, and evaluates the coefficients of apparent permeability and intracellular accumulation in various conditions (pH, temperature, opening of cell junctions, presence of anions).

fluoride


Input: The results indicate that fluoride is an element with moderate absorption (< 70%) in both directions (absorptive and secretory).

fluoride


Input: Both in absorption (apical-basolateral) and in secretion (basolateral-apical) there is transport by the paracellular pathway, which may be considered predominant.


Input: Absorption and secretion of fluoride increase at acid pH levels, possibly because of its non-ionized state at these pHs and/or because of participation of a F (-)/H (+) cotransporter or a F (-)/OH (-) antiporter.

fluoride

F (-)

H (+)

F (-)

OH (-)


Input: The results also suggest transcellular participation of mechanisms involved in transport of Cl (-) and of an active transport in the secretory direction.

Cl (-)


Input: The present study extend the knowledge on the cellular transport of fluoride and provide the basis for future studies aimed at identifying potential transporters involved in human fluoride absorption.

fluoride

fluoride


Input: Bombesin receptor subtype-3 (BRS-3), a novel candidate as therapeutic molecular target in obesity and diabetes.

Bombesin


Input: BRS-3 KO-mice developed obesity and unbalanced glucose metabolism, suggesting an important role of BRS-3 receptor in glucose homeostasis.

glucose

glucose


Input: We explored BRS-3 expression in skeletal muscle from normal, obese or type-2 diabetic (T2D) patients, and the effect of [D-Phe (6), beta-Ala (11), Phe (13), Nle (14)] bombesin (6-14)-BRS-3-agonist-peptide (BRS-3-AP)-on glucose-related effects, before or after BRS-3 gene silencing.

D-Phe

beta-Ala

Phe

Nle

bombesin

glucose


Input: In muscle tissue and primary cultured myocytes from altered metabolic states, BRS-3 gene/protein expressions were down-regulated.


Input: In normal, obese and T2D cells: A) BRS-3-AP as insulin enhanced BRS-3 and GLUT-4 mRNA/protein levels; improving glucotransporter translocation to plasma membrane, and B) BRS-3-AP caused a concentration-related-stimulation of glucose transport, being obese and T2D myocytes more sensitive to the ligand than normal.

glucose


Input: Wortmannin and PD98059, but not rapamycin, abolished the stimulatory action of BRS-3-AP on glucose transport.

Wortmannin

rapamycin

glucose


Input: BRS-3 plays an important role in glucose metabolism, and could be use as a molecular target, and/or its ligand, as a therapeutic agent for obesity and diabetes treatments.

glucose


Input: Aryl hydrocarbon receptor activation attenuates Per1 gene induction and influences circadian clock resetting.

Aryl hydrocarbon


Input: Light-stimulated adjustment of the circadian clock is an important adaptive physiological response that allows maintenance of behavioral synchrony with solar time.


Input: Our previous studies indicate that the aryl hydrocarbon receptor (AhR) agonist 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin attenuates light-induced phase resetting in early night.

aryl hydrocarbon

2, 3, 7, 8-tetrachlorodibenzo-p-dioxin


Input: However, the mechanism of inhibition remains unclear.


Input: In this study, we showed that another potent AhR agonist-beta-naphthoflavone (BNF)-significantly decreased light-induced phase shifts in wild-type (WT) mice, whereas AhR knockout mice had an enhanced response to light that was unaffected by BNF.

beta-naphthoflavone

BNF

BNF


Input: Mechanistically, BNF blocked light induction of the Per1 transcript in suprachiasmatic nucleus and liver in WT mice, and BNF blocked forskolin (FSK)-induced Per1 transcripts in Hepa-1c1c7 (c7) cells.

BNF

BNF

forskolin

FSK


Input: An E-box decoy did not affect BNF inhibition of FSK-induced Per1 transcripts in c7 cells.

BNF

FSK


Input: cAMP-response element (CRE)-dependent induction of Per1 promoter activity in response to FSK in combination with phorbol 12-tetradecanoate 13-acetate was suppressed in cells that expressed high levels of AhR (c7) compared with cells lacking functional AhR activity (c12).

cAMP

FSK

phorbol 12-tetradecanoate 13-acetate


Input: In addition, the inhibitory effect of BNF on FSK-induced Per1 was dependent on phosphorylation of JNK.

BNF

FSK


Input: Together, these results suggest that AhR activation inhibits light-induced phase resetting through the activation of JNK, negative regulation of CREs in the Per1 promoter, and suppression of Per1.


Input: Preparation, preliminary screening of new types of steroid conjugates and their activities on steroid receptors.

steroid

steroid


Input: There were synthesized new types of ribbon type steroidal dimers derived from three types of steroidal skeletons (cholic acid, etienic acid, estrone) using Cu (I) catalyzed 1, 3-dipolar cycloaddition reaction.

cholic acid

etienic acid

estrone

Cu (I)


Input: Steroid parts of the molecular " ribbons " are linked by heterocyclic moiety, namely by 2, 6-bis ((1H-1, 2, 3-triazol-1-yl)-methyl) pyridine.

Steroid

2, 6-bis ((1H-1, 2, 3-triazol-1-yl)-methyl) pyridine


Input: Compounds synthesized possess different cytotoxic and hormone receptor modulating activities.


Input: Altered matrix mineralization in a case of a sclerosing osteosarcoma.


Input: Little is known about the tumor matrix mineralization of highly sclerotic osteosarcoma.


Input: We used quantitative backscattered electron imaging (qBEI) to determine the Bone mineralization density distribution (BMDD) of a highly sclerosing osteosarcoma of the proximal tibia as well as adjacent normal bone of a 10-year-old girl following chemotherapy according to the EURAMOS-1 protocol.


Input: Data were compared to recently published normative reference data for young individuals.


Input: Backscattered electron imaging of the tumor region revealed a dense accumulation of mineralized tumor bone matrix (up to 90% of the medullar space).


Input: The BMDD was shifted tremendously towards higher matrix mineralization (CaMean + 18. 5%, CaPeak + 22. 5%, CaHigh + 100 fold) compared to normal bone.


Input: Additionally the BMDD became much wider, indicating a higher heterogeneity in mineralization (CaWidth + 40%).


Input: In contrast to lamellar bone, which mineralizes via a mineralization front, the mineralization of the tumor matrix starts by randomly distributed spots of mineral clusters fusing together to a highly mineralized non-lamellar bone matrix.


Input: We also found an altered BMDD of the patient' s normal bone when compared with the reference BMDD of young individuals.


Input: In conclusion this high radiodensity region of the sclerosing sarcoma is not only due to the high amount of tumor matrix but also to its high mineralization density.


Input: Chemotherapy may lead to altered matrix mineralization of normal bone due to suppression of bone turnover.


Input: The mechanism of matrix mineralization in a sclerosing osteosarcoma warrants further studies.


Input: Pregabalin abuse and dependence in Germany: results from a database query.

Pregabalin


Input: PURPOSE: Pregabalin (PRG) is approved for the treatment of neuropathic pain, partial seizures and generalised anxiety disorder in many countries and currently under study for other indications.

Pregabalin

PRG


Input: Supported by case reports and the results of a limited number of studies there is an ongoing debate on the potential of PRG to cause addictive behaviours.

PRG


Input: However, currently available evidence on this issue is sparse, and any definitive assessment of PRG' s potential for abuse and dependence is not yet in sight.

PRG


Input: The aim of our study was to identify the number of cases of PRG abuse or dependence reported to the database of a German medical regulatory body and to obtain insights into further usage-specific parameters.

PRG


Input: METHODS: We conducted a query of the entire database of the German Federal Institute for Drugs and Medical Devices (BfArM) regarding reports of PRG abuse or dependence and analysed these cases on the basis of several parameters.

PRG


Input: RESULTS: A total of 55 reports of PRG abuse or dependence were identified (mean age 36 years, 64% of reports involved males).

PRG


Input: The first reports were submitted to BfArM in 2008, and the reporting frequency has increased up to the present.


Input: Mean daily PRG dosage was 1424 mg.

PRG


Input: Current or previous polytoxicomania was present in 40 and 42% of cases, respectively.


Input: Psychiatric diagnoses other than substance-related disorders were reported in 13 (24%) cases.


Input: In about one-third of the patients withdrawal syndromes subsequent to discontinuation of PRG were reported.

PRG


Input: CONCLUSIONS: Cases of PRG abuse or dependence have been reported to the BfArM since 2008, with a marked increase of such reports in subsequent years.

PRG


Input: Male sex and a history of polytoxicomania may be possible risk factors for the development of addictive behaviours related to PRG.

PRG


Input: Marked decline in beta cell function during pregnancy leads to the development of glucose intolerance in Japanese women.

glucose


Input: The aim of this study is to investigate glucose metabolism longitudinally during pregnancy to explore mechanisms underlying gestational diabetes mellitus (GDM).

glucose


Input: We reviewed a total of 62 pregnant Japanese women who underwent a 75g oral glucose tolerance test (OGTT) twice during pregnancy (median: early, 13; late, 28 weeks' gestation) because of positive GDM screening.

glucose


Input: All showed normal OGTT results in early pregnancy.


Input: Based on late OGTT, 15 had GDM (late-onset GDM) and 47 normal glucose tolerance (NGT).

glucose


Input: In early pregnancy, there were no significant differences in insulin sensitivity (insulin sensitivity index derived from OGTT [ISOGTT] and homeostasis model assessment for insulin resistance [HOMA-IR]) and insulin secretion (a ratio of the total area-under-the-insulin-curve to the total area-under-the-glucose-curve [AUCins/glu] and insulinogenic index [IGI]) between the NGT and late-onset GDM groups.

glucose


Input: In each group, insulin sensitivity significantly decreased from early to late pregnancy, most in the late-onset GDM group (each p < 0. 05).


Input: The insulin secretion showed no significant changes with advancing pregnancy in both of the groups, although late-onset GDM showed significantly lower IGI compared with NGT in late OGTT (p < 0. 05).


Input: When assessed beta cell function by OGTT-derived disposition index (i. e. Insulin Secretion-Sensitivity Index-2 and IGI/fasting insulin), the indices significantly decreased from early to late pregnancy in the both groups (each p < 0. 05).


Input: Women with late-onset GDM showed significantly lower indices compared with NGT (each p < 0. 05).


Input: The failure of beta cell to compensate for decreased insulin sensitivity could contribute to the development of the late-onset GDM.


Input: Expanding the genetic code in Xenopus laevis oocytes.


Input: Heterologous expression of ligand-gated ion channels (LGICs) in Xenopus laevis oocytes combined with site-directed mutagenesis has been demonstrated to be a powerful approach to study structure-function relationships.


Input: In particular, introducing unnatural amino acids (UAAs) has enabled modifications that are not found in natural proteins.

amino acids


Input: However, the current strategy relies on the technically demanding in vitro synthesis of aminoacylated suppressor tRNA.


Input: We report here a general method that circumvents this limitation by utilizing orthogonal aminoacyl-tRNA synthetase (aaRS)/suppressor tRNA (CUA) pairs to genetically encode UAAs in Xenopus oocytes.


Input: We show that UAAs inserted in the N-terminal domain of N-methyl-D-aspartate receptors (NMDARs) serve as photo-crosslinkers that lock the receptor in a discrete conformational state in response to UV photo treatment.

N

N-methyl-D-aspartate


Input: Our method should be generally applicable to studies of other LGICs in Xenopus oocytes.


Input: Plasmon-Mediated Synthesis of Silver Cubes with Unusual Twinning Structures Using Short Wavelength Excitation.

Silver


Input: The plasmon-mediated synthesis of silver nanoparticles is a versatile synthetic method which leverages the localized surface plasmon resonance (LSPR) of nanoscale silver to generate particles with non-spherical shapes and control over dimensions.

silver

silver


Input: Herein, a method is reported for controlling the twinning structure of silver nanoparticles, and consequently their shape, via the plasmon-mediated synthesis, solely by varying the excitation wavelength between 400, 450, and 500 nm, which modulates the rate of Ag (+) reduction.

silver

Ag (+)


Input: Shorter, higher energy excitation wavelengths lead to faster rates of reaction, which in turn yield structures containing a greater number of twin boundaries.


Input: With this method, silver cubes can be synthesized using 450 nm excitation, which represents the first time this shape has been realized by a plasmon-mediated synthetic approach.

silver


Input: In addition, these cubes contain an unusual twinning structure composed of two intersecting twin boundaries or multiple parallel twin boundaries.


Input: With respect to their twinning structure, these cubes fall between planar-twinned and multiply twinned nanoparticles, which are synthesized using 500 and 400 nm excitation, respectively.


Input: Effects on gene expression in rat liver after administration of RXR agonists: UAB30, 4-methyl-UAB30, and Targretin (Bexarotene).

Targretin

Bexarotene


Input: Examination of three retinoid X receptor (RXR) agonists [Targretin (TRG), UAB30, and 4-methyl-UAB30 (4-Me-UAB30)] showed that all inhibited mammary cancer in rodents and two (TRG and 4-Me-UAB30) strikingly increased serum triglyceride levels.

retinoid

Targretin

TRG

TRG

triglyceride


Input: Agents were administered in diets to female Sprague-Dawley rats.


Input: Liver RNA was isolated and microarrayed on the Affymetrix GeneChip Rat Exon 1. 0 ST array.


Input: Statistical tests identified genes that exhibited differential expression and fell into groups, or modules, with differential expression among agonists.


Input: Genes in specific modules were changed by one, two, or all three agonists.


Input: An interactome analysis assessed the effects on genes that heterodimerize with known nuclear receptors.


Input: For proliferator-activated receptor alpha/RXR-activated genes, the strongest response was TRG > 4-Me-UAB30 > UAB30.

TRG


Input: Many liver X receptor/RXR-related genes (e. g., Scd-1 and Srebf1, which are associated with increased triglycerides) were highly expressed in TRG and 4-Me-UAB30-but not UAB30-treated livers.

triglycerides

TRG


Input: Minimal expression changes were associated with retinoic acid receptor or vitamin D receptor heterodimers by any of the agonists.

retinoic acid

vitamin D


Input: UAB30 unexpectedly and uniquely activated genes associated with the aryl hydrocarbon hydroxylase (Ah) receptor (Cyp1a1, Cyp1a2, Cyp1b1, and Nqo1).

aryl hydrocarbon


Input: Based on the Ah receptor activation, UAB30 was tested for its ability to prevent dimethylbenzanthracene (DMBA)-induced mammary cancers, presumably by inhibiting DMBA activation, and was highly effective.

dimethylbenzanthracene

DMBA

DMBA


Input: Gene expression changes were determined by reverse transcriptase-polymerase chain reaction in rat livers treated with Targretin for 2. 3, 7, and 21 days.

Targretin


Input: These showed similar gene expression changes at all three time points, arguing some steady-state effect.


Input: Different patterns of gene expression among the agonists provided insight into molecular differences and allowed one to predict certain physiologic consequences of agonist treatment.


Input: Assessing the quality of absolute hydration free energies among CHARMM-compatible ligand parameterization schemes.


Input: Multipurpose atom-typer for CHARMM (MATCH), an atom-typing toolset for molecular mechanics force fields, was recently developed in our laboratory.


Input: Here, we assess the ability of MATCH-generated parameters and partial atomic charges to reproduce experimental absolute hydration free energies for a series of 457 small neutral molecules in GBMV2, Generalized Born with a smooth SWitching (GBSW), and fast analytical continuum treatment of solvation (FACTS) implicit solvent models.


Input: The quality of hydration free energies associated with small molecule parameters obtained from ParamChem, SwissParam, and Antechamber are compared.


Input: Given optimized surface tension coefficients for scaling the surface area term in the nonpolar contribution, these automated parameterization schemes with GBMV2 and GBSW demonstrate reasonable agreement with experimental hydration free energies (average unsigned errors of 0. 9-1. 5 kcal/mol and R (2) of 0. 63-0. 87).


Input: GBMV2 and GBSW consistently provide slightly more accurate estimates than FACTS, whereas Antechamber parameters yield marginally more accurate estimates than the current generation of MATCH, ParamChem, and SwissParam parameterization strategies.


Input: Modeling with MATCH libraries that are derived from different CHARMM topology and parameter files highlights the importance of having sufficient coverage of chemical space within the underlying databases of these automated schemes and the benefit of targeting specific functional groups for parameterization efforts to maximize both the breadth and the depth of the parameterized space.


Input: Deletion of STK40 protein in mice causes respiratory failure and death at birth.


Input: STK40 is a putative serine/threonine kinase and was shown to induce extraembryonic endoderm differentiation from mouse embryonic stem cells.

serine

threonine


Input: However, little is known about its physiological function in vivo.


Input: Here, we generate Stk40 knock-out mice and demonstrate that loss of the Stk40 gene causes neonatal lethality at birth.


Input: Further examination reveals that the respiratory distress and atelectasis occur in the homozygous mutants.


Input: The maturation of lung and alveolar epithelium is delayed in the mutant, as indicated by narrowed air spaces, thickened interstitial septa, and increased glycogen content in the lungs of Stk40 (-/-) mice.


Input: The reduction in levels of T1-alpha, SP-B, and SP-C indicates delayed maturation of both type I and type II respiratory epithelial cells in Stk40 (-/-) lungs.


Input: Moreover, Stk40 is found to be most highly expressed in lungs of both fetal and adult mice among all organs tested.


Input: Mechanistically, a genome-wide RNA microarray analysis reveals significantly altered expression of multiple genes known to participate in lung development.


Input: The expression of some genes involved in lipid metabolism, immune response, and glycogen metabolism is also disrupted in the lung of Stk40 (-/-) mice.


Input: Protein affinity purification identifies RCN2, an activator of ERK/MAPK signaling, as an STK40-associated protein.


Input: Consistently, Stk40 deficiency attenuates the ERK/MAPK activation, and inhibition of ERK/MAPK activities reduces surfactant protein gene expression in lung epithelial cells.


Input: Collectively, this study uncovers an important role of STK40 for lung maturation and neonatal survival.


Input: STK40 may associate with RCN2 to activate ERK/MAPK signaling and control the expression of multiple key regulators of lung development.


Input: Dietary exposure of mink (Mustela vison) to fish from the upper Hudson River, New York, USA: effects on organ mass and pathology.


Input: The authors evaluated effects of feeding ranch mink (Mustela vison) diets containing polychlorinated biphenyl (PCB)-contaminated fish from the upper Hudson River (New York, USA) on adult and offspring organ mass and pathology.

polychlorinated biphenyl

PCB


Input: Diets contained 2. 5 to 20% Hudson River fish, providing 0. 72 to 6. 1 micro g Sigma PCBs/g feed (4. 8-38 pg toxic equivalents [TEQWHO 2005]/g feed).

PCBs


Input: Absolute thyroid and adrenal gland masses were increased in adult females and 31-week-old juveniles, respectively, and absolute liver and heart masses were decreased in six-week-old kits exposed to dietary PCBs.

PCBs


Input: Dietary concentrations of 0. 72 micro g Sigma PCBs/g feed (4. 8 pg TEQWHO 2005/g feed) and greater induced mandibular and maxillary squamous epithelial proliferation in adult animals.

PCBs


Input: The dietary concentration of Sigma PCBs predicted to result in 20% incidence of the jaw lesion (EC20) was 2. 3 micro g Sigma PCBs/g feed (15 pg TEQWHO 2005/g feed), and the hepatic concentration was 2. 8 micro g Sigma PCBs/g liver (89 pg TEQWHO 2005/g liver).

PCBs

PCBs

PCBs


Input: The EC20 values were greater than the dietary and hepatic concentrations predicted to result in a 20% increase in kit mortality (LC20) at six weeks of age (0. 34 micro g Sigma PCBs/g feed or 2. 6 pg TEQWHO 2005/g feed and 0. 80 micro g Sigma PCBs/g liver or 13 pg TEQWHO 2005/g liver).

PCBs

PCBs


Input: However, the EC20 values reflect exposure of adults to PCBs for approximately six months, and the LC20 values reflect exposure of offspring from conception onward.

PCBs


Input: Antigenotoxic potencies of a lichen species, Evernia prunastri.


Input: In this article, the genotoxic and antigenotoxic effects of methanol extract of Evernia prunastri (Huds.) Willd.

methanol


Input: (MEP) were studied using WP2, Ames (TA1535 and TA1537) and sister chromatid exchange (SCE) test systems.


Input: The results obtained from bacterial test systems demonstrated that MEP has strong antimutagenic potencies on TA1537 and WP2 strains.


Input: The highest inhibition rates for MEP on TA1537 and WP2 strains were 37. 70% and 69. 70%, respectively.


Input: According to the SCE test system, MEP reduced the genotoxic effects of aflatoxin.

aflatoxin


Input: In order to clarify the mechanism underlying the antigenotoxic effects of MEP, the antioxidants were determined.


Input: Cotreatments of 5, 10 and 20 micro g/mL concentrations of MEP with aflatoxin B (1) decreased the frequencies of SCE and the malondialdehyde level and increased amount of superoxide dismutase, glutathione and glutathione peroxidase which were decreased by aflatoxin.

aflatoxin B (1)

malondialdehyde

superoxide

glutathione

glutathione

aflatoxin


Input: The data obtained from this work have clearly shown that MEP has significant antigenotoxic effects which are thought to be partly due to the antioxidant activities and antioxidant inducing capability of MEP.


Input: This is the first report indicating the antigenotoxic activities of MEP against several mutagen agents such as N-methyl-N'-nitro-N-nitrosoguanidine, acridin and aflatoxin.

N-methyl-N'-nitro-N-nitrosoguanidine

acridin

aflatoxin


Input: Effects of trona on the redox status of cellular system of male rats.

trona


Input: The effects of trona (Kaun), a food additive, on the redox status of the liver and kidney of male Wistar rats were investigated.

trona

Kaun


Input: A total of 60 male rats (145 +/- 2. 52 g) were grouped into four: A, B, C and D, where group A (the control) received 1 mL of distilled water orally while those in groups B, C and D (test groups) received orally, same volume of trona preparation corresponding to 100, 200 and 400 mg/kg body weight, respectively, for 28 days.

trona


Input: Administration of trona significantly reduced (p < 0. 05) alkaline phosphatase activity in the liver and kidney with corresponding increases in the serum enzyme.

trona


Input: Acid phosphatase activity increased significantly (p < 0. 05) in the liver and kidney with no significant change (p > 0. 05) in the activity of the serum enzyme.


Input: The activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and the levels of reduced glutathione, vitamins C and E in the liver and kidney of the animals decreased significantly (p < 0. 05).

superoxide

glutathione

glutathione

reduced glutathione

vitamins C and E


Input: In contrast, malondialdehyde and lipid hydroperoxide of trona-treated animals increased significantly (p < 0. 05) in liver and kidney.

malondialdehyde

hydroperoxide

trona


Input: Overall, data from this study revealed that trona exhibited its toxic effect by suppressing or depleting the antioxidant systems and increasing the risk of attack by oxidants generated either from its metabolites or from other in vivo means on the rat cellular system.

trona


Input: In vitro assessment of drug-drug interaction potential of boceprevir associated with drug metabolizing enzymes and transporters.

boceprevir


Input: The inhibitory effect of boceprevir (BOC), an inhibitor of hepatitis C virus nonstructural protein 3 protease was evaluated in vitro against a panel of drug-metabolizing enzymes and transporters.

boceprevir

BOC


Input: BOC, a known substrate for cytochrome P450 (P450) CYP3A and aldo-ketoreductases, was a reversible time-dependent inhibitor (k (inact) = 0. 12 minute (-1), K (I) = 6. 1 micro M) of CYP3A4/5 but not an inhibitor of other major P450s, nor of UDP-glucuronosyltransferases 1A1 and 2B7.

BOC

UDP


Input: BOC showed weak to no inhibition of breast cancer resistance protein (BCRP), P-glycoprotein (Pgp), or multidrug resistance protein 2.

BOC


Input: It was a moderate inhibitor of organic anion transporting polypeptide (OATP) 1B1 and 1B3, with an IC (50) of 18 and 4. 9 micro M, respectively.


Input: In human hepatocytes, BOC inhibited CYP3A-mediated metabolism of midazolam, OATP1B-mediated hepatic uptake of pitavastatin, and both the uptake and metabolism of atorvastatin.

BOC

pitavastatin

atorvastatin


Input: The inhibitory potency of BOC was lower than known inhibitors of CYP3A (ketoconazole), OATP1B (rifampin), or both (telaprevir).

BOC

ketoconazole

rifampin

telaprevir


Input: BOC was a substrate for Pgp and BCRP but not for OATP1B1, OATP1B3, OATP2B1, organic cation transporter, or sodium/taurocholate cotransporting peptide.

BOC

sodium

taurocholate


Input: Overall, our data suggest that BOC has the potential to cause pharmacokinetic interactions via inhibition of CYP3A and CYP3A/OATP1B interplay, with the interaction magnitude lower than those observed with known potent inhibitors.

BOC


Input: Conversely, pharmacokinetic interactions of BOC, either as a perpetrator or victim, via other major P450s and transporters tested are less likely to be of clinical significance.

BOC


Input: The results from clinical drug-drug interaction studies conducted thus far are generally supportive of these conclusions.


Input: Identification and characterization of new DNA G-quadruplex binders selected by a combination of ligand and structure-based virtual screening approaches.


Input: Nowadays, it has been demonstrated that DNA G-quadruplex arrangements are involved in cellular aging and cancer, thus boosting the discovery of selective binders for these DNA secondary structures.


Input: By taking advantage of available structural and biological information on these structures, we performed a high throughput in silico screening of commercially available molecules databases by merging ligand-and structure-based approaches by means of docking experiments.


Input: Compounds selected by the virtual screening procedure were then tested for their ability to interact with the human telomeric G-quadruplex folding by circular dichroism, fluorescence spectroscopy, and photodynamic techniques.


Input: Interestingly, our screening succeeded in retrieving a new promising scaffold for G-quadruplex binders characterized by a psoralen moiety.


Input: Mathematical modeling of oral absorption and bioavailability of a fluoroquinolone after its precipitation in the gastrointestinal tract.

fluoroquinolone


Input: Abstract 1.


Input: The objective was to characterize the in vivo absorption and bioavailability (BA) of a low solubility, high permeability fluoroquinolone (CNV97101) that precipitates in the gastrointestinal (GI) tract by mathematical modeling approach.

fluoroquinolone


Input: In situ rat intestinal perfusion studies were performed to characterize the absorption mechanism.


Input: The oral fraction absorbed in vivo was lower than the predicted based on the in situ intestinal permeability.


Input: Two additional routes of administration, intraduodenal (ID) and intraperitoneal (IP) were investigated to explore if precipitation in stomach and subsequent partial re-dissolution were the causes of the lower in vivo BA.


Input: Ex vivo precipitation studies with the stomach content of fasted rats were also carried out.


Input: Fitting procedures were performed with NONMEM VII 1. 2.


Input: The in situ experiments confirmed simultaneous passive and carrier-mediated absorption processes.


Input: The ex vivo experiments confirmed precipitation in stomach lowering in vivo the oral fraction absorbed compared with the IP and ID administrations.


Input: Due to the almost complete availability of CNV97101 following IP administration, a first hepatic pass could be excluded.


Input: The ex vivo assay results and the pharmacokinetic modeling of in vivo data supported the hypothesis of precipitation in the stomach and partial re-dissolution.


Input: Nevertheless, other factors such as residence time in the GI may reduce the fraction absorbed even for low oral doses for which re-dissolution was almost complete in vivo.


Input: Arundinols A-C and arundinones A and B from the plant endophytic fungus Microsphaeropsis arundinis.

Arundinols A-C

arundinones A and B


Input: Three new ent-eudesmane sesquiterpenoids, arundinols A-C (1-3), one isochroman-1-one, arundinone A (4), and a polyoxygenated benzofuran-3 (2H)-one dimer, arundinone B (5), were isolated from the extract of a plant endophytic fungus, Microsphaeropsis arundinis.

ent-eudesmane sesquiterpenoids

arundinols A-C

arundinone A

polyoxygenated benzofuran-3 (2H)-one

arundinone B


Input: Their structures were elucidated primarily by NMR experiments, and 1 was confirmed by X-ray crystallography.


Input: The absolute configuration of 1 was assigned by X-ray crystallography using Cu K alpha radiation, whereas those of the C-11 tertiary alcohols in 2 and 3 were deduced via the circular dichroism data of the in situ formed [Rh (2) (OCOCF (3)) (4)] complexes.

Cu

tertiary alcohols

[Rh (2) (OCOCF (3)) (4)]


Input: Arundinone B (5) represents the first dimeric benzofuran-3 (2H)-one, showing cytotoxicity against T24 and A549 cells.

Arundinone B

benzofuran-3 (2H)-one


Input: The co-isolated known compound 6 showed a modest inhibitory effect against Staphylococcus aureus.


Input: Inhibitors of the Yersinia protein tyrosine phosphatase through high throughput and virtual screening approaches.

tyrosine


Input: The bacterial protein tyrosine phosphatase YopH is an essential virulence determinant in Yersinia pestis and a potential antibacterial drug target.

tyrosine


Input: Here we report our studies of screening for small molecule inhibitors of YopH using both high throughput and in silico approaches.


Input: The identified inhibitors represent a diversity of chemotypes and novel pTyr mimetics, providing a starting point for further development and fragment-based design of multi-site binding inhibitors.


Input: We demonstrate that the applications of high throughput and virtual screening, when guided by structural binding mode analysis, is an effective approach for identifying potent and selective inhibitors of YopH and other protein phosphatases for rational drug design.


Input: S-nitrosoglutathione covalently modifies cysteine residues of human carbonyl reductase 1 and affects its activity.

S-nitrosoglutathione

cysteine

carbonyl


Input: Carbonyl reductase 1 (CBR1 or SDR21C1) is a ubiquitously-expressed, cytosolic, monomeric, and NADPH-dependent enzyme.

Carbonyl

NADPH


Input: CBR1 participates in apoptosis, carcinogenesis and drug resistance, and has a protective role in oxidative stress, cancer and neurodegeneration.


Input: S-Nitrosoglutathione (GSNO) represents the newest addition to its diverse substrate spectrum, which includes a wide range of xenobiotics and endogenous substances.

S-Nitrosoglutathione

GSNO


Input: GSNO has also been shown to covalently modify and inhibit CBR1.

GSNO


Input: The aim of the present study was to quantify and characterize the resulting modifications.


Input: Of five candidate cysteines for modification by 2 mM GSNO (positions 26, 122, 150, 226, 227), the last four were analyzed using MALDI-TOF/TOF mass spectrometry and then quantified using the Selected Reaction Monitoring Approach on hyphenated HPLC with a triple quadrupole mass spectrometer.

GSNO


Input: The analysis confirmed GSNO concentration-dependent S-glutathionylation of cysteines at positions 122, 150, 226, 227 which was 2-700 times higher compared to wild-type CBR1 (WT-CBR1).

GSNO

S-glutathionylation

cysteines


Input: Moreover, a disulfide bond between neighboring Cys-226 and Cys-227 was detected.

disulfide

Cys

Cys


Input: We suggest a role of these two cysteines as a redox-sensitive cysteine pair.

cysteines


Input: The catalytic properties of wild-type and enzyme modified with 2 mM GSNO were also investigated by steady state kinetic experiments with various substrates.

GSNO


Input: GSNO treatment of CBR1 resulted in a 2-5-fold decrease in kcat with menadione, 4-benzoylpyridine, 2, 3-hexanedione, daunorubicin and 1, 4-naphthoquinone.

GSNO

menadione

2, 3-hexanedione

daunorubicin

1, 4-naphthoquinone


Input: In contrast, the same treatment increased kcat for substrates containing a 1, 2-diketo group in a ring structure (1, 2-naphthoquinone, 9, 10-phenanthrenequinone, isatin).

1, 2-diketo

1, 2-naphthoquinone

9, 10-phenanthrenequinone

isatin


Input: Except for 9, 10-phenanthrenequinone, all changes in kcat were at least in part compensated for by a similar change in Km, overall yielding no drastic changes in catalytic efficiency.

9, 10-phenanthrenequinone


Input: The findings indicate that GSNO-induced covalent modification of cysteine residues affects the kinetic mechanism of CBR1 both in terms of substrate binding and turnover rate, probably by covalent modification of Cys-226 and/or Cys-227.

GSNO

cysteine

Cys

Cys


Input: Daily sperm production: application in studies of prenatal exposure to nanoparticles in mice.


Input: We investigated the influence of maternal airway exposure to nanoparticulate titanium dioxide (TiO2, UV-Titan) and carbon black (CB, Printex90), on male reproductive function in the two following generations.

titanium dioxide

carbon black


Input: Time-mated C57BL/6J mice were exposed by inhalation to UV-Titan, or by intratracheal instillation with Printex90.


Input: Body and testicle weight, sperm content per g testicular parenchyma and daily sperm production (DSP) were assessed.


Input: The protocol for assessment of DSP was optimized for application in mice (C57BL/6J) and the influence of different parameters was studied.


Input: Maternal particulate exposure did not affect DSP statistically significantly in the F1 generation, although TiO2 tended to reduce sperm counts.


Input: Overall, time-to-first F2 litter increased with decreasing sperm production.


Input: There was no effect on sperm production in the F2 generation originating after TiO2 exposure.


Input: F2 offspring, whose fathers were prenatally exposed to Printex90, showed lowered sperm production.


Input: Furthermore, we report statistically significant differences in sperm production between mouse strains.


Input: SKF83959 is a potent allosteric modulator of sigma-1 receptor.


Input: SKF83959 (3-methyl-6-chloro-7, 8-hydroxy-1-[3-methylphenyl]-2, 3, 4, 5-tetrahydro-1H-3-benzazepine), an atypical dopamine receptor-1 (D (1) receptor) agonist, has shown many D (1) receptor-independent effects, such as neuroprotection, blockade of Na (+) channel, and promotion of spontaneous glutamate release, which resemble the effects of the sigma-1 receptor activation.

3-methyl-6-chloro-7, 8-hydroxy-1-[3-methylphenyl]-2, 3, 4, 5-tetrahydro-1H-3-benzazepine

dopamine

Na (+)

glutamate


Input: In the present work, we explored the potential modulation of SKF83959 on the sigma-1 receptor.


Input: The results indicated that SKF83959 dramatically promoted the binding of (3) H (+)-pentazocine (a selective sigma-1 receptor agonist) to the sigma-1 receptor in brain and liver tissues but produced no effect on (3) H-progesterone binding (a sigma-1 receptor antagonist).

(3) H (+)-pentazocine

(3) H-progesterone


Input: The saturation assay and the dissociation kinetics assay confirmed the allosteric effect.


Input: We further demonstrated that the SKF83959 analogs, such as SCH22390 [(R)-(1)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2, 3, 4, 5-tetrahydro-1H-3-benzazepine hydrochloride] and SKF38393 [(+/-)-1-phenyl-2, 3, 4, 5-tetrahydro-(1H)-3-benzazepine-7, 8-diol hydrobromide], also showed the similar allosteric effect on the sigma-1 receptor in the liver tissue but not in the brain tissue.

(R)-(1)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2, 3, 4, 5-tetrahydro-1H-3-benzazepine hydrochloride

(+/-)-1-phenyl-2, 3, 4, 5-tetrahydro-(1H)-3-benzazepine-7, 8-diol hydrobromide


Input: Moreover, all three tested chemicals elicited no significant effect on (3) H-1, 3-di (2-tolyl)-guanidine ((3) H-DTG) binding to the sigma-2 receptor.

(3) H-1, 3-di (2-tolyl)-guanidine

(3) H-DTG


Input: The present data uncovered a new role of SKF83959 and its analogs on the sigma-1 receptor, which, in turn, may reveal the underlying mechanism for the D (1) receptor-independent effect of the drug.


Input: Direct transcriptional regulation of human hepatic cytochrome P450 3A4 (CYP3A4) by peroxisome proliferator-activated receptor alpha (PPAR alpha).


Input: The nuclear receptor peroxisome proliferator-activated receptor (PPAR) alpha is known primarily as a regulator of fatty acid metabolism, energy balance, and inflammation, but evidence suggests a wider role in regulating the biotransformation of drugs and other lipophilic chemicals.

fatty acid


Input: We investigated whether PPAR alpha directly regulates the transcription of cytochrome P450 3A4, the major human drug-metabolizing enzyme.


Input: Using chromatin immunoprecipitation in human primary hepatocytes as well as electrophoretic mobility shift and luciferase reporter-gene assays, we identified three functional PPAR alpha-binding regions (PBR-I,-II, and-III) within ~ 12 kb of the CYP3A4 upstream sequence.


Input: Furthermore, a humanized CYP3A4/3A7 mouse model showed in vivo induction of CYP3A4 mRNA and protein by [4-chloro-6-(2, 3-xylidino)-2-pyrimidinylthio] acetic acid (WY14, 643) in liver but not in intestine, whereas hepatic occupancy of PBRs by PPAR alpha was ligand independent.

4-chloro-6-(2, 3-xylidino)-2-pyrimidinylthio] acetic acid

WY14, 643


Input: Using lentiviral gene knock-down and treatment with WY14, 643 in primary human hepatocytes, PPAR alpha was further shown to affect the expression of a distinct set of CYPs, including 1A1, 1A2, 2B6, 2C8, 3A4, and 7A1, but not 2C9, 2C19, 2D6, or 2E1.

WY14, 643


Input: Interestingly, the common phospholipid 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16: 0/18: 1-PC), previously proposed to reflect nutritional status and shown to be a specific endogenous ligand of PPAR alpha, induced CYP3A4 (up to 4-fold) and other biotransformation genes in hepatocytes with similar selectivity and potency as WY14, 643.

1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine

WY14, 643


Input: These data establish PPAR alpha as a direct transcriptional regulator of hepatic CYP3A4.


Input: This finding warrants investigation of both known and newly developed PPAR alpha-targeted drugs for their drug-drug interaction potential.


Input: Furthermore, our data suggest that nutritional status can influence drug biotransformation capacity via endogenous phospholipid signaling.


Input: Polymeric triamcinolone acetonide nanoparticles as a new alternative in the treatment of uveitis: In vitro and in vivo studies.

Polymeric triamcinolone acetonide


Input: The purpose of this work was to improve the efficacy of triamcinolone acetonide (TA) in the treatment of endotoxin-induced uveitis (EIU) using a polymeric nanoparticulate drug delivery system.

triamcinolone acetonide


Input: Poly (d, l-lactide-co-glycolide) (PLGA) nanoparticles were prepared using a modified emulsification/solvent diffusion method.

Poly (d, l-lactide-co-glycolide)

PLGA


Input: Processing factors affecting loading and size were also studied.


Input: After physicochemical studies including in vitro release, X-ray powder diffraction, differential scanning calorimetry, and scanning electron microscopy, in vivo studies were conducted using nanoparticles sized 195nm with 3. 16% drug loading.


Input: Inflammatory factors such as flare, cell, and fibrin were studied in rabbit' s eye over 96h period, using laser flare meter and slit lamp examination.


Input: Inflammatory mediators such as NO, PGE2, cell, and protein were measured quantitatively 36h after intravitreal injection of endotoxin in aqueous humor, and the therapeutic effects were compared in different groups.

NO


Input: Results indicated statistically significant differences between the effect of nanoparticles in the treatment of EIU compared to microparticles of TA and prednisolone acetate (PA).

prednisolone acetate


Input: There were no significant differences between the effects of TA injection and TA nanoparticles.


Input: In conclusion, sustain release biodegradable TA nanoparticles are potential new topical treatment options which can provide better patient compliance.


Input: Effect of A and B-site cations on surface exchange coefficient for ABO3 perovskite materials.

perovskite


Input: A novel approach, called isothermal isotope exchange (IIE), was applied to varying A-and B-site lanthanum manganites, ferrites, and cobaltites in the perovskite crystal structure in order to extract accurate surface exchange coefficients (k *).

lanthanum manganites

ferrites

cobaltites

perovskite


Input: Pure electronic conductors revealed temperature dependent isotope exchange, while for mixed ionic and electronic conductors (MIEC) the extent of exchange was independent of temperature.


Input: MIEC materials have higher k * values than pure electronic conductors in the temperature range from 500-850 degrees C, demonstrating the importance of both electronic species and oxygen vacancies being present for surface exchange.

oxygen


Input: Strontium doped perovskites exhibited opposite temperature dependencies to parent materials.

Strontium doped perovskites


Input: Some perovskites exhibited an apparent negative activation energy for k *, the behavior of which is explained by a precursor-mediated mechanism for dissociative adsorption.

perovskites


Input: The results have significant implications for the improvement of the oxygen reduction reaction for fuel cells, metal-air batteries, and numerous other energy technologies.

oxygen


Input: Dissection of pilus tip assembly by the FimD usher monomer.


Input: Type 1 pili are representative of a class of bacterial surface structures assembled by the conserved chaperone/usher pathway and used by uropathogenic Escherichia coli to attach to bladder cells during infection.


Input: The outer membrane assembly platform-the usher-is critical for the formation of pili, catalysing the polymerisation of pilus subunits and enabling the secretion of the nascent pilus.


Input: Despite extensive structural characterisation of the usher, a number of questions about its mechanism remain, notably its oligomerisation state, and how it orchestrates the ordered assembly of pilus subunits.


Input: We demonstrate here that the FimD usher is able to catalyse in vitro pilus assembly effectively in its monomeric form.


Input: Furthermore, by establishing the kinetics of usher-catalysed reactions between various pilus subunits, we establish a complete kinetic model of tip fibrillum assembly, able to account for the order of subunits in native type 1 pili.


Input: A new scheme for significant enhancement of the second order nonlinear optical response from molecules to ordered aggregates.


Input: How to achieve maximum nonlinear optical (NLO) properties from the molecular to the macro block is very crucial to the development of nonlinear optical materials, which is the impetus of the present work.


Input: Buckybowls present large first hyperpolarizability ascribed to noncentrosymmetric charge distribution due to the curved shape of the system.


Input: The role of their packing pattern in maximizing the NLO response of buckybowl aggregates is investigated.


Input: In (corannulene) (10) and (sumanene) (10) aggregates, the first order hyperpolarizabilities (beta (0)) per molecule are enhanced 5. 59 and 6. 21 times with respect to a single entity respectively.

corannulene

sumanene


Input: For a larger buckybowl, C (36) H (12), the beta (0) value per molecule of its pentamer reaches 191. 4 x 10 (-30) esu which is much higher than conventional dipolar or octupolar NLO chromophores ones.

C (36) H (12)


Input: The cohesive coupling among electric dipoles in packing of buckybowls is responsible for significant enhancement of the nonlinear optical response of the aggregates, which could pave the way for designing large 2nd order NLO materials with a good balance of nonlinearity, transparency, and stability.


Input: Endocrine disrupting effects of ochratoxin A at the level of nuclear receptor activation and steroidogenesis.

ochratoxin A


Input: Ochratoxin A (OTA) is a mycotoxin and extrolite of fungi which has been reported in a range of foods.

Ochratoxin A

OTA


Input: This study uses mammalian reporter gene assays (RGAs) with natural steroid receptors and the H295R steroidogenesis assay to assess the endocrine disrupting activity of OTA.

OTA


Input: At the receptor level, OTA (within a concentration range of 0. 25-2500 ng/ml) did not induce an agonistic response in an oestrogen, androgen, progestagen or glucocorticoid RGA.

OTA

oestrogen

androgen

progestagen


Input: An antagonistic effect was observed in all of the RGAs at the highest concentration tested (2500 ng/ml).


Input: However, while there was no significant cytotoxic effect observed in the MTT (thiazolyl blue tetrazolium bromide) cell viability assay at this concentration, there was a corresponding change in cell morphology which may be related to the resulting antagonistic effect.

MTT

thiazolyl blue tetrazolium bromide


Input: At the hormone production level, H295R cells were used as a steroidogenesis model and exposed to OTA (within a concentration range of 0. 1-1000 ng/ml).


Input: Treatment of the cells with 1000 ng/ml OTA increased the production of estradiol (117 +/- 14 ng/ml) over 3 times that of the solvent control (36 +/- 9 pg/ml).

estradiol


Input: Western blotting confirmed an increase in aromatase protein.


Input: Overall the results indicate that OTA does not appear to interact with steroid receptors but has the potential to cause endocrine disruption by interfering with steroidogenesis.


Input: This is the first study identifying the effect OTA may have on production of the steroid hormone estradiol.

steroid

estradiol


Input: Comparison of tolerance to morphine-induced respiratory and analgesic effects in mice.

morphine


Input: Morphine is responsible for severe poisonings in chronically treated patients.

Morphine


Input: We hypothesize that toxicity could be related to the development of weaker tolerance for morphine-induced deleterious respiratory effects in comparison to analgesic effects.

morphine


Input: Our objectives were to compare tolerance to both effects in mice and investigate possible mechanisms for such possible differences.


Input: Tolerance to morphine-induced analgesia and respiratory effects was assessed using hot plate response latencies and plethysmography, respectively.

morphine


Input: Mechanisms of tolerance were investigated using binding studies to mu-opioid receptors (MOR) and adenylate cyclase (AC) activity measurement in homogenates of cell membranes from the periaqueductal gray region (PAG) and brainstem.


Input: Morphine (2. 5 mg/kg) was responsible for analgesia with significant increase in inspiratory time.

Morphine


Input: Acute tolerance to analgesia (p < 0. 01) and effects on respiratory frequency (p < 0. 05) was observed in mice pre-treated with 100 mg/kg morphine in comparison to saline.

morphine


Input: Following repetitive administration (2. 5 mg/kg/day during 10 days), we observed a 13-fold increase in the effective dose-50% (ED 5 0) of morphine-induced analgesia in comparison to a 2-or 4-fold increase in the ED 5 0 of its related increase in inspiratory time determined in air and 4% CO 2, respectively.

morphine

CO 2


Input: No significant alteration in MOR expression was observed in either PAG or brainstem following repeated morphine administration.

morphine


Input: However, in PAG, in contrast to brainstem, superactivation of AC was observed in morphine-treated mice in comparison to controls (p < 0. 05).

morphine


Input: In conclusion, tolerance to morphine-induced respiratory effects is much more limited than tolerance to its analgesic effects in repeatedly morphine-treated mice.

morphine

morphine


Input: The difference in morphine-induced AC activation between the brainstem and the PAG contributes to the observed difference in tolerance between both morphine effects.

morphine

morphine


Input: Membrane-initiated estradiol signaling in immortalized hypothalamic N-38 neurons.

estradiol


Input: Regulation of sexual reproduction by estradiol involves the activation of estrogen receptors (ERs) in the hypothalamus.

estradiol

estrogen


Input: Of the two classical ERs involved in reproduction, ER alpha appears to be the critical isoform.


Input: The role of ER alpha in reproduction has been found to involve a nuclear ER alpha that induces a genomic mechanism of action.


Input: More recently, a plasma membrane ER alpha has been shown to trigger signaling pathways involved in reproduction.


Input: Mechanisms underlying membrane-initiated estradiol signaling are emerging, including evidence that activation of plasma membrane ER alpha involves receptor trafficking.


Input: The present study examined the insertion of ER alpha into the plasma membrane of N-38 neurons, an immortalized murine hypothalamic cell line.


Input: We identified, using western blotting and PCR that N-38 neurons express full-length 66kDa ER alpha and a 52kDa ER alpha spliced variant missing the fourth exon-ER alpha Delta 4.


Input: Using surface biotinylation, we observed that treatment of N-38 neurons with estradiol or with a membrane impermeant estradiol elevated plasma membrane ER alpha protein levels, indicating that membrane signaling increased receptor insertion into the cell membrane.

estradiol

estradiol


Input: Insertion of ER alpha was blocked by the ER antagonist ICI 182, 780 or with the protein kinase C (PKC) pathway inhibitor bisindolylmaleimide (BIS).

ICI 182, 780

bisindolylmaleimide

BIS


Input: Downstream membrane-initiated signaling was confirmed by estradiol activation of PKC-theta (PKC theta) and the release of intracellular calcium.

estradiol


Input: These results indicate that membrane ER alpha levels in N-38 neurons are dynamically autoregulated by estradiol.

estradiol


Input: The effect of remelting on the physical properties of borotellurite glass doped with manganese.

borotellurite

manganese


Input: A systematic set of borotellurite glasses doped with manganese (1-x) [(B (2) O (3)) (0. 3) (TeO (2)) (0. 7)]-xMnO, with x = 0. 1, 0. 2, 0. 3 and 0. 4 mol%, were successfully synthesized by using a conventional melt and quench-casting technique.

borotellurite

manganese (1-x) [(B (2) O (3)) (0. 3) (TeO (2)) (0. 7)]-xMnO


Input: In this study, the remelting effect of the glass samples on their microstructure was investigated through density measurement and FT-IR spectra and evaluated by XRD techniques.


Input: Initial experimental results from XRD evaluation show that there are two distinct phases of glassy and crystallite microstructure due to the existence of peaks in the sample.


Input: The different physical behaviors of the studied glasses were closely related to the concentration of manganese in each phase.

manganese


Input: FTIR spectra revealed that the addition of manganese oxide contributes the transformation of TeO (4) trigonal bipyramids with bridging oxygen (BO) to TeO (3) trigonal pyramids with non-bridging oxygen (NBO).

manganese oxide

TeO (4)

oxygen

TeO (3)

oxygen


Input: Signalling Pathways that Inhibit the Capacity of Precursor Cells for Myelin Repair.


Input: In demyelinating disorders such as Multiple Sclerosis (MS), targets of injury are myelin and oligodendrocytes, leading to severe neurological dysfunction.


Input: Regenerative therapies aimed at promoting oligodendrocyte maturation and remyelination are promising strategies for treatment in demyelinating disorders.


Input: Endogenous precursor cells or exogenous transplanted cells are potential sources for remyelinating oligodendrocytes in the central nervous system (CNS).


Input: Several signalling pathways have been implicated in regulating the capacity of these cell populations for myelin repair.


Input: Here, we review neural precursor cells and oligodendrocyte progenitor cells as potential sources for remyelinating oligodendrocytes and evidence for the functional role of key signalling pathways in inhibiting regeneration from these precursor cell populations.


Input: Liver transplantation and cell therapies for inborn errors of metabolism.


Input: Liver transplantation is now very successful with > 85% long term survival into adult life.


Input: When considering the impact of liver transplantation for metabolic disease two independent factors need to be considered; whether or not the defect causes liver disease and whether or not it is confined to the liver.


Input: When considering transplantation many factors need to be considered including the local success of transplantation, the impact of the metabolic disease on the patient and family and the potential for future therapeutic developments.


Input: Where transplantation is undertaken for a liver based defect there is a lifelong complete correction of the defect.


Input: Where there is a residual extrahepatic defect this will have an impact on the outcome of liver transplantation and the severity of this defect must be considered as part of the transplant assessment process.


Input: Access to a multi-disciplinary team with expertise in metabolic disease, liver disease and other relevant organ based specialists is crucial.


Input: Most children will receive transplantation from cadaveric donor but living related transplantation from a heterozygote parent is usually safe and effective.


Input: Auxiliary liver transplantation has a small but useful role where partial correction of the defect is helpful and there is a future prospect of gene therapy.


Input: The first-generation of hepatocyte transplants have shown proof of principle but to date have had a rather modest and temporary metabolic effect.


Input: Stem cells may have the potential to produce a more sustained and significant metabolic correction, but must be shown to be effective in controlled trials.


Input: Effect of Wine Polyphenol Resveratrol on the Contractions Elicited Electrically or by Norepinephrine in the Rat Portal Vein.

Polyphenol Resveratrol

Norepinephrine


Input: We investigated the effects of resveratrol on rat portal vein (RPV) contractility without endothelium.

resveratrol


Input: Contractions were produced by electrical field stimulation of perivascular nerves (EFS), norepinephrine (NE), adenosine 5'-triphosphate (ATP), high K (+) solution and by calcium chloride (CaCl (2)) in Ca (2 +)-free and high K (+), Ca (2 +)-free solution.

norepinephrine

adenosine 5'-triphosphate

ATP

K (+)

calcium chloride

CaCl (2)

Ca (2 +)

K (+)

Ca (2 +)


Input: The EFS-evoked contractions were more sensitive to resveratrol and to NS1619-selective openers of big calcium-sensitive (BK (Ca)) channels, than NE-evoked contractions.

resveratrol

calcium

Ca


Input: Effects of resveratrol on the ATP-evoked contractions were weak.

resveratrol

ATP


Input: Blockers of BK (Ca) channels partly inhibited the effect of resveratrol only in EFS-contracted preparations.

Ca

resveratrol


Input: Western blotting showed that RPV expressed K (Ca) 1. 1 protein.

K

Ca


Input: Inhibitors of ATP-and voltage-sensitive K (+) channels did not modify the effects of resveratrol.

ATP

K (+)

resveratrol


Input: None of the antagonists of K (+) channels affected the resveratrol inhibition of NE-evoked contractions and effect of high concentrations of resveratrol on the EFS-evoked contractions.

K (+)

resveratrol

resveratrol


Input: Resveratrol more potently inhibited CaCl (2) than potassium chloride contractions of RPV.

Resveratrol

CaCl (2)

potassium chloride


Input: Thus, BK (Ca) channels partly mediate the inhibitory effect of resveratrol on the neurogenic contractions of RPV.

Ca

resveratrol